NL8103538A - Antihyperglycaemic oxazolidine 2,4:diones - substd. on the 5-position by a heterocycle - Google Patents

Abstract

Racemic and optically active oxazolidine-2,4-diones of formula (I), and their salts are new, (where R is H, 1-4C alkanoyl, benzoyl, 2-4C carbalkoxy, 1-3C alkyl- 5-7C cycloalkyl-, and di(1-3C alkyl)- carbamoyl; R1 is (a) a group of formula (II)-(IV) (where R' is 1-4C alkyl or phenyl; R" is H or R'; X is halogen) (b) a group (V) (where Y is H, 1-3C alkoxy, Y' is H or 1-3C alkyl; Y" is H or halogen) (c) a group (VI or (VII) where Z' is H, halogen, or 1-3C alkoxy; Z" is H or halogen; (d) a group (VIII) where W is H or halogen on any position; n is 1 or 2; (e) a group (IX)-(XI) where Q is S or O; V is H or 1-3C alkyl; (f) a group (XII) or (XIII) attached through any position, where Y = O or S; X is H, halogen, methyl, phenyl, benzoyl or 1-3C alkoxy; X1 is H or CH3; X2 is H or halogen). Used as antihyperglycemic agents.

Description

V

* Ψ 'Τ

Hypoglyemic 5-substituted oxazolidine-2,2-dione

The invention relates to hypoglyemic 5-substituted oxazolidine-2,4-diones, more particularly certain fur-5-yl »thien-5-yl» chroman-5-yl »2,3-dihydrobenzo- / b7furanyl, pyrid-5-yl, quinol-5-yl pyrrol-5-yl, indol-5-yl, 5 thiazol-5-yl, oxazol-5-yl, isothiazol-5-yl and isoxazol-5-yl derivatives of oxazolidine-2,1 * -dione, which are useful as hypoglyemic agents.

Despite the early discovery of insulin and the subsequent widespread use in diabetes treatment, and the subsequent discovery and use of sulfonyl. urea compounds (e.g., chloropropamide, tolbutamide, acetohexamide, tolazamide) and biguanide (e.g., fenformin) as oral hypoglyemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, which is required in a high percentage of diabetics, for whom the available synthetic hypoglyemic agents are ineffective, requires multiple daily, usually self-injection.

Determining the appropriate insulin dose requires repeated determinations of the sugar in the urine or in the blood. The administration of an excess dose of insulin causes hypoglycemia, with consequences ranging from mild abnormalities in blood glucose to coma or even death. If effective, a synthetic hypoglycemic agent is preferred over insulin because it is easier to administer and less likely to lead to severe hypoglyemic reactions. However, the clinically available hypoglyemic agents are unfortunately associated with other toxic symptoms, limiting their use. In any case, where one of these means is not sufficient in an individual case, another may be sufficient. An ongoing need for hypoglyemic agents, which may be less toxic or sufficient where other failures, will be apparent.

81 03 538

«L

C 1 * - 2 -

In addition to the hypoglycemic agents listed above, several other compounds have been reported to have this type of activity, as briefly summarized by Blank / Burger's Medicinal Chemistry, 4 Ed., Part II, 5 John Wiley and Sons, N.Y. (1979), biz. 1057-10807.

The oxazolidine-2, U-dions according to the invention are new compounds, despite the fact that the oxazolidine-2, U-dions are widely known as a class of compounds / "" for a detailed overview, see Clark-Lewis , 10 Chem. Rev. 58, pp. 63-99 (1958) 7. Compounds known in this class include 5-phenoxazolidine-2,2-dione, alternately described as an intermediate for certain β-lactam antibacterial agents (U.S. Pat. No. 2,721,197), as an antidepressant (U.S. Pat. No. 3,699 .229) and as an anticonvulsant / "Brink and

Freeman, J. Neuro. Chem. 19 (7), pp. 1783-1788 (1972) 7; a number of 5-phenyloxazolidine-2, h-diones substituted in the phenyl ring, e.g. 5 - (^ - methoxyphenyl) oxazolidine-2, U-dione / King and Clark-Lewis, J. Chem. Soc., Pp. 3077-3079 (1961) 7.5 - (1-chloro-2-phenyl) oxazolidine-2-dione / Najer et al., Bull. soc. chim. France, pp. 1226-1230 (1961) 7.5- (k-methylphenyl) oxazolidine-2, U-dione / "Reibsomer v.s., J.A.C.S. 61, p. 3 ^ 91-3 ^ 93 (1939) 7,5- (U-arninophenyl) oxazolidine-2, U-dione (DOS 108,026) and 5- (pyr-2-ryl) -oxazolidine-2, U -dion / “Ciamacian and Silber, Gazz. chim. ital.

25, 16, 357 (1886); ber. 19, 1708-171¾ (1886) 7. The latter compound, of which no previous utility is known, shows only relatively weak hypoglycemic activity (see Table A below).

Oxazolidine-2, U-dione and substituted oxazoli-20dine-2, U-dions (in particular the 5-methyl and 5,5-dimethyl derivatives) have been described as acidic groups suitable for forming acid addition salts with the hypoglycemic basic biguanides (U.S. Patent 2,961,377).

We have established that neither oxazolidine-2, U-dione itself, nor 5,5-dimethyloxazolidine-2,1-dione have the hypoglycemic activity of the compounds of the invention.

Briefly, a group of spiro-oxazolidine-2,4-dione derivatives, which are aldose reductase inhibitors, have been described and are therefore used in the treatment of certain complications of diabetes (U.S. Patent 4,200,61 * 2).

A method for the synthesis of 3-aryloxazolidine-2,4-diones (in which the aryl group contains 6-12 carbon atoms and is unsubstituted or substituted by one or more halogen, methyl or methoxy groups) has been the subject of the recent in U.S. Patent 4,220,787. The usefulness of these compounds is not further specified.

The invention relates to compounds of formula 1, wherein R represents hydrogen, an alkanoyl group with 1-¾ carbon atoms (eg formyl, acetyl, isobutyryl), benzoyl group, a carbalkoxy group with 2-4 carbon atoms (eg, carbomethoxy, carbethoxy, carboisopropoxy ), an alkylcarbamoyl group with 1-3 carbon atoms (eg N-methylcarbamoyl, N-propyl-carbamoyl), an eyeloalkylearbamoyl group with 5-7 carbon atoms (eg N-cyclohexylcarbamoyl), or di-alkyl (with 1-3 carbon-20 material atoms) carbamoyl (eg Ν, Ν-dimethylcarbamoyl); and R 1 represents a group of formula 2, formula 3 or formula 4, wherein R 'represents an alkyl group of 1-4 carbon atoms or a phenyl group, R "represents hydrogen, an alkyl group of 1-4 carbon atoms or a phenyl group, and X represents halogen (fluorine, chlorine, bromine or iodine); these formulas are intended to include both pyrrol-2-yl and pyrrol-3-yl and indolyl derivatives with substituents as indicated; (b) a group containing formula 5, wherein Y is hydrogen or an alkoxy group of 1-3 carbon atoms, Y 'is hydrogen or an alkyl group of 1-3 carbon atoms and Y' is hydrogen or halogen; (c) a group of formula 6 or formula 7, wherein Z 'is hydrogen, halogen or an alkoxy group of 1-3 carbon atoms and Z' is hydrogen or halogen; (D) a group of formula 8, wherein W is hydrogen 8103538 η.

X 'i' - Λ - or halogen n stands for 1 or 2; these formulas include 6- or T-halo-8-chromanyl and 5- or 6-halo-T-benzofuranyl derivatives; (e) a group of formula 9 or formula 10, wherein 5 Q is sulfur or oxygen and V is hydrogen or an alkyl group of 1-3 carbon atoms; or (f) a group of formula 11, wherein Q is sulfur or oxygen; and V represents hydrogen or an alkyl group of 1-3 carbon atoms; these formulas include 3-, and 5-isothiazolyl and isoxazolyl derivatives; (g) a group of formula 12 or formula 13, wherein Y is sulfur or oxygen, X represents hydrogen, fluorine, chlorine, "bromine, iodine, a methyl, phenyl, benzoyl group or an alkoxy group having 1-3 carbon atoms; represents hydrogen, 15 or a methyl group and Xg represents hydrogen, fluorine, chlorine, bromine or iodine; when hydrogen is, the first formula encompasses the entire range of 5- (fur-2-yl) -, 5- (fur-3- yl) -, 5- (thien-2-yl) - and 5- (thien-3-yl) derivatives of oxazolidine-2, dione, in which substituents X may be attached to any free carbon plate other than furan / thiophene ring, ie

a compound of formula 1U, formula 15, formula 16, formula 17, formula 18 or formula 19, wherein X and Y have the above meanings and Ox is used as an abbreviation for the oxazolidine-2, dione ring which is on the 5- place bound; When both X and X ^ are not hydrogen, the second substituent may be placed at any free position in any of these six variants; the second group of formulas is intended to include compounds in which the oxazolidine is substituted in the 2-, 3- or 7-position of the benzo / b7furan / henzo / b7thio-30-phenene ring system, ie a compound of formula 20, formula 21 or formula 22.

The invention also includes the pharmaceutically acceptable cation salts of compounds of formula 1, wherein R is hydrogen, as well as the pharmaceutically acceptable acid addition salts thereof, when R 1 contains a basic nitrogen 8103538-5 group.

It is believed that the inherent high activity of these compounds lies primarily in those compounds wherein R is hydrogen, and that the compounds wherein R consists of any of the various carbonyl derivatives described above are the so-called no. precursor drugs, ie the carbonyl side chain is removed by hydrolysis under physiological conditions to obtain the fully active compounds, wherein R is hydrogen, the expression "pharmaceutically acceptable cation salt" is used to define salts such as the alkali metal salts ( eg sodium and potassium), alkaline earth metal salts (eg, calcium and magnesium), aluminum salts, ammonium salts and salts with organic amines, such as benzathine (Ν, Ν'-dibenzyl-15 ethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (ïï-methylglucamine) , benethamine (N-benzylphenethyl-araine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethylpropane-1,3-diol), procaine.

The term "pharmaceutically acceptable acid addition salt" includes salts such as the hydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulfate, dihydrogen phosphate, mesylate, maleate and succinate.

The compounds of the invention have hypoglycemic activity, making them clinically useful for reducing blood glucose levels of hypoglycemic mammals, including humans, to normal values. They offer the special advantage of lowering blood glucose levels to a normal range without the risk of causing hypoglycemia. The compounds of the invention are tested for hypoglycemic (anti-hyperglycemic) activity in rats using the so-called no. glucose tolerance tests, as will be further described below.

Preferred compounds because of their better hypoglycemic activity are the compounds wherein R is hydrogen or the pharmaceutically acceptable salts thereof. Under 8103538

a

-6 - V t compounds of formula 1, wherein R is hydrogen, because of their excellent hypoglycemic activity, the most preferred compounds are: 5- (1-methyl-pyrrol-2-yl) oxazolidine-2, k -dion; 5- (1-ethyl-pyrrol-2-yl) oxazolidin-2, U-dione; 5- (1-phenyl-pyrrol-2-yl) oxazolidin-2,1-dione; 5- (2-methoxy-pyrid-3-yl) oxazolidin-2, U-dione; 5- (2-ethoxy-pyrid-3-yl) oxazolidin-2, k-dione; 5- (5-chloro-2-methoxy-pyrid-3-yl) oxazolidine-2, 10-dione; 5- (5-chloro-2-ethoxy-pyrid-3-yl) oxazolidin-2, dione; 5- (quinol-8-yl) oxazolidin-2, U-dione · 5- {7-methoxy-quinol-8-yl) oxazolidin-2,1-dione; 5- (6-chloro-quinol-8-yl) oxazoli dine-2, H-dione; 5- (6-fluoro-quinol-8-yl) oxazolidin-2, k-dione; 5- (benzthiazol-2-yl) oxazolidin-2 + dione; 5- (thiazol-2-yl) oxazolidin-2,1-dione; 5- (6-chloro-chroman-8-yl) oxazolidin-2, H-dione; 5- (6-fluoro-chroman-8-yl) oxazolidin-2, U-dione; 5- (5-chloro-2,3-dihydro-benzophuran-7-yl) oxazolidin-2, U-dione; 5- (3-methyl-isoxazol-5-yl) oxazolidin-2, U-dione; 5- (thien-3-yl) oxazolidin-2, k-dione; 5 - ((bromo-thien-3-yl) oxazolidin-2, U-dione; 5- (U-ethoxy-thien-3-yl) oxazolidin-2, U-dione; 5- (U-ethoxy-2-methyl-thien-3-yl) oxazolidin-2, U-dione | 5 - (1 - methoxy-2-methyl-thien-3-yl) oxazolidin-2, U-dione; 5- (3-methyl-thien-2-yl) oxazolidin-2, l-dione; 5- (3-methoxy-thien-2-yl) oxazolidin-2, U-dione; 5- (fur-3-yl) oxazolidin-2, H-dione; 5- (fur-2-yl) oxazolidin-2, U-dione; 5- (3-bromofur-2-yl) oxazolidin-2, U-dione; 5- (5-chlorofur-2-yl) oxazolidin-2, H-dione; 8103538 s'. r.

% - 7- 5- (7-benzo / "b7thienyl) oxazolidire-2, U-dione and 5- (5-chloro-7-benzo /" "b7furanyl) oxazolidiffi-2, U-dione;

The compounds of the invention are prepared by various methods, as summarized in Scheme A, which has the meaning above, Rg is a short chain alkyl group (eg methyl or ethyl), R8 represents hydrogen, a short chain alkyl or phenyl group, and R 1 represents hydrogen or an acyl group, such as acetyl, or a benzoyl group.

A particularly suitable synthesis for compounds of the invention is via carbonimidate of formula 25. The latter compound is reacted with phosgene in an inert solvent, such as tetrahydrofuran in the presence of 2-2.3 equivalents of a tertiary amine (eg triethyl-15 amine or N-methylmorpholine). An additional equivalent of tertiary amine is used when the carbon imidate is added as the acid addition salt (e.g., hydrochloride salt).

The temperature of the reaction is not critical, but lower temperatures (eg -10 ° C to + 10 ° C) are preferred during the initial stages of the reaction, especially when it is desired to use the intermediate U-alkoxyoxazole-2 isolate one (formula 26). Isolation of this intermediate is performed by simple evaporation of the reaction mixture. With continued reaction at higher temperatures (e.g. 20-150 ° C) or with aqueous work-up, the intermediate of formula 26 is converted into the desired oxazolidine-2,1 * -dione.

When a primary or secondary amine group is desired in the final product, this group can be introduced via an oxazolidine-2, k-dione, which contains a group which can be selectively reduced (eg, by catalytic hydrogenation or acid / metal couple) to the primary or secondary amine. For example, an N-benzylindole can are used as a precursor to an indole derivative.

The carbon imidate of formula 25 is conveniently prepared from the corresponding aldehyde according to scheme B.

8103538 T f

V

- 8 -

The aldehyde of formula 33 is converted to the cyanohydrin of formula 35 by standard methods (e.g., via the bisulfite adduct, which is reacted with cyanide in a two phase aqueous organic solvent system).

Alternatively, the aldehyde can be converted to the trimethylsilyl cyanohydrin of formula 3 ^ by reaction with trimethylsilylcarbonitrile in the presence of a catalytic amount of a Lewis acid, e.g. zinc iodide. A solvent inert under the reaction conditions (e.g., methylene chloride or ether) is generally used when the aldehyde is a solid, but may optionally be used if the aldehyde is a liquid. The temperature of the reaction is not critical, but it is conveniently carried out at a reduced temperature (b, v. 0-5 ° C) and allowed to proceed at room temperature for several hours or days as necessary to complete the reaction. initiate the reaction. If desired, the trimethylsilyl ether can be hydrolyzed to cyanohydrin, suitably at a reduced temperature (eg, -10 ° C) in a two phase strong aqueous acid / organic solvent system.

Either the cyanohydrin of formula 35 or the trimethylsilyl ether of formula 3 ^ is converted to the carbon imidate of formula 25 by strong acid catalyzed alcoholysis (using perfectly anhydrous conditions). A suitable method consists of simply dissolving a nitrile in alcohol, which is saturated with hydrogen chloride, and the solution is left to stand until the formation of the carbon imidate is complete. The temperature is not critical, although lower temperatures (e.g. 0-25 ° C) generally lead to higher yields.

The aldehydes required for the above syntheses are widely available either commercially or through literature methods. N-alkylpyrrol-2-carbaldehydes are e.g. obtained by alkylating pyrrol-2-carbaldehyde 35 (Weygand, Organic Preparations, Interscience, New York, 19 ^ 5 8103538-9 - biz. 1 * 03) using the conditions specified below for the preparation of N- alkyl pyrroles, or by Reimer-Tieman formulation of If alkyl pyrrol (see Weygand, supra); 3-formylindoles are similarly obtained from indoles (see Boyd and Robson, Biochem J. 29, p.

555 (1935; Shabica et al., J.A.C.S. 68, 1156 (19 ^ 6));

Rosenmund hydrogenation of the corresponding acid chloride / eg. 3-furaldehyde; Hayes, J.A.C.S. T1 »2581 (191 * 927, from halomethyl compounds with the Sommelet reaction / e.g.

3-thenaldehyde; Campaigne and LaSuer, J.A.C.S. T0, 1557 (19 ^) 7, formylation / "eg 2-thenaldehyde, 3-methyl-2-thenaldehyde, 5-methyl-2-thenaldehyde; Watson and Michaels, JACS 72, 1U22 (1950), Or. Synt. 31 108 (1951) 3-bromo-2-thenaldehyde; Elliott et al., J. Chem. Soc. (C), 2551 (1971) 7; reduction of 15 chloromethyl-substituted aldehydes / "e.g. 5-methyl-2-furaldehyde, Spence and Wild, J, Chem. Soc., 338 (193527, oxidation of the corresponding alcohol / "eg 2-thenaldehyde; Emerson and Patrick, J. Org. Chem., 11 *, 790 (191 * 927, action of Grignard reagent on orthomic acid esters /" eg 2- then-20 aldehyde; Cagniant, Bull. soc. chim. France 16, 81 * 9 (19 ^ 927, decarboxylation of α-keto acids / "eg 2-thenaldehyde; Barger and Easson, J. Chem, Soc., 2100 (193827 and halogeners, eg, 2-bromo-3-thenaldehyde; Elliot et al, supra, 7; several of the currently required aldehydes are further available by hydrolysis of gem dihalides, oxidation of primary alcohols, reaction of Grignard reagents with orthomic acid esters, and others. Methods known in the art Further methods are mentioned in the preparation methods further described below.

Another suitable precursor for the oxazolidine-2,1 * dions according to the invention which do not contain a primary or secondary amine group is the α-hydroxyamide of formula 27. The latter compound is converted into the desired oxazolidine-2,1 * -dione of formula 1, or by reaction of alkyl chloroformate in the presence of a basic catalyst 8103538

V

10 such as potassium carbonate, or by reaction with a dialkyl carbonate in the presence of a stronger basic catalyst, such as sodium methanolate or potassium tert-butoxide. An alcohol is generally suitable as a solvent for the latter reaction, using 1-3 equivalents of both dialkyl carbonate and base, preferably 2-3 equivalents of each. When a primary or secondary amine group is desired in the final product, this group can be introduced via an oxazolidine-2, dione containing a suitable precursor group, as described above.

The required α-hydroxyamide is suitably prepared from cyanohydrin of formula 35 or from α-hydroxy acid or ester of formula 28 according to scheme C.

Suitable conditions for the hydrolysis of the cyanohydrin of formula 35 consist of treating the cyanohydrin in formic acid with excess concentrated hydrochloric acid. A temperature range of 0-75 ° C is generally satisfactory depending on the stability of the particular amide in this medium. If desired, as an intermediate, a formate ester of the compound of formula 27 can be isolated under these conditions. Further hydrolysis to the acid can be avoided by monitoring the reaction with thin layer chromatography, as further described below. Suitable conditions for the aminolysis of the ester of formula 28 are simple heating of the ester in warm concentrated ammonium hydroxide.

The α-hydroxy ester of formula 28 itself can also be used as the immediate precursor of the desired oxazolidine-2,1 + -dione. The ester is reacted with urea (or one of the certain substituted ureas, such as phenylurea or 1-acetyl-3-methylurea) in the presence of a basic catalyst, such as sodium ethanolate (suitably 1 equivalent) in alcohol at a temperature of 50- 110 ° C. The ester to be used for this purpose is by no means limited to a simple short chain alkyl ester, but can be selected from 8103538-11 - a wide variety of esters, e.g. a phenyl, benzyl or the like ester. In addition, the ester can be replaced by a 1,3-dioxolan-4-one, an α-acyloxyester or a thioester, e.g. of formula 36, formula 37 or formula 38 and the urea 5 can be replaced by a urethane.

Two other precursors suitable for the synthesis of the desired oxazolidine-2,1 * -dione are the thio compounds of formula 29 and formula 30. The 2-thioxo compound of formula 29 is converted into the desired oxazolidine-2,2 -diones under oxidizing conditions, eg with mercury (II) ions, aqueous bromine or chlorine, meta periodate or aqueous hydrogen peroxide, usually in excess and in the presence of an auxiliary solvent, such as a short chain alcohol. The temperature of the reaction is not critical, and generally a temperature in the range of 25-100 ° C is satisfactory. Other methods usually preferred when an amine group is, because competitive oxidation of the nitrogen can lead to a decrease in yield and make isolation of the desired product difficult; however, it has been found that when the product contains a tertiary amine (e.g. pyridine, quinoline), periodate or bromine are suitable agents for this purpose. The oxazolidine-2, U-dions are obtained from the alkylthio compounds of the formula 8 by simple acid or base catalyzed hydrolysis. Preferred conditions are aqueous hydrochloric acid in a temperature range of 0-50 ° C.

The precursor 2-thioxo compound of formula 29 is prepared from the corresponding aldehyde of formula 33, which is generally done in an aqueous acidic medium by the action of thiocyanate (1-1.1 equivalents) and cyanide 3q (1-1.2 equivalents) ) at 0-70 ° C, according to the method of Lindberg and Pederson, according to which method the preparation of 5- (thien-2-yl) -2-thiooxazolidine-2-one is reported / “Acta Pharm. Suecica 5 (1), pp. 15-22 (1968); C. A. 69, 52050k7 · The precursor 2-alkylthio compounds of formula 30 can be prepared by alkylating the 2-thioxo compounds of formula 29, 8103538 - 12 - e.g. with an alkyl halide or dialkyl sulfate, preferably in the presence of at least two equivalents of a base, such as a short chain alkoxide, in an inert solvent, such as a short chain alkanol, under the reaction conditions. The 5-alkyl derivative can be a by-product of this reaction.

Also suitable as a precursor is the 2-imino-oxazolidine-U-derivative of the formula 31, which is readily hydrolyzed to the oxazolidine-2, H-dione, preferably under aqueous acidic conditions. The desired 2-iminooxazolidine-10 4 -one is obtained by condensation of the α-hydroxy ester of formula 28 with guanidine or with thiourea in the presence of one equivalent of a strong base, such as sodium alkoxide, by aminolysis of the 2-alkoxy compound (isomer with the compound of formula 26) or the 2-thioalkyl compound of formula 30, alkali-induced cyclization of the appropriate α-halo urides (R 1 CH 2 CONCHONHR 2, wherein Z is a halogen, such as chlorine or bromine), or by condensation of the appropriate alkyl α-haloacetates (R ^ CH2COOR ^) with urea or with a substituted urea (R ^ NHCONHg).

Amminolysis of the 1 + alkoxy derivatives of formula 26 yields U-imino derivatives (isomers with the compound of formula 31). The latter compounds are also readily hydrolyzed to oxazolidine-2, H-dions. The H-alkoxy derivatives themselves are also prepared from the silver salt of the desired oxazolidine-2, U-dione.

The dialuranic acids and acyl dialuranic acids of formula 32 are also very useful as a precursor to the oxazolidine-2, U-dione of the invention. These are easily converted under weakly basic conditions to the desired oxazolidine-2-dione. The methods suitable for the preparation of precursor dialuranic acids of formula 32 are shown in Scheme D wherein the substituents R 1, and R 2 have the meaning above and M stands for Li, MgCl,

MgBr, Mgl, or other suitable metal.

A general method for the preparation of 8103538 - 13 - dialuranic acids suitable as precursors of the oxazolidine-2, H-dions according to the invention is based on the malonic acid ester derivatives of formula 39, with a two-stage base catalyzed condensation with urea and oxidation of the hydroxy or acyloxy compound. When the first stage consists of oxidation, the intermediate is a so-called tartronic acid derivative of formula HO, while, when the first stage is condensation, the intermediate is a so-called barbituric acid of formula U1. When R1 contains an amine group (eg 2-aminophenyl), it is preferable to carry out the oxidation as a first step, thereby avoiding possible complications of nitrogen oxidation. When condensation is the second stage, the dialuranic acid is usually not isolated, at least not in pure form, and is further converted to the oxazolidine-2, H-dione under basic condensation conditions.

The substituted malonic esters necessary for the above syntheses, if not commercially available, are obtained from methods known in the art such as alcoholysis of α-cyano esters, see Steele, J.A.C.S. 53, 286 (19307, carbaloxylation of esters / "see Horning and Finelli, Org. Synt. 30, k3 (195027) and decarbonylation of o-esters obtained by condensation of dialkyl oxalate with carboxylic acid esters /" Reichstein and Morsman, Helv. Chim. Acta 17, 1123 (193 * 0; Blicke and Zienty, JACS 63, 25 29U6 (19H1) 7

A less common method for preparing the appropriate dialuranic acid intermediate is the reaction of an electron-rich heteroaryl / aryl compound, e.g. according to schedule E, schedule F or schedule G.

There is currently another method available for the preparation of certain dialuranic acid intermediates. This method, which is preferred when the suitable starting materials are readily available, is based on the reaction of alloxan (preferably in anhydrous form) with the appropriate organic metal derivative (eg organo-lithium, 8103538] - -

Grignard reagent). E.g. according to scheme H. Protective measures are required when using this method for the preparation of certain oxazolidine-2+ dions, which carry a substituent incompatible with reactions with organic metal compounds, e.g. an acyl group is protected as its ethylenic ketal. In other cases, such as when R contains a group such as nitro or amino, this 1he-fc method generally cannot be used successfully.

It will be apparent to those skilled in the art that the preferred process for the preparation of the oxazolidine-2-dione according to the invention differs from one particular meaning of R 1 to another depending on factors such as the availability of starting materials, yields, the ability to remove unwanted impurities from the final products, the chemical nature of the substituent groups present in the final products, and the like.

The pharmaceutically acceptable cation salts of the compounds of the invention, which form such salts, are readily prepared by reacting the acid form with a suitable base, usually one equivalent, in a cosolvent. Typical bases are sodium hydroxide, sodium methanolate, sodium ethanolate, sodium hydride, potassium methanolate, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benethamine, diethylamine, piperazine and tromethamine. The non-direct precipitation salts 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 another salt of the cation (sodium ethyl hexanoate, magnesium oleate) using a solvent in which the desired cation salt precipitates, or else can be isolated by concentrating and adding a non-solvent.

The pharmaceutically acceptable acid addition salts of the compounds of the invention, which can form such salts, are readily prepared by reacting the base forms with a suitable acid, usually an equivalent, in an auxiliary solvent. Typical acids are hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, methanesulfonic, maleic, succinic. Those salts, which do not precipitate immediately, are isolated by concentration to dryness or by adding a non-solvent.

3-acylated derivatives of the compounds of the invention are readily prepared using standard acylation conditions, e.g. the reaction of the oxazolidine-2, H-dione salt (or formed as such or suitably in situ by addition of an equivalent of a tertiary amine, such as triethylamine or N-methylmorpholine with an equivalent of the appropriate acid chloride or anhydride), or reaction of the oxazolidine-2,2-dione with the appropriate organic isocyanate, optionally in the presence of a catalytic amount of a tert-amine base. In both cases, the reaction is carried out in a solvent inert under the reaction conditions, such as toluene, tetrahydrofuran or methylene chloride.

The temperature is not critical and can vary over a wide range (eg 0-150 ° C). It will be apparent to those skilled in the art that such acylation is disturbed by competition or even selective side chain (R1) acylation when the side chain contains a primary or secondary amine group.

It will be clear to a person skilled in the art that the compounds according to the invention are asymmetrical and can therefore exist in two optically active enantiomeric forms.

The racemic compounds of the invention, which are acids when R is hydrogen, form salts with organic amines.

These racemic forms are therefore generally capable of being separated into optically active forms by the classical method of forming diastereomeric salts with optically active amines, which can then be separated by selective crystallization; instead, the compounds containing a basic amine group can be separated by forming a salt with an optically active acid, preferably a strong organic acid, such as sulfonic acid. In general, one of the enantiomeric forms appears to have a greater activity than the others.

The reactions used for the preparation of the compounds of the invention can generally be followed by standard thin layer chromatography methods using commercially available plates. Suitable eluents are the usual solvents, such as chloroform, ethyl acetate or hexane or suitable combinations thereof, which separate starting materials, products, by-products and in some cases intermediates. The use of these methods known in the art allows for further improvement in the methodology of the specific examples listed below, e.g. the choice of a more optimal reaction time and temperature, as well as promotion in the choice of optimal processes.

The oxazolidine-2, U-dions of the invention can readily be made suitable for clinical use as an antidiabetic agent. The hypoglycemic activity required for this clinical application is determined by the Lucose tolerance test method described below. Intact male albino rats are the experimental animals used for these purposes. The test animals are fasted at about 18 to 2b hours. The rats are weighed, numbered and divided into groups of five or six as needed. Each group of animals is then dosed intraperitoneally with glucose (1 g / kg) and orally with either water (comparison animals) or the compound (at a level usually chosen within the range of 0.1 to 100 mg / kg) . Blood glucose levels (mg / 100 ml.) Are measured on tail blood samples over 3 hours in both the control groups and the treated groups. With equal 35 blood glucose levels at the hour zero in comparison and 8103538 y * - 17 - "treated groups, the percent decrease in blood glucose after half an hour, 1 hour, 2 hours, and 3 hours is calculated as: /” comparison blood glucose7 - / " treated blood glucose / --1 - = - x 100% / ~ comparative blood glucose7 Clinically useful hypoglycemic agents exhibit activity in this trial. The hypoglycemic activity determined for compounds of the invention is summarized in Table A. This table lists the percent blood glucose decrease after half an hour and after 1 hour. A blood glucose decrease of 9% or more generally means statistically significant hypoglycemic activity in this test. Of the compounds which show such significant activity only after 2 or 3 hours, this activity is mentioned in footnotes.

Table A

Hypoglycemic action of oxazolidine-2, U-dions q in the rat glucose tolerance test. Λ λ p '/ xsj> NH% decrease in blood o Ar dose - (mg / kg) 0.5 hours Ί hours thien-2-yl 10 11 8 5-benzoyl- 25 10 7 3-bromine- 10 8 6 (a) 5-bromo-100 36 19 5-chloro-100 26 17 3-methoxy- 5 13 16 5-methoxy- 25 97 3-methyl- 100 30 17 10 1 ^ 12 5-methyl 50 18 10 5-phenyl 50 1 5 (b) thien-3-yl 10 23 20 5 20 17 U-bromine- 100 31 25 10 ih 9 8103538 - 18 -

Table A (continued)% reduction in blood-Ar dose of glucose level (mg / kg) 0.5 hours 1 hour

It-methoxy- 5 11 8 lt-methoxy-2-methyl- 5 16 lit lt-ethoxy- 5 19 19

It-ethoxy-2-methyl-5 7 12

It-propoxy- 5 11 6 fur-2-yl 100 27 23 10 11 7 3-bromo- 25 18 10 5 11 11 5-bromo- 50 19 20 10 2 11 5-chloro- 25 21 20 3-methoxy- 25 10 10 5 - methyl- 100 27 19 5-phenyl- 25 6 It (c) fur-3-yl 10 17 13 5 1 * t 8 2,5-dimethyl- 100 33 (e) 16 (f)

It-iodine- 25 19 (e) 0 (f) 3-benzo / b7thienyl100 11 '5 7-benzo / b7thienyl 100 -It 12 (d) 7-benzo / B7furanyl - - 5-chloro- 10 23 (e) 10 (f) chroman-8-yl - - 6-chloro- 10 - 11 6-fluoro- 10 - 9 2,3-dihydrobenzofuranyl - - - 5-chloro- 25 - 23 (g) 8103538 - 19 -

Table A (continued)% decrease in blood

Ar dose gtoops content- (mg / kg) 0.5 hour 1 hour pyrrol-2-yl 100 11 8 1-methyl- 100 18 17 1-ethyl- 100 1 ^ 16 1- (1-butyl) - 100 U 13 1 -phenyl 100 30 32 indol-3-yl - - 5-bromine- 100 9 10 1 -methyl- 100 11 8 pyrid-3-yl - - 2-methoxy 10 - 13 2-ethoxy- 25 - 20 2-methoxy- 5-chloro- 25 22 17 2- ethoxy-5-chloro- 10 - 2k (g) quinol-5-yl - - é-methoxy- 20 - 7 (h) quinol-8-yl 18 19 16 6-chloro 10 - 16 6-fluoro- 10 - 15 7-methoxy- 10 - - (i) thiazol-2-yl 75 11 10 benzthiazol-2-yl- 50 8 10 xsoxazol-5-yl - - - 3-methyl- 100 k 7 (j) (a) 11 after 2 hours (h) 9 after 2 hours (b) 9 after 2 hours (i) 12 after 3 hours (c) 10 after 3 hours (j) 2k after 2 hours, (d) 16 after 2 hours; 10 after 3 hours 1H after 3 hours.

(e) after 0.75 hours (f) after 1.5 hours (g) after 0.75 hours 8103538 - 20 - ►

The oxazolidine-2,1+ dions of the invention are administered clinically to mammals including humans, either by oral or parenteral route. Oral administration is preferred because it is easier and avoids the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication or is hindered absorption after oral administration, such as due to illness or other abnormality, it is important that the drug be administered parenterally.

In both ways, the dosage is in the range of 0.10-50 mg / kg body weight of the patient per day, preferably 0.20-20 mg / kg body weight per day, administered in a single dose or as a divided dose. However, the optimal dose for the individual patient being treated is determined by the person in charge of the treatment, generally smaller doses are administered at the beginning and then the doses are increased to determine the most appropriate dose. depending on the particular compound used and the patient being treated.

The compounds can be used in pharmaceutical preparations containing the compound or a pharmaceutically acceptable acid salt thereof, in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers are inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound is present in such pharmaceutical compositions in an amount 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 preparations may optionally contain additional ingredients such as flavors, sweeteners, excipients and the like. For parenteral administration 8103538-21, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Solutions in sesame oil or groundnut oil, aqueous propylene glycol and the like may e.g. 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 intrarauscular administration being preferred for humans.

The invention is further elucidated by means of the examples below, however it will be understood that the invention is not limited to the specific details of these examples.

Example I

Methyl star of 2-methoxyoyridine-3-carboxylic acid

Thionyl chloride (50 ml) was added to 2-methoxypyridine-3-carboxylic acid (5 g) in 50 ml of carbon tetrachloride and the mixture was heated under reflux for 2 hours. The reaction mixture is cooled, evaporated to solid and treated several times with amounts of fresh carbon tetrachloride. The acidic hydrochloric acid obtained is dissolved in excess methanol (50 ml), stirred at room temperature for 16 hours, then evaporated to an oil and taken up in chloroform. The cKLoroform-25 solution was washed with two amounts of saturated sodium bicarbonate and then an amount of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as an oil / ,U, 63 g; k.m.r./CDCl^/delta (ppm): 3.9 and U, 1 (2s, 6h); 6.9 (m. 1H); 8.2 (m. 2H) 7.

By the same method, 1-methylpyridine-3-carboxylic acid is converted into a methyl ester of U-methylpyridine-3-carboxylic acid.

35 8103538 - 22 -

Example II

3-Methanesulfinylmethylcarbonyl-2-methoxypyridine Sodium hydride (2.69 g, 50% dispersion in oil, 0.056 mol) was washed 3x with petroleum ether. After the third decantation, traces of petroleum ether were removed by evaporation in vacuum. Dimethyl sulfoxide (30 ml) was added and the mixture was heated at 75 ° C for 1 * 5 min on an oil bath,

After which period hydrogen development had ceased. The mixture was cooled on an ice-water bath and diluted with 30 ml of dry tetrahydrofuran. The title compound of the previous example (1 *, 63 g; 0.028 mol) in 10 ml dry tetrahydrofuran was added dropwise over 5 min. The reaction mixture was warmed and stirred at room temperature for 30 min, poured into 180 ml of water, acidified to pH 1 * with 1N hydrochloric acid and extracted with three volumes of chloroform. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title product as an oil / ~ 1 *, 97 g * pm / CDCl / delta (ppm); 2.8 (s, 3H), 1 *, 1 (s, 3H); 1 *, 1 * and i *, 7 (2d, 2H); 7.0 (m. 1H); 8.3 (m. 2H] 7.

By the same method, the U-methyl compound of the previous example was converted to 3-methanesulfinyl-methylcarbonyl-H-methylpyridine.

Example III

S-methyl ester of 2-acetoxy-2- (2-methoxypyrid-3-yl) -thioacetic acid ......

The title compound of the previous example (3.97 g), sodium acetate (3.97 g) and acetic anhydride (1 * 0 ml) were combined in 80 ml of toluene and heated at 115 ° C for 16 hours. The mixture is cooled and evaporated to dryness in vacuo to yield crude product. The latter is chromatographed on 200 g of silica gel with 2: 1 chloroform: ethyl acetate as eluent, viewed by thin layer chromatography and collected in fractions of 10 ml each. The 8103538 * 1.

23 - pure product fractions 58-79 were combined and concentrated to an oil. To remove possible traces of residual acetic anhydride, the oil was taken up in wet ethanol, kept dissolved in it for 15 min, evaporated again, rinsed with toluene, taken up in chloroform, dried over anhydrous magnesium sulfate, filtered and evaporated again, the aforementioned product was obtained as an oil / 3.16 g; Rf 0.60 (3: 1 ethyl acetate: methanol); m / e 255; ir (CH 2 Cl 2) 17.8, 1686, 1582, 1U60, 1205 cm.

According to the same method, a methyl compound of the previous example is converted into the S-methyl ester of 2-acetoxy-2- (1-methylpyrid-3-yl) thioacetic acid.

Example IV

5- (2-methoxynyrid-3-yl) oxazolidine-2-dione 15 Sodium methanolate (632 mg, 11.7 mmol) was taken up in 50 ml of absolute ethanol and the solution was cooled in an ice-water bath. Urea (231 * mg; 3.9 mmol) was added, followed by the title compound of the previous example (1.0 g; 3.9 mmol) in 5 ml of ethanol. The mixture was heated under reflux for 16 hours, then cooled to room temperature, neutralized with 11.7 ml of 1N hydrochloric acid and evaporated to a gum, which was rinsed with toluene.

The gum was chromatographed on 10 g of silica gel with 1: 2 ethyl acetate: chloroform as eluent, 25 fractions were viewed by thin layer chromatography and 10 ml fractions were collected. The product-containing fractions 6-15 were combined and evaporated to a viscous oil, which was crystallized from water / 75 mg, mp 183-186 ° C,

Rf 0.32 (1: 2 ethyl acetate: chloroforn 2.

According to the same method, the methyl compound from the previous example is converted into 5- (k-methylpyrid-3-yl) oxazolidine-2, U-dione.

8103538

Example V

v ï> t Γ - 2h -

Ethyl ester of 2-ethoxypyridine-3-carboxylic acid 2-ethoxypyridine-3-carboxylic acid (U g) was converted into its acid chloride hydrochloride by refluxing with 8.6 ml of thionyl chloride for 60 min. The reaction mixture was evaporated to solid, flushed with toluene to remove excess thionyl chloride. The residue is taken up in 80 ml of ethanol and kept at 0 ° C for 16 hours, then evaporated to solid which was partitioned between 10 toluene and Tn sodium hydroxide. The aqueous layer is extracted with fresh toluene and the two organic layers are combined, washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title product as an oil. 3.2 g; kmr / CDCl 3 / delta (ppm) 1.6 (2s, 6H); UU-5.0 (2q, kfl); 7.2 and 8.2 (m, 3H) 7.

Example VI

2-ethoxy-3-methanesulfinylmethylcarbonylpyridine Using methylene chloride instead of chloroform in isolation, the method of Example II was used to convert the product of the previous Example (3.0 g) into the title product. 2.63 g, mp.

89-91 ° C; pm / CDCl / delta (ppm) 1.5 (t, 3H), 2.8 (s, 3H); 1 *, 2-U, 8 (s and q, kü); 6.8-7.1 and 8.0-8, U (3H) 7.

Example VII

S-methyl ester of 2-acetoxy-2- (2-ethoxypyrid-3-yl) -thioazine acid

Using a reaction time of U hours at 100 ° C and then U8 hours at room temperature, the method of Example werd was used to convert the product of the previous Example (2.5 g) into crude product, which was isolated as a oil by evaporation of the reaction mixture. The oil was taken up in ethyl acetate, washed successively with three portions of 1N sodium hydroxide, one portion of water and one portion of saturated brine, dried over 8103538-25 anhydrous magnesium sulfate and evaporated to give the title product as an oil. 2.96 g;

Rf 0.78 (10: 1 ethyl acetate: methanol); m / e 2697

Example VIII

2- (2-ethoxypyrid-3-yl) -2-hydroxyacetamide

Product from the previous example (2.9 g) was combined with 30 ml of ethanol and 30 ml of concentrated 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 170g silica gel using ethyl acetate as the eluent and viewed by thin layer chromatography. Pure product fractions were combined and evaporated to give the title product as an oil / 0.9 g; Rf 0.6 (10: 1 ethyl acetate: methanol); km / CDCl / delta (ppm) 1. U (t, 3H); U, 5 (q, 2H); 5, U (s, 1H); 6.2-8.2 (m, 5H) 7.

Example IX

5- (2-ethoxyl-yrid-3-yl) oxazolidine-2H-dione Product from the previous example (900 mg; 20.6 mmol) was combined with 25 ml of t-butanol. Dimethyl carbonate (1.08 g; 9.2 mmol) and then potassium t-butoxide (1.03 g; 9.2 mmol) were added and the reaction mixture was heated under reflux for 3 h. The reaction mixture was cooled, poured into 10 ml of 1N hydrochloric acid, adjusted to pH 25 ° P 7.0 and extracted with two volumes of ethyl acetate.

The aqueous layer was saturated with salt and extracted with additional ethyl acetate. Three organic layers were combined, backwashed with a small amount of water and then saturated brine, dried over anhydrous magnesium sulfate and evaporated to give crude product as a viscous oil. Purified in the preamble, said product was obtained by recrystallization from toluene (295 mg; mp. 1 ^ 0-1 ^ 3 ° C; m / e 272).

Anal. Ber. for Ο ^ Η ^ Ο ^ Ν ^: C ® ^, 5 ^; R 12.61.

35 Case: C 5MU; H U, 85; N 12.70.

8103538 T * '

Example X.

- 26 - methyl ester of 5-chloro-2-methoxypyridine-3-carboxylic acid_

According to the method of Example I, 5-chloro-5-2-methoxypyridine-3-carboxylic acid / Sarges et al., J. Med, Chem. 19, 709 (1976); 10 g7 converted to its acid chloride, which was added all at once to 150 ml of methanol (slightly exothermic), then basified with triethylamine (about 1.1 equivalents).

The reaction mixture was evaporated to solid and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with fresh water and then with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title product / 975 g, mp 79-8 ° C; kmr / CDCl 3. / delta (ppm) 15 3.8 (s, 3H); U, 1 (s, 3H); 8.1 (d, 1H); 8.3 (d, 1H) 7

Example XI

5-c hLoor-3-with hanesulfinylmethylcarbonyl-2-methoxypyridine

According to the method of Example II, the product of the previous example (9.7 g * 0.05 mol) was converted into the title product, which was isolated as a viscous oil (10.3 gm / e 2U9 / 2U7).

Example XII

S-methyl ester of 2-acetoxy-2- (5-chloro-2-25 methoxypyrid-3-yl) thioacetic acid

Using the reaction time of 19 hours at 100 ° C, the methods of Example III and the isolation methods of Example VII were used to convert the product of the previous Example (10.3 g) into the product mentioned in the preamble form of a viscous oil (8.8 g; kmr / CDCl 2 contains a singlet at 6.0 µm / e 291/289).

Example XIII

2- (5-c HLoor-2-methoxypyrid-3-yl) -2-hydroxy-acetamide 35 Methanol (125 ml) was saturated with anhydrous 8103538

* J

- 27 - ammonia at 0-5 ° C. The product from the previous example (8.8 g) in 25 ml of methanol was added and the reaction mixture was stirred at room temperature overnight, then concentrated to a viscous oil (7.3 g). The oil was chromatographed on 100 g silica gel using 1: 1 chloroform: ethyl acetate as eluent, viewed by thin layer chromatography and recovery of 10 ml fractions each. Pure product fractions 190-270 were combined and evaporated to give the title product 10 / 1.3 g; mp 110-113 ° C; m / e 218/216; ir (KBr) 3 ^ A, 3U1Q, 168¼ cnf 1_7.

Example XIV

5- (5-Chloro-2-methoxypyrid-3-yl) oxazolidine-2,4-dione Using a reflux heating for 15 hours, the lead of Example IX was used to make the product of the previous Example ( 1.25 g, 5.8 mmol) to the product mentioned in the opening paragraph.

Before isolation, the reaction mixture was cooled to room temperature and the pH was adjusted to 3 with 1N hydrochloric acid. The mixture was then evaporated in vacuo to a somewhat rubbery solid, from which filterable crude product was obtained upon stirring with 25 ml of water (1, Cpg; mp 199-2 ° C). Recrystallization from 15 ml of ethanol yielded the above-mentioned product / U70 mg purified in the preamble; m.p. 212-21U ° C; m / e 2UU / 2U2; ir (KBr)

317¼. 307U, 2980, 1830, 1752 cm Example XV

2- (6-Chloroquinol-8-yl) -2-hydroxyacetamide etbyl ester of 2- (6-Chloroquinol-8-yl) -2-hydroxy-30-acetic acid (1.6g) in 300ml concentrated ammonium hydroxide under reflux heated. Since no complete solution occurred, the reaction mixture was cooled, diluted with 50 ml of ethanol and heated again at reflux for half an hour. The reaction mixture was concentrated to a volume of 100 ml, cooled slowly and a harvest in the title 8103538% (4-28) product (320 mg, mp 195-198 ° C) was recovered by filtration. Additional product (1 5 mg) was recovered by concentrating the mother liquor to 50 ml and extracting with three portions of ethyl acetate. The combined organic 5 layers were washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness.

By the same method, the ethyl ester of 2- (6-chloro-2,3-dihydro-T-benzo / "b7furanyl) -2-hydroxyacetic acid 10 is converted into ethyl 2- (6-chloro-2,3-dihydro-) 7-benzo [b7furanyl] -2-hydroxyacetamide.

Example XVI

5- (6-c Chloroquinol-8-yl) -oxazolidine-2.H-dione

Potassium tert-butoxide (292 mg; 2.6 mmol) was dissolved in 20 ml of t-butanol. Dimethyl carbonate (23 µg, 2.6 mmol) and then the title compound of the previous example (300 mg; 1.3 mmol) were added.

The reaction mixture was heated to reflux for 18 hours, then cooled to room temperature, adjusted to pH 3 with 1N hydrochloric acid and diluted with 1N hydrochloric acid and ethyl acetate. The aqueous layer was washed with two additional amounts of ethyl acetate. The organizers were combined, washed with two volumes of fresh 1N hydrochloric acid and then with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil (130mg). Crystallization of the oil from isopropyl ether gave purified product, "58 mg; mp 207-210 ° C; ir (KBr) 1839, 1825, 17 cm -1".

By the same method, the benzofuran derivative of the previous example was converted to 5- (6-chloro-2,3-dihydro-7-benzo / "b7furanyl) oxazolidine-2,1 * -dione.

Example XVII

2- (6-fluoroquinol-8-yl) -2-hydroxyacetamide

Ethyl ester of 2- (6-fluoroquinol-8-yl) -2-hydroxy-acetic acid (1.1 g) was heated under reflux for 10 min in 300 ml concentrated ammonium hydroxide. The reaction mixture was cooled slightly, filtered by filtration and evaporated to solid. Trituration of the residue with 25 ml of toluene gave the title product (860 mg; mp, 169-171 ° C).

Example XVIII

5 '(6-fluoroquinol-8-yl) oxazolidin-2, U-dione

Using reflux heating for 3 hours, the product of the previous example (8U mg; 3.8 mmol) was converted to the title product according to the method of Example XVI. In this case, a pE of 2 was used in isolation without adding an excess of 1N hydrochloric acid and the crude product was recrystallized from toluene / 120mg; m.p. 2Q2-20U ° C; m / e 2U6; ir (KBr) 1819, 17 ^ 3, 1363 cm -1 ".

Example XIX

5- (quinol-8-yl) oxazolidine-U-one-2-thione

Potassium thiocyanate (U8Umg; U, 9mmol) and potassium cyanide (370mg; 5.7mmol) were combined in 5ml of water and cooled to 0 ° C. Quinoline-8-carbaldehyde / “« Γ. Org. Chem.

Ui, 957 (1976); 779 mg; U, 9 mmol7 was added, followed by dropwise addition of hydrochloric acid (30 # -ig; 1.9 ml). After stirring at 0 ° C for 25 min, the reaction mixture was warmed to 90-100 ° C for 25 min, cooled, poured into crushed ice, adjusted to pH 8 with sodium bicarbonate and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness (163 mg). The product thus obtained was partitioned between 1N 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 give the title product / 72 mg; Rf 0.65 (ethyl acetate27. The original pH 8 aqueous layer was converted to salt and extracted with ethyl acetate to give an additional crop (11U mg). The final aqueous phase was acidified and extracted with ethyl acetate to yield a third crop (T15 mg), 8103538-30 was obtained.

According to the same method, 7-chloroquinoline-8-carbaldehyde is converted into 5- (7-c-Hlorol-8-yl) oxazolidin-1 * -on-2-thione.

5 Example XX

5- (quinol-8-yl) oxazolidine-2, ** - dione The title compound of the previous example (230 mg; 0.9 ^ mmol) was taken in 6 ml 2: 1 methanol: water and cooled to 0 ° C. Bromine (0.07ml; 21.7mg, 10 2.7mmol) was added and the reaction mixture was allowed to warm slowly to room temperature then stirred for 1 hour. The reaction mixture was evaporated to dryness and the residue was partitioned between 1N sodium hydroxide and ethyl acetate. The aqueous layer was separated, acidified and extracted with two fresh ethyl acetate. The acidic extracts were combined, dried and evaporated to an oil (1UH mg). Crystallization from toluene-chloroform and recrystallization from toluene gave purified title product (UO mg; m / e 228).

20 Anal. Ber. for: 1 ^ 0 ^^. 0.33 ^ 0: C 61.5 * 1; H 3.70; N 11.96 Found: C 61.50; H 3.89; N 11.52

According to the same method, the chlorine compound of the previous example is converted into 5- (7-chloro-25-cinol-8-yl) -oxazolidine-2, U-dione.

Example XXI

5- (6-methoxyc Enol-5-yl) oxazolidine-U-on-2-thione According to the procedure of Example XIX, 6-methoxyquinoline-5-carbaldehyde (0.77 g) was converted into the title compound . After pouring into ice, a first crop (190 mg) was isolated by extracting with ethyl acetate, drying over anhydrous magnesium sulfate and evaporating to dryness.

A second crop (176 mg) is similarly isolated by adjusting the aqueous phase to pH 8 with bicarbonate and extracting with additional ethyl acetate. Both harvests 8103538 - 31 - had m / e of 27b. The second crop also had an m / e of 258, indicating contamination with the product from the next step.

Example XXII

5- (6-methoxy-quinol-5-yl) -oxazolidin-2,1-dione

The combined product harvests from the previous example (0.36 g; 1.31 mmol) were taken up in 15 ml of methanol. Sodium meta periodate (0.56g; 2.62mmol) in 7.2ml 5% sodium bicarbonate was added dropwise. After stirring at room temperature for 3 hours, the reaction mixture was diluted with water, acidified and extracted with two volumes 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 pF7 and further crude product (100 mg) was obtained by extracting with ethyl acetate. The crude harvests were combined, taken up in 1N sodium hydroxide, acidified to pHU with acetic acid and extracted with fresh ethyl acetate. The latter organic extracts were combined and evaporated to dryness. Triturate the residue with ether, mixing

the mixture was allowed to stand until crystallization was complete to give the title product (3 µg; mp 1H-1h-6 ° C). Example XXIII

5- (7-with hoxyquinol-8-yl) oxazolidine-U-on-2-thion 25 Following the method of Example XIX but using adjustment to pH7 with bicarbonate after dilution and ethyl acetate for extraction, 7-methoxyquinoline -8-carbaldehyde (2.0g; 10.7mmol) converted to the title product / 1.17g; Rf 0.7 (2: 1 ethyl acetate: 30 cKorofornO7. This product was not partitioned between aqueous base and ethyl acetate, nor was a second crop isolated by salting out the aqueous phase and further extracting.

Example XXIV

5- (7-Methoxyquinol-8-yl) oxazolidin-2-dione 35 Product from the previous example (0.7 g; 8103538

f X

t - 32 - 2.7 mmol) was combined with 30 ml of methanol and 15 ml of 5% sodium bicarbonate. Sodium meta periodate (1.15g, 5.4mmol) in 15ml water was added dropwise. After stirring at room temperature for 3 hours, the reaction mixture was diluted with water, acidified to pE2-3, and extracted with two volumes of ethyl acetate. The extracts were combined, dried and evaporated to dryness (3.0 mg). Recrystallization from water gave purified product in the title (100 mg; mp 207-208 ° C).

1Q Anal. Ber. for C ^ H ^ NgO ^. 1.2HgO: C 59.4θ; Η 4.34; N 10.66

Found: C 59.33; H 4.01; N 10.66

Example XXV

5-Hydroxy-5- (1-methyl-pyrrol-2-yl) -2,4,6- (1H.3H.5H) pyrimidinetrione ^ Alloxanhydrate (3.2 g; 0.02 mol) is dissolved in 50 ml ethanol by heating. 1-methylpyrrole (1.6 g; 0.02 mol) was added and the mixture was heated on a steam bath for 5 min, followed by passing hydrogen chloride. After standing at room temperature for half an hour, the reaction mixture was evaporated to dryness and the residue triturated with water to give it

the title product was obtained as a solid / 2.9 g; m / e 223; Rf 0.5 (1: 1 ethyl acetate: hexane / 5% acetic acid) 7 Example XXVI

5- (1-methylpyrrol-2-yl) oxazolidine-2,4-dione 2 Product of the previous example (2.8 g) was combined with 25 ml of 1N sodium hydroxide and heated on a steam bath for 30 min after the period complete solution had taken place. A gum precipitated on acidification, which solidified on trituration with water (1.2 g). Recrystallization from 2q methanol-ether purified in the preamble gave the product mentioned / 0.70 g; m.p. 108-114 ° C (dec.); m / e 18o7.

Anal. Ber. for C 53.33; H 4.48; N 15.55

Found: C 53.16; H 4.72; N 15.28.

8103538 - 33 -

Example XXVII

5-hydroxy-5- (1-ethylpyrrol-2-yl) -2,6,6 (1H, 3H, 5H) -pyrimidinetrione

Potassium pyrrol / "<T. Chem. Soc., P. 52 (1931); 5 1 g; 0.01 mol7 was slurried in 5 ml of tetrahydrofuran. Ethyl iodide (1 ml; 0.012 mol) was added, a slight exotherm was observed. The mixture was stirred for half an hour, refluxed for half an hour, cooled to room temperature, diluted with 15 ml of water and extracted with 10 ml of ether. The ethereal extract was washed with 5 ml of water, then added to alloxan hydrate (1.6 g), which was dissolved in 25 ml of ethanol by heating.

The ether was boiled off and the ethanolic residue was heated to reflux for half an hour, then evaporated to a water-soluble gum. The gum was taken up in 25 ml of ethyl acetate, washed with two aliquots of 10 ml of water and re-evaporated to give the title product as a gum (0.6 g; m / e 237).

Example XXVIII

5- (1-ethyl-pyrrol-2-yl) oxazolidin-2'-U-dione

The method of the previous example was repeated on a triple scale. The original isolated product gum (0.03 mole of the pyrimidine trione) was stirred with 60 ml of 1N sodium hydroxide for half an hour, then acidified with concentrated 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 silica gel with 1: 1 ethyl acetate: hexane as eluent and viewed by thin layer chromatography. Early fractions contain the desired product; these were combined and evaporated to an oil which crystallized on standing. Trituration with water gave purified product in the preamble named product (170 mg; mp 90-93 ° C; m / e 19 * 0.

Anal. Ber. for C9H1 () 03N2.0.25H2 O: C 5b, b0-, H 5.32; N lb, 10

Found: C 5 ^ 37; H 5.16; N 13.76.

8103538 <X '* - 3h -

Example XXIX

5-hydroxy-5 - / - 1- (1-butyl) -pyrrol-2-yl) -2, U, 6- (1H, 3H, 5H) pyrimidinetrion_

Potassium pyrrole (3.0 g; 0.03 mol), 1-iodobutane (9.2 g; 0.05 mol) and 10 ml of tetrahydrofuran were combined and heated under reflux for 11 hours at which time the reaction mixture was a thick mass become. The reaction mixture was diluted with 30 ml of water and extracted with 35 ml of ether.

The ether was backwashed with water and then added to a solution of anhydrous alloxan (U, 8 g; 0.03 mol) obtained by heating in 50 ml of ethanol. The ether was distilled off, 6N hydrochloric acid (5 ml; 0.03 mol) was added and the mixture was refluxed for 3 min, cooled, evaporated to a gum and triturated with water to give the title product obtained / ** 5.1 gmp. 135 (dec.); m / e 2657.

Example XXX

5--1- (1-butyl) fur-2-yl7oxazolidine-2'H-dione Product from the previous example (5.1 g; 0.019 mol) was combined with 1N sodium hydroxide (38 ml; 0.038 mol) and 10 min stirred at room temperature. The reaction mixture was filtered, washed with ether, cooled in an ice-water bath, acidified with concentrated hydrochloric acid and extracted with three portions of ethyl acetate. The organic extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to a rubbery solid. The latter was chromatographed on silica gel with ethyl acetate as the eluent and viewed by thin layer chromatography to obtain the partially purified product isolated as an oil (95Chg).

The latter was re-chromatographed using 1: 1 ethyl acetate: hexane as the eluent to give purified product as an oil, 0.59 g; m / e 222; Rf 0.72 (ethyl acetate Yf.

8103538 * $ - 35 -

Anal. Ber. for C.,, ^ Ο ^. 0.51 ^ 0: C 57.38; Η 6.57; N 12.17.

Case: C 57, 0; H 6.35; N 12.15.

Example XXXI

Sodium 5- / "1- (1-butyl) -fur-2-yl7oxazolidine-2,4-5 dione

Product from the previous example (370mg; 1.66mmol) was dissolved in 5ml with ianol. Sodium bicarbonate (90 mg; 1.66 mmol) was added. The resulting solution was evaporated to dryness and the solid residue was triturated with ether to make it into the product mentioned

obtained / 300 mg; m.p. 123-126 ° C (dec.); thin layer chromatographic mobility with 1: 1 ethyl acetate: hexane / 5% acetic acid as eluent identical to the free base form7 Example XXXII

15 5-hydroxy-5- (1-phenylpyrrol-2-yl) -2, U- 6- (1B, 3H, 5H) nvriminetinion 1-phenylpyrrol (1.5 g; 0.01 mol), alloxanhydrate (1.6 g; 0.01 mol) and 50 ml of ethanol were combined and heated under reflux for 15 min. No reaction was detected by thin layer chromatography. In hydrochloric acid (10ml; 0.01 mol) was added and the acidified mixture was heated under reflux for 15 min. Incomplete reaction was determined by thin layer chromatography. A second amount of alloxanthydrate (1.6 g; 0.01 mol) was added and the mixture was stirred for an additional 15 min.

Heated to reflux, cooled and evaporated to dryness.

Trituration of the residue with water gave the title product / 2.3 g; m / e 285; snpt. 232-23H ° C (dec.);

Rf 0.3 (1: 1 ethyl acetate: hexane) 27.

Anal. Ber. for C 4 H 4 ON 2 0.25 4 O: C 58.01; Η MO; N 1150 50 Found: C 57.8U; EU, 05; N 1U, 56

Example XXXIII

5- (1-Phenyluyrrol-2-yl) oxazolidine-2, U-dione The product of the previous example (1 g) was heated on a steam bath for 20 min with 20 ml of 1N sodium hydroxide. The mixture was then cooled in an ice-water bath 8103538

X A

-36 - acidified with concentrated hydrochloric acid and the supernatant was decanted from the rubbery precipitate formed. The gum was taken up in ethyl acetate, washed with water and evaporated to an oil (Otbf g). The aqueous decantate 5 was also extracted with ethyl acetate, the extract was 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-chexane as eluent and viewed by thin layer chromatography. The early product fractions were combined, evaporated to an oil (U10 mg) and the oil was crystallized from ether-hexane to give the above-mentioned purified product. 280 mg.

130-132 ° C; m / e 2 ^ 2; Rf 0, UT (1: 1 ethyl acetate: hexane | 7

Anal. Ber. for ^^ 3®jq ^ 3 ^ 2: ^ 6U, U6; H U, 16; N 11.57.

15 Cases: C 64, U0; H 1 *, 35; N 11.56.

Example XXXIV

5-hydroxy-5- (1-methylindol-3-yl) -2, U, 6- (1H, 3H, 5H) - pyrimidinetrion_

Alloxan hydrate (1.6 g; 0.01 mol), 1-methylindole (1.3 g; 0.01 mol) and ethanol (50 ml) were combined and the mixture was refluxed for half an hour, then until half-volume concentrated, diluted with water and the resulting product recovered by filtration / 2.7 g; Rf *

0.5 (1: 1 ethyl acetate hexane / 5% acetic acid) 7 Example XXXV

5- (1-methylindol-3-yl) oxazolidin-2-dione Product from the previous example (2 g) was heated on a steam bath with 35 ml of sodium hydroxide for 15 min. The reaction mixture was cooled to room temperature, acidified to pH 1 with concentrated hydrochloric acid and decanted from a small amount of gum (130 mg). The decantate was purified by filtration, cooled in an ice-water bath and the resulting solids (330 mg) were recovered by fSLtration. The filtrate was extracted with ethyl acetate; The extract was backwashed with water and evaporated to solid 8103538-37 (0.61 g). The solid products were combined and recrystallized from ethyl acetate / hexane to give the title product (0.33 g; mp 152-153.5 ° C). Anal. Ber. for c12H10 ° 3N2 * ° * 125H20: C 61.99; HU, 1 * 5; N 12.05 Found: C 61.99; H 4.1 * 5; N 12.02.

Example XXXVI

5-hydroxy-5 (5-bromoindol-3-yl) -2,4,6 (1 h, 3H, 5H) - pyrimidinetrione

Allox anhydrous (1.6 g; 0.01 mol) was dissolved in 40 ml of ethanol under heating. 5-Bromoindole (1.96 g; 0.01 mol) was added and heating close to reflux temperature was continued for 15 min. Thin layer chromatography did not indicate that a reaction had taken place. 1N hydrochloric acid (10 ml) was then added, while the reaction mixture was kept at a temperature near the reflux temperature.

After 10 min, the reaction mixture was concentrated to wet solid. Trituration of this wet solid with water gave the title product, 3.17 g, m.p. 250 ° C;

Rf 0.45 (1: 1 ethyl acetate: hexane / 5% acetic acid); Rf 0.3 (1: 5 ethyl acetate: hexane / 5% acetic acid) /

Example XXXVII

5- (5-Bromoindol-3-yl) oxazolidin-2-U-dione Product from the previous example (3.1 g) heated for 15 min on a steam bath with 50 ml of 1N sodium hydroxide, then cooled and crude product (1.25 g) was precipitated by acidification with concentrated hydrochloric acid. Chromato graphing on silica gel using 1: 1 ethyl acetate: hexane as eluent and viewed by thin layer chromatography provided purified product / 0.41 g; m.p. 185-189 ° C; Rf 0.55 30 (1: 5 ethyl acetate: hexane / 5% acetic acid27

Anal. Ber. for C 1 H 2 O 2 Ng Br: C 44.76; H2.38; N 9.49.

Gev. C U5.10; H 2.68; N 9.58.

Example XXXVIII

5-hydroxy-5- (2-thiazolyl) -2,4,6 (1H, 3H, 5H) pyrimidine-trion 35 ---

Thiazole (1.7 g; 0.02 mol) was dissolved in tetra-8103538 + + -38-hydrofuran (35 ml) and cooled to -60 ° C. Butyl lithium (9 ml of a 2.4 molar solution in hexane; 0.0216 mol) was added dropwise over 20 min and the reaction mixture was stirred an additional 30 min at -60 ° C. In this way, 5 tazol-2-yl lithium was formed. Anhydrous alloxan (3 g; 0.021 mol) was dissolved in 20 ml of tetrahydrofuran and added dropwise over 20 min keeping the temperature at -60 ° C. The stirred reaction mixture was warmed to room temperature in 30 min and then cooled again to 0 ° C. 1N salt-10 acid (25 ml) was added in portions and the diluted reaction mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate extract was backwashed with 15 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to yield the title product / 1.9 g; m / e 227; Rf 0.4 (1: 1 ethyl acetate: hexane / 5% acetic acid | 7.

Oxazole is converted to 5-hydroxy-5- (oxazol-2-yl) -2,4,6- (1H, 3H, 5H) pyrimidinetrione by the same method. Example XXXIX

5- (thi azol-2-yl) oxazolidine-2,4-dione

The product mentioned in the preamble of the previous example (1.37 g) was stirred at room temperature with 24 ml of 1N sodium hydroxide. The reaction mixture was allowed to stand for 25 min, after which it was acidified with 3 ml glacial acetic acid and extracted with two 50 ml portions of ethyl acetate each. The extracts were individually dried over sodium sulfate, filtered and evaporated to a solid, the first yielding 184 mg and 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 eluent and viewed by thin layer chromatography. Pure product fractions were combined, evaporated to dryness and the residue triturated with hexane to give purified title product (155 mg; mp.

150-152 ° C).

8103538 - 39 -

Anal. Ber. for C 8 H 2 O HgS: C 39.13; H 2.19; N, 15.21 Found: C, 39.53; H 2.52; ff 1 ^ 95

Using the same method, the other product of the previous example was converted to 5- (2-oxazolyl) oxazolidine-5, 2-dione.

Example XL · 5-hydroxy-5- (benzthiazol-2-yl) -2, U, 6 (1H, 3H, 5H) • pyrimidinetrione

According to the method of Example XXXVIII, 10 benzthiazole (2.7 g; 0.02 mol) was converted into 2-lithium derivative and then reacted with anhydrous alloxan to give the title product originally isolated as an oil. The latter was crystallized from ether-hexane / 2.2 g; Rf 0.55 (1s1 ethyl acetate: 15 hexane / 5% acetic acid) 7

Example XL ·! 5- (Benzthiazol-2-yl) oxazolidin-2-dione Product from the previous example (2.15 g) was stirred with 30 ml of 1N sodium hydroxide for 30 min. The reaction mixture was extracted with ether and product (0.16 g) was precipitated by acidifying the aqueous layer with 6N hydrochloric acid. Chromatograph on 50 ml of silica gel with 1: 1 ethyl acetate: hexane / 5% acetic acid as eluent and viewing by thin layer chromatography, followed by recrystallization from acetone isopropyl ether, yielded purified in the title product / "110 mg; mp 2lh-2l6 ° C (dec.) 7

Anal. Ber. for C 21 H 25 S: C 51.29; H 2.58; N 11.96 Found C 51.51; H 2.99; N 12.21

Example XLII

2- (6-chlorochroman-8-yl) -2-trimethylsiloxyethane-nitrile-6-chlorochroman-8-carbaldehyde (7 g; 0.036 mol) in 70 ml of methylene chloride was cooled to 0-5 ° C. Zinc iodide (100 mg) was added, followed by dropwise addition of trimethylsilylcarbonitrile (h, 26 g; 0.03 mol). The reaction mixture was stirred at room temperature for 61 hours at room temperature, then washed successively with three portions of saturated sodium bicarbonate solution and an amount of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the preamble mentioned product was obtained as an oil / 9.5 g; iriCHgClg) 2857, 1 ^ * 79, 1215, 1190, 1060 cm- ^ 7

Example XLIII

ethyl 1- (6-chlorochroman-8-yl) -1-hydroxymethane-10 carbon imidate hydrochloride_

To cold (0-5 ° C), saturated ethanolic hydrochloric acid (250 ml) was added dropwise product from the previous example (9.29 g) in 15 ml of ethanol, keeping the temperature below 10 ° C. The mixture was stirred at 0-5 ° C for 35 min and then evaporated to an oil. Crystallization from ethanol-ether gave the product mentioned in the preamble / 5.7 g. M.p. 125-127 ° C (dec.); m / e 271/2697.

Example XLIV

5- (6-chlorochroman-8-yl) oxazolidine-2 * -dione 20 Product from the previous example (5.1 * g; 18.6 mmol) was suspended in 250 ml of tetrabydrofuran, cooled in an ice-water bath and triethylamine (6.01 g; 0.06 mol) was added. The cold mixture was rinsed with phosgene for 30 min, stirred at room temperature for 1 hour and then poured into 1 l of crushed ice. The reaction mixture thus diluted was extracted with three amounts of methylene chloride. The combined extracts were washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to solid. The residue was recrystallized from toluene to give the above-mentioned purified product (3.28 g; mp 170-172 ° C; m / e 269/267).

Anal. Ber. for C 12 H 10 NCl C 53.81 *; H 3.77; N 5.23.

Found: C 53.73; H 3.83; N 5.1 * 8 8103538 f] - in -

Example XLV

2- (6-fluorochroman-8-yl) -2-trimethylsiloxyethane-nitrile_

According to the method of Example XLII, 6-5 fluorochroman-8-carbaldehyde (3.2 g; 0.0178 mol) was converted to the title product as an oil / µ, 51 g; m / e 279; ir (CHCl 2) 11 * 98, 1205, 1066 cnf1_7.

Example XLVI

ethyl 1- (6-fluorohroman-8-yl) -1-hydroxymethane-1Qf carbon imidate hydrochloride___

Using a reaction time of 1 hour at 0-5 ° C, the method of Example XLIII was used to convert the product of the previous Example (1 *, 1 * g) into the product mentioned in the preamble / * *! * , 1 g, m.p. 12 * 1250C 15 (onti), m / e 2537.

Example XLVII

5- (6-fluorochroman-8-yl) oxazolidine-2. 1 * -dione According to the method of Example XLIV, product from the previous example (3.9 g; 0.013 mol) was converted into crude product mentioned in the preamble. Crude solid was taken up in 1N sodium hydroxide and extracted with two volumes of ether. Product was reprecipitated by slowly adding the basic aqueous layer to excess 3N hydrochloric acid. Recrystallization from toluene purified in the preamble gave product 25 / "2.73 8" sa ** · 17 ^ -17β ° 0; m / e 2517.

Anal. Ber. for C 1 H 30 ONN: C 57.37; HI, 0.015 N 5.58 Found: C 57.7 J H 3.91; H 5, ^ 0.

Example XLVIII

2- (5-chloro-2,3-dihydro-7-benzo / "b7furanyl) -2-30 trimethylsiloxyethane nitrile-5-chloro-2,3-di hydrobenzo / b7furan-7-carbaldehyde (900mg, 1 *, 9mmol) ) was dissolved in 25 ml of ether Zinc iodide (20 mg) and then trimethylsilylcarbonitrile (970 mg; 9.8 mmol) were added and the mixture was stirred at room temperature for 16 hours, then diluted with 50 ml of ether, washed with 8103538 - 1 + 2 - ti three amounts of saturated sodium bicarbonate solution and an amount of saturated saline, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title product as an oil 5 / 1.1 + g / m / e 283 / 281; irfCHClg) 11 + 79, 1 ^ 57, 1 ^ 35, 1180, 866, 81 + 8 cm "^ 7 ·

By the same method, 5-fluoro-2,3-dihydro-benzo / b7f uran-7-carbaldehyde was converted into 2- (5-fluoro-2,3-dihydro-T-benzo / "b7furanyl) -2-trimethylsiloxyethane nitrile.

«* Mm

10 Example XLIX

ethyl 1- (5-chloro-2,3-dibydro-7-benzo / b7furanyl) -1-hydroxymethane carbonimidate hydrochloride According to the method of Example XLIIII, the compound mentioned in the preamble of the previous example was converted (1.37 g) in the product mentioned in the opening paragraph. The originally isolated solids were repulped twice in ether to obtain purified product / 1.28 g; m.p. 11 + 9-152 ° C (dec.); m / e 257/255; ir (KBr) 3162, 2875, 1650, 1521+, 11 + 58 cm -1_7.

The same method, the fluorine compound of the previous example is converted into ethyl 1- (5-fluoro-2,3-dihydro-7-benzo / "b7furanyl) -1-hydroxymetane carbonimidate hydrochloride.

Example L

5- (5-chloro-2,3-dihydro-7-benzo / b7furanyl) oxazolidine-2. l + -dion

According to the method of Example XLIV, the compound (1.1 g) mentioned in the preamble of the previous example was converted into toluene recrystallized in the preamble mentioned product / "630 mg; mp 197-199 ° C; m / e 255/253; ir (KBr) 3081+, 1833, 1810, 17 ^ 6 cm -1_7.

According to the same method, the corresponding fluorine compound from the previous example was converted into 5- (5-fluoro-2,3-dihydro-7-benzo / "b7furanyl) oxazolidine-2,1 + -dione.

35 Example LI

. 8103538 - 43 -

Example LI

2- (3-with hylisoxazol-5-yl) -2-trimethylsilylet rooster nitrile

According to the method of Example XLII, 3-5 methylisoxazole-5-carbaldehyde (3.4 g; 0.032 mol) was converted into the product mentioned in the preamble, which was isolated as an oil (6.5 g; no aidelydeproton according to kmr, ).

By the same method, isotózole-5-carbaldehyde is converted to 2- (thiazol-5-yl) -2-trimet hylsilylet cock-10 nitrile and 5-methylisoxazole-3-carbaldehyde (Kane et al.,

Japan 62 / 17,572) converted to 2- (5-methylisoxazol-3-yl) -2-trimethyl-silylethane nitrile.

Example Lil et hyl 1-hydroxy-1- (3-methylisoxazol-5-yl) methane-15 carbon imidate hydrochloride

The product mentioned in the preamble of the previous example (6.5 g) was dissolved in cold, saturated, ethanolic hydrochloric acid (50 ml) and kept at 5 ° C for 16 hours. The product mentioned in the preamble was recovered by filtration (3.3 g / mp. 119-121 ° C).

By the same method, the other products of the previous example were converted to ethyl 1-hydroxy-1- (iso-tbiazol-5-yl) methanecarbonimidate hydrochloride and ethyl 1-hydroxy-1- (5-methylisoxazol-3-yl) methanecarbonimidate lydrochloride.

Example LIII

5- (3-methylsoxazol-5-yl) oxazolidine-2,4-dione

According to the method of Example XLIV, the product mentioned in the heading of the previous example (2.2 g) was converted into the product mentioned in the preamble. After diluting in crushed ice, the product was extracted with ether, the combined fractions were dried and evaporated to an oil (1.4 g). Further extraction with ethyl acetate and evaporation provided additional oil (0.4 g). The oil fractions were combined and partitioned between 25 ml of 1N sodium hydroxide and 25 ml of ether. The basic aqueous phase was separated, 8103538

V

t * - kk - acidic with concentrated hydrochloric acid and extracted with 25 ml of ethyl acetate. The ethyl acetate extract was backwashed with water, evaporated to dryness, ht residue triturated with pus (1U6 mg; mp 173-175 ° C). The ether triturate was evaporated to dryness and triturated with fresh ether (238 mg; mp 175-177 ° C.

According to the same method, the other products from the previous example are converted into resp. 5- (iso-thiazol-5-yl) oxazolidin-2, U-dione and 5- (5-methylisoxazol-3-yl) oxazolidin-2,2-dione Example LIV

5- (5-c-chloro-2-ethoxypyrid-3-yl) oxazolidin-2, U-dione ________ 5- (2-ethypypyrid-3-yl) oxazolidin-2, U-dione (125 mg) was dispersed in 1 00 ml of water and dissolved by heating at 56 ° C. ChLoor became 30min. bubbled through the warm solution, during which time the temperature slowly dropped to 3 ° C and a precipitate formed. The reaction mixture was passed for 30 min with nitrogen and crude product was recovered by filtration (101 mg, mp, 119-12 ° C). Recrystallization twice from 2: 1 ethanol: water purified in the title product / 2k mg; m.p. 1U5-1VT ° C; Rf 0.56 (1: 1 ethyl acetate: c Horoform); m / e 2567.

By the same method but using 10% fluorine in nitrogen, 5- (2-etoxypyrid-3-yl) oxazolidine-2, 2-dione was converted to 5- (5-fluoro-2-ethoxypyrid-3-yl) oxazolidine-1,2-dione.

Example LV

2- (fur-3-yl) -2-trimethylsiloxetane nitrile. To a mixture of 3-furaldelyde (1.92 g; 20 mmoles) and 100 mg of zinc iodide in 25 ml of ether trimethylsilylcarbonitrile (U, 7U g; H8 mmol) added dropwise, the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and in vacuo 8103538

η X

Evaporated to give 2- (fur-3-yl) -2-trimethylsiloxyethane nitrile / 2.2 g; k.m.r./CDCl^/delta: 0.2 (s, 9E); 5, **

(s, 1H); 6.1 * (m. 1H); 6.1 * (m, 1F); 7.3 (m, 1 $; 7.5 (m, 1H) 7. Example LVI

5 et fryl 1 -hydroxy-1 - (fur-3-yl) with rooster carbonimidate hydroc KLoride 2- (fur-3-yl) -2-trimethylsiloxyethane nitrile (1.0 g) was dissolved in 10 al at 0-5 ° C saturated ethanolic hydrochloric acid. The resulting solution was kept at 5 ° C for 16 hours.

The reaction mixture was concentrated to about half volume and diluted with ether. Filtration, washing with ether gave etlyi 1-hydroxy-1- (fur-3-yl) with cock carbonimidate hydrochloride (7h6mg; mp 113-115 ° C) m / e 169).

Example LVII

5- (fur-3-yl) oxazolidin-2,1 * -dione ethyl 1-hydroxy-1- (fur-3-yl) with cock carbonimidate hydrochloride (1.5 g; 7.5 mmol) was combined with 5 0 ml of tetrahydrofuran and trietlylamine (2.21 µl 21.9 mmol) and cooled to 1cPc. Phosgene was bubbled through the cooled reaction mixture for 20 minutes. After the mixture was stirred for an additional 30 minutes, nitrogen was passed through the mixture for 10 minutes. The reaction mixture was slowly poured into 100 g of crushed ice. The product was extracted in two volumes of ether and crude product was isolated as an oil by evaporation.

The oil was taken up in 5 ml of 1N sodium hydroxide and extracted with ether. The basic aqueous phase was acidified and extracted with fresh ether. The product was isolated as a rubbery solid (600 mg) by evaporation of the latter ethereal extract. Trituration with chloroform gave purified 5- (fur-3-yl) oxazolidine-2,1 * dione (1 mg; mp 86). -88 ° C; m / e 167). Addition of hexane to the chloroform triturate gave a second crop of product (66 mg; mp 86-88 ° C; m / e 167).

Anal .: Ber. for C 3 H 3 O N: C 50.31; H 3.01; N 8.38 35 Found: C 1 * 9.97; H 3.13; N 8.37.

8103538 - U6 -

-ί A

Example LVIII

2- (5-c KLorfur-2-yl) -2-trimethylsiloxyethane-nitrile 5-cboorfur-2-aldehyde (2.7 g; 21 mmol) was dissolved in 30 ml ether. Trimethylsilylcarbonitrile (6.3ml; 50mmol) and zinc iodide (50mg) were added and the mixture was stirred at room temperature for 11 hours, at which time it appeared from thin layer chromatography (hexane ethyl acetate 8: 1) complete reaction. Concentrate to dryness to provide 2- (5-chlorofur-2-10 yl) -2-trimethylsiloxyethane nitrile as an oil (5 * 5 g; kmr / CDCl 3 / delta: 0.3 (s, 9H); 5. ^ (s, 1H); 6.1 (d, 1H); 6.5 (d, 1O7.

Example LIX

ethyl 1- (5-c-chlorofur-2-yl) -1-hydroxymethane-15 carbonimidate hydrochloride 2- (5-chlorofur-2-yl) -2-trimethylsiloxyethane nitrile (2.3 g) was dissolved in saturated etlanolic hydrochloric acid ( 25 ml) at 0 ° C. The solution was kept at 5 ° C for 2 hours and then concentrated to an oil. Trituration with 20 ml of ether gave crystalline ethyl 1- (5-chlorofur-2-yl) -1-hydroxymethane carbonimidate tydroc KLoride (1.2 g; mp 112-11U ° C; m / e 203).

Example LX

5- (5-c-chlorofur-2-yl) oxazolidin-2 2-dione 2 5 ethyl 1- (5-c-chlorofur-2-yl) -1-hydroxy methane carbon imidate tydroc KLoride (1.2 g; 5 ramol ) was suspended in 50 ml of tetralydrofuran and cooled in an ice bath. After adding triet lylamine (2.1 ml; 15 mol), phosgene was bubbled into the reaction mixture for 20 min, keeping the temperature at 10-20 ° C. The mixture was purged with nitrogen and slowly poured into 100 ml of crushed ice. The diluted reaction mixture was extracted with 100 ml of ether and the ether was back-extracted with saturated brine and concentrated to an oil. The oil was taken up in 15 ml of fresh ether, the solution was purified and extracted with 10 ml of 1N sodium hydroxide. The basic extract was acidified with 8103538 * - U7 - concentrated hydrochloric acid, the product was extracted with ethyl acetate. After back extraction with water, the ethyl acetate layer was concentrated to an oil (550 mg). Part of this oil (500 mg) was chromatographed on 50 ml of silica-5 dioxide gel with 5-hexane: ethyl acetate, containing 5% acetic acid, as eluent. The column was viewed by thin layer chromatography (same eluent). The last eluted product-containing fractions were combined, evaporated to dryness and triturated with hexane to give 5- (5-chlorofur-2-10 µl) oxazolidine-2, k-dione / 177 mg m.p. 112-11U ° C; m / e 201; Rf 0.25 (5: 1 hexane: ethyl acetate with 5% acetic acid) 7.

Anal .: Ber. for C 20 O NCl: C U 1, 71; H 2.00; N 6.95

Case: U1.80; H 2.21; N 6.77

Example I XI

2- (5-Bromofur-2-yl) 2-trimethylsiloxyethane-nitrile-5-bromo-2-furaldehyde (1.1 g; 6 mmol) was dissolved in 50 ml ether. A catalytic amount (50 mg) of zinc iodide was added and then trimethylsilylcarbonitrile 20 (7U6 mg; 1.2 equiv.) Was added dropwise. The reaction was viewed with infrared (disappearance of the characteristic carbonyl absorption) and kmr (disappearance of the characteristic aldehyde protonics). After 60 min. At room temperature, the reaction mixture was washed with saturated sodium bicarbonate solution, twice with water and finally with saturated brine, dried over anhydrous sodium sulfate and evaporated to give 2- (5-bromofur-2-yl) -2-trimethylsiloxyethane nitrile was obtained as an oil / 1 2 g; kmr / CDCl 3 / delta: 0.3 (s, 9H); 5.6 (s. 1H); 6, U (d, 1H); 6.6 (d. 1H] 7.

30 Example LXII

ethyl 1- (5-bromofur-2-yl) -1-hydroxymethane carbon imidate hydrochloride_

According to the method of Example LVI, except that the reaction mixture was not concentrated before the addition of ether, 2- (5-bromofur-2-yl) -2-8103538

X X

- 48 - trimethylsiloxyethane nitrile (1.2 g) converted to ethyl 1- (5-bromo fhr-2-yl) -1-hydroxymethane carbonimidate hydrochloride (H80 mg; mp 120-122 ° C; m / e 2 ^ 7 »2 ^ 9). A less pure second crop (235 mg; mp 10U-106 ° C) was recovered by evaporation of mother liquor and trituration of the residue with ether.

Example LXIII '5- (5-bromofur-2-yl) oxazolidin-2,2'-dione ethyl 1- (5-bromofur-2-yl) -1-hydroxymethanecarbonimidate hydrochloride (982 mg; 3.1 * mmol) converted to 5- (5-10 bromofur-2-yl) oxazolidin-2, U-dione / 126mg; m.p. 126-129 ° C *; m / e 2U5, 2 ^ 7, 0.2 (5: 1 hexane: ethyl acetate with 5% acetic acid | 7 according to the method of Example LVII.

Example LXIV

2- (3-Bromofur-2-yl) -2-trimethylsiloxyethane-nitrile. Following the method of Example LV, 3-bromo-2-furaldehyde (1.75 g, 10 mmol) in 50 ml of ether was reacted with trimethylsilylcarbonitrile (8 , 8 ml; 70 mmol) in the presence of 100 mg of zinc iodide. After a reaction time of 16 hours, the above ether was decanted from the solid and evaporated to dryness to give 2- (3-bromofur-2-yl) -2-trimethylsiloxyethane nitrile / 3 g; 0.7 (3: 1 hexane: ethyl acetate | 7.

Example LXV

ethyl 1- (3-bromofur-2-yl) -1-hydroxymethane carbon-25 imidate hydrochloride

2- (3-Bromofur-2-yl) -2-trimethoxysilylethane nitrile (6.8 g) was dissolved in 70 ml of saturated ethanolic hydrochloric acid at 0 ° C and kept at 5 ° C for 2 hours. Concentration to dryness and trituration with acetone gave ethyl 1- (3-bromofur-2-yl) -1-30 hydroxymethane carbonimidate hydrochloride / b9k g; m.p. 117-119 ° C

(dec.) 7

Example LXVI

5- (3-bromofur-2-yl) oxazolidin-2, -dione According to the method of Example LX, except that phosgene is bubbled into the reaction mixture at 0-10 ° C, 8103538- ^ 9-tΛ became ethyl 1- (3-bromofur-2-yl) -1-hydroxymethane carbonimidate hydrochloride g) converted to purified 5- (3-bromofur-2-yl) oxazolidine-2, H-dione / 8 ^ 7 mg, m.p. 128-130 ° C; 0.20 (5: 1 hexane: ethyl acetate containing 5% acetic acid 27.

5 Anal .: Ber. for C ^ H ^ O ^ NBr: C 3 ^ 16; H 1.63; N 5.69

Found: C3, 3.0, H 1.88; N 5.67.

Example LXVII

2- (fur-2-yl) -2-trimethylsiloxyethane nitrile 2-furaldehyde (2h g; 0.25 mol) was cooled to 0-5 ° C, zinc iodide (500mg) was added and the mixture was stirred. Trimethylsilylcarbonitrile (30 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred at room temperature for 6 hours.

The reaction mixture was diluted with methylene chloride, extracted two times with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, treated with activated carbon, filtered and evaporated to give 2- (fur-2-yl) -2-trimethylsiloxyethane nitrile as an oil. 36 g; 7k% 1 b.m.r./CDCl^/delta: 0.2 (s, 9H); 5.6 (s. 20 1H); 6, k (m, 1H); 6.6 (m. 1H); 7, U (d, 1H) 7.

Example LXVIII

etlyl 1- (fur-2-yl) -1-hydroxymetane carbonimidate According to the method of example LVI, 2- (fur-2-yl) -2-trimethylsiloxyethane nitrile (15 g) was reacted with saturated ethanolic hydrochloric acid, except that a reaction time of 2 hours was used. Crude product was isolated by evaporation of the reaction mixture to an oil.

The oil was partitioned into 100 ml of chloroform and saturated sodium bicarbonate solution. The chloroform was washed twice with 30 more saturated sodium bicarbonate solution, washed once with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated to give ethyl 1- (fur-2-yl) -1-hydroxymethane carbonimidate as a oil / 10.6 g; 81% \ pm / CDCl / delta: 1.3 (t, 3H); 35.1 (<1.2H); 5.1 (s. 1H); U, 8-5.2 (m, 1H); 6.3 (m. 2H); 7.3 (d. 1H) 7.

8103538

X X

- 50 -

Example LXIX

5- (fur-2-yl) oxazolidine-2,5-dione ethyl 1- (fur-2-yl) -1-hydroxymethane carbonimidate (10.5 g; 6.2 mmol) was dissolved in 125 ml stirred tetrahydro-5 furan and cooled to 0-5 ° C. Triethylamine (12.5 g, 0.12 moles) was added and the cold solution was then bubbled with phosgene, warmed to room temperature and stirred for 16 hours. The reaction mixture was slowly poured into 11 ice and water. The product was extracted with three volumes of ethyl acetate. The extracts were combined and the product was extracted with four 1N sodium hydroxide. The combined aqueous extracts were acidified with 6N hydrochloric acid, and the product was extracted with four amounts of chloroform. The combined chloroform extracts were dried over anhydrous magnesium sulfate, treated with activated charcoal, filtered and evaporated to yield crude product as an oil (2.1 g). Column chromatography on 100 g of silica gel with 2: 1 chloroform: ethyl acetate solvent in fractions of 10 ml each, viewed with 20 thin layer chromatography yielding purified 5- (fur-2-yl) oxazolidine-2, on fractions of the fractions. 1 + -dione (281 mg; mp 99-102 ° C; m / e 167). Recrystallization from toluene gave higher purified product (235 mg; mp 101-103 ° C).

Anal .: Ber. for C 25 O H: C 50.31; H 3.02; N 8.38 Found: C 50, Onion; H 3.25; N 8.28

Example LXX

5-hydroxy-5- (3-methoxyfur-2-yl) -2,1 *, 6 (1H, 3H, 5H) - pyrimidinetrion-3-methoxyfuran (3.5 g; about 50% pure as per preparation 10) ), alloxan hydrate / 5,5-dihydroxy-2,1 *, 6 (1H, 3H, 5H) -pyrimidinetrione; 1 *, 8 g7 and 75 ethanol were combined and heated at reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated to dryness. Trituration of the residue with 25 ml of water gave 35 5-hydroxy-5- (3-methoxyfur-2-yl) -2,1 * 6 (1H, 3H, 5H) -pyrimidinetrione / 8103538

f J

- 5T - / 1.9 gm. 120-130 ° C (dec.); m / e 2Uo7.

Example LXXI

5- (3-methoxyfur-2-yl) oxazolidine ~ 2,2-dione 5-hydroxy-5- (3-methoxy-fur-2-yl) -2,6,6 (1H, 3H, 5H) -5 pyrimidine trione (1.7 g) was stirred with 1N sodium hydroxide (1U ml; mmol) for 20 min. The reaction mixture was anhydrated with acetic acid and the product was extracted with ethyl acetate and isolated in crude form by evaporation to an oil. Chromatography on 100 ml silica gel, viewed by thin-layer chromatography, gave 5- (3-with hoxyfur-2-yl) oxazolidine-

2, U-dione / 1 * 70 mg; m.p. 102-10H ° C; R ^ 0.6 (1: 1 hexane: ethyl acetate with 5% acetic acid27 Example LXXII

2- (5-phenylthien-2-yl) -2-trimethylsiloxyethane-15-nitrile-5-phenyl-2-thenaldehyde (0.9 g) in 35 ml ether was reacted with 1 ml trimethylsilylcarbonitrile in the presence of 50 mg zinc iodide . After stirring at room temperature for 1 hour, thin layer chromatography revealed that the reaction was complete. Evaporation to dryness gave 2- (5-enylthien-2-yl) -2-trimethylsiloxyethane nitrile / 1.65 g; Rf 0.5 (5: 1 hexane ethyl acetate with 5% acetic acid) 7

Example LXXIII

ethyl 1-hydroxy-1- (5-phenylthien-2-yl) methane-25 carbonimidate hydrochloride 2- (5-phenylthien-2-yl) -2-trimethylsiloxyethane nitrile (1.6 g) was dissolved in 30 ml cold, saturated ethanolic hydrochloric acid and kept at 0-5 ° C for 17 hours. The reaction mixture was evaporated to dryness and triturated with ethyl acetate to give ethyl 30 1-hydroxy-1- (5-phenylthien-2-yl) methane carbonimidate hydrochloride / 0.9 g; k.m.r./DMSO/delta: includes 1.1 (3H); M (2H); 5.2 71E); 6.5 (1H] 7.

Example LXXIV

5- (5-phenylthien-2-yl) oxazolidin-2, dione 3, 5 Ethyl T-hydroxy-1- (5-phenylthien-2-yl) with lane-8103538 -52- 'carbonimidate hydrochloride (790 mg; 2.6 mmol) and triethylamine (1.1 H ml; 10 mmol) were reacted with phosgene and product isolated by the method of Example XII, except that the eluent in chromatography consisted of 2: 1 ethyl acetate: hexane, whereby 5- (5-phenylthien-2-yl) oxazolidin-2,1 * -dione was obtained (172 mg; mp 233-235 ° C).

Anal .: Ber. for C 25 H NS: C 60.23; H 3.50; N 5, ^ 0

Case: C 59.9U; H 3.65; N 5.38

Example LXXV

2- (3 hi-2-yl) -2-trimethylsiloxyethane nitrile

According to the method of Example LXVII, 2-thenaldehyde (56.1 g; H6.8 ml; 0.5 mol) was reacted with trimethylsilylcarbonitrile (60 ml) in the presence of zinc iodide (0.5 g) for 16 hours, whereby 2- (thien-2-yl) -2-15 trimethylsiloxyethane nitrile was obtained as an oil / "92 g; m / e 211; kmr / CDCl 3 / delta: 0.2 (s, 9H); 5.8 (s , 1H); 6.9-7.5 (m, 3H) 7.

Example LXXVI

ethyl 1-hydroxy-1- (thien-2-yl) methane carbonimidate 2- (thien-2-yl) -2-trimethylsiloxyethane nitrile (1 * 5 g) was dissolved in 1 * 50 ml absolute ethanol. The solution was cooled to 0-5 ° C and flushed with hydrogen chloride for 1 * 0 min. The mixture was kept at 5 ° C for 16 hours and evaporated to dryness. The residue was triturated with four 200 ml portions of ether and then partitioned between 1 * 00 ml of methylene chloride and saturated sodium bicarbonate solution.

The organic phase was washed twice with saturated sodium bicarbonate solution, treated with activated charcoal, filtered and concentrated to give ethyl 1-hydroxy-1- (thien-2-yl) methane carbonimidate as an oil which solidified on standing. g; kmr / CDCl 3 / delta: 1.2 (t, 3E); H, 1 («i, 2H); 5.2 (s, 1H); 5.9 (s, 1H); 6.8- 7.3 (m, 3H), 7.3-8.1 (s, 1H] 7.

35 8103538 -53--

Example LXXVII

5- (thien-2-yl) oxazolidin-2, H-dione ethyl 1-hydroxy-1- (thien-2-yl) methanecarbon imidate (10 g; 5, 1 mmol) and trietlylamine (15.1 ml; 10.8 mmol) 5 were dissolved in 100 ml of tetrahydrofuran. The solution was cooled to 0-5 ° C and flushed with phosgene for 1 * 5 min. Stirring was continued for 5 hours and 0-5 ° C. The reaction mixture was slowly poured onto 1500 ml of crushed ice. The product was extracted with 1.1 L of ethyl acetate in three amounts.

The combined ethyl acetate extracts were then extracted twice with saturated sodium bicarbonate solution and once with 1: 1 saturated sodium carbonate solution: water.

The combined bicarbonate and carbonate washings were acidified to pH 1-2 with 6N hydrochloric acid and product extracted with different amounts of ether. The combined ethereal extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, treated with activated charcoal, filtered and evaporated to yield product (3.0 g). Recrystallization from toluene 20 gave 5- (thien-2-yl) oxazolidin-2, U-dione (1.8 g; mp.

138-11 * 0 ° C / m / e 183).

Anal .: Ber. for C ^ I ^ S: C1 * 5.89} H2.75; N 7.65

Found: C 1: 5.99} H2.87; N 7.62.

Example EXXVIII

2- (3-methylthien-2-yl) -2-trimethylsiloxyethane nitrile

According to the method of Example LXVII, 3-methyl-2-thenaldehyde (31.6 g; 0.25 mol) was reacted with trimetlylsilylcarbonitrile (30 ml) in the presence of 500 mg of zinc iodide for 16 hours. The reaction mixture was diluted with 200 ml of methylene chloride and further isolated as in Example XIII to give 2- (3-methylthien-2-yl) -2-trimethylsiloxyethane nitrile / 52 g; 93% \ pm / CDCl / delta: 0.2 (s, 9H); 2.3 (s. 3H); 5.7 (s. 1H); 6.8 (d. 1H); 7.25 35 (d. 1H] 7.

8103538 - 5h -

Example LXXIX

ethyl 1-hydroxy-1- (3-methylthi en-2-yl) methane carbon imidate 2- (3-methylthien-2-yl) -2-trimethylsiloxyethane-5 nitrile (13 g) was added dropwise to 100 ml cold ethanol saturated hydrogen chloride, keeping the temperature at & * 1 + ° C. After 1 hour at 0-1 + ° C, the reaction mixture was evaporated to dryness. The residue was triturated three times with 100 ml aliquots of ether and then partitioned between 300 ml of methylene chloride and saturated sodium bicarbonate solution. The separated methylene chloride layer was washed with two additional amounts of saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated to give ethyl 1-hydroxy-15 1- (3-metlylthien-2-yl) methane carbonimidate (8.0 g; 69% \ mp.

73-7 ° C; m / e 199) was obtained.

Example LXXX

5- (3-methylthien-2-yl) oxazolidin-2, Π-dione ethyl 1-hydroxy-1- (3-methylthien-2-yl) methane-20 carbon imidate (6.0 g; 0.03 mol) dissolved in 75 ml of tetrahydrofuran and cooled to 0-5 ° C. Triethylamine (6.07 g; 8.37 ml; 0.06 mol) was added, the solution was flushed with phosgene for 35 min and poured slowly into 1 l of ice and water. The product was extracted with three portions of ethyl acetate. The ethyl acetate extracts were combined and the product was extracted with four volumes of saturated sodium bicarbonate solution. The combined aqueous extracts were acidified with 6N hydrochloric acid and the product was extracted again with six volumes of fresh ethyl acetate. The combined fresh organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to yield the product as an oil (2.1 g; 1 + 1%) which crystallized on scratching. Recrystallization from toluene gave purified 5- (3-methylthien-2-yl) oxazolidin-2,1 + -dione (1.81+ g; 31% total; mp 119-121 ° C; m / e 197).

8103538 - 55 -

Anal .: Ber. for C 25 N 2 NS: C 48.72; H 3.58; N 7.10

Case: C 1 + 8.65; H 3.58; N 7.01

A second crop of product (0.63 g) was obtained by extracting the original ethyl acetate extract with three amounts of 1N sodium hydroxide, followed by further isolation as described above.

Example LXXXI

2- (5-methylthien-2-yl) -2-trimethylsiloxyethane-nitrile 10 5-methyl-2-thenaldehyder. (25 g; 0.2 mol}, zinc iodide (266 mg) and 100 ml ether were combined and stirred at room temperature Trimethylsilylcarbonitrile (23.5 g; 0.24 mol) was added dropwise and the reaction mixture was stirred for an additional 2 hours If the reaction mixture was diluted with 100 ml ether, washed with two 50 ml portions each. $ sodium bicarbonate, washed with two aliquots of 25 ml of saturated saline each, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give 2- (5-methylthien-2-yl) -2-trimethylsiloxyethane nitrile 20 / "" 1 + 2 g; kmr / CDClg / delta: 0.2 (s, 9H); 2.2 (s, 3H); 5.6 (s, 1H); 6.6-7Λ (m, 2H) 7.

Example LXXXII

Ethyl 1-hydroxy-1- (5-methylthien-2-yl) methane-carbonimidate hydrocloride 25 While cooling to 0-5 ° C, ethanol (550 ml) was saturated with hydrogen chloride. 2- (5-methylthien-2-yl) -2-trimethylsiloxyethane nitrile (42 g) was dissolved in portions and the solution was kept at 0 ° C for 2 h. The reaction mixture was evaporated to dryness and the residue was triturated with diethyl 30 ether to give ethyl 1-hydroxy-1- (5-methylthien-2-yl) methane carbon imidate hydrochloride / 33 g; m.p. 122-123 ° C; r.m.r./DMSO/delta: 1.1-1.6 (3H); 2.5 (3H); 4.6 (2H); 5.9 (1H); 6.6-7.2 (2H) 7.

35 8103538 * f - 56 -

Example LXXXIII

5- (5-Methylthien-2-yl) oxazolidin-2.U-dione Ethyl 1-hydroxy-1 - (5-methylfur-2-yl) methane-carbonimidate hydrochloride (10 g; 0tOk2 mol) was combined with triethylamine ( 1 µg, 0.1U mol) in 250 ml tetrahydrofuran and cooled to 0-5 ° C. The cold reaction mixture was rinsed with phosgene for 30 min, warmed to room temperature and poured in portions onto 275 ml of crushed ice. The product was extracted with two aliquots of 200 ml of ethyl 10 acetate each. The ethyl acetate extracts were combined and extracted with two aliquots of 15 ml 1N sodium hydroxide each. The combined aqueous extracts were acidified with hydrochloric acid and then extracted with two aliquots of 250 ml fresh ethyl acetate each. The last combined organic extracts were dried over anhydrous magnesium sulfate, filtered

and evaporated to give 5- (5-ethylethyl-2-yl) oxazolidin-2, U-dione (7.2 g). Recrystallization from chloroform / hexane gave purified product (910 mg, mp 108-109 ° C; m / e 197). Example LXXXIV

2- (5-chloro-hien-2-yl) -2-trimethylsiloxyethane-nitrile 5-chlorothenaldehyde (5 g; mmol) was combined with zinc iodide (50 mg) and 30 ml diethyl ether and cooled to 0 ° C. Trimethylsilylcarbonitrile (,0h g; hO mmol) was added dropwise and the reaction mixture was warmed to room temperature and then stirred for an hour. Additional equal amounts of trimethylsilylcarbonitrile and zinc iodide were added and the reaction mixture was stirred for an additional 16 hours. The reaction mixture was diluted with ether, washed with two 30 ml aliquots of 30 ml 5% sodium bicarbonate each, washed 1x with 30 ml saturated brine, dried over anhydrous magnesium sulfate and evaporated to give 2- (5-chlorothien-2- yl) -2-trimethylsiloxyethane nitrile was obtained as an oil ΓΜg ', kmr / CDCl 2 / delta: 0.3 (s, 9H); 5.7 (s. 1H); 7.0 35 (q, 2H) 7. By the same method, 3-fluoro-2-thenaldehyde, 8103538-57 - U-fluoro-2-thenaldehyde, 5-fluoro-2-thenaldebyde, 5-fluoro-3-thenaldehyde / "Gronowitz and Rosen, Chem. Ser. 1 , "biz. 33-3 (1971); C.A. 75, 20080c7, H-fluoro-3-thenaldebyde, U-methoxy-3-thenaldehyde and U-methylthio-3-thenaldehyde, respectively. converted to 5 2- (3-fluoro lien-2-yl) -2-trimethylsiloxyethane nitrile, 2- (1f-fluoro hien-2-yl) -2-trimethylsiloxyethane nitrile, 2- (5-fluoroorthien-2-yl) -2-trimet hyls iloxyet rooster nitrile, 2- (5-fluor hien-3-yl) -2-trimethyl siloxyeth rooster nitrile, 2- (U-fluorothien-3-yl) -2-trimethyl siloxyet rooster nitrile, 10 2- ( U-met hoxythien-3-yl) -2-trimethylsiloxyethane nitrile,

2- (U-methylthiothien-3-yl) -2-trimettylsiloxyethane nitrile. Example LXXXV

ethyl 1- (5-chlorothien-2-yl) -1-hydroxymethane-carhonimidate tydroc KLoride 15 2- (5-chlorothien-2-yl) -2-trimethylsiloxyethane nitrile (U g) was dissolved in absolute ethanol (100 ml) . The solution was cooled to 0-5 ° C and saturated with hydrogen chloride. The reaction mixture was kept at 0 ° C for 16 hours, evaporated to dryness and triturated with ether to give solid ethyl 1- (5-C Hear Hn-2-yl) -1-hydroxymethane carbonimidate hydrochloride / 3 g; r.m.r./DMSO/delta: 1.2 (3H); bs2 (2H); 5.3 (1E); 6.6 (1H); 6.9 (1H); 7, ¾ (1H); 8, ¾ (1H) 7.

According to the same method, the other nitriles from the previous example are converted into resp. ethyl 1- (3-fluoro-25 thien-2-yl) -1-hydroxymethane carbonimidate hydrochloride, ethyl 1- (U-fluorothien-2-yl) -1-hydroxymethane carbonimidate hydrochloride, ethyl 1- (5-fluorothien-2-yl ) -1-hydroxymetric carbon imidate hydrochloride, ethyl 1- (5-fluorothien-3-yl) -1-hydroxy-methane carbonimidate hydrochloride, ethyl 1- (U-fluorothien-3-yl) -1-30 hydroxymethane carbonimidate hydrochloride, ethyl 1-hydroxy- 1- (U-methoxythien-3-yl) methane carbonimidate hydrochloride and 1-hydroxy-1- (U-methylthiothien-3-ylmethane carbonimidate hydrochloride.

Example LXXXVI 5- (5-chlorothien-2-yl) oxazolidine-2 Λ-dione

Ethyl 1- (5-chlorothien-2-yl) -1-hydroxymethane-8103538

* *

- 58 - carbon imidate hydrochloride (3.0 g; 12 mmol) and triethylamine (U, 0 g; 39 mmol) were combined in 90 ml tetrahydrofuran and cooled to 0 ° C. The slurry was flushed with phosgene for 30 min, warmed to room temperature and stirred for 16 hours. The reaction mixture was slowly poured into 100 ml of crushed ice and the product was extracted in two aliquots of 100 ml of ethyl acetate each. The combined ethyl acetate extracts were backwashed with two aliquots of 50 ml of water and 50 ml of saturated sodium chloride 10 solution each, dried over anhydrous magnesium sulfate, filtered and evaporated to a semisolid (2.5 g). Recrystallization from toluene gave purified 5- (5-chlorothien-2-yl) oxazolidin-2, U-dione (0.6 g; mp 126-130 ° C).

Anal. Ber. for O 2 O C 3 C: 38.64; H 1.84; N 6.44. Found: C, 38.17; H 2.07; N 6.91

Similarly, the other iminoethers from the previous example are converted to resp. 5- (3-Fluorothien-2-yl) oxazolidin-2, Ji-dione, 5- (H-Fluorothien-2-yl) oxazolidin-2,4-dione, 5- (5-Fluorothien-2-yl) oxazolidine -2,4-dione, 5- (5-fluorothien-20 3-yl) oxazolidine-2,4-dione, 5- (4-fluorothien-3-yl) oxazolidine-2,4-dione, 5- (4 -methoxythien-3-yl) oxazolidine-2,4-dione and 5- (4-methyl-thiothien-3-yl) oxazolidine-2,2-dione.

Example LXXXVII

2- (4-bromine hi en-3-yl) 2-trimethylsiloxyethane-25 nitrile 1-bromo-3-thenaldehyde (5.5 g; 29 mmol) in 75 ml methylene chloride was cooled to 0-5 ° C. Zinc iodide (50 mg) was added, followed by dropwise addition of trimethylsilylcarbonitrile (3, 7 g; 35 mmol) over a period of 3 min. The mixture was warmed to room temperature, stirred for 16 hours, washed twice with saturated sodium bicarbonate carbonate solution, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2- (4-bromothien-3-yl) -2-trimethylsiloxyethane-35 nitrile as an oil (7.6 g, 90% strength) m / e 291/289).

8103538 - 59 -

Example LXXXVIII

et lyl 1 - (1 * -bromothien-3-yl) -1-hydroxymethane-carbon imidate-2- (U-bromothien-3-yl) -2-trimethylsiloxyethane-5 nitrile (7.5 g) in 200 ml ethanol, chilled in an ice bath, rinsed with chlorine hydrogen for 1 * 5 min. After an additional 20 min at 0-5 ° C, the reaction mixture was evaporated to dryness and triturated with ether to yield the hydrocarbon salt of the product as a hygroscopic solid. The salt was taken up in a mixture of methylene chloride and saturated sodium bicarbonate solution. The separated methylene chloride layer was washed twice with saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give ethyl 1- (1 * bromothien-3-yl) -1-hydroxymethane carbonimidate as a oil (6.1 g; 89 m / e 265/263).

Example LXXXIX

5- (U-bromine hien-3-yl) oxazolidin-2'U-dione 20 Ethyl 1- (U-bromothi en-3-yl) -1-hydroxymethane carbon imidate (6.0 g; 23 mmol) and triethyl amine ( 5.15 g; 51 mmol) were combined in 250 ml of tetrahydrofuran, cooled in an ice-water bath and flushed with phosgene for 35 min. The reaction mixture was warmed to room temperature, stirred for 1 hour, poured slowly on 1 L of crushed ice, and product was extracted into three portions of methylene chloride.

The combined methylene chloride extracts were evaporated to an oil, crystallized by adding a small amount of ether and hexane and triturated in 1 * 0 ml ether to give 5- (1 * -bromothien-3-yl) oxazolidine-3,1 * -dione was obtained (3.1 * g; 56%; mp 158-161 ° C). Recrystallization from 1 * 0 ml of toluene gave purified product (2.51 µm mp. 161 * -166 ° C; m / e 263/261).

Instead, the ethereal solution of the lithium derivative of 3,1 * -dibromothiophene is reacted 8103538-6o-ϊ Λ · with 1.05 equivalent alloxan according to the method of Example LIV to give 5 - (- - bromothien-3 -yl) -5-hydroxy-2tkt6 (1E, 3H, 5f) pyrimidinetrione is obtained. According to the method of Example LV, the latter compound is converted into the desired 5- (U-bromothien-3-yl) oxazolidine-2,1 * -dione.

Example XC

2- (tfaien-3-yl) -2-trimethylsiloxyethane nitrile 3-thenaldehyde (10 g; 0.69 mole), zinc iodide (120 mg) and ether (60 ml) were combined and stirred.

Trimethylsilylcarbonitrile (10.6 g; 0.107 mol) was added dropwise over a 10 min drop and the reaction mixture was stirred for 16 hours, diluted with 60 ml of ether, washed with two aliquots of 30 ml of 5% sodium bicarbonate each, washed with 30 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2- (thien-3-yl) -2-trimethylaloxyethane nitrile as an oil / µL, 3 g; kmr / CDCl3 / delta: 0.2 (9H); 5.6 (1H); 7.0-7.5 (3H) 7.

Example XCI

Etyl 1-hydroxy-1- (thien-3-yl) methane carbonimidate

At 0-5 ° C, 2- (tlien-3-yl) -2-trimethylsiloxyethane nitrile (ih, 3 g) was dissolved in portions in 500 mL of ethanol previously saturated with hydrogen chloride at 0-5 ° C. The 2? solution was kept at 0 ° C for 16 hours and the product was isolated as a hydrochloride salt by evaporating the reaction mixture to dryness and triturating the residue with ether. The salt was taken up in CO 2 ml of chloroform and 100 ml of saturated sodium bicarbonate solution. The separated KLoroform layer 30 was washed with an additional 100 ml of saturated sodium bicarbonate solution, washed with saturated brine, dried over magnesium sulfate, filtered and evaporated to give ethyl 1-hydroxy-1- (thien-3-yl) methane carbonimidate / " 12.5 g; pm / CD / Cl / Delta: 1.0-1.3 (3H); ^ 8-5.3 35 (2H)? 5.0 (1H); 6.9-7.2 (3H); 7.3-8.0 (1H) 7.

8103538 - βΐ -

Example XCII

5- (thien-3-yl) oxazolidin-2Λ-dione ethyl 1-hydroxy-1- (thien-3-yl) methanecarbon imidate (12.5 g; 0.067 mol) and triethylamine (16.1 g; 0.159 mol ) 5 were combined in 600 ml of tetralydrofuran and cooled to 0 ° C.

The mixture was flushed with phosgene for 30 min, warmed to room temperature and left to stand for 16 h. The mixture was slowly poured onto 600 ml of ice and water (foaming of excess phosgene), and extracted twice with 10 ml portions of 600 ml of ethyl acetate each. The combined extracts were washed with two 300 ml portions of 1N sodium hydroxide each.

The combined basic extracts were acidified with hydrochloric acid and the product was re-extracted with two fresh aliquots of 300 ml each of ethyl acetate. The combined fresh extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to solid (8.0 g). Recrystallization from hot toluene gave purified 5- (thien-3-yl) oxazolidin-2,2dione (5-5 g; mp 133-136 ° C). A second recrystallization from ethyl acetate / hexane provided additional purification (first crop: 2.352 g; mp 136-138 ° C; m / e 183; ir (KBr): 5.5; 5.8 µm).

Example XCIII

The hrl 2-hydroxy-2- (thien-3-yl) acetate 3-thenaldehyde (10 g; 0.089 mol) and sodium bi-25 sulfite (13.8 g; 0.133 mol) were stirred at 50-60 ° C for 2 hours heated in 152 ml of water to form the bisulfite adduct in situ. The reaction mixture was cooled to 5 ° C and 200 ml of ethyl acetate were added. To the stirred two-phase system, potassium cyanide (17 µg; 0.267 mol) in 75 ml of water was added dropwise over 30 min. The reaction mixture was warmed to 2cPc and kept at that temperature for 1 hour. Additional potassium cyanide (5.7 g; 0.088 mol) was added and the mixture was stirred at 20 ° C for 10 min. The layers were separated and the aqueous layer was washed with 50 ml of ethyl acetate. The combined ethyl acetate layers were washed 8103538 with saturated sodium chloride solution to give a clear solution of the cyanohydrin of 3-thenaldehyde in ethyl acetate.

The cyanohydrin solution of 3-thenalde-5 hyde in ethyl acetate was stirred at room temperature and mixed with 1 + 1.6 g (52.7 ml; 10 equiv.) Of ethanol and concentrated. triturated hydrochloric acid (15.2 ml; 0.182 mol) and the mixture was heated at reflux for 17 hours. The reaction mixture was cooled to 25 ° C, washed with 100 ml of water and then 10 with saturated sodium bicarbonate to pH 7.0, dried over anhydrous magnesium sulfate, treated with activated charcoal, filtered and evaporated to an oil (about 11.5 g) which, upon addition of 1 + 6 ml of 1: 1 toluene / isooctane, gave crystalline ethyl 2-hydroxy-2- (thien-3-yl) acetate (7 µg, 5 L, 15 mp. 55-57 ° C).

Example XCIV

2-hydroxy-2- (thien-3-yl) acetamide ethyl 2-hydroxy-2- (thien-3-yl) acetate (168 g, 0.903 mol) was slurried in 15n ammonium hydroxide (1 + 20 ml) 6.3 mol) and heated under reflux for 2 hours. The resulting solution was cooled to 70 ° C and toluene (81 + 0 ml) was added. The stirred mixture was allowed to cool to 20 ° C after which it was granulated for 1 hour. Filtration and washing with toluene gave 2-hydroxy-2- (thien-3-yl) acetamide (105.9 g; 75% mp 120-126 ° C). A second crop (10.3 g; mp. 111 + -120 ° C) was obtained by evaporation of the aqueous filtrate layer to 50 ml and granulation with 100 ml of toluene. Recrystallization of the first and second crops from ethyl acetate gave 77-79% of the recovered purified product (mp 127-130 ° C).

30 Example XCV

5- (thien-3-yl) oxazolidine-2.1 + -dione At 25 ° C, 2-hydroxy-2- (thien-3-yl) acetamide (10.0 g; 0.061+ mol) was added to a solution of sodium -methylate (10 g; 0.185 mol) and diethyl carbonate (22.0 ml; 0.182 mol) in 200 ml of ethanol. The reaction mixture was heated to reflux for 3 hours, cooled to 20 ° C and slowly diluted with 100 ml of water. Ethanol was removed by evaporation and the aqueous residue was treated with activated charcoal and filtered. The filtrate was layered with ethyl acetate 5 and the pH adjusted to 1.0 with concentrated hydrochloric acid.

The aqueous layer was separated and washed with 100 ml of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous magnesium sulfate. The ethyl acetate was removed by vacuum distillation with displacement through 10 toluene to a final volume of 150 ml. The resulting slurry was warmed to reflux (solution), cooled to 0 ° C and filtered to give 5- (thien-3-yl) oxazolidine ·

2.dione was obtained (8.92 g; 76.5% mp 135-138 ° C). Example XCVI

Sodium 5- (thien-3-yl) oxazolidin-2 Λ-dione 5- (thien-3-yl) oxazolidin-2, U-dione (3.0 g; 16, U mmol) was dissolved in 60 ml ethyl acetate and treated with 300 mg of activated carbon. After stirring at 20 ° C for 10 min, the mixture was filtered and washed with ethyl acetate. Methanolic sodium hydroxide (3.8n; U, 2ml) was added and the sodium salt was allowed to crystallize. After 30 min, 0.3 ml of water was added. The slurry was granulated at room temperature for 30 min, then cooled to 5 ° C and granulated for another 30 min. Filtration gave sodium 5- (thien-3-yl) oxazolidine-2,1 * dione as the monohydrate (3.37 g; 95% mp, 208-21 cPc).

Anal .: Ber. for C ^ O ^ SNa. ^ O: N 6.28; 0 28.67; S1.37; C, 37.67; H 2.71; After 10.30; HgO 8.07 Found: C, 37.35; H 3.03; N 6.2U; 0 27.83; S 1U, 33;

After 10.76; H2 O 8.30.

When replacing sodium hydroxide with an equivalent of potassium hydroxide, diethanolamine, meglumine or piperazine, the corresponding salts are obtained. The solvent is removed by evaporation or a non-solvent, such as ether or hexane, is added as necessary to facilitate precipitation of the product.

8103538 - 61 * - * \ ·

The same methods are used to prepare the pharmaceutically acceptable salts of the other oxazolidine-2,4-dione according to the invention.

Example XCVII

2- (3-bromothien-2-yl) -2-trimethylsiloxyethane-nitrile 3-bromo-2-thenaldehyde (6 g; 31 mmol) and zinc iodide (50 mg) were combined with 180 ml of methylene chloride. Trimethylsilylcarbonitrile (U, 0g; 5.2ml; Ui mmol) was added 10 drops. The reaction mixture is stirred at room temperature for 2 hours, diluted with 50 ml of methylene chloride, washed with 60 ml of 5% sodium bicarbonate solution and then with 50 ml of saturated saline, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2- (3-15 bromothien -2-yl) -2-trimethylsiloxyethane nitrile (7.2 g; oil; m / e 291/289) was obtained.

Example XCVIII

ethyl 1- (3-bromothien-2-yl) -1-hydroxymethane-carbonimidate hydrochloride - 20 2- (3-bromothien-2-yl) ~ 2-trimethylsiloxyethane-nitrile (7.0 g; 2k mol) was added at 0 ° C dissolved in 210 ml ethanol which was saturated with hydrogen chloride at 0 ° C. After stirring at the same temperature for 30 minutes, the reaction mixture was evaporated to dryness. Trituration of the solid residue with ether 25 gave ethyl 1- (3-bromothien-2-yl) -1-hydroxymethane carbonimidate hydrochloride (7.0 g; mp 120-122 ° C).

Example XCIX

5- (3-bromothien-2-yl) oxazolidin-2. -Dione Ethyl 1- (3-bromothien-2-yl) -1-hydroxymethane-30 carbon imidate hydrochloride (6.8 g; 23 mmol) and triethylamine (7 6 g, 10.5 ml, 76 mmol) were combined in 250 ml of tetrahydrofuran. The mixture was cooled to 0-5 ° C, rinsed with phosgene for 30 min, warmed to room temperature, stirred for 16 h, and poured slowly into 3CO ml of crushed ice. The diluted reaction mixture was extracted twice with amounts of 200 ml of chloroform each. The combined chloroform extracts were washed with 60 ml of saturated solution, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. Addition of hexane and ether gave crystalline product. Recrystallization from toluene gave 5- (3-bromothien-2-yl) oxazolidin-2, U-dione (2.25 g; mp 138-139 ° C) Analysis: Ber. for C 20 O SBr: C 32.09; H1.59; N 5.3U; S 12.21 Found: C 32 In; H 1.75; N 5, ^ 9; S 12.6l.

Example C

10 5- (5-bromothien-2-yl) -2-thioxooxazolidin-4-one

Potassium cyanide (7.9 g; 0.123 mol) and potassium thio cyanate (10 g; 0.10 mol) were combined in 8.5 ml water and stirred at 0 ° C. 5-Bromo-2-thenaldehyde (20 g; 0.10 mol) was added to give a slurry. Hydrochloric acid 15 (30%; 50.7 ml) was added to give a ball of oil, the reaction mixture was diluted with 10 ml of water and stirred for 8 hours after which time a granular solid had formed. The solid was recovered by filtration and partitioned between chloroform and 5% sodium bicarbonate solution. The mixture was filtered and the aqueous layer was separated, acidified and the precipitated product was recovered by filtration. Recrystallization from toluene gave purified 5- (5-bromothien-2-yl) -2-thioxo-oxazolidin-U-0n (2.08 g; mp 119-120 ° C; m / e 279/277).

25 Analysis: Ber. for C 20 BrNo: C 30.23; H 1.95; H 5.0¾

Found: C 30.5 ^; H 1.72; N 5.26

Example Cl 5- (5-bromothien-2-yl) oxaaolidin-2, U-dione 5- (5-bromothien-2-yl) -2-thioxooxazolidin-4-one 30 (1.5 g) was dissolved in 1 : 1 water: ethanol (10 ml) at 50 ° C.

Hydrogen peroxide (30%; 7.0 ml) was added to the stirred solution, which became slightly cloudy. Turbidity was reduced by adding 1 ml of ethanol. The mixture was heated at 70 ° C for 30 min, cooled slightly, diluted with 100 ml of water and extracted with chloroform. The chloroform- 8103538

+ K

% - 66 extract was washed with two volumes of 50 ml each of sodium bicarbonate solution. The combined aqueous extracts were purified by filtration, acidified with hydrochloric acid to pH 1.0 and filtered to yield 5- (5-bromothien-2-yl) oxazolidine-2,4-dione (0.51 g; 36 %% m.p. 139-139.5 ° C; m / e 263/261) was obtained.

Analysis: Ber. for C 21 BrNO S: C 32.08; Η 1.54; N 5.34 Found: C 32.16; H1.69; N 5.47

Example Gil 10 5-Hydroxy-5- (3-methoxythien-2-yl) -2,4,6 (1H, 3H, 5H) -pyrimidinetrion 3-methoxythiophene / ~ 2.4 g, crude material prepared according to Arkiv. Kemi. 12, 239-246 (1958); C.A. 52, 20115d7 and alloxan hydrate (3.2 g) were dissolved in 25 ml of ethanol by heating. Hydrochloric acid (1η, 3 ml; 3 mmol) was added and the mixture was heated at reflux for 3 min. The mixture was cooled to room temperature and diluted with 15 ml of water to cause further crystallization of the product. Filtration with 1: 1 ethanol: water and then washing with water 20 gave 5-hydroxy-5- (3-methoxythien-2-yl) 2,4,6 (1H, 3H, 5H) -pyrimidinetrion / 1.5 g » m.p. 190-210 ° C (dec.); R 0.3. (1: 1 hexane: ethyl acetate with 5% acetic acid); m / e 2567.

Example CIII

5- (3-methoxythien-2-yl) oxazolidin-2-4-dione 25 5-hydroxy-5- (3-methoxythien-2-yl) -2,4,6 (1H, 3H, 5H) -pyrimidinetrione ( 1 g) was dissolved in 1N sodium hydroxide (20 ml) and stirred for 1 hour. The mixture was acidified, purified, extracted twice with 50 ml portions of etlyl acetate each. The combined ethyl acetate extracts were back-washed with water and evaporated to dryness (0.5 g solid).

Chromatography on 85 ml of silica gel, viewed by thin layer chromatography, gave 5- (3-methoxythien-2-yl) oxazolidine-2,4-dione (300 mg; mp 156-158 ° C).

Analysis: Ber. for CgB2 O2 NS: C 45.08; H 3.31; N 6.57 35 Found C 45.21; H 3.39; N 6.47.

8103538 \ t - 67 -

Example CIV

5-Hydroxy-5- (5-phenylfur-2-yl) -2,4,6 (1H, 3H, 5H) -pyrimidinetrione 2-phenylfuran (5 »76g; 1 * 0mmol) was combined with 100 ml of tetrahydrofuran and cooled to -30 ° C. Butyl lithium in hexane (2.3 molar; 19.1 ml) was added dropwise over 5 min, keeping the temperature between -20 ° C and -30 ° C. The reaction mixture was allowed to warm to room temperature and then cooled back to -30 ° C. Sublimed alloxan (5.96 g; 1 * 2 mmol) in 1 * 0 ml tetrahydrofuran was added over 5 min, again keeping the temperature between -2CPc and -30 ° C. The reaction mixture was allowed to warm to room temperature and then cooled again to 0 ° C and 50 ml. In hydrochloric acid were added portionwise over 2-3 min.

The diluted reaction mixture was extracted with 100 ml of ethyl acetate. Ebt extract was filtered through bed of anhydrous magnesium sulfate and evaporated to give 5-hydroxy-5- (5-phenylfur-2-yl) -2,1 *, 6 (1H, 3H, 5H) pyrimidinetrione / ~ 9.1 * Si rubbery solid; Rf 0.75 (1: 1 hexane: ethyl acetate / 20 5% acetic acid) 7, contaminated with starting material (Rf 0.1 * 5).

Example resume

5- (5-phenylfur-2-yl) oxazolidin-2 * 1 -dione 5-hydroxy-5- (5-phenylfur-2-yl) -2,1 *, 6 (1H, 3H, 5H) -pyrimidinetrione (0.7 g) was dissolved in 15 ml of 1N sodium hydroxide, stirred at room temperature for 15 min, extracted with ethyl acetate, made weakly acidic with 1 ml glacial acetic acid and extracted with 25 ml ethyl acetate. The latter ethyl acetate extra was backwashed with 6.5 ml of water, filtered over a bed of anhydrous magnesium sulfate and evaporated to give solid 5- (5-phenylfur-2-yl) oxazolidine-2,1 * -dione / 100 mg ;

m.p. 216-218 ° C; R ^ 0.6 (1: 1 hexane: ethyl acetate / 5% acetic acid27 Example CVI

5-hydroxy-5- (5-methylfur-2-yl) -2,1 * 6 (1H, 3H, 5H) -pyrimidinetrion-35 2-methylfuran (3.28g; 3.58ml; 1 * 0 mmol) was combined with 100 ml of tetrahydrofuran. The reaction mixture 8103538 + * - 68 - was purged with nitrogen and cooled to -30 ° C.

Butyl lithium (19.1 ml of a 2.3 molar solution in hexane) was added over 10 min, keeping the temperature between -20 ° C and -30 ° C. The reaction-5 mixture was warmed to room temperature and then cooled again to -30 ° C. Sublimed alloxan (5.96 g) in Uo ml of tetrahydrofuran was added dropwise over 10 min, the temperature being between -20 and -30 ° C was held. The reaction mixture was warmed to room temperature, cooled to 10 ° C and 50 ml of 1N hydrochloric acid was added in portions keeping the temperature between (Pc and 5 ° C.) The reaction mixture was extracted with 100 ml of ethyl acetate. Ifet extract was backwashed with 25 ml of water, filtered through a bed of anhydrous magnesium sulfate and evaporated to give solid 15 5-hydroxy-5- (5-methylfur-2-yl) -2, H, 6 (1 H, 3H, 5H) pyrimidinetrione (6.3 g; m / e 22U) was obtained.

Example CVII

5- (5-methylfur-2-yl) oxazolidin-2.U-dione 5-hydroxy-5- (5-methylfur-2-yl) -2,6 (1H, 3H, 5H) 20 pyrimidinetrione (6.3 g) was dissolved in 50 ml In sodium hydroxide and stirred at room temperature for 15 min. The reaction mixture was extracted with 50 ml of ethyl acetate and acidified with glacial acetic acid. The product was then extracted with fresh ethyl acetate (three 30 ml portions). The combined ethyl acetate extracts were filtered through a bed of anhydrous magnesium sulfate and evaporated to an oil. The oil was chromatographed on 50 ml of silica gel with 1: 1 hexane: ethyl acetate / 5% acetic acid as eluent. The column was viewed by thin layer chromatography using the same eluent. Pure product-containing fractions were combined, evaporated to dryness and triturated with hexane (311 mg; mp 135-138 ° C). Recrystallization from methanol / water gave purified 5- (5-methylfur-2-yl) oxazolidin-2, U-dione (1.2 mg; mp 136.5-137.5 ° C).

Analysis: Ber. for 0 Η_Ν0ι: C 53, OU; H3.90; N 7.73

Found: C, 52.82; H ^, C3; N 7.65.

8103538 - 69 -

Example CYIII

5-hydroxy-5- (thien-3-yl) -2,4,6 (1H, 3H, 5H) pyrimidinetrione

Isopropyl ether (40 ml) was cooled to -70 ° C.

Butyl lithium in hexane (2.4 molar; 10ml, 24mmol) was added over 10min keeping the temperature between -7cPc and -6o ° C. 3-Bromothiophene (1.9 ml; 20 mmol) was added over 20 min, keeping the temperature between -72 ° C and -68 ° C. the mixture was stirred for an additional 30 minutes at -72 ° C to 10 -70 ° C. Sublimed alloxan (3g; 21mmol) in 25ml tetratydrofuran was taken in 40min. added, keeping the temperature at -7CPc to -65 ° C, stirring at this temperature was continued for 15 min. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour, then cooled to 5 ° C. Hydrochloric acid (1η; 40 ml) was added slowly and the organic phase separated. The aqueous phase was extracted with 35 ml of ethyl acetate. The combined organic phase / extract was washed with 10 ml of water, dried over anhydrous sodium sulfate and concentrated to give solid 20 5-hydroxy-5- (thien-3-yl) -2,4,6 (1H, 3H, 5H) pyrimidintrion (1.41 g; 31% im / e 226) was obtained.

When performing this reaction in tetra lydrofuran with reverse addition of a 3-bromothiophene to butyl lithium, with immediate addition of 0.5 equivalent of alloxan hydrate instead of 1 equivalent of anhydrous alloxan, the product consisted of a mixture of the above trion and 5- (3-bromothien-2-yl) -5-hydroxy-2,4,6 (1H, 3H, 5H) pyrimidine trione, which in turn was converted into a mixture of 5- (3-bromo-thien- 2-yl) oxazolidine-2,4-dione and 5- (thien-3-yl) oxazolidine-2,4-30 dione according to the method of Example LV.

Example CIX

5- (t-lien-3-yl) oxazolidine-2,4-dione 5-hydroxy-5- (t-hien-3-yl) -2,4,6 (1H, 3H, 5H) pyrimidine trion (1, 16g; 5 * 1mmol) was dissolved in 1n sodium hydroxide (11ml; 11mmol) and allowed to stand at room temperature 8103538-70 for 15 min. The solution was acidified with acetic acid and the product was allowed to crystallize for 35 min. Filtration gave 5- (t hien-3-yl) oxazolidine-2, U-dione (U80 mg; 51% mp. 133-135 ° C) . An additional crop of product was obtained by extracting the mother liquor with ethyl acetate. The extract was washed back with water and evaporated to dryness (80 mg; contaminated with starting material).

Example CX

5- (fur-3-yl) -5-hydroxy-2, U, 6 (1H, 3H, 5H) pyrimidine-10 trion

The method of Example CVIII was followed in detail, but using 3-bromofuran (2, µg; 1.8 ml; 20 mmol) instead of 3-bromothiophene, to make 5- (fur-3-yl) 5-Lydroxy-2,6 (1H, 3H, 5H) pyrimidinetrion (1.62 g; oil; m / e 15 210).

Example CXI

5- (fur-3-yl) oxazolidin-2, U-dione 5- (fur-3-yl) -5-hydroxy-2, U, 6 (1H, 3H, 5H) pyrimidine trion (1.62 g ) was dissolved in 15 ml of 1N sodium hydroxide and left to stand at room temperature for 15 min after which time it was extracted with 5 ml of ethyl acetate. The aqueous layer was acidified with glacial acetic acid (1.5 ml) and the product was extracted with 25 ml of ethyl acetate. The extract was backwashed with 5 ml of water, filtered through a bed of anhydrous sodium sulfate and evaporated to give a crude product as an oil (Vf0 mg; m / e 167). Crystallization from chloroform gave purified 5- (fur-3-yl) oxazolidin-2,1-dione (129 mg; mp.

88-90 ° C; m / e 167). A second, lower melting crop was obtained from mother liquor.

30 Example CXII

3-thenalde fardé cyan fardrine

Sodium bisulfite (30.2 g; 0.29 mol) was dissolved in 190 ml of water and warmed to 50 ° C. 3-thenaldelyde (25 g; 0.22 mol) was added and the reaction mixture was stirred for 35 min.

held at 50-55 ° C after which time all but a small amount of rubber wax was dissolved in solution. The mixture was cooled to 5 ° C and layers were formed with 190 ml of isopropyl ether. With stirring, sodium cyanide (2 *, 8 µg 0.25 mol) in 190 ml water was added dropwise for 20 min, keeping the temperature below 10 ° C. Stirring was continued for 1 hour at room temperature. The organic layer was separated and the aqueous phase extracted with fresh isopropyl ether (300 ml). The combined organic extracts were washed with saturated brine, dried 1 O over anhydrous magnesium sulfate, filtered and concentrated to give 3-thenaldehyde cyanohydrin as an oil (28.3 g; 92%).

Example CXIII

2-Hydroxv-2- (thien-3-yl) acetate amide 15 Formic acid (0.5 ml) was cooled in an ice water bath. 3-Thenaldehyde (cyanohydrin (1.0 g) and then concentrated hydrochloric acid (0.5 ml) were added. The reaction mixture was stirred at room temperature for 1 hour, poured onto crushed ice and extracted with three portions of ethyl acetate. The combined extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil which partially crystallized out by scratching Recrystallization from ethyl acetate gave 2-hydroxy-2- (thien-3-yl) acetamide 25 (389 mg; 35% mp 123-126 ° C; m / e 157).

Example CXIV

Mixed methyl / ethyl esters of 2-benzoyl-2- (thien-3-yl) malonic acid

Commercially available mixed esters of 2- (thien-3-yl) malonic acid (1 * 7% diethyl, 1 * 3 1 methyl / ethyl, 10% dimethyl; 11.1 * g), portions were added to a dispersion of sodium hydride in oil (50 2.1 * g) stored in a slurry in 70 ml of toluene. An exotherm was observed, the temperature rising to 1 * 5 ° C. The reaction mixture was stirred at room temperature for 3 hours and then cooled in an ice-water bath. Benzoyl peroxide (8 g) in 100 ml of toluene was added over 1 hour keeping the temperature at 10-20 ° C. The mixture was stirred at room temperature for 30 min, diluted dropwise with 50 ml of water (foam was initially observed), and finally diluted with 50 ml of ether. The organic phase was separated, backwashed with three 25 ml portions of water and evaporated to give mixed methyl / ethyl esters of 2-benzoyloxy-2- (thien-3-yl) -malonic acid as an oil (15.5 g, 10 in which 1.2 g of oil from the sodium hydride dispersion).

Example CXV

5- (t-hien-3-yl) oxazolidine-2, U-dione Sodium (0.006 g; 20 mmol) was dissolved in 50 ml of absolute ethanol. To the resulting warm solution of sodium 15 ethanolate (about 60 ° C), crude mixed esters of 2-benzoyloxy-2- (thien-3-yl) malonic acid (7 g; about 20 mmol, as prepared in Example LX) were added, followed through urea (1.2 g; 20 mmol), dissolved in 20 ml of hot ethanol. The reaction mixture was heated on an oil bath at 105-110 ° C for Ug hours. The reaction mixture was cooled, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. Hs extract was backwashed with water and concentrated to an oil. Trituration with 20 mL of 1: 1 ethershexane gave a mixture of 5- (thien-3-yl) oxazolidin-2,1-dione and intermediate 5-benzoyloxy-5- (thLen-3-yl) 2,6,6 (1H .3H, 5H) pyrimidinethione (0.8 g). Part of this mixture (0.3 g) was dissolved in 1N sodium hydroxide (5 ml) and left at room temperature for 20 min. The reaction mixture was purified by filtration and acidified with acetic acid to precipitate 5- (thien-3-yl) oxazolidin-2, U-dione (1CD mg; mp 136-138 ° C).

Example CXVI

2- (3-benzo / b7t hienyl) -2-trimethylsiloxyethane-nitrile

Benzo / 7thiophene-3-carbaldehyde / ~ 1.8 g; 11 mmol, 35 J. Chem. Soc. C., pp. 339-3 ^ 0 (199 | 7 and 100 mg of zinc iodide 8103538-73) were combined in 35 ml of ether. Trinetlylsilylcarbonitrile (1.98 g; 20 mmol) was added dropwise. After about 1 hour, the reaction mixture was washed successively with saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate and filtered and evaporated to give 2- (3-benzo / "b7thienyl} -2-trimethylsiloxyethane nitrile / 2.5 g" oil; 7 (1: 2 ethyl acetate: hexane) 7 was obtained.

Example CXVII

10 ethyl 1- (3-benzo / ”b7thienyl-1-hydroxymethane-carbon imidate hydrochloride

While cooling in an ice-water bath, 2- (3-benzo- / bthienyl) -2-trimethylsiloxyethane nitrile (2.3 g) was dissolved in 10 ml of saturated ethanolic hydrochloric acid and kept at about 15 ° C for 16 hours. The reaction mixture was evaporated to dryness and triturated with ether to give 1- (3-benzo [b] thienyl) -1-hydroxymethane carbonimidate lydrochloride (2.2 g; mp 128-131 ° C; m / e 235).

Example CXVIII

5- (3-benzo / bthienyl) oxazolidine-2, U-dione

Ethyl 1- (3-benzo / b7thienyl) -1-hydroxymetane carbonimidate hydrochloride (2.36g; 8.7mmol) and triethylamine (2t6bg; 26mmol) were combined in 50ml tetralydrofuran and cooled to 10 ° C Phosgene was bubbled through the cooled reaction mixture for 30 min, followed by purging with nitrogen for 10 min. The reaction mixture was slowly poured into 100 ml of ice and extracted twice with ether. The combined ethereal extracts were backwashed with water and then saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a rubbery solid (1.7 g); This crude product was dissolved in 1N sodium hydroxide, washed twice with ether and acidified with 6N hydrochloric acid to give purified 5- (3-benzo / b7 thienyl) oxazolidine-2,4-dione (950mg; mp 35 202-205). ° C; m / e 233) was obtained.

8103538 i J.

- 74 -

Analysis; Ber. for C ^ H ^ O ^ NS; C, 56.64; H 3.02; N 6.00 Found C 56.74; H 3.18; N 5.69

Example CXIX

2- (7-benzo / "b7thienyl) -2-trimethylsiloxyethane-nitrile_

Benzo / thiophene-7-carbaldehyde / 1.3 g; 8 mmol; J. Org. Chem. 39, 2829 (197427 was dissolved in 35 al ether. Trimethylsilylcarbonitrile (1.5ml; 12mmol) and zinc iodide (about 50mg) were added and the mixture was stirred at room temperature for 1h, after which time thin layer chromatography showed. that the reaction was complete The reaction mixture was evaporated to dryness to yield 2- (7-benzo / H-thienyl) -2-trimethylsiloxyethane nitrile / 2.2 g oil, 0.6 (1: 5 ethyl acetate: hexane) / 5% acetic acid) 7 was obtained.

15 Example CXX

ethyl 1- (7 "benzo /" h7thienyl) -1-hydroxymethane-carbon imidate hydrochloride Following the method of Example CXII, 2- (7 "benzo /" b7thienyl) -2-trimethylsiloxyethane nitrile (2.1 g) 20 using 35 ml saturated etbanolic hydrochloric acid converted to ethyl 1- (7-benzo / b7thienyl) -1-hydroxymethane carbonimidate hydrochloride (1.1 g; mp 120-122 ° C), after recrystallization from acetone.

Example CXXI

5- (7-benzo / "b7thienyl) oxazolidine-2,4-dione

Following the method of Example CXVIII, ethyl 1- (7-benzo / "b7thienyl) -1-hydroxymethane carbonimidate hydrochloride (1.1g, 4mmol) and triethylamine (1.7ml; 12mmol.) Were reacted with phosgene . The crude product, isolated as an oil, was dissolved in 25 ml of ether and the product was extracted with 50 ml of 1N hydroxide. This aqueous extract was acidified with concentrated hydrochloric acid and the product was extracted with fresh ether, which was backwashed with water and in vacuum was evaporated to a solid residue (670 mg). This residue was recrystallized to give 5- (7-benzo / bthienyl) oxazoli-8103538-75-dine-2, U-dione (0.15 g; mp 130-132 ° C).

Analysis: Ber. for C 25 H 25 NS: C 56.6 U; H 3 * 02; N 6.00 Found: C 56.1 * 2; H 3.18; N 5.91.

Example CXXII

5 5-Hydroxy-5- (5-methoxythien-2-yl) -2,6 (1H, 3H, 5H) nyrimidinetrione 2-methoxythiophene (2.3 g; 20 mmol) was dissolved in 35 nil ether. Under cooling, butyl lithium in hexane (2.0 U molar; 9 ml; 21.6 mmol) was added dropwise over 15 min, the temperature rising to 35 ° C during this addition. The reaction mixture was stirred at room temperature for 1 hour. While keeping the temperature between -20 ° C and -15 ° C, sublimed alloxan (3 g; 21 mmol) in 20 ml of tetrahydrofuran was added over 10 min. The mixture was warmed to room temperature, stirred for half an hour, then cooled to 5 ° C and diluted by adding 35 ml of 1N hydrochloric acid in portions. The organic phase was separated and the aqueous phase was extracted with 25 ml of ethyl acetate. The combined organic phase and extract were backwashed with water, concentrated to dryness and triturated with hexane to give solid 5-hydroxy-5- (methoxythien-2-yl) -2,6 (1H, 3H, 5H) -pyrimidinetrione (1.1 µg; m / e 256) was obtained.

Example CXXIII

5- (5-methoxythien-2-yl) oxazolidin-2'U-dione 25 5-hydroxy-5- (5-methoxythien-2-yl) -2,6,6 (1H, 3H, 5H) -pyrimidinetrione ( 1.1 g) was dissolved in 10 ml of 1N sodium hydroxide, left to stand at room temperature for 1 hour and then extracted with ether, acidified with acetic acid, diluted with 15 ml of water and filtered to give product 30/567 mg , m.p. 1 ^ -146 ° C (dec.) 7 was obtained. Om crystalline

serene from acetone-hexane gave purified 5- (5-methoxythien-2-yl) oxazolidin-2 + dione in two harvests / ~ 8 mg. m.p. 1U7-11 + 8 ° C

(dec.) 7

Analysis: Ber. for C 8 H 20 O NS: C 5 5.08; H 3.31; N 6.57.

Found: C1 * 5.08; H 3, ^ 1; N 6.39 8103538 * * - 76 -

Example CXXIV

5- / '5- (2-phenyl-1,3-dioxolan-2-yl) thien-2-yl7- 2.4,6 (1H.3H «5H) pyrimidinetrion_ (2-phenylthien-2-yl) 1,3-dioxolan (3.26 g; 5 14 mmol) was dissolved in 35 ml ether at room temperature.

Butyl lithium in hexane (2.4 molar; 6.25 ml; 15 mmol) was added dropwise over 15 min with the temperature rising to 33 ° C. The mixture was stirred at room temperature for 75 min and then cooled. While the temperature was maintained between 10-15 ° C and -20 ° C, sublimed alloxan (2.13 g, 15 mmol) in 20 ml of tetrahydrofuran was added dropwise over 10 min. The reaction mixture was stirred at room temperature for 30 min, cooled to 5 ° C, diluted with 35 ml of 1N hydrochloric acid, which was added in small amounts, and extracted with 25 ml of ethyl acetate. The organic layer was backwashed with 15 ml of water, filtered through a bed of anhydrous sodium sulfate and evaporated to give 5- / 5- (2-phenyl-1,3-dioxolan-2-yl) thien-2-yl7-2,4,6 ( 1H, 3H, 5H) pyrimidinetrion / "oil, 0.25 (1: 1 hexane: ethyl acetate / 5% acetic acid) 7

20 was obtained, contaminated with starting material (R ^ 0.8). Example CXXV

5- / "5- (2-phenyl-1,3-dioxolan-2-yl) thien-2-yl7 oxa2olidine-2,4-dione

The whole crude product from the previous example was taken up in 35 ml of 1N sodium hydroxide and the solution was allowed to stand for 30 min. After acidification, the product was extracted with isopropyl ether. The extract was backwashed with water and evaporated to give 5- / ~ 5- (2-phenyl-1,3-dioxolan-2-yl) thien-2-yloxazolidine-2,4-dione / ~ 0.4 g;

30 Rf 0.65 (1: 1 ethyl acetate: hexane / 5% acetic acid | 7 was obtained. Example-0CXVI

5- (5-benzoylthien-2-yl) oxazolidine-2,4-dione 5- / ~ 5- (2-phenyl-1,3-dioxolan-2-yl) -thien-2-yl7-oxazolidine-2, 4-dione (0.40 g) was dissolved in 30 ml ether 35 and stirred at room temperature for 1 hour with 10 ml 6N hydrochloric acid.

8103538 - TT -

Ethyl acetate (10 ml) was added and the organic layer was separated and evaporated to dryness in vacuo (0.388 g). Chromatography on 50 ml of silica gel eluted with 1: 1 hexane: ethyl acetate / 5% acetic acid and viewed by 5 thin layer chromatography yielded purified 5- (5-benzoylthien-2-yl) oxazolidine-2, U-dione (5) 0.22 g; mp. 153-155 ° C; m / e 28?)

Analysis: Ber. for C 25 H 25 NS: C 58.52; H 3.16; N U, 87 Found: C, 58.69; H 3.50; N

10 Example CXXVII

5- (thien-3-yl) oxazolidin-2, Λ-dione capsules The following ingredients were combined and mixed for 30 minutes.

Sodium 5- (thien-3-yl) oxazolidine-2, U-dione 15 monohydrate 30, ½

Lactose, anhydrous, U.S.P. , 05 g

Corn Starch, Dried, U.S.P. 5.00 g equivalent with 25 g of active drug (unsolvated free acid).

The mixture was ground (0.10 cm plate) and mixed for an additional 30 min. Magnesium stearate, sodium lauryl sulfate, and 90/10 mixture (1.00 g) were added and the mixture was mixed for an additional 20 min. The mixture was filled into No. 0 gelatin capsules (505 mg filling weight) to give capsules 2 µ with 250 mg strength. ,

Larger capsules are used to make higher strength capsules.

The same method was followed to prepare 100 mg strength capsules from the following ingredients: Sodium 5- (thien-3-yl) oxazolidine-2, -dione 3 € monohydrate 12.18 g

Lactose, anhydrous, U.S.P. 32.32 g

Corn Starch, Dried, U.S.P. - 5.00 g

Magnesium stearate / lauryl sulfate (90/10 mixture) 0.50 g 35 Equivalent to 10 g active ingredient (unsolvated 8103538 - 78-)

If quite acidic).

A lower active ingredient content in the mixture is used to make lower strength capsules.

5 Example CXXVIII

Tablets

A tablet base is prepared by mixing the following ingredients in the indicated weight ratio:

Sucrose, U.S.P. 80.3 10 Tapioca starch 13.2

Magnesium stearate 6.5

In this tablet base, sufficient sodium 5- (thien-3-yl) oxazolidin-2, U-dione monohydrate is admixed to form tablets containing 50 mg, 100 mg or 250 mg of active drug (weight equivalent to the free acid).

The ratio of the mixture to active drug is within the limits of 1-0.167 to 1-1, e.g. in extreme cases, 60.2 mg of sodium salt monohydrate and 300 mg of mixture in 50 mg tablet or 30 ^ 6 mg of sodium salt monohydrate and 25 mg of mixture in one 250 mg tablet.

Example CXXIX

Injectable preparation

Sterile sodium 5- (thien-3-yl) oxazolidin-2, U-dione is filled dry into vials to contain 670.1 mg of sodium salt monohydrate per vial (equivalent to 550 mg of free acid). Before use, sterile water for injection (11 ml) is added and the mixture is shaken to form a solution containing 50 mg / ml active drug, and then suitable for intravenous, intramuscular or subcutaneous injection.

Instead, the vials can be filled by a freeze-drying method. Two ml of a sterile aqueous solution containing 335 mg / ml sodium salt monohydrate is placed in each vial. The vials are freeze-dried on sheets, 8103538 - 79 -

Example CXXX

3-ethoxycarbonyl-5- (thien-3-yl) oxazolidine-2'U-dione

Sodium 5- (thien-3-yl) oxazolidine-2,4-dione mono-5 hydrate is dewatered by vacuum drying at elevated temperature (50-70 ° C). The anhydrous salt (2.05 g; 10 mmol) is suspended in 35 nl 1,2-dichloroethane. Ethyl chloroformate (1.1 * 1 g; 10 mmol) is added and the mixture heated at reflux for 2 hours. The reaction mixture is cooled to room temperature, by-product sodium chloride is removed by filtration and the filtrate is concentrated to dryness to give 3-ethoxycarbonyl-5- (thien-3-yl) oxazolidin-2, U-dione.

Replacement of the ethyl chloroformate with an equivalent amount of acetyl chloride, isobutyryl chloride, N, H-dimethyl carbamoyl chloride or benzoyl chloride, respectively. 3-acetyl-5- (thien-3-yl) oxazolidine-2,4-dione, 3-isobutyroyl-5- (thien-3-yl) oxazolidine-2,4-dione, 3- (N, N-dimethylcarbamoyl ) -5- (thien-3-yl) oxazolidin-2,1x-dione and 3-benzoyl-5- (thien-3-yl) -20 oxazolidin-2,2-dione.

Example CXXXI

3-acetyl-5- (thien-3-yl) oxazolidin-2-dione

Method a 5- (thien-3-yl) oxazolidin-2,1 * dione (1.83 g; 25 mmole) and triethylamine (0.1 ml; 10 mmole) were combined with 25 ml of 1.2 at room temperature -dichloroethane. Acetyl chloride (0.72 ml; 10 mmol) was added dropwise over a few minutes and the reaction mixture was stirred for 3 hours. The reaction mixture is evaporated to dryness and the residue is partitioned between saturated sodium bicarbonate solution and chloroform. The chloroform layer is washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 3-acetyl-5- (thien -3-yl) oxazolidin-2, U-dione is obtained.

35 Method b 5- (thien-3-yl) oxazolidin-2,1 * dione (1.83 g; 8103538 * * - 80 - 10 mmol) and acetic anhydride (1.1¼ ml; 12 mmol) are combined with 20 ml of tetrahydrofuran and stirred for 0 hours. The reaction mixture is evaporated to dryness and 3-acetyl-5- (thien-3-yl) -oxazolidine-2, U-dione is further isolated as in method a.

5 The same method but replacing acetic anhydride with an equivalent acetomic acid reagent / a solution of acetomic anhydride in acetic acid; see Blackwood et al., JACS, 82, 519¼ (196027 propionic anhydride or benzoic anhydride leads to the formation of the corresponding 3-formyl-5- (thien-3-yl) oxazolidin-2, U-dione, 3-propionyl, respectively 5- (thien-3-yl) oxazolidin-2, Η-dione and 3-benzoyl-5- (thien-3-yl) oxazolidin-2, U-dione.

Example CXXXII

3- (N-methylcarbamoyl) -5- (thien-3-yl) oxazolidine- 2 Λ-dione-5- (thien-3-yl) oxazolidine-2, U-dione (1.83 g, 10 mmol) and a drop of triethylamine are combined in 35 ml of 1,2-dichloroethane. Ethyl isocyanate (0.58 ml; 10 mmol) is then added and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with 35 ml of 1,2-dichloroethane, washed with saturated sodium bicarbonate solution and then with saturated brine, dried over magnesium sulfate, filtered and concentrated to give 3- (N-methyl) -5- (thien-3-yl) oxazolidine-2,1 * -dione is obtained.

Example CXXXIII

3- (U-methoxy-thien-3-yl) -2-trimethylsiloxyethane-nitrile

According to the method of example LV, U-30 methoxy-3-thenaldehyde (2.6 g; 18.3 mmol) and trimethylsilyl carbonitrile (2.15 g; 21.7 mmol) in 250 ml ether in the presence of 50 mg zinc iodide converted to the title product as an oil (3.9 g; m / e 2 ^ 1).

8103538 <- 81 -

Example CXXXIV

Methyl 1-hydroxy-1- (4-methoxy-thien-3-yl) -methanecarbonimidate hydrochloride_

Saturated methanolic hydrochloric acid (100 ml) was kept at 0-5 ° C in an ice bath. The product mentioned in the preamble of the previous example (3.9 g) in 20 ml of methanol is added dropwise and the mixture is kept at 0-5 ° C for 1 hour.

The reaction mixture is concentrated on solid and the residue is triturated with ether to give the product mentioned in the opening paragraph 2.76 g; m.p. 94-99 ° C (dec.27) obtained. Recrystallization from methanol-ether yielded purified product / 1.51 g m.p. 112-114 ° C (dec.); M / e 2017.

Example CXXXV

5- (4-methoxythien-3-yl) oxazolidine-2,4-dione

According to the method of Example LVII, dilute the product from the previous example (1.3 g} 5.5 mmol) and triethylamine (1.7 g> 17 mmol) in 50 ml tetrahydrofuran for 30 min at 0-5 ° C to reacted with phosgene. The reaction mixture is stirred overnight at room temperature. The reaction mixture was poured slowly onto 500 ml of crushed ice and extracted with three 50 ml portions of chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated with solid.

Recrystallization from toluene afforded the above-mentioned product purified / 510 mg; m.p. 120-122 ° C; ir (KBr) 1377, 1732, 1767, 1808 cm -1 ".

Analysis: Ber. for C 8 H 25 O NS: C 45.06; H 3.31; N 6.57. Found: C 45.31; Η 3.41; N 6.85.

Example CXXXVI

3- (4-ethoxythien-3-yl) -2-trimethylsiloxyethane-nitrile ______________

According to the method of Example LV, 4-ethoxy-3-thenaldehyde (8.1 g; 0.062 mol) and trimethylsilyl 8103538

* I

- 82 - carbonitrile (6.13 g; 0.062 mol) in 300 ml ether in the presence of 50 mg zinc iodide converted into the title product (13 g) as a viscous oil; from k.m.r. the absence of the aldehyde proton works.

5 Example CXXXVII

ethyl 1-hydroxy-1- (U-ethoxythien-3-yl) methane carbon imidate hydrochloride_

Using ethanol instead of methanol but otherwise using the method of Example 10 CXXXIV, the product of the previous Example (13 g) was converted into the title compound 9.23 g; m.p. 126-128 ° C (dec.27)

Example CXXXVIII

5- (U-ethoxythien-2-yl) oxazolidine-2-dione 15 Using a 1 hour phosgene pass at 0-5 ° C and a further reaction time of 1 hour at room temperature, the product from the previous example (9.2 g) converted to the title product. To isolate the product, the reaction mixture was poured into 1.51 of crushed ice and extracted with three portions of 200 ml each of chloroform. The organic layers were combined and extracted with three aliquots of 150 ml 1N sodium hydroxide each. The basic extracts were combined, backwashed with 200 ml of fresh chloroform, acidified again with 3N hydrochloric acid and extracted with three amounts of 200 ml of chloroform each. The latter three organic extracts were combined, washed with saturated brine, dried over magnesium sulfate, filtered, evaporated to solid and the residue was recrystallized from toluene to give the title compound rt06 g; sipps. 1UU-1U6 ° C; m / e 227; ir (KBr) 1822, 1737, 1568 cm @ -1.

Analysis: Ber. for C 25 O NS: C 1 * 7.57; H 3.99; N 6.17

Case: C U7.18; H 1 *, ol *; N 6.06. The backwash chloroform was again extracted with three aliquots of 150 ml of fresh 1N sodium hydroxide each. These basic extracts were combined and additional product (980 mg; mp. 14U-1U6 ° C) was recovered in a corresponding manner.

5 Example CXXXIX

2- / ~ k- (n-propoxy) thien-3-yl7-2-trimethylsiloxyethane nitrile

Following the method of Example LV, U- (n-propoxy) -3-thenaldehyde (3.1g; 18mmol) and trimethylsilyl-10 carbonitrile (2.28g; 2.9ml; 23mmol) in 250ml ether in the presence of 50 mg of zinc iodide converted to the product mentioned in the preamble as an oil, 6 g; m / e 269; ir (CHgClg) 2936, 1558 cm-7.

Example CXL

Ethyl 1-hydroxy-1 - / - * - (n-propoxy) -thien-3 - :, r7-methane carbonimidate hydrochloride Using a reaction time of 20 min after completion of the addition, the method of Example CXXXVII was used to convert the product from the previous example (U, 5 g) into the in the preamble of the

present example product / 3.05 g; m.p. 12T-129 ° C

(Dec. 27.

Example CXLI

5- / k- (n-propoxy) -thien-3-yl7oxazolidin-2-dione 25 Following the method of Example CXXXV, the product of the previous Example (2.8 g; 0.01 mol) was converted into toluene recrystallized 5 - / - ^ - (n-propoxy) thien-3-yl7 oxazolidin-2, U-dione / 1.63 g; m.p. 13U-136 ° C; m / e 1U1; ir (KBr) 1827, 17 ^ 7, 156U cm -1.

30 Example CXLII

2- (1 * -methoxy-2-methylthien-3-yl) -2-trimethylsiloxyethane nitrile_

Following the method of Example LV, U-methoxy-2-methyl-3-thenaldehyde (5.2g; 33.3mmol) and 35 trimethylsilylcarbonitrile (3.96g; 40mmol) in 350ml ether 8103538

*. X

Skin presence of 50 mg of zinc iodide converted to the title product, which was isolated to a viscous oil / "7.3 egg m / e 255 .mu. (Cl 4 Cl 1575, 120U, 1075 and" 1 7).

Example CXLIII

Ethyl 1-hydroxy-1- (U-methoxy-2-methylthien-3-yl) -methane-arbonimidate hydrochloride. The method of Example CXXXVII was applied to the product of the previous example (7.2 g) to obtain 5.8 g of product. forms consisting of a mixture of the compound mentioned in the preamble 10 and the corresponding ethoxy ether (from kmr

estimated to consist of about KO% methyl ether and 60% ethyl ether; shows both m / e 2 ^ 3 and 229).

Part of this mixture (2.5 g) was taken up in 100 ml of ethanol which was cooled to 0-5 ° C, and hydrogen chloride was passed through for 1 hour. After stirring for an additional 1 hour at 0 ° C, the reaction mixture was evaporated to a viscous oil. Crystallization from ether gave the title product / 2.1 g; m.p. 123-125 ° C (dec.); m / e 2297.

The corresponding methyl imidate ester of the product mentioned in the opening paragraph is obtained by reacting the product of the previous example directly with methanolic hydrochloric acid according to the method of example CXXXIV.

Example CXLIV

Ethyl 1- (hydroxy) -1- (U-ethoxy-2-methylthien-3-yl) -methanecarbonimidate hydrochloric acid. Part of the mixed methyl and ethyl ether of the previous example (2.5 g) was taken up in 100 ml of ethanol and cooled to 0 ° C. The cold solution was rinsed with hydrogen chloride for 1 hour, stirred at 0 ° G for 1 hour and then evaporated to an oil. The oil was crystallized by trituration with ether. Re-pulping in ether gave the title product / 2.07 g m.p. 105-107 ° C (dec.) J m / e 2U37.

35 Example CXLV

8103538 - 85 -

Example CXLV

5 - (^ - methoxy-2-methylthien-3-yl) oxazolidine-2, U-dione

With a reaction time of 3 hours at room temperature, but otherwise according to the method of Example LVII, the product of Example CXLIII (2.0 g; 7.5 mmol) was converted into the product recrystallized from toluene in the preamble. 0.52 g; mp 179-181 ° C; m / e 227; ir (KBr) 1820, 1750, 1727, 1583 cm "V ·

10 Example CXLVI

5 - (^ - ethoxy-2-methylthien-3-yl) oxazolidine-2, U-dione

According to the method of the previous example, the product of Example CXLIV (1.9 g) was converted into the product mentioned in the preamble / 2 ^ 5 mg; mp 136-138 ° C; m / e 2 µl; KBr) 182U, 17 ^ 3 cm -1 ^ /.

Example CXLVII

5-Hydroxy- (2,5-dimethylfur-3-yl) -2,6 (1H, 3H, 5H) pyrimidiirtrion 20 Isopropyl ether (35ml) was cooled to -68 ° C.

Butyl lithium (5 ml of a 2.1 molar solution in hexane; 10.5 mmol) was added, allowing the temperature to rise to -60 ° C. 2,5-dimethyl-3-iodofuran / "j.A.C.S. 70, p. 739 (19 ^ 8); 1.2 ml; 9 mmol / was then added dropwise keeping the temperature between -65 ° C and -68 ° C. After stirring at -68 ° C for half an hour, anhydrous alloxan (1.5 g; 10.6 mmol), dissolved in 15 ml of tetrahydrofuran, was added dropwise over 30 min, the temperature being at -65 ° C to -60 ° C was held. The stirred reaction mixture 30 was warmed to 0 ° C in 15 min. 1N hydrochloric acid (25 ml) was added and the organic phase separated. The aqueous phase was extracted with 20 ml of ethyl acetate. The combined organic layers were washed with 10 ml of water and evaporated to give the title product 35/1 g, 0.05 (1: 5 ethyl acetate: hexane / 5% acetic acid) 710103538

t X

- 86 -

Example GXLVIII

5- (2,5-dimethylfur-3-yl) oxazolidine-2,4-dione Product from the previous example (1 g) was taken up in 10 ml of 1N sodium hydroxide and stored for 15 min. The solution was extracted with 5 ml of ethyl acetate, acidified with acetic acid and extracted with 25 ml of ethyl acetate. The acidic extract was backwashed with 5 ml of water and evaporated to solid (340 mg), which was chromatographed on 50 ml of silica gel using 1: 1 ethyl acetate: hexane as eluent and viewed by thin layer chromatography. Clean fractions were combined, evaporated to dryness and the residue was recrystallized from ether-hexane to give purified title product / 170 mg; m.p. 144-145 ° C; m / e 195; Rf 0.3 (1: 5 ethyl acetate: hexane / 15% acetic acid); R ^ 0.55 (1: 1 ethyl acetate: hexane 27.

Analysis: Ber. for C 4 H 4 O N: C 55.38; H 4.65; N 7.18

Found: C 55.15; H 4.76; H 7.04

Example CXLIX

5-Hydroxy-5- (4-iodofur-3-yl) -2,4,6 (1H, 3H, 5H) - 20 pyrimidine trion_____________________ 3,4-diodofuran (0.96 g; 3 mmol) in 5 ml ether slowly added to a cold (-65 ° C) solution of butyl lithium (2 ml of a 2.3 molar solution in hexane; 4.6 mmol) in 15 ml of ether. The mixture was stirred at -65 ° C for 20 min. Anhydrous alloxan (0.57 g; 4 mmol) was dissolved in 10 ml of tetrabydrofuran and slowly added to the 4-iodofur-3-yl lithium solution at -65 ° C. After 10 minutes at the same temperature, the reaction mixture was warmed to 15 ° C, acidified with 15 ml of 1N hydrochloric acid and extracted with ether. The ethereal extract was backwashed with 10 ml of water, concentrated to dryness and the residue triturated with 2 ral hexane to give the title product / 108 mg; m / e 336; Rf 0.5 (1: 1 ethyl acetate: hexane / 5% acetic acid) 7.

35 8103538 - 87 -

Example CL

5- (U-iodofur-3-yl) oxazolidine-2, U-dione Product of the previous example (100 mg) was allowed to stand at room temperature for 15 min with 1 ml of sodium hydroxide. The reaction mixture was acidified with acetic acid and extracted with 3 ml of ethyl acetate. Hst organic extract was backwashed with 1 ml of water and evaporated to a gum (63 mg). Crude material (120 mg) prepared in this manner was chromatographed on 50 ml of silica gel 10 using 1: 1 ethyl acetate: hexane as eluent and viewed by thin layer chromatography. The first fraction from the column was combined and evaporated to a gum (78 mg, which crystallized with ehLoroform to give purified title product (U5 mg, mp 1U-1UU ° C).

15 Analysis: Ber. for C 1 H 2 O N N: C 28.69; H 1.38; N k, 78

Found: C 28.37; H 1.62; N MU

Example CLI

5- (5-Chloro-7-benzo / bfuranyl) oxazolidine-2.U-dione The product mentioned in the preamble of Example L (100 mg; 0.39 mmol) was suspended in 6 ml of chloroform and di- (trimethylbilsilyl) ) trifluoroacetamide (100mg; 0.10U ml; 0.39mmol) by adding it all at once. After stirring for 1 min, N-bromosuccinimide (69 mg; 0.39 mmol) was added along with a trace (a single crystal) of benzoyl peroxide. The mixture was heated to reflux for 2 hours, cooled to room temperature, filtered from insolubles and evaporated to semisolid under a nitrogen stream.

The residue was partitioned between 1N sodium hydroxide and ethyl acetate. The aqueous layer was separated, washed with fresh ethyl acetate, acidified with 1N hydrochloric acid and extracted with three amounts of chloroform. The cKLoroform extracts were combined, dried over anhydrous magnesium sulfate, filtered off, concentrated to an oil and the title product crystallized from toluene (UU mg; mp.

35 15M57 ° C; m / e 251/253).

81 03 538 i * - 88 -

According to the same method, the corresponding fluorine compound from Example L was converted into 5- (5-fluoro-7-benzo - / b7furanyl7oxazolidine-2, kdione).

Method of preparation 1 5 2-ethoxypyridine ~ 3-carboxylic acid

Sodium ethanolate was prepared by adding sodium (1.1 g; 0.06 mol) in portions to 50 ml anhydrous ethanol. The solution was diluted with 20 ml of ethanol and g of 2-cKloropyridine-3-carboxylic acid was added. The reaction mixture was heated in a steel pressure vessel at 17 ° C for 6 hours. The vessel was cooled and the contents were evaporated to dryness in vacuo.

The residue was taken up in 150 ml of water and acidified to constant pH U.5. The aqueous solution was saturated with salt and extracted with four portions of ethyl acetate. The combined ethyl acetate layers were backwashed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title product (U, 33 g; mp 85-88 ° C).

Preparation method 2 20 2-methoxypyridine-3-carboxylic acid

A stainless steel stirred autoclave was charged successively with methanol (2.8 L), sodium methanolate 259 g) (in portions, keeping the temperature below 35 ° C) and 2-chloropyridine-3-carboxylic acid (190 g). The autoclave 25 was closed and the reaction mixture was heated at 110 ° C (3.5 kg / cm gauge pressure) for 8 hours. The reaction mixture was cooled to 25 ° C and drained from the autoclave. Solid was recovered by filtration. Concentration of the filtrate yielded a second crop. These process steps were repeated until nearly all of the methanol had been removed. The different solid harvests were combined, taken up in 2.5 L of water and acidified with concentrated hydrochloric acid to pH 2.7 keeping the temperature below 20 ° C. The precipitated product was granulated at 15 ° C for 30 min and recovered by filtration (1 µl g). Purified in the preamble, the product mentioned was obtained by recrystallization from ethyl acetate-hexane (120.5 g; mp 1 ^ 8-15 ePe).

Preparation 3

Ethyl ester of 2- (6-chloroquinol-8-yl) -2-oxo-5-acetic acid 8-bromo-6-chloroquinoline / J. It. Chem. 6.2U3-2U5 (1969); 6 g; 0.025 mol7 in 50 ml tetralydrofuran was added dropwise over 10 min to a mixture of butyl lithium (2.3 molar in hexane; 12.2 ml; 0.028 mol) and 10 ml tetrahydrofuran kept at -70 ° C. After an additional 30 min at this temperature, a cold (0 ° C) solution of dietlyl oxalate (1U, 6 g; 0.10 mol) in 50 ml of tetrahydrofuran was added dropwise. The reaction mixture was kept at 0 ° C for 1 hour, then diluted 0-5 ° C with glacial acetic acid (17ml) in 50 ml of tetra hydrofuran. After warming to room temperature, the diluted mixture was poured into 500 ml of water and then diluted with 500 ml of ethyl acetate and 500 ml of saturated sodium bicarbonate solution. 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 each gave the title product (2.3 g; mp 107-110 ° C; m / e 265/263).

Preparation h 25 ethyl ester of 2- (6-chloroheinol-8-yl) -2-hydroxy-acetic acid

Sodium borohydride (2.5 g> 0.066 mol) was dissolved in 300 ml of ethanol at 10 ° C and added all at once to a solution of the product from the previous preparation cooled at 10 ° C (2.0 g; 0.0076 mol) ) 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 portions of 250 ml each of saturated saline, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title product, originally as an oil, which crystallized on standing (1.87 g; mp 121-124 ° C; m / e 267/265). Preparation method 5 5 ethyl ester of 2- (6-fluoroquinol-8-yl) -2-oxoacetic acid

By the method of preparation 3, 8-bromo-6-fluoroquinoline / T was added. It. Chem. 6.2 ^ 3-2 ^ 5 (1969); U, 5 g; 0.02 mol 7 converted into hexane triturated in the title product (1.6 g; mp 11U-117 ° C).

10 Preparation method 6 ethyl ester of 2- (6-fluoro-hunol-8-yl) -2-hydroxy-acetic acid ......

Using the method of preparation method U, the product of the previous example (1.5 g; 6.1 mmol) was converted into the product mentioned in the opening paragraph. The product, which was originally obtained as a cloudy oil, was taken up in ethyl acetate, washed with saturated brine, dried, filtered and evaporated to an oil which crystallized out quickly (1.23 g, mp 8U-87 ° C); Preparation 7 6-hydroxycinoline-5-carbaldehyde sodium hydroxide (25 g) was dissolved in 35 ml of water under cooling, β-hydroxyclinoline (5 g) in 15 ml of chloroform was added and the reaction mixture was refluxed for 12 hours ( 9CPc), during which two more 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 was recovered by filtration, the crude product was dissolved in 125 ml of hot water treated with activated carbon, filtered hot, cooled and acidified with acetic acid and filtered to give the title product obtained / 2.5 g; m.p. 136-137 ° C; m / e 173; k.m.r./CDClg shows an aldehyde proton at 10.5 ppm and aromatic protons at 7.2-9, ¾ ppm735 8103538 - 91 -

Preparation 8 6-methoxycH.noline-5-carbalde hrde Product from the previous preparation (1.7 g; 9.8 mmol) in 85 ml acetone was combined with 5 potassium carbonate from 1.21 g; 8.8 mmol). Dimethyl sulfate (0.83 ml; 8.8 mmol) was added and the mixture was stirred at room temperature for 16 hours. Additional potassium carbonate (0.3ug; 2.5mmol) and dimethyl sulfate (0.23ml; 2.5mmol) were added and the mixture was stirred at room temperature for an additional hour and then at 60C for 10 hours. The reaction mixture was cooled to room temperature, salts were removed by filtration and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate, washed successively with two amounts of 1N sodium hydroxide, one amount of water and an amount of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title product. 78 g; Rf 0.35 (2: 1 ethyl acetate: chloroform; r.m.r./CDCl^/delta (ppm): M (s, 3H), T, M, 1 (m, 5H); 10.3 (s, 1H) 7.

Preparation 9 7-Hydroxycilolin-8-carbaldehyde According to the method of Preparation 7, 7-hydroxycolinoline (5 g) was converted into the title product (3.3 g; mp 127-130 ° C; m / e 173; kmr / CDCl2 shows aldehyde proton at 10.8 ppm, aromatic protons at 7.0-3.9 ppm.

Preparation method 7-Methoxyquinoline-8-carbaldehyde According to the method of Preparation Method 8, the product from the previous preparation method (3.3 g; 19 mmol) was converted into the title product / 2.1 g; k.m.r./CDCl3 / delta (ppm): U, 1 (s, 3H), 7.5-9.0 (m, 5H), 11.2 (s, 11) 7. Preparation 11 6-c Hoorcroman 35 Mossy zinc (75 g), 7.5 g of mercury (ll) chloride, 125 ml of water and U ml of concentrated hydrochloric acid were combined, shaken 8103538 for 92 minutes for 5 min. it was allowed to settle, and the liquids were decanted from the resulting amalgamated zinc.

A mixture of 100 ml of water and 126 ml of concentrated hydrochloric acid and then 6-chlorochroman-U-one (15 g) were added to the metal 5 and the mixture was heated at reflux for 1 hour, cooled to room temperature, decanted from the zinc and the decantate was extracted with three volumes of ether. The combined extracts were dried over anhydrous magnesium sulfate, filtered, concentrated to an oil (1¾ g). The oil was chromatographed on 100 g of silica gel using 9: 1 hexane: ether as an eluent, viewed by thin layer chromatography and tapping fractions of 15 ml each. Pure product fractions were combined and evaporated to give the title product as an oil / T8.72 g; kmr / CDCl 3 / delta (ppm): 2.0 (m, 2H); 3.7 (t. 2H); U, 1 '(t, 2H); 6.9 (m. 3H); m / e 170/168; Rf 0.88 (2: 1 hexane: ether 27.

Preparation 12 6-chlorochroman-8-carbaldehyde 20 Product from the previous preparation (8.6 µg 0.051 mol) in 75 ml methylene chloride was cooled in an ice-water bath. Titanium tetrachloride (19.3 µg; 11.2 ml; 0.102 mol) was added, followed by the dropwise addition of 1,1-di-. chloromethyl methyl ether (6.2 g; 0.05 mol). The reaction mixture was stirred at 0 ° C for 30 min, then poured slowly into 0 ml of saturated sodium bicarbonate solution. The aqueous phase was extracted with three fresh amounts of methylene chloride. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, filtered and evaporated to yield the title product / 7.9 g; m.p. 83-86 ° C; k.m.r./CDCl^/delta (ppm): 2.0 (m, 2H); 2.8 (t. 2H); k, 2. (t, 2H); 7.1-7.5 (m. 2H); 10.2 (s. 1H); m / e 198/1967.

8103538 - 93 -

Method of preparation 13 6-fluorochroman

According to the method of preparation method 11, 6-fluoro-H-chromanone (15 g) was converted to chromatographed 6-fluoro-chromane / 5.7 g; oil; k, mr / CDCl 4 / 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 1527

Preparation Method 6-Fluorochroman-8-carbaldehyde 10 According to the method of Preparation Method 12, the product of the previous example (5 g, 0.036 mol) was converted into the title product originally isolated as a viscous oil, which crystallized from hexane (3.4 g; mp. 5 ^ -57 ° C; m / e 180).

Preparation 15 3-methylisoxazole-5-carboxamide 3-methylisoxazole-5-carboxylic acid (20 g) was heated under reflux 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 triturated several times with hot hexane and the combined hexane titrates were evaporated to give the acid chloride (16.2-21 g) as a solid.

While stirring, the acid chloride (35 g) prepared in this way was added in portions to 300 ml of concentrated ammonium hydroxide at room temperature. After granulation for 1 hour, the title product was recovered by filtration (2.1 g, mp. 180). -182 ° C).

Preparation method 16 30 3-methylisoxa2ol-5-carbonitrile

Product from previous preparation (5 g) was thoroughly mixed with phosphorus pentoxide (10 g) and placed in an oil bath preheated to 1k ° C, the bath temperature was raised to 200 ° C and the title product was recovered by vacuum distillation / 2.9 g; 8103538 i »- 9b - ir (film) nitrile tape at 2220 cm ^, no amide peak in the region of 1700 cm” V.

Preparation 17 3-methylisoxazole-5-carbaldehyde 5 Product from previous preparation (1.08 g; 0.01 mol) was dissolved in 25 ml ether and cooled to -1 ° 0 ° C. Diisobutyl lithium hydride (12 ml of 1 molar solution in hexane; 0.012 mol) was added at -U0 ° C over 15 min. The mixture was stirred at -30 ° C to -35 ° C for 10 min. While the temperature was kept at -20 ° C, 60 ml of ethyl acetate were added. While the temperature was kept at -25 ° C, methanol (15 ml) was added dropwise and while the temperature was kept below -20 ° C, 3 ml of 1 hydrochloric acid were added. The reaction mixture was warmed to 5 ° C and the organic phase was 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 the eluent. Product fractions were combined and evaporated to give the title product (0.002 g; mp. 39-1 ° C). A small sample further purified by sublimation showed a m.p. of U3-5 ° C.

Preparation 18 5-Chlorobenzo [b7furan-2-carboxylic acid 25 5-chlorosalicylaldehyde (31.3 g; 0.2 mol) was dissolved in 200 ml of butan-2-one. Potassium carbonate (82.9 g; 0.6 mol) and then diethyl 2-bromalonate (95.6 g; 0.1 U mol) were added and the mixture was heated under reflux for 5 hours, then cooled, filtered from the salts and concentrated 30 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 aliquots of 250 ml of fresh ether. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to a second oil. The second oil 8103538 - <4 - 95 - was dissolved in 100 ml of 10% ethanolic potassium hydroxide, heated at reflux for 1 hour and concentrated to solid. The solid was dissolved in 1500 ml of water, filtered from a trace of insoluble material, acidified with 6N hydrochloric acid 5 and precipitated solid was recovered by filtration.

Purified in the preamble said product was obtained by reprocessing the solid and 1 L water (19 mp 259-262 ° C; m / e 198/196).

According to the same method, 5-fluorosalicyl-10 aldehyde and 6-cKlorosalicylaldehyde, respectively. converted to 5-fluorobenzo / b7furan-2-carboxylic acid and 6-chlorobenzo / b7furan-2-carboxylic acid.

Preparation 19 5-οΜ.οο ^ 6ηζο / “^ 7ί \ ιτηη 15 The compound mentioned in the preamble of the previous preparation method was combined with copper powder (700 mg) and quinoline (50 ml) and the mixture was heated to reflux for 50 min, then cooled to room temperature and diluted with 500 ml ether. Insoluble components were removed by filtration and the filtrate was washed successively with five aliquots of 200 ml 2N hydrochloric acid and an amount of saturated brine, dried over anhydrous magnesium sulfate and concentrated to an oil (6.2 g). The oil was chromatographed on 200 g of silica gel using ether as eluent and 300 ml fractions were collected. Fraction 1 and 2 were combined and evaporated to give the title product as an oil (6.1 g ).

By the same method, the other benzo-furan carboxylic acids from the previous preparation method were converted into 5-fluorobenzo / "b7furan and 6-chlorobenzo /" b7furan.

Preparation 20 5-chloro-2,3-dihydrobenzo / bfuran Pd / C (5% 12.2 g) in kOO ml of acetic acid was pre-hydrogenated at atmospheric pressure and 25 ° C. The compound (6.1 g) in 100 ml of acetic acid mentioned in the preamble of the preceding preparation method (96 g) was added and hydrogenation was continued until slightly more than an equivalent of hydrogen was taken up. The catalyst was recovered by filtration over diatomaceous earth. The filtrate was neutralized with saturated potassium carbonate solution and extracted with four 200 ml portions of ether. The combined extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. The oil was chromatographed on 400 g of silica gel using hexane-3% ether as the eluent, 15 ml fractions were collected and viewed by thin layer chromatography. Pure product fractions 70-90 were combined and evaporated to give the title product / 2.15 g; oil; Rf 0.32 (hexane); m / e 156/15 ^ 7.

By the same method, the other benzo furans from the previous preparation methods were converted into 5-fluoro-2,3-dihydrobenzo / b7furan and 6-chloro-2,3-dihydrobenzo / b7furan.

Preparation 21 5-c Chloro-2,3-dihydrobenzo / b7fiiran-7-carbaldehyde By the method of Preparation 12, the compound (2.1 g) mentioned in the preamble mentioned above preparation was converted into crude product, contaminated with an isomeraldehyde . Purified in the preamble said product was obtained by digesting the crude product in 50 ml of boiling hexane, filtering and cooling the filtrate (0.93 g; mp 79-8l ° C; Rf 0.55 (chloroform) m / e 18U / 182).

According to the same method, the 5-fluorine compound of the previous preparation method is converted into 5-fluoro-2,3-dihydrobenzo / "b7furan-7-carbaldehyde. According to the method of preparation method 3, the. 6-chloro compound is converted into the ethyl ester of 2 - (6-chloro-2,3-dihydro-7-benzo / b7furanyl) -2-oxoacetic acid, then by the method of preparation ^ 35 in the ethyl ester of 2- (6-chloro-2,3-dihydro- 7-benzo / b7 furanyl - 8103538 - 97 - 2-hydroxyacetic acid.

Method of preparation 22 7-chloroquinoline-8-carbaldehyde 7-chloro-8-methylquinoline (1 g) / Bradford 5 et al., J. Chem. Soc., 437 (1947) 7 is dissolved in 20 ml of benzene and brominated with an equivalent of N-bromosuccinimide in the presence of catalytic amounts of peroxide. The product, 7-chloro-8-bromomethylquinoline, is isolated by evaporation. The bromine compound is subjected to solvolysis to 7-chloro-8-hydroxymethylquinoline by heating with excess alcoholic potassium hydroxide. To isolate the product, the reaction mixture is neutralized with hydrochloric acid, the salts are separated by filtration and the filtrate is 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 pyridinium chlorochromate in 20 ml of methylene chloride. The exothermic reaction is controlled by the addition rate, use of a reflux condenser and occasional cooling in a cooling bath. The reaction mixture is diluted with ether and the supernatant is separated by decantation and filtration. The product is purified by filtration through a short magnesium silicate column with ether as the eluent and isolated by removal of the solvent under vacuum.

Preparation 23 3-furaldehyde 3-furylmethanol (19 * 6 g; 0.2 mol) in 50 ml of methylene chloride was added dropwise to a slurry of pyridinium chlorochromate (64.5 g; 0.3 mol) in 450 ml of methylene chloride. The exothermic reaction leading to violent reflux was controlled by occasional cooling with an ice bath. Rubbery solids had precipitated at the end of a 60 minute period. The reaction mixture was diluted with 600 ml of ether and the supernatant became 8103538

It * - 98 - separated by a combination of decanting and filtering.

The filtrate was passed through Florisil (trade name for synthetic magnesium silicate) contained in a short column, with ether as the eluent. Collected fractions were eomomed and evaporated to an oil. Distillation of the oil gave 3-furaldehyde (7-6 g; bp 68-72 ° C / + + 0-5 nm).

Instead, this aldehyde is prepared by Rosenmund reduction of 3-furanic acid chloride ~ Hayes, J.A.C.S. 71, 2581 (19 * 19) 7.

Preparation 2k 2- (fur-2-yl) -1,3-dioxolane-2-furaldehyde (1 + 2 ml; 0.5 mol) ethylene glycol (50 ml; 0.9 mol) and p-toluenesulfonic acid (about 200 mg) were in 150 ml of toluene and the mixture was refluxed for 6 hours while by-product water was collected in a Dean-Stark trap. The mixture was cooled, diluted with 500 ral ether and purified by filtration.

The filtrate was washed with 200 ml of saturated sodium bicarbonate solution and the organic phase was purified again by filtration. The second filtrate was washed with 200 ml of water and the organic layer was concentrated to dryness to give 2- (fur-2-yl) -1,3-dioxolan as an oil (U5 g).

Preparation 25 25 2- (5-chloro-fur-2-yl) -1,3-dioxolan 2- (fur-2-yl) -1,3-dioxolan (1 * + g; 0.1 mol) was dissolved in 100 ml of tetrahydrofuran and the solution was cooled to -25 ° G to -20 ° C. While maintaining the temperature in this range, butyl lithium in hexane (* + 5 ml of a 2.2 molar solution; 0.1 mol) was added over 10 min.

The mixture was allowed to warm to 0 ° C in 25 min after which it was again cooled to -30 ° C. While maintaining the temperature in the range from -30 ° C to -25 ° C, hexachloroethane (23.7 g; 0.1 mol) in 50 ml of tetrahydrofuran was added over 5 min. The reaction mixture is warmed to room temperature, stirred for 8103538 - 99 h, recooled to 5 ° C and diluted slowly with 500 ml of water. The product was extracted with ether (2 x 500ml) and recovered as an oil (15.8g) by evaporation to dryness.

The oil was chromatographed on a 200 ml volume of silica-5 dioxide gel using 8: 1 hexane: ethyl acetate as eluent and viewed by silica gel thin layer chromatography using the same eluent. The early product-containing fractions were combined and evaporated to give purified 2- (5-chlorofur-2-yl) -1,3-dioxolane as an oil / 5 µg R »0.6 (8: 1 hexane: ethyl acetate) 7 - I -

Preparation 26 5-c-Ear-2-furaldehyde 2- (5-chlorofur-2-yl) -1,3-dioxolan (0.8 g) was dissolved in 20 ml of pus. 6N hydrochloric acid (10ml) was added and the biphasic mixture was stirred at room temperature for 1 hour.

The ethereal phase was separated, washed with water and evaporated to give 5-chloro-2-furaldehyde as an oil (2.8 g).

Preparation 27 20 5-Bromo-2-furylcarboxamide 5-Bromo-2-furanecarboxylic acid (20 g) was heated under reflux with 60 ml of thionyl chloride for 3 hours and the corresponding acid chloride was isolated as an oil by concentration. The acid chloride was added dropwise to 150 ml of stirred concentrated ammonium hydroxide. Filtration gave 5-bromo-2-furylcarbonamide (17.0 g; mp 1U-1U3 ° C). Preparation 28 5-Bromo-2- »furylcarbonitrile 5-Bromo-2-furylcarbonamide (10 g) was combined with 50 ml of phosphorus oxychloride and heated under reflux for 2 hours. The mixture was poured onto ice, the product was extracted with ether, and 5-bromo-2-furyl-carbonitrile was evaporated as an oil (6.1 µg) on evaporation.

35 8103538 i * - 100 -

Preparation 29 5-Bromo-2-furaldehyde 5-Bromo-2-furylcarbonitrile (2.3 g; 13 mmol) was dissolved in 50 µl ether and cooled to 5-10 ° C under a nitrogen blanket. Diisobutylaluminum hydride (1.9 g; 13 mmol) was added dropwise as a 25% solution in toluene, keeping the temperature close to -10 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was cooled to 0-5 ° C, diluted with 1 ml of methanol, acidified with 3N hydrochloric acid, washed with water and evaporated to give 5-bromo-2-furaldehyde (1.2 g; mp 7 ^ -76 ° C ) was obtained.

Preparation 30 3-Bromo-2-furaldehyde 15 Phosphorus oxychloride (6.5 g; 70 mmol) was added to dimethylformamide (5.1 g; 70 mmol) at 0-10 ° C. The resulting slurry was diluted with 10 ml of ethylene dichloride. While the mixture was kept at a temperature near 10 ° C, 3-bromofuran (9.2 g; 63 mmol) was added. The reaction mixture was then heated to 586 ° C for 1 hour and then cooled again to 10 ° C. Sodium acetate trihydrate (15 g), dissolved in 25 ml of water, was added slowly with good stirring keeping the temperature in the range of 10-30 ° C. The mixture was again heated at 68-72 ° C for 20 min, cooled to room temperature and diluted with 20 ml of water.

The product was extracted with 75 ml of ether and the ether was backwashed with water and concentrated to give 3-bromo-2-furaldehyde as an oil / 0.9 g; Rf 0.65 (3: 1 hexanesethyl acetate27).

30 Method of preparation 31 3-iodofuran

3-Bromofuran (11.7 g; 0.1 mol) in 100 ml ether was cooled to -70 ° C. Butyl lithium (k2 ml of a 2.0 M molar solution; 0.1 mol) in hexane was added dropwise over half an hour, with the temperature in the range of -70 ° C

8103538 ft * 1 - 101 - to -65 ° C. Iodine (25 g; 0.1 mol) in 200 ml ether was then added over 1 hour, maintaining the same temperature range. The reaction mixture was warmed to room temperature and then cooled again to 2 ° C. Water 5 (100 ml) was added dropwise. The ethereal layer was separated, washed with aqueous thiosulfate and then with water, dried over anhydrous sodium sulfate, evaporated to an oil and distilled to give 3-iodofuran (15.7 g, bp U8 ° C / 28 nm).

Preparation 32 3-methoxyfuran

Sodium metal (5.6 g; 0.2U mol) was dissolved in 150 ml of dry methanol. 3-iodofuran (15.7 g, 0.08 mol) and copper (i) oxide (8 g, 0.1 mol) were added and the mixture was heated under reflux for 2 h for 2 hours.

The reaction mixture was cooled to room temperature, diluted with 200 ml of water and the product was extracted with 100 ml of ether. The ethereal extract was backwashed with 15 ml of water, dried over anhydrous sodium sulfate and evaporated to give crude 3-methoxyfuran (about 3 µg in 50% purity) suitable for further processing.

Preparation 33 5-phenyl-2-thenaldehyde 25 1-phenylthiophene / 1.6 g; 0.01 mol, prepared according to J.A.C.S. U6, 2339 (192 * 07 was dissolved in 20 ml of tetrahydrofuran and cooled to -U0 ° C. Butyl lithium in hexane (¾ ^ ml of a 2.2 molar solution) was added over 3 min to bring the temperature into the range was maintained from -U0 ° C to -30 ° C.

The mixture was warmed to 0 ° C and then cooled again to -U0 ° C. Dimethylformamide (1.2 ml; 15 mmol) was added keeping the temperature in the range of -0 ° C to -3cPc. The mixture was warmed to room temperature and held for half an hour, then cooled to 0 ° C, diluted with 6 ml of 6N hydrochloric acid, diluted with 10 ml of water and extracted with 20 Ö 3 5 3 8 ί * - 102 - ml of ether. Evaporation of the ethereal extract to dryness yields crude product (1.9 g). Recrystallization from 35 ml of hexane gave purified 5-phenyl-2-thenaldehyde (0.9 g; mp 90-92 ° C).

Preparation method 3 ^ U-bromo-3-thenalde tyde 3, -1-dihromothiophene / 15 g; 0.062 mol; J. Org. Chem. 36, 2690 (1971) 7 in 20 ml ether was cooled to -70 ° C and butyl lithium in hexane (3.3 ml of a 2.1 molar solution; 0.073 mol) was added dropwise over 5 min. . After 5 min.

stirring at -70 ° C, the solution was transferred through a nylon tube under nitrogen pressure to a solution of dimethyl-formamide (6.8 g; 0.093 mol) in 35 ml ether. The resulting mixture was refluxed for 2 hours, cooled to room temperature, washed successively with two amounts of 1N hydrochloric acid, an amount of saturated sodium bicarbonate solution and an amount of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was distilled twice to give 20 U-bromo-3-thenaldehyde (5.7 g; bp 81-8U ° C / 0.8 nm; m / e 192/190).

Preparation 35 2-phenylfuran

Aniline (^ 6.5 g; 0.5 mol) was combined with 500 ml of water and 100 ml of concentrated hydrochloric acid and to -5 ° C

cooled. Sodium nitrite (36.2 g; 0.525 mol) in 100 ml of water was added dropwise over U5 min, keeping the temperature in the range from -3 ° C to -5 ° C.

After the addition was complete, the mixture was 30 minutes. stirred at -5 ° C and zinc chloride (68 g) was added. Maximum precipitation of the diazonium salt was obtained by adding 100 g of sodium chloride. The mixture was stirred for 5 min. While the cooling bath was removed and filtered carefully without washing and air dried for 2 hours.

(Incorrect vacuum drying of this product resulted in explosive decomposition). The intermediate diazonium salt was suspended in 750 ml furan at 0 ° C. With vigorous stirring, powdered sodium hydroxide (5 g) was added, followed by anhydrous sodium acetate (10 g). The reaction mixture was stirred at 0 ° C for 5 hours and then at room temperature for 16 hours. Solids were removed by filtration and the filtrate was evaporated to crude (25 ml of oil). Distillation gave 1-phenylfuran (9.2-9.6 g; bp 87-95 ° C / 15 mm; bp 50 ° C / 1 mm).

Preparation 36 10 2-phenyl-2- (thien-2-yl) -1,3-dioxolan 2-benzoylthiophene (19 g> 0.1 mol), ethylene glycol (11 ml; 0.2 mol), toluene (150 ml) and p-toluenesulfonic acid (about 0.2 g) were combined and heated at reflux for 6 hours. Water formed as a by-product was collected in a Dean-Starkval. Thin layer chromatography (1: 9 ethyl acetate: hexane) indicated that the reaction was about half percent complete.

More ethylene glycol (30ml) was added and the refluxing was continued for 35 hours. The response was still incomplete. The reaction mixture was diluted with 2 GD ml of ether, washed twice with 150 ml of water and concentrated to dryness. The residue was chromatographed on 5CO ml of silica gel with 1: 8 ethyl acetate: hexane as eluent, viewed by thin layer chromatography. Faster moving product-containing fractions were combined and evaporated, yielding 2-phenyl-2- (thien-2-yl) -1,3-dioxolane / 8 g; oil; 0.6 (1: 8 ethyl acetate: hexane) 7 Preparation 37 methyl fr-methoxy-3-thenoate

Methyl 4-acetoxy-3-thenoate (U.S. Pat. No. 3,1HU.235; 10 g) was dissolved in 20 ml of methanol and added to 100 ml of methanol containing 0.31 ml of concentrated sulfuric acid. The mixture was heated under reflux for days, then neutralized with 0.6 g of sodium acetate and the solvent was removed by evaporation. The residue 35 was taken up in 200 ml of ether. The ethereal solution was washed successively with two aliquots of 50 ml of water each, two aliquots of 50 ml of 1N each of sodium hydroxide and two aliquots of 50 al of saturated saline each, dried over anhydrous magnesium sulfate, filtered and evaporated to a oil which crystallized on standing (4.35 g; mp 64-66 ° C).

When this reaction mixture was worked up after 1 day, only a small yield of the desired product (2.2 g) was isolated. The two 1N sodium hydroxide extracts were combined and acidified to precipitate methyl 4-hydroxy-3-thenoate (5 »13g). When this alcohol was dissolved in 100 ml of methanol containing 0.3% of concentrated sulfuric acid and refluxed for 3 days, the above work-up gave the title product (2.10 g; m.p.

64-66 ° C).

Preparation 38 1- (4-methoxythien-3-yl) methanol methyl 4-methoxy-3-thenoate (U.S. Patent 4,144,235; 3.9 g; 23 mmol) was dissolved in 50 ml of toluene and cooled in a acetone dry ice bath. diisobutylaluminum hydride (46 ml of a 1 molar solution in hexane; 46 mmol) was added dropwise over 30 min. The mixture was stirred at bath temperature for an additional 2 hours and then allowed to warm to room temperature. While the temperature was kept below 30 ° C, methanol (14, T g; 18.6 ml; 0.46 mol) was added slowly. The mixture was then stirred at room temperature for 16 hours, after which time a granular precipitate had formed. The mixture was filtered over diatomaceous earth with methanol washing, with combined filtrate, and the washings were concentrated to give the title product as an oil (2.8 g; m / e 144). Preparation 39.

4-methoxy-3-thenaldehyde

Pyridinium chlorochromate (6.4 g; 29.7 mmol) was dissolved in 10 ml with tylene chloride and added in one go 8103538 - 105 - to a solution of the product from the previous preparation (2.8 g; 19.8 mmol) also in 100 ml of methylene chloride. The reaction mixture was stirred at room temperature for 3 hours, diluted with 200 ml of pus and decanted from the black precipitate.

The precipitate was washed with two 100 ml portions of ether. The combined decantate and washings were filtered, washed successively with two amounts of hydrochloric acid, an amount of water, two amounts of sodium hydroxide and one amount of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title product was obtained as an oil / 2.6 g; m / e 1U2; ir (CH 3 Clg) 1688, 15 ^ 4 cm. ^ 7. Preparation U 0

Ethyl Ethoxy-3-Thenoate 15 Following U.S. Patent No. 1,100,235, methyl U-acetoxy-3-thenoate (20 g) was dissolved in 2 ml of ethanol and 0.62 ml of concentrated sulfuric acid was added. The reaction mixture was refluxed gently for 79 hours, then neutralized with sodium acetate (1.2 g) and evaporated to an oil. The latter was partitioned between HOO ml of ether and 50 ml of water. The organic layer was separated and washed successively with 75 ml of water, three amounts of 50 ml 1N each of sodium hydroxide and two amounts of 75 ml of saturated saline each, dried over anhydrous magnesium sulfate, filtered and evaporated to yield the title product obtained as an oil / "1U, 9 g / kmr indicates complete ethyl ester, no methyl ester7 ·

Preparation method frl 1 - (U-et hoxythien-3-yl) with hanol

By the method of preparation method 38, the product from the previous preparation method (11 g) was converted into the title product as an oil (9.15 g).

8103538 i r 't' - 106 -

Preparation method b2 U-ethoxy-3-thenalde hyde

By the method of preparation method 39, the product from the previous preparation method (9.15 g) was converted into the product indicated in the preamble, which was first isolated as an oil, which crystallized rapidly upon cooling ,18.18 g; m.p. te-1 * 5 ° C; m / e 156; ir (KBr) 3090, 2977, 1688 cm "V." Preparation method 1 * 3 n-nropyl b- (n-pronoxy) -3-thenoate 10 According to the method of preparation method U0, using a reaction reflux time of 10 days, methyl H acetoxy-3-tbenoate (6 g) in 750 ml of propan-1-ol, containing 0.19 ml of concentrated sulfuric acid, converted to the title product as an oil (5.5 µg / e 228).

15 HU preparation method

1 n-pronoxy) -3-thienyl) with hanol

According to the method of preparation method 38, the product from the previous preparation method (5.1 g) was reduced to the compound mentioned, isolated as an oil 20 (3.3 g / m / e 172).

Method of preparation ^ 5 1 * - (n-uropoxy) 3-t henaldehyde According to the method of preparation method 39, the product from the previous preparation method (3.3 g) was converted into the compound mentioned in the hitch (3.19 g). M / e 170; ir (C 12 C 12) 1689, 1539 cm -1).

Preparation method 1 * 6

Ethyl U-methoxy-2-methyl-3-thenoate

Ethyl U-hydroxy-2-methyl-3-t henoate (Chem. Ber.

3.08, 593 (1915); 7.8 g) was combined with 600 ml of methanol and 0.25 ml of concentrated sulfuric acid and heated under reflux for 21 hours. The reaction mixture was evaporated to an oil, taken up in 500 ml of ether, washed with two amounts of 50 ml 1N each of sodium hydroxide and then one amount of saturated saline, dried over anhydrous magnesium sulfate and evaporating to give 10% the aforementioned product was obtained as an oil (7.8 µm / e 200; kmr

CDCl3 contains singlet OCE (protons at 3.9 ppm). The product is contaminated with a minor amount of the 5 corresponding to lyl ester.

Preparation kj (k-methoxy-2-mgthylthien-3-yl) with hanol The product from the previous preparation (7.8 g; 0.039 mol) was dissolved in 100 ml hexane and 75 rl 10 toluene and cooled to -78 ° C . Diisobutylaluminum hydride (78 ml of 1 molar solution in hexane; 0.078 mol) was added dropwise for 0 min. The mixture was stirred at -78 ° C for 2 hours, warmed to room temperature and stirred for an additional 16 hours. Methanol (25.0 g; 31.6 ml; 0.78 mol) was added dropwise to the reaction mixture, keeping the temperature below 3CPc. After stirring for 1 hour at room temperature, the reaction mixture was purified by filtration over diatomaceous earth with thorough washing with methanol and pulping the cake again, and finally washing with methylene chloride. The combined filtrate and washings were dried over anhydrous magnesium sulfate, filtered and evaporated to give the title product as an oil (5.56 g; m / e 158; ir (CH 2 Cl 3) 3598, 1582, 1708 cm "1).

Preparation method U8 U-metoxy-2-methyl-3-thenaldehyde According to the method of preparation method 39, the product from the previous preparation method (5 µg 0.03k mol) was converted into the title compound, which was used as an oil isolated / 5.23 g; 0.36 (chloroform) 710103538

Claims (7)

1. Racemic or optical active 5-substituted oxazolidine-2, U-diones of formula 1, wherein R represents hydrogen, an alkanoyl group with 1-H carbon atoms, benzoyl, a carbaloxy group with 2-h carbon atoms, an alkyl carbamoyl group with 1-3 carbon atoms in the alkyl group, a cycloalkyl carbamoyl group with 5-7 carbon sib atoms in the cycloalkyl group, or a dialkyl carbamoyl group with 1-3 carbon atoms in any alkyl group, and represents 10 (a) a group of formula 2, formula 3 or formula U, wherein R 'is an alkyl group with 1-¾ carbon atoms or a phenyl group, R "is hydrogen, an alkyl group with 1-¾ carbon atoms or a phenyl group, and X is halogen; or (b) a group of formula 5, wherein Y represents white matter 15 / or an alkoxy group with 1-3 carbon atoms, Y 'represents hydrogen or an alkyl group with 1-3 carbon atoms and Y "represents hydrogen or halogen; or (c) a group of formula 6 or formula 7 wherein Z 'represents hydrogen, halogen or an alkoxy group having 1 to 3 carbon atoms and Z' represents hydrogen or halogen; or (d) a group of formula 8, wherein W represents hydrogen or halogen and n equals 1 or 2 or (e) a group of formula 9 or formula 10, wherein Q represents sulfur or oxygen and V represents hydrogen or an alkyl group of 1-3 carbon atoms; or (f) a group of formula 11, wherein Q represents sulfur or oxygen and V represents hydrogen or an alkyl group of 1-3 carbon atoms; or (g) a group of formula 12 or formula 13, wherein 30 represents sulfur or oxygen; X stands for hydrogen, halogen, a metlyl, phenyl, benzoyl group or an alkoxy group with 1-3 carbon atoms; X ^ stands for hydrogen or a methyl group and Xg stands for hydrogen or a halogen; or a pharmaceutically acceptable cation salt 35 thereof, when R is hydrogen, or a pharmaceutical 8103538-109 - accepted baric acid addition salt thereof, when it contains a basic nitrogen group. 2. 5-substituted oxazolidine-2, U-dione according to claim 1, characterized in that R 1 is a group of formula 5, wherein Y is an alkoxy group with 1 or 2 carbon atoms and Y 'represents hydrogen, chloro or fluorine, 3,5-substituted oxazolidine-2, U-dione according to claim 1, characterized in that it represents a group of formula 8 wherein W represents chlorine or fluorine in the 5-position 10 and n equals 1 or 2. U. 5-substituted oxazolidine-2, H-dione according to claim 1, characterized in that R 1 is a group of formula 7, wherein Z 'represents hydrogen and Z "represents chlorine" or fluorine. 5. 5-substituted oxazolidine-2, U-dione according to claim 1, characterized in that R ^ represents a group of formula 12, wherein Y is sulfur, X ^ is in the 2 position, X is in the U position and the bond is in the 3 place, or is a group of formula 12, where Y is a sulfur, X is a group 20 0C in the 3 place, X is hydrogen and the bond is in the 2 place. the former group of formula 12 X is an alkoxy group with 1 or 2 carbon atoms and X ^ represents hydrogen or a methyl group. 6. 5-substituted oxazolidine-2, H-dione, characterized in that R 1 represents a group of formula 12, in which Y is oxygen, X represents hydrogen or halogen and when X is in the 5 position free bond is in 2nd place, if X is in 3rd place a free bond is in 2nd place and if X is in U position the free bond is in 30th place. 7. 5-substituted oxazolidine derivative of the formula lUf, characterized in that R 1 is an alkyl group having 1 to 3 carbon atoms and R 8 represents (a) a group of formula 2, formula 3 or formula k, wherein R 1 is a alkyl group with 1-¾ carbon atoms or 8103538. * t - 110 - is a phenyl group, or (b) a group of formula 8 wherein W is hydrogen or halogen and n is 1 or 2, or (c) a group of formula 9, wherein Q stands for sulfur or oxygen and V stands for. hydrogen or an alkyl group with 1-3 carbon atoms, or (d) a group of formula -12 or formula 13, wherein Y represents sulfur or oxygen, X represents hydrogen, halogen, a metlyl, phenyl or benzoyl group or an alkoxy group 10 with 1-3 carbon atoms represents hydrogen or a methyl group and Xg represents hydrogen or halogen. Precursor of the compound according to claim 7, characterized in that the compound satisfies formula 15 wherein Rg and Rg have the meanings stated in claim 7. Novel compound of formula 1, characterized in that Rg represents the meanings stated in claim 7. 10. New compound of formula 17 [characterized in that R 1 represents hydrogen, a short chain 20 alkanol or benzoyl group and R 1 has the meaning defined in claim 1. 11. New compound of formula 18 *, characterized in that R 1 represents hydrogen, a short chain alkyl or phenyl group and R 2 has the meaning as defined in claim 1. Novel compound of formula 19 (characterized in that R 1 has the meaning defined in claim 1. Novel compound of formula 20 {30, characterized in that in R 2 has the meaning defined in claim 1 and R 8 is an alkyl group with 1 to 3 carbon atoms. 1U. Precursor of the compound according to claim 13, characterized in that it satisfies formula 2 /, wherein R 1 and R 5 have the meaning as defined in claim 13 and R 1 represents hydrogen, a short chain alkanol or benzoyl-8103538-tn - group. 15. 5-substituted oxazolidine-2 * i -diones, as well as pharmaceutically acceptable salts thereof and certain 3-acylated derivatives thereof, as described herein. SI ü o 5 3 8 cp xo? Tx ° 1 '2 3 *' 4> 5 7 "T ·. 'Y> ΥΎΤ TT I Tl ΓΓ # 1 z'XyA N') d) {^ yA °)> 6 7 8 9 Oö -bt £ R- o ·. 10 11 12 13 1 T rf \ <X Τ '* X "Οχ x Y Ox Y x T 1Q 15 16 17 18, y 0 ^ CH a ^> iV_xOx J ó Χίπι ΓΓ1 Lil Al0 ajc ^ LI ^ y ^ Ox y 'R' o 20 21 0x22 36 37 ao ^ ° / oh d / cn r <o / ~ nih i r4- <1 r4 / or r '\ X> ° / VSCH, VtJ V ° Ri OSi (CHsij '> ~ NH Rl o X Lc' 16 '17' 38 14 15 Ov S / ° \ * SR / 0R4 “TT TT TT Y- vv» v ö ls 81 0 3 5 3 8 PFIZER INC., New York, New York, United States America * · (- - A. OH OH 0- ^ ° 'JL, NH, JL / 0Rx 1 \ P ^ C ^ Ρ ^ Ύ R ^ N Ri g- s ”, r K \ »0B mr_r ^“ —- ^ r Ri'V '^ R' n ° 3 ° '' Vy 23 2S R, o Vnh P- \ S «ΛΪ«, -V ~ «V * 32 30 - 29 0Si (CH,) 3 A. Rn CN 34 \ OH A .OR.r.cho κ, 33r 33 \. NH \ I y 25 \. OH> y R ^ CN 35 81 0 3 5 3 8 PFIZER INC., in New York, New York, United States of America -C- OH OH, ORa —- * “T '35/28 \ a OH ^ K1 o R, HR; 0 V-NH ° R: rX> o ~ - R, - '0Ri <f- "H C00R» RM p A 40 1 Ί Vnh “or, R, \ / 0 R, ch 0 ^ —NH COORj 41 '39 - - *" V-nh ί * N > / Vo CH. CH H O V_ NH 3 0 ^ - Br Br / “NV. -F · Oj> —► Η H OCH. 0 - (V-NH _G. ^ -> - O-vT> 0 y Y ho "> - nh 0 <ny. O 8103538 Pfizer Ine., New York, New York, United States of America £ - i -Η- € *> - ^ n li ay ° HO V- NH ot PFIZER INC., in New York, New York, United States of America 8102228