IE51664B1 - Pyrimidinetrione intermediates for hypoglycemic 5 substituted oxazolidine 2,4-diones - Google Patents

Description

This application is a divisional from Patent Application I.e. filed on July 27, 1981.

It relates to certain pyrimidinetriones which are useful as intermediates in the preparation of certain oxazolidine-2,4-dione hypoglycemic agents as is described in said Patent Application No. 516 6 2 Thus according to the invention there are provided compounds of the formula :- wherein R is hydrogen, lower alkanoyl or benzoyl and R1 is or R wherein R' is (Cj-C^)alkyl or phenyl, R is hydrogen, (C1-C4)alkyl or phenyl and X is halo; (b) wherein Y is hydrogen or ) alkoxy, Y* is hydrogen or (C.j-C3)alkyl and Y is hydrogen or halo; wherein Z' is hydrogen, halo or (C^-C^Jalkoxy and Z is hydrogen or halo; (d) Ή2) wherein W is hydrogen or halo, and n is 1 or 2; (e) wherein Q is sulfur or oxygen and V is hydrogen or alkyl; wherein Q is sulfur or oxygen; and V is hydrogen or alkyl; wherein Y is sulfur or oxygen; X is hydrogen, halo, methyl, phenyl, benzoyl or (C^-C^alkoxy; X1 is hydrogen or methyl; and X2 is hydrogen or halo; or (h) 5-(2-phenyl-l,3-dioxolan-2-yl)thien-2-yl; 4 . with the proviso that when R is as defined m (h), R is 10 hydrogen.

Methods suitable for the preparation of the compounds of the invention are shown in the Flowsheet, wherein the substituents R1 and R4 are as defined above, M is Li, MgCl, 2 MgBr, Mgl, or other suitable metal, and R is lower alkyl 15 (e.g. methyl or ethyl).

A general method for preparing the compounds is from the malonic ester derivatives (A), involving the two stages of base catalyzed condensation with urea and oxidation to the hydroxy or acyloxy compound. When the first stage is oxidation, the intermediate is a so-called tartronic acid derivative (B), while when the first stage is condensation, the intermediate is a so-called barbituric acid (c) When R contains an amine function (e.g. 2-aminophenyl), it is preferred to carry out oxidation as the first stage, preventing possible complications of nitrogen oxidation. - 5 When condensation is the second stage, the dialuric acid is usually not isolated, at least in pure form, and can be further converted, under basic conditions of the condensation, to the oxazolidine-2,4-dione 5 hypoglycemic end products.

Flowsheet (C) COOR2 1' 4 R C-OR 1 2 COORZ (B)· A COOR2 1 < rach 1 2 COOR (A) The substituted malonic esters required for the above syntheses, when not available commercially, are obtained by literature methods, such as alcoholysis of alpha-cyano esters [cf. Steele, J. Am. Chem. Soc. 53, 286 (1931)], carbalkoxylation of esters [cf.

Horning and Finelli, Org. Syntheses 30, 43 (1950)] and decarbonylation of alpha-keto esters obtained by the condensation of dialkyl oxalate with carboxylate esters [Reichstein and Morsman, Helv. Chim. Acta 17, 1123 (1934); Blicke and Zienty, J. Am Chem. Soc. 63, 2946 (1941)].

A less general method for the preparation of the appropriate dialuric acid intermediate is to react an electron rich heteroaryl/aryl compound, e.g., Now available is yet another method for the preparation of certain dialuric acid intermediates.

This method, preferred when the appropriate starting materials are readily available, involves the reaction of alloxan (preferably in anhydrous form) with the appropriate organometal derivative (e.g., organolithium, Grignard reagent). For example: HO λ—NH a The following Examples illustrate the invention :SXAMPLS 1 -Hydroxy-5-(l-raethyl-2-pyrrolyl)-2,4,6(lH,3H,5H)pyrimidinetri0ne_ Alloxan hydrate (3.2 g., 0.02 mole, was dissolved in 50 ml. of ethanol by warming. 1-Methylpyrrole (1.6 g., 0.02 mole) was added and the mixture warmed for 5 minutes on a steam bath, while perfusing with hydrogen chloride. After standing at room temperature for 0.5 hour, the reaction mixture was evaporated to dryness and the residue triturated with water to yield title product as a solid [2.9 g.; ra/e 223; Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic acid)]. 51634 - 8 EXAMPLE 2 -Hydroxy-5-(l-ethyl-2-pyrrolyi)-2,4,6_(1H,3H,5H)pyrimidinetrione_ Potassium pyrrole [J. Chem. Soc., p. 52 (1931); 1 g.; 0.01 mole] was slurried in 5 ml. of tetrahydrofuran. Ethyl iodide (1 ml., 0.012 mole) was added, a slight exotherm being noted. The mixture was stirred for-0.5 hour, heated to reflux for 0.5 hour, coole,d to room temperature, diluted with 15 ml. of water and extracted with 10 ml. of ether. The ether extract was washed with 5 ml. of water, then added to alloxan hydrate (1.6 g.) which had been dissolved in 25 ml. of ethanol by heating. The ether was boiled off and the ethanolic residue refluxed for 0.5 hour, then evapo— rated to a water-soluble gum. The gum was taken up in ml. of ethyl acetate, washed with two 10 ml. portions of water and re-evaporated to yield title product as a gum (0.6 g., m/e 237). - 9 EXAMPLE 3» -Hydroxy-5-(1-(1-butyl)-2-pyrrolyl)2,4,6-(IB,3B,5H)pyrimidinetrione Potassium pyrrole (3.0 g., 0.03 mole), 1-iodo5 butane (9.2 g., 0.05 moles) and 10 ml. of tetrahydrofuran were combined and refluxed for 1.5 hours by which time the reaction mixture had become a thick mass. The reaction mixture was diluted with 30 ml. of water and » extracted with 35 ml. of ether. The ether was back10 washed with water, then added to a solution of anhydrous alloxan (4.8 g., 0.03 mole) obtained by heating in 50 ml. of ethanol. The ether was distilled away, 6N hydrochloric acid (5 ml., 0.03 raol'e) was added, and the mixture refluxed for 3 minutes, cooled, evaporated to a gum, and triturated with water to afford title product (5.1 g.; m.p. 135 (dec); m/e 265J. - 10 EXAMPLE 4 -Hydroxy-5-(l-phenyl-2-pyrrolyl)-2,4,6_(lH,3H,5H)pyrimidirietri0he’ 1-Phenylpyrrole (1.4 g., 0.01 mole), alloxan 5 hydrate (1.6 g., 0.01 mole) and 50 ml. of ethanol were combined and refluxed for 15 minutes. No reaction was noted by tic. IN Hydrochloric acid (10 ml., 0.01 mole) was added and the acidified mixture refluxed for % minutes. Incomplete reaction was noted by tic. A 10 second portion of alloxan hydrate (1.6 g., 0.01 mole) was added and the mixture refluxed another 15 minutes, cooled and evaporated to dryness. Trituration of the residue with water gave title product [2.3 g.; m/e 285; m.p. 232-234eC. (dec); Rf 0.3 (1:1 ethyl acetate: hexane)].

Anal. Calcd. for C, ,H, .O.N-.0.25H.O: 11 4 3 2 C, 58.01; H, 4.00; N, 14.50. C, 57.84; H, 4.05; N, 14.56.

Found: - 11 EXAMPLE 5 -Hydroxy-5-{1-methy1-3-indolyl)-2,4,6,1H,3H,5H)pyrimidinetrione_ .Alloxan hydrate (1.6 g., 0.01 mole) 1-methylindole 5 (1.3 g., 0.01 mole) and ethanol (50 ml.) were combined and the mixture refluxed for 0.5 hour, then concentrated to half-volume, diluted with water and the resulting product recovered by filtration [2.7 g., Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic acid)].

EXAMPLE 6 -Hydroxy-5-(5-bromo-3-indolyl)-2,4,6(IH,3H,58[pyrimidinetrione Alloxan hydrate (1.6 g., 0.01 mole) was dissolved in 40 ml. of ethanol by heating. 5-Bromoindole (1.96 g., 15 0.01 mole) was added and heating near reflux continued for 15 minutes. Tic did not indicate that reaction had occured. IN Hydrochloric acid (10 ml.) was then added while maintaining the reaction near reflux.

After 10 minutes, the reaction was concentrated to wet 20 solids. Trituration of these wet solids 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)]. 516 6 4 - 12 EXAMPLE 7 -Hydroxy-5-(2-thiazolyl)-2,4,5(1H, 3 H, 5 H)pyrimidinetrione Thiazole (1.7 g., 0.02 mole) was dissolved in 5 tetrahydrofuran (35 ml.) and cooled to -60°C. Butyllithium (9 ml. of 2.4M in hexane, 0.0216 mole) was added dropwise over 20 minutes, and the reaction mixture stirred for an additional 30 minutes at -60°C.

In this manner 2-thiazolyllithium was formed. Anhydrous alloxan (3 g., 0.021 mole) was dissolved in 20 ml. of tetrahydrofuran and added dropwise over 20 minutes, keeping the temperature at -60°C. The stirred reaction mixture was warmed to room temperature over 30 minutes, then recooled to 0°C. IN Hydrochloric acid (25 ml.) was added portion wise and the quenched reaction mixture extracted with 50 ml. of ethyl acetate. The ethyl acetate extract was back-washed with 15 ml. of water, dried over anhydrous sodium sulfate, filtered and evaporated to yield title' product [1.9 g.; m/e 227; Rf 0.4 (1:1 ethyl acetate:hexane/5% acetic acid)].

By the same procedure, oxazole is converted to 5hydroxy-5-(2-oxazolyl)-2,4,6-(IH,3H,5H)pyrimidinetrione. - 15 EXAMPLE12 -Hydroxy-S-{5-methyl-2-furyl)2,4,6(IH,3H,5H)pyrimidinetrione 2-Methylfuran (3.28 g., 3.58 ml., 40 mmoles) was 5 combined with 100 ml. of tetrahydrofuran. The reaction mixture, flushed with nitrogen, was cooled to -30eC. and butyl lithium (19.1 ml. of 2.3M in hexane) was added over a period of 10 minutes, maintaining the temperature at -20 to -30*C. The reaction mixture was warmed to room temperature and then back to -30'C.

Sublimed alloxan (5.96 g.) in 40 ml. of tetrahydrofuran was added dropwise over 10 minutes, keeping the temperature at -20 to -30°C. The reaction mixture was warmed to room temperature, cooled to 0’C. and 50 ml. of IN hydrochloric acid added portionwise, keeping the temperature at 0 to 5’C. The reaction mixture was extracted with 100 ml. of ethyl acetate. The extract was back washed with 25 ml. of water, filtered through a bed of anhydrous magnesium sulfate and evaporated to 20 yield solid 5-hydroxy-5-(5-methyl-2«furvl)-2,4,6(l3,3K,5H)pyrimidinetrione (6.3 g.; m/e 224). - 16 EXAMPLE 13 -Hydroxy-5-(3-thienyl)2,4,6(1H,3H,5H)pyrimidinetrione Isopropyl ether (40 ml.) was cooled to -70’C.

Butyl lithium in hexane (2.4M, 10 ml., 24 mmoles) was added over 10 minutes, keeping the temperature -70° to -60°C. 3-Bromothiophene (1.9 ml., 20 mmoles) was added over 20 minutes, keeping the temperature -72° to -68°C. The mixture was stirred for an additional minutes at -72° to -7Q°C. Sublimed alloxan (3 g., mmoles) in 25 ml. of tetrahydrofuran was added over 40 minutes, keeping the temperature -70° to -65°C.

Stirring at this temperature was continued for.15 minutes. The cooling bath was removed and the reaction mixture stirred for one hour at room temperature, then cooled to 5°C. Hydrochloric acid (IN, 40 ml.) was added slowly, and the organic phase separated. The aqueous phase was extracted with 35 ml. of ethyl acetate. The combined organic phase/extract was washed with 10 ml. of water, dried over anhydrous sodium sulfate and concentrated to yield solid 5-hydroxy-5-(3-thienyI)2,4,6(IH,3H,5H)pyrimidinetrione (1.41 g., 31%; ra/e 226) .

When this reaction was carried out in tetrahydro25 furan with reverse addition of the 3-bromothiophene to butyl lithium, with immediate addition of 0.5 equivalent of alloxan hydrate in place of 1 equivalent of anhydrous alloxan, the product was a mixture of the above trione and 5-(3-bromo-2-thienyl)-5-hydroxy-2,4,6(1H,3H,5H)30 pyrimidinetrione, which in turn was converted to a mixture of 5-(3-bromo-2-thienyl)oxazolidine-2,4-dione and 5-(3-thienyl)oxazolidine-2,4-dione by the method of Example 55 of Patent Application No. - 17 EXAMPLE 14 -(3-Furyl)-5-hydroxy2,4,6(IH,3H,5H)pyrimidinetrione The detailed procedure of Example 13, but substitut5 ing 3-bromofuran (2.94 g., 1.8 ml., 20 mmoles) for the 3-bromothiophene, was employed to produce 5-(3-furyl)5-hydroxy-2,4,6(lH,38,5H)pyrimidinetrione (1.62 g., oil, m/e 210).

EXAMPLE 15 -Hydroxy-5-(3-methoxy-2-thienyl,2,4,6(IH,3H,5H)-pyrimidinetrione 2-Methoxythiophene (2.3 g., 20 mmoles) was dissolved in 35 ml. of ether. With cooling, butyl lithium in hexane (2.4M, 9 ml., 21.6 mmoles) was added dropwise over 15 minutes, the temperature rising as high as 35’C. during this addition. The reaction mixture was stirred for 1 hour at room temperature. While maintaining the temperature between -20° and -15°c., sublimed alloxan (3 g., 21 mmoles) in 20 ml. of tetrahydrofuran was added during 10 minutes. The mixture was warmed to room temperature, stirred for 0.5 hour, cooled to 5’C. and quenched by adding 35 ml. of IN hydrochloric acid in portions. The organic phase was separated and the aqueous phase extracted 25 with 25 ml. of ethyl acetate. The combined organic phase and extract were back-washed with water, concentrated to dryness and triturated with hexane to yield solid 5-hydroxy-5-(5-methoxy-2-thienyl)-2,4,6(IH,3H,5H)pyriraidinetrione (1.4 g., m/e 256).

- Ill EXAMPLE 16 -Hydroxy-5-[5-(2-phenyl-l,3-dioxolan-2-yl)2-thienyl]-2,4,6(IH,3H,5H)-pyrimidinetrione At room temperature, 2-phenyl-2-thienyl-l,35 dioxolane (3.26 g., 14 mmoles) was dissolved in 35 ml. of ether. Butyl lithium in hexane (2.4M, 6.25 ml., mmoles) was added dropwise over 15 minutes, the temperature rising to 33°C. The mixture was stirred for 75 minutes at room temperature and then cooled. 1Θ Maintaining the temperature between -15°C and'-20°C., sublimed alloxan (2.13 g., 15 mmoles) in 20 ml. of tetrahydrofuran was added dropwise over 10 minutes.

The reaction mixture was stirred at room temperature for 30 minutes, cooled to 5°C., quenched with 35 ml. of IN hydrochloric acid, added in small portions, and extracted with 25 ml. of ethyl acetate. The organic layer was back-washed with 15 ml. of water, filtered through a bed of anhydrous sodium sulfate, and evaporated to yield the title compound [oil, Rf 0.25 (1:1 hexane: ethyl acetate/5% acetic acid)] contaminated with starting material (Rf 0.8). - 19 EXAMPLE 17 -Hydroxy-(2,5-Dimethyl-3-furyl)2,4,6(1H,3H,5H)pyrimidinetrione Isopropyl ether (35 ml.) was cooled to -68,’C.

Butyl lithium (5 ml. of 2.1M in hexane, 10.5 mmoles) was added, allowing the temperature to rise to -60*C. 2,5-Dimethyl-3-iodofuran [J. Am. Chem. Soc. 70, p. 739 (1948); 1.2 ml, 9 mmoles] was then added dropwise keeping the temperature between -65 and -68’C.' After stirring for 0.5 hour at -68°C., anhydrous alloxan (1.5 g., 10.6 mmoles) dissolved in 15 ml. of tetrahydrofuran was added dropwise over 30 minutes, keeping the temperature -65 to -60°C. The stirred reaction mixture was warmed over 15 minutes to 0*C., IN hydro15 chloric acid (25 ml.) was added and the organic phase' separated. The aqueous phase was extracted with 20 ml. of ethyl acetate. The combined organic layers were washed with 10 ml. of water and evaporated to yield title product (1 g., Rf 0.05 (1:5 ethyl acetate: hexane/5% acetic acid)]. 51664· - 20 EXAMPLE 18 S-Hydrcxy-5-(4-iodo-3-furyl)2,4,6(1H,3H,5H)pyrimidinetrione 3,4-Diiodofuran (0.96 g., 3 mmoles) in 5 ml. of 5 ether was added slowly to a cold (-65°C.) solution of butyl lithium (2 ml. of 2.3M in hexane, 4.6 mmoles) in 15 ml. of ether. The mixture was stirred for 20 minutes at -65°C. Anhydrous alloxan (0.57 g., 4 mingles) was dissolved in 10 ml. of tetrahydrofuran and added slowly to the 4-iodo-3-furyl 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 IN hydrochloric acid and extracted with ether. The ether extract was back-washed with 10 ml. of water, concentrated to dryness and the residue triturated with 2 ml. of hexane to yield title product [108 mg.; m/e 336; R^ 0.5 (1:1 ethyl acetate:hexane/5% acetic acid)1. - 21 The following Preparations illustrate the preparation of certain starting materials:PREPARATION1 3-Iodofuran 3-Bromofuran (14.7 g., 0.1 mole) in 100 ml. of ether was cooled to -70eC. Butyl lithium (42 ml. of 2.4M, 0.1 mole) in hexane was added dropwise over 0.5 hour, maintaining the temperature from -70· to -65*C. Iodine (25 g., 0.1 mole) in 200 ml. of ether was then added over 1 hour maintaining the same temperature range. The reaction mixture was warmed to room temperature and then back to 2’C. Water (100 ml.) was added dropwise. The ether layer was separated, washed with agueous thiosulfate and then water, dried over anhydrous sodium sulfate, evaporated to an oil and distilled to yield 3-iodofuran (15.7 g., b.p. 48·/28 ram.).

PREPARATION 2 3-Methoxyfuran Sodium metal (5.6 g., 0.24 mole) was dissolved in 150 ml. of dry methanol. 3-Iodofuran (15.7 g., 0.08 mole) and cuprous oxide (8 g., 0.1 mole) were added and the mixture was refluxed with vigorous stirring for 42 hours. The reaction mixture was cooled to room temperature, diluted with 200 ml. of water, and product extracted into 100 ml. of ether.

The ether extract was back-washed with 15 ml. of water, dried over anhydrous sodium sulfate and evaporated to yield crude 3-methoxyfuran (approximately 3-4 g. of approximately 50% purity) suitable for further processing. - 22 PREPARATION 3 2-Phenylfuran Aniline (46.5 g., 0.5 mole) was combined with 500 ml. of water and 100 ml. of concentrated hydro5 chloric acid and cooled to -5°C. Sodium nitrite (36.2 g., 0.525 mole) in 100 ml. of water was added dropwise over 45 minutes, keeping the temperature -3° to -5°C. After addition was complete, the mixture was stirred for 30 minutes at -5°C., and zinc chloride (68 g.) was added. Maximal precipitation of the diazonium salt was obtained by the addition of 100 g. of sodium chloride. The mixture was stirred for 5 minutes, with the cooling bath removed and cautiously filtered, without wash, and air dried for 2 hours.

(Previous vacuum drying of this product led to explosive decomposition). The intermediate diazonium salt was suspended in 750 ml. of furan at O’C. With vigorous stirring, powdered sodium hydroxide (5 g.) was added, followed by anhydrous sodium acetate (10 g.). The reaction mixture was stirred for 5 hours at O’C. and then for 16 hours at room temperature. Solids were removed by filtration and the filtrate evaporated to crude product (25 ml. of oil). Distillation afforded 2-phenylfuran (9.2-9.6 g., b.p. 87-95’/15 mm., b.p. 50’/l mm.). - 23 PREPARATION 4, 2-Phenyl-2-(2-thienyl)-1,3-dioxolane 2-Benzoylthiophene (19 g., 0.1 mole), ethylene glycol (11 ml., 0.2 mole), toluene (150 ml.) and p5 toluenesulfonic aoid (about 0.2 g.) were combined and refluxed for 6 hours. By-product water was collected in a Dean-Stark trap. Tic (1:8 ethyl acetate:hexane) indicated reaction to be about 40% complete. More ethylene glycol (30 ml.) was added and reflux con10 tinued for 35 hours. Reaction was still incomplete..

The reaction mixture was diluted with 200 ml. of ether, washed twice with 150 ral. portions of water and concentrated to dryness. The residue was chromatographed on about 500 ml. of silica gel, with 1:8 ethyl acetate:hexane as eluant, monitored by tic. Faster moving, product containing fractions were combined and evaporated to yield 2-phenyl-2-(2-thienyl)-l,3-dioxolane [8 g., oil, Rf 0.6 (1:8 ethyl acetate:hexane)].

Claims (1)

1. CLAIM:

1. A compound of the formula I R wherein R' is (C^-C^)alkyl or phenyl, R is hydrogen, (C^-C^)alkyl or phenyl and X is halo; 10 wherein Y is hydrogen or (C^-C^) alkoxy, Y' is hydrogen or (C.,-C^) a Iky 1 and Y is hydrogen or halo; (c) wherein Z' is hydrogen, halo or (C^-C^) alkoxy and Z is hydrogen or halo; (d) - 25 Vn wherein W is hydrogen or halo, and n is 1 or 2; V (e) .λ or wherein Q is sulfur or oxygen and V is hydrogen or 5 (Cj^-Cj) alkyl; wherein Q is sulfur or oxygen; and V is hydrogen or alkyl; (9) or 10 wherein Y is sulfur or oxygen; X is hydrogen, halo, methyl, phenyl, benzoyl or (C^-Cj)alkoxy; X 1 is hydrogen or methyl; and X 2 is hydrogen or halo; or (h) 5-(2-phenyl-l,3-dioxolan-2-yl)thien-2-yl; 1 4 with the proviso that when R is as defined in (h), R is 15 hydrogen.