IE51663B1 - Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones - Google Patents

Description

This application is a divisional from Patent Specification No. 516 62.

It relates to certain intermediates useful in the preparation of the hypoglycemic 5-substituted-oxazolidi: 2,4-diones claimed in Patent Specification Ho. $166 2 These intermediates have the formula wherein R1 is (C^-C^)alkyl or phenyl, R is hydrogen, (C^-C^)alkyl or phenyl and X is halo; ~ (to) Y' wherein Y is hydrogen or (C^-C^)alkoxy, Y' is hydrogen or (C^-C4)alkyl and Y is hydrogen or halo; (c) -3wherein 2' is hydrogen, halo or (Cg-Cg)alkoxy and Z is hydrogen or halo; wherein W is hydrogen or halo, and n is 1 or 2; wherein 0 is sulfur or oxygen and V is hydrogen or (Cj-Cj)alkyl; (f) V, wherein Q is sulfur or oxygen; and V is hydrogen or (Cg-Cg)alkyl; or (g, X wherein Y is sulfur or oxygen; X is hydrogen, halo, methyl,phenyl, benzoyl or (Cg-Cg)alkoxy; X1 is hydrogen or methyl; and X2 is hydrogen or halo; R2 is (Cg-Cg alkyl); and ϋ* is hydrogen, lower alkanoyl or benzoyl. -4These intermediates can be prepared as described in the following Examples and Preparations. They can be converted to the hypoglycemic oxazolidin-2,4-diones as described in the said Patent Specification No. 51662. -5EXAMPLE 1 Methyl 2-Methoxypyridine-3-carboxylate Thionyl chloride (50 ml.) was added to 2-methoxypyridine-3-carboxylic acid (5 g.) in 50 ml. of carbon 5 tetrachloride and the mixture refluxed for 2 hours.

The reaction mixture was cooled, evaporated to solids and chased with multiple portions of fresh carbon tetrachloride. The resulting acid chloride hydrochloride was dissolved in excess methanol (50 ml.), stirred for 16 hours at room temperature, then evaporated an oil and taken up in chloroform. The chloroform solution was washed with two portions of saturated sodium bicarbonate and then one portion of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an .oil (4.63 g.; pnmr/CDClj/delta (ppm): 3.9 and 4.1 (2s, 6H), 6.9 (m, IH), 8.2 (ra, 2H)] .

By the same procedure, 4-methylpyridine-3-carboxylic acid is converted to methyl 4-methylpyridine-3-carboxy20 late. -6EXAMPLE 2 3-Methanesulfinylmethylcarbonyl-2-Methoxypyridine Sodium hydride {2.69 g., 50% dispersion in oil, 0.056 mole) was washed three times with petroleum ether. Following the third decantation, traces of petroleum ether were removed by evaporation in vacuo. Dimethylsulfoxide (30 ml.) was added and the mixture heated in an oil bath at 75°C. for 45 minutes,· by which time hydrogen evolution had ceased. The mixture was cooled in an ice-water bath and diluted with ml. of dry tetrahydrofuran. Title compound of the preceding Example (4.63 g., 0.028 mole) in 10 ml. of dry tetrahydrofuran was added dropwise over 5 minutes. The reaction mixture was warmed and stirred at room IS temperature for 30 minutes, poured into 180 ml. of water, acidified to pH 4 with IN hydrochloric acid and extracted with three portions of chloroform. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to yield title product as an oil [4.97 g.; pnmr/CDClj/delta (ppm); 2.8 (s, 3H), 4.1 (s, 3H), 4.4 and 4.7 (2d, 2H), 7.0 (m, 1H),.8.3 (m, 2H)J.

By the same procedure the 4-methyl compound of the preceding Example is converted to 3-methanesulfinyl methylcarbonyl-4-methylpyridine. -7EXAMPLE 3 S-Methyl 2-Acetoxy-2-(2-methoxy-3-pyridyl) thioacetate Title compound of the preceding Example (3.97 g.), sodium acetate (3.97 g.) and acetic anhydride (40 ml.) were combined in 80 ml. of toluene and heated at 115° for 16 hours. The mixture was cooled and evaporated to dryness in vacuo to yield crude product. The latter was chromatographed on 200 g. of silica gel with 2:1 chloroform:ethyl acetate as eluant, tic monitoring and collecting 10 ml. fractions. Clean product fractions 58-79 were combined and concentrated to an oil. To remove possible traces of residual acetic anhydride, the oil was taken into wet ethanol, held for 15 minutes, re-evaporated, chased with toluene, taken up in chloroform, dried over anhydr.ous magnesium sulfate, filtered, and re-evaporated to yield the title product as an oil, (3.16 g.; Rf 0.60 (3:1 ethyl acetate: methanol); m/e 255; ir (CH^Clj) 1748, 1686, 1582, 1460, 1205 cm-1].

By the same procedure the methyl compound of the preceding Example is converted to S-methyl 2-acetoxy2-(4-methyl-3-pyridyl) thioacetate. -8EXAMPLE 4 Ethyl 2-Bthoxypyridine-3-carboxylate 2-Ethoxypyridine-3-carboxylic acid (4 g.) was converted to its acid chloride hydrochloride by reflux5 ing with 8.6 ml. of thionyl chloride for 60 minutes.

The reaction mixture was evaporated to solids with toluene chase to removed the excess thionyl chloride.

The residue was taken into 80 ml. of ethanol and held for 16 hours at 0°C., then evaporated to solids, which were partitioned between toluene and IN sodium hydroxide. The aqueous layer was extracted with fresh toluene and the two organic layers combined, washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [3.2 g.; pnmr/CDCl^/delta (ppm) 1.6 f2s, 6H,, 4.45.0 (2q, 4H), 7.2 and 8.2 (m, 3H)].

EXAMPLE 5 2-Ethoxy-3-methanesulfinylmethyl _carbonylpyridine_ Using methylene chloride in place of chloroform 5 in the isolation, the procedure of Example 2 was employed to convert product of the preceding Example (3.0 g.) to title product (2,63 g.; m.p. 89-91°C.; pnmr/CDC13/delta (ppm), 1.5 (t, 3H), 2.8 (s, 3H), 4.24.8 (s and g, 4H), 6.8-7.1 and 8.0-8.4 (3H1J.

EXAMPLE 6 S^Methyl 2-Acetoxy-2-(2-ethoxy-3-pyridyl)_thioacetate_ Using a reaction time of 4 hours at 100°C. and then 48 hours at room temperature, the procedure of Example 3 was employed to convert the product of the preceding Example (2.5 g.) to crude product, isolated as an oil by evaporation of the reaction mixture. The oil was taken up in ethyl acetate, washed in sequence with three portions of IN sodium hydroxide, one of water and one of brine, dried over anhydrous magnesium sulfate and evaporated to yield title product as an oil [2.96 g.; Rf 0.78 (10:1 ethyl acetatezmethanol); m/e 269]. -10EXAMPLE 7 Methyl 5-Chloro-2-methoxypyridine-3-, carboxylate By the procedure of Example 1, 5-chloro-25 methoxypyridine-3-carboxylic acid [Sarges et al., J.

Med. Chem. 19, 709 (1976); 10 g.) was converted to its acid chloride, which was added in one portion to 150 ml. of methanol (slight exotherm), then made basic with triethylamine (approximately 1.1 equivalents).

The reaction mixture was evaporated to solids and the residue partitioned between ethyl acetate and water.

The ethyl acetate layer was washed with fresh water and then brine, dried over anhydrous magnesium sulfate, filtered 'and evaporated to yield title product [9.75 g., m.p. 79-81’C.; pnmr/CDClg/deita (ppm) 3.8 (s, 3H) , 4.1 (s, 3H), 8.1 (d, IH), 8.3 (d, IH)].

EXAMPLE 8 S-Chloro-S-methanesulfinylmethylcarbonyl_2 -methoxypyridine_ By the procedure of Example 2, the product of the preceding Example (9.7 g., 0.045 mole) was converted to title product isolated as a visous oil (10.3 g., m/e 249/247). -1> EXAMPLE 9 S-Methyl 2-Acetoxy-2-(5-chloro-2-methoxy-3_pyridyl) thioacetate_ Using a reaction time of 19 hours at 100°C-, the 5 procedure of Example 3 and the isolation method of Example 6 were employed to convert product of the preceding Example (10.3 g.) to title product in the form of a viscous oil (8.8 g.; pnmr/CDCl3 includes singlet at 6.4? ra/e 291/289). -12PREPARATION 1 2-Ethoxy-3-pyridinecarboxylic Acid Sodium ethoxide was prepared by adding sodium (1.4 g., 0.06 mole) portion wise to 50 ml. of anhydrous 5 ethanol. The solution was diluted with 20 ml. of ethanol and 4.5 g. of 2-chloropyridine-3-carboxylic was added. The reaction mixture was heated in a steel pressure vessel at 170®C. for 6 hours. The vessel was cooled and the contents evaporated to dryness in vacuo.

The residue was taken up in 150 ml. of water and acidified to constant pH 4.5. The water solution was saturated with salt and extracted with four portions of ethyl acetate. The combined ethyl acetate layers were back washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product (4.33 g., m.p. 85-88°C.). 13PREPARATION 2 2-Methoxy-3-pyridinecarboxylic Acid A stainless steel stirred autoclave was charged sequentially with methanol (2.8 1.), sodium methoxide 5 (259 g.) (in portions, keeping the temperature less than 35°C.), and 2-chloro-3-pyridinecarboxylic acid (190 g.). The autoclave was sealed and the reaction mixture heated at 110’C. (50 psig) for 48 hours. The reaction mixture was cooled to 25°C. and discharged from the autoclave. Solids were recovered by filtration. Concentration of the filtrate gave a second crop. These process steps were repeated until virtually all of the methanol had been removed. The several crops of solids were combined, taken up in 2.5 liters of water and acidified with cone, hydrochloric acid to pH 2.7 keeping the temperature below 2O’d. The precipitated product was granulated for 30 minutes at 15’C. and recovered by’filtration (141 g.). Purified title product was obtained by reerystallization from ethyl acetate-hexane (120.5 g., m.p. 148-150eC.).

Claims (1)

1. CLAIM

1. A compound of the formula wherein R' is (C 1 ~C 4 )alkyl or phenyl, R” is hydrogen, (C 1 -C 4 )alkyl or phenyl and X is halo; Y* Y(b) wherein Y is hydrogen or (C^-Cj)alkoxy, Y' is hydrogen or (C 1 ~C 4 )alkyl and Y is hydrogen or halo; (c) -15wherein Z* is hydrogen, halo or (C^-CjJalkoxy and Z is hydrogen or halo; wherein W is hydrogen or halo, and n is 1 or 2; wherein Q is sulfur or oxygen and V is hydrogen or ) alkyl; (f) V wherein Q is sulfur or oxygen; and V is hydrogen or (03-03)alkyl; or or wherein Y is sulfur or oxygen; X is hydrogen, halo, methyl,phenyl, benzoyl or (C.-C.)alkoxy; x 3 is hydrogen 2 1 J or methyl; and X is hydrogen or halo; R 2 is (Ct-C, alkyl); 4 x j and R is hydrogen, lower alkanoyl or benzoyl.