NO771021L - PROCEDURES FOR THE PREPARATION OF ANTIHYPERTENSIVE 1-TERT.-ALKYL-3- (SUBSTITUTED FURYL) -UREA DERIVATIVES - Google Patents

Abstract

Process for the preparation of anti-. hypertensive 1-tert-alkyl-3- (substituted furyl) urea compounds

Description

The present invention relates to a process for the production of 1-tert.-alkyl-3-(substituted furyl)-ureas.

In US patent 3,969,370 of 13 July 1976, these antihypertensive ureas are described, as well as one method for their production. This method involves heating equimolar amounts of a tertiary alkylurea and a 2,4-furandione in benzene or other suitable solvent with the possibility of water removal, such as in a Dean-Stark water separator, in the presence of a catalytic amount of a strong acid .

Isolation and purification of the furandion intermediates by this method is trivial and inefficient due to their thermal instability and water solubility. Isolation and purification of tertiary alkyl-3-(substituted furyl)ureas is also difficult due to the presence of impurities.

According to the invention, there is provided a method for producing compounds of formula I in significantly higher yields than with the known methods. In addition, the problem with the furandion intermediates is avoided by converting these into stable, easily isolated phenylhydrazine derivatives, which derivatives are new compounds. Furthermore, isolation and purification of the end products is easy due to fewer contaminants.

where

R 1 = H or C 1 -C 4 alkyl,

R 2 = H or CH 3 , provided that one of R 2 or R 2 must be H,

R-> = tert-butyl or tert-amyl,

The kari procedure is schematically illustrated as follows:

where R = H or C,-C. alkyl,

1

R 2 = H or CH 3 , provided that one of R 2 or R 2 must

be H,

R^= tert-butyl or tert-amyl,

X and Y = are independently equal to H, methyl, ethyl, tri-fluoromethyl,

phenyl, F, Cl,. Br, NO 2 , -OCH 3 or -COOH or esters thereof.

The process starts with the reaction of a suitable substituted 2,4-furandione (tetronic acid) (A) with phenylhydrazine or substituted phenylhydrazine (B) to form .(4-( 2-phenylhydrazino) - 2(5H) -furanone (C). The compounds of formula C are novel. The compounds of C are then cleaved by catalytic hydrogenation to form 4-amino-2-(5H)-furanone (D).

The 4-amino-2-(5H)-furanones (D) are not basic, organic amines, but vinyl-like amides which are neutral. Therefore, the compounds of D cannot be converted into compounds of formula I under the usual conditions described! the literature [cf. Synthetic Methods of Organic Chemistry, by W. Theilheimer, vol. 18, page 241 (no. 544), ibid., vol. II, page 113 (no. 323)], namely through a tertiary alkyl isocyanate with or without catalysts with a tertiary alkyl amine , e.g. triethylamine. However, it has been found that sufficiently strong bases convert the vinyl-like amides A into salts (in a similar way as primary amides can be converted into salts), which readily react with tertiary alkyl isocyanates to form compounds of formula I. Examples of strong bases are potassium tert-butoxide, sodium hydride, sodium methoxyd, lithium N-isopropyl-cyclohexylamine, trityl sodium etc. It is desirable that the by-product from the reaction between the strong base and the compound of formula D is not reactive towards tertiary alkyl isocyanate, and in this respect sodium methoxyd less preferred than the other bases due to the formation of methanol which competitively reacts with the salt of compound D for isocyanate.

A preferred catalyst for the hydrogenation step is Raney nickel which provides rapid and complete reductive cleavage of the hydrazine group. Other catalysts such as palladium on bone charcoal can be used, but are often slower and may require regulation of the medium to be effective.

Phenylhydrazine is usually preferred over substituted hydrazines, because of its availability and because it does not lead to any complications, in the reductive cleavage step: e.g. p-chlorophenylhydrazine leads to aryl chloride cleavage with formation of subsequent very troublesome nickel salts.

The following examples illustrate the invention. All parts are by weight, and temperatures in degrees Celsius unless otherwise stated.

Example 1 N-(2,5-dihydro-2-methyl-5-oxo-3-furanyl)-N'-(1,1-dimethylethyl)urea

A. 5- methyl- 4-( 2- phenylhydrazino)- 2( 5H)- furanone

To a stirred solution of 200 g (1.39 mol) of ethyl propionyl acetate in 500 ml of CH 2 Cl 2 cooled in an ice bath, 222 g (1.39 mol) of bromine were added dropwise. The mixture was allowed to warm to room temperature and was stirred in the presence of air for 16 hours. The solution was poured into ice water. The organic layer was separated, dried (MgSO 4 ), and evaporated to give ethyl 4-bromopropionylacetate.

The 4-bromopropionyl acetate was dropped into 1 liter of a stirred, cold (-10 to 0°C) 2.5N potassium hydroxide solution. The mixture was stirred at this temperature for 3 hours, and then poured into a mixture of ice and 500 ml of 6N hydrochloric acid so that the temperature did not exceed 0°C. '[The resulting solution contained 5-methyl-2,4-furandione which can be isolated by repeated extraction with large volumes of ether. The ether solution is then evaporated, and the residue is recrystallized twice from its volume of isopropyl acetate (cooled to -10°C) to give a 20% yield of 5-methyl-2,4-furandione, mp 120.5 - 122°C. The pure 5-methyl-2,4-furandione can then be treated with phenylhydrazine as described in Example 3. This isolation procedure is trivial and requires the use of large volumes of a highly flammable solvent, giving -lower total yields of 5-methyl -4-(2-phenylhydrazino)-2(5H)-furanone than by the in situ procedure described here].

150 g is added to the above-mentioned solution

(1.39 moles) of phenylhydrazine. The mixture is stirred at room temperature for 16 hours and then cooled to 0°. The solid material is filtered off, washed (water) and dried. The solid material is stirred for 5 - 10

minutes with hot toluene and allowed to cool to room temperature. The orange crystals were filtered off and first washed with

cold toluene, then with pentane to give 127 g (45% overall yield) of 5-methyl-4-(2-phenylhydrazino)-2(5H)-furanone, m.p. 147 - 149°C (decomposition). The compound is dimorphic, and occasionally exhibits a melting point of 158 - 160°C (decomposition).

Analysis for C11<H>12<N>2°2<:><B>ere9net: c 64.68; H 5.93; N 13.72

Found: C 64.56; H 5.91; N 13.41

B. 4-amino-5-methyl-2(5H)-furanone

A mixture of 51.0 g (0.25 mol) 5-methyl-4-(2-phenyl-hydrazino)-2(5H)-furanone, 200 ml alcohol and 2 teaspoons Raney nickel was hydrogenated in a shaking apparatus with an initial pressure" of 3 atm until uptake was complete (typically 16 - 60 hours). The catalyst was filtered off and the filtrate was evaporated to remove alcohol. The residue was triturated with ether to form crystals. The crystals were filtered off, washed and dried to give 25.0 g (88%) of 4-amino-5-methyl-2(5H)-furanone, mp 150-152°C.

C. N-(2,5-dihydro-2-methyl-5-oxo-3-furanyl)-N'-(1,1-dimethylethyl)-urea ' ' • ■-

(1) To a stirred solution of 77.9 g (0.69 mol) of 4-amino-5-methyl-2(5H)-furanone in 1400 ml of wax-free tetrahydrofuran was added 105.0 g (0.93 mol) of potassium tert.-butoxyd. Then 75.0 g (0.76 mol) tert-butyl isocyanate was rapidly added dropwise while the temperature was maintained at approx. 25°C. The mixture was stirred for 2 hours. Then 90 ml of glacial acetic acid was added dropwise while the temperature was kept at 25°C. 1150 ml of water was added and the tetrahydrofuran was removed by evaporation. The solid was filtered off, washed (water), dried and recrystallized from 900 mL acetonitrile to give 73.9 g (50% yield) N-(2,5-dihydro-2-methyl-5-oxo-3- f uranyl)-N"-(1,1-dimethylethyl)-urea, with m.p_. 204 - 206°C (decomposition). (2) To a stirred mixture of 0.24 g (0.006 mol) 56%' s sodium hydride in mineral oil, 20 ml anhydrous tetrahydrofuran and 1.1 g (0.01 mol) 4-amino-5-methyl-2(5H)-furanone was added 1.0 g (0.01 mol) tert-butyl isocyanate . The mixture was stirred at ambient temperature for 4 hours. Then 1 ml of glacial acetic acid was added. The mixture was poured into water. The precipitate was filtered off, washed (water), dried and recrystallized from acetonitrile to give 0.55 g (47 %) N-(2,5-dihydro-2-methyl-5-oxo-furanyl)-N'-(1,1-dimethyl)-urea, with mp 207 - 208°C (decomposition). IR the spectrum was identical to the spectrum of the urea compound obtained in part (1). (3) Using 0.6 g (0.11 mol) of sodium methoxide in place of sodium hydride in C(2) gives 0.5 g of impure N-(2, 5th hydro-2-methyl-5-oxo-3-furanyl)-N"-(1,1-dimethyl)-urea, m.p. 196 - 198°C (decomposition). The IR spectrum was identical to the spectrum of the urea compound obtained in part (1).

Example 2 N-(2,5-dihydro-2-methyl-5-oxo-3-furanyl)-N'-1,1-dimethylprdipyl)-urea

The procedure of Example 1C (1) was followed using tert-amyl isocyanate instead of tert-butyl isocyanate to form N-(2,5-dihydro-2-methyl-5-oxo-3-furanyl)- N'-(1,1-dimethylpropyl)-urea, with m.p. 140 - 141°C.

Analysis for cnH18^2°3: Calculated: C 58.39; H 8.02; N 12.38

Found-: C 58.51; H 8.09; N 12.35

Example 3 N-(2,5-dihydro-2-ethyl-5-oxo-3-furanyl)-N'-(1,1-dimethylethyl)-urea

Ai 5- ethyl- 4-( 2- phenylhydrazino)- 2-( 5H)- furanone

To a stirred solution of 35.6 g (0.33 mol) of phenylhydrazine and 90 ml of glacial acetic acid in 150 ml of ethanol and 360 ml of water was added 38.4 g (0.3 mol) of 5-ethyl-2,4-furandione. The mixture was heated at reflux for 30 minutes and then allowed to cool to room temperature. The mixture was evaporated until the alcohol was removed. The yellow crystals were filtered from the aqueous mixture to give 50.8 g (78%) of 5-ethyl-4-(2-phenylhydrazino)-2-(5H)furanone, m.p. 181 - 182°C. The same product is obtained by starting with an impure solution of 5-ethyl-2,4-furandione obtained analogously to example IA.

B. 4-amino-5-ethyl-2(5H)-furanone

A mixture of 21.8 g (0.1 mol) of 5-ethyl-4-(2-phenylhydrazino)-2(5H)-furanone, 200 ml of alcohol and 2 teaspoons of Raney nickel was hydrogenated in a shaking apparatus at a initial pressure of 3 atm until absorption was complete (approx. 16 hours). The catalyst was filtered off and the filtrate was evaporated to remove alcohol. The residue was triturated with ether to form crystals. The crystals were filtered off, washed and dried to give 9.3 g (73%) of 4-amino-5-ethyl-2(5H)-furanone, m.p. 143.145.5°C.

Analysis for C6HgN02: Calculated: C 56.68;. H 7.14; N 11.02

Found: C 56.85; H 6.46; N 11.20

C. N-(2,5-dihydro-2-ethyl-5-oxo-3-furanyl)-N'-(1,1-dimethylethyl)-urea

The reaction is carried out as described in example 1C with the exception that 4-amino-5-ethyl-2(5H)-furanone is used instead of 4-amino-5-methyl-2(5H)-furanone. There is obtained N-(2,5-dihydro-2-ethyl-5-oxo-3-furanyl)-N<1->(1,1-dimethylethyl)-urea, with m.p. 142-144°C.

Example 4 N-(2,5-dihydrob-4-methyl-5-oxo-3-furanyl)-N<1->(1,1-dimethylethyl)urea

A. 3- methyl- 4-( 2- phenylhydrazino)- 2-( 5H)- furanone

The procedure according to example 3A is followed using 3-methyl-2,4-furandione. There is obtained 3-methyl-4-(2-phenyl-hydrazino)-2-(5H)-furanone, with m.p. 201 - 202°C.

Analysis for cnHi2N2°2: Calculated: c 64.69; H 5.92; N 13.72

Found: C 64.89; H 5.72; N 13.76

B. 4-amino-3-methyl-2-(5H)-furanone

(1) The procedure' according to example 3B is followed using 3-methyl-4-(2-phenylhydrazino)-3-(5H)-furanone. There is obtained 4-amino-3-methyl-2-(5H)-furanone, with m.p. 215 216°C.

Analysis for C5H7N02: Calculated: C 53.09; H 6.24; N 12.39;

Found: C 53.24; H 6.21; N 12.00

(2) A mixture of 7.2 g (0.035 mol) 3-methyl-4-(2-phenylhydrazino)-2-(5H)-furanone, 200 ml alcohol, 5 ml concentrated hydrochloric acid and 0.5 g 10 %'s palladium on bone charcoal is hydrogenated in a Parr shaking apparatus with an initial pressure of 3 atm 20 hours. (There is no observable absorption of hydrogen after .2 hours when hydrochloric acid

is omitted. The catalyst is removed by filtration, and the filtrate is evaporated. The residue is dissolved in a little water. The solution is cooled in an ice bath during the formation of crystals, with m.p. 180 - 200°C. Chromatography on 100 - 200 mesh silica gel with 60:20:20 tolueneethyl acetate-methanol gives a fraction that can be recrystallized from aceto-

nitrile. The crystals (0.5 g) melt at 214 - 215°C.

C. N-(2,5-dihydro-4-methyl-5-oxo-3-furanyl)-N'-(1,1-dimethylethyl) urea •

The procedure according to example 1C is followed using 4-amino-3-methyl-2-(5H)-furanone. There is obtained N-(2,5-dihydro-4-methyl-5-oxo-3-furanyl)-N'-(1,1-dimethylethyl)urea, with m.p. 244°C (decomposition).

Analysis for: C10H16N2°3: Calculated: C 56.59; H 7.60; N 13.20

Found: C 56 . 58; 7 . 47; N 12 . 98

Example 5 N-(2,5-dihydro-4-methyl-5-oxo-3-furanyl)-N1-(1,1-dimethylethyl)urea

A. 3- methyl- 4-( 2- p- chlorophenylhydrazino)- 2-( 5H)- furanone

To a stirred mixture of 19.7 g (0.11 mol) p_-chlorophenyl-. hydrazine hydrochloride, 15.0 g (0.11 mol) sodium acetate trihydrate,

11.4 g (0.1 mol) of 3-methyl-2,4-furandione are added to 120 ml of water, 50 ml of alcohol and 30 ml of glacial acetic acid. The mixture is boiled under reflux for 30 minutes and then cooled to room temperature. The mixture is evaporated to remove the alcohol, whereupon a yellow solid separates. The solid material is filtered off, washed with water and dried to form 9.5 g of a yellow solid material. Recrystallization from toluene affords 18.5 g (85% yield) .3-methyl-4-(2-p_-chlorophenylhydrazino)-2-(5H)-furanone, m.p. 152 - 154.5°C.

Analysis for c1iH11clN2°2: Calculated: C 55.35; H 4.65; N 11.74

Found: C 55.46; H 4.53; N 11.71

B. 4-amine6-3-methyl-2-(5H)-furanone

3-methyl-4-(2-β-chlorophenylhydrazino)-2-(5H)-furanone is hydrogenated analogously to 3-methyl-4-(2-phenylhydrazino)-2-(5H)-furanone as described in example 4B .4-amino-3-methyl-2-(5H)-furanone can then be converted to N-(2,5-dihydro-4-methyl-5-oxo-3-furanyl)-N<1->(1, 1-dimethylethylurea as described in Example 4C.

Claims (4)

1. Procedure for the preparation of compounds of the formula: ,- ' • - ^ • • -.... _ ■ where R 1 = H or C 1 -C 4 alkyl; R 2 = H or CH 3 , provided that one of R x or R 2 must be H; R3 = tert-butyl or tert-amyl; characterized in that a compound of the formula: reacted with a compound of the formula: in the presence of a strong base. 2. Connection of the formula: where Rx = H or C₁ -C₁ alkyl; R 2 = H or CH 3 , provided that one of R 2 or R 2 must be H; X and Y. are independent = H, methyl, ethyl, trifluoromethyl, phenyl, F, Cl, Br, NO 2 , -OCH 3 or -COOH or esters thereof. 3. Method according to claim 2, characterized in that X and Y = H. 4. Connection of the formula: where Itj^ = H or C^-C^ alkyl; R2 = H or CH3, provided that one of or R2 must be H.