IE44844B1 - Substituted tetrahydrofuran-2-ones - Google Patents

Description

This invention relates to certain novel substituted tetrahydrofuran-2-ones, and their preparation.

Compounds according to the invention have the formula: CaH5.

CHgNHR Formula 1 wherein R represents lower alkyl, lower cycloalkyl or phenyl lower alkyl.

The term lower alkyl as used herein means a straight or branched chain alkyl radical of up to six carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, amyl, hexyl and isohexyl.

The term lower cycloalkyl as used herein means cycloalkyl radicals having from four to eight carbon atoms inclusive, namely cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cyclopentyl and cyclohexyl are preferred lower cycloalkyl radicals.

Examples of the term phenyl lower alkyl as used herein are benzyl, phenethyl, phenpropyl and a-methylbenzyl.

The 4,5-dihydro-3,3-diphenyl-4-hydrocarbylaminomethylfuran-2(3K)ones of Formula I are useful as precursors for l-hydrocarbyl-3,3-diphenyl-4-hydroxymethyl-2-pyrrolidinones which are the subject of our Application No. 2085/76 (Specification No. 44843 ) from which the present application has been divided. Also the compounds of the present invention form fluosilicic acid addition salts which are 8 4 useful as mothproofing agents.

The compounds of Formula I may be prepared by the following procedure: R-^^>-C( Cells )SCN (II) %SO4(dil) CHsNHR * c6H5_l__^cHsira: (I) wherein R is as defined above.

According to this procedure an α,a-diphenyl-a(l-hydrocarbyl-3-azetidinyl)acetonitrile II is reacted with dilute sulphuric acid (e.g. 70% by weight sulphuric acid) resulting in the formation of the 4,5-dihydrofuran-2 . (3H)one ring I. The reaction may be carried out with the application of heat, e.g. at a temperature of from about 110°C to about 140°C. for an extended period, e.g. of from about 35 hours to about 60 hours. The product compound I can be obtained from the reaction mixture by various methods but is preferably isolated by pouring the acidic reaction mixture onto ice, separation of the aqueous-organic layers, acid-base extraction of the organic layer and recrystallization of the product from a suitable solvent.

The a,a-diphenyl-ct-(l-hydrocarbyl-3-azetidinyl) acetonitriles II may be prepared from l-hydrocarbyl-3azetidinols by the following procedure: -> R-N CN R- I- + (CeHs)aC M .c(ce%)2cNr (IV) (III) (II) -'3 wherein R is as defined above, Z is a lower alkylsulphonyloxy radical, an arylsulphonyloxy radical or a halide radical, preferably chloride, and M+is an alkali metal cation, preferably sodium or potassium According to this procedure an alkyl or aryl sulphonate ester III or an azetidinyl halide III is prepared by methods known to the art. The alkali metal salt of diphenylacetonitrile is prepared in a similar solvent by reacting diphenylacetonitrile with an alkali metal hydride or an alkali metal amide. The sodium and potassium metal hydrides and amides are preferred.

The solution of the alkyl or aryl sulphonate ester or the azetidinyl halide is then reacted with the alkali metal salt of diphenylacetonitrile at an elevated temperature, preferably at the reflux temperature of the organic solvent used. The a,a-diphenyl-a-(l-hydrocarbyl-3azetidinyl)acetonitrile II thus prepared is isolated from the reaction mixture by known procedures and further purified by crystallization from a suitable solvent or solvents.

The l-hydrocarbyl-3-azetidinols are known compounds or they can be prepared as described by V.R. Gaertner, Tetrahedron Letters No. 39, pages 4691—4 (1966), by Okutani et al, Chem. Pharm. Bull. 22 (7) 1490—7 (1974), or by procedures disclosed in U.S. Patent 3668196.

The a,a-diphenyl-a~(l-hydrocarbyl-3-azetidinyl)acetonitriles of Formula II as well as the a,a-diphenyl-a(l-hydrocarbyl-3-azetidinyl)acetamides prepared from them by partial hydrolysis in concentrated sulphuric acid have antiarrhythmic properties.

The following Preparations and Examples illustrate the invention. 448 44 Preparation 1 a,α-Diphenyl-0:-(l-isopropyl-5-azetidinyl)acetonitrile.

A mixture of 168 g. (0.87 mole) of diphenylacetonitrin.o and 40.42 g. (0.96 mole) of 57# sodium hydride in one liter of dry toluene was stirred at reflux temperature for three hours.

A stirred solution of l-isopropyl-3-azetidinol (100 g., Ο.87 mole) and 101 g. (1.0 mole) of triethylamine in 300 ml. of dry benzene was treated dropwise with 100 g. (Ο.87 mole) of methylsulfonyl chloride and after stirring for two hours at room temperature the mixture was filtered and the filter cake IQ was washed with dry benzene.

The benzene solution of l-isopropyl-3-azetidinylmethane sulfonate was added dropwise to the stirred refluxing toluene mixture containing the sodium salt of diphenylacetonitrile and ' refluxing continued for 1.5 hours after addition. The cooled reaction mixture wa3 treated with water, the layers separated, and the organic layer extracted with dilute hydrochloric acid and water. The combined extracts were basified using dilute sodium hydroxide and the base insoluble material extracted with chloroform. The dried extract was concentrated and the residual material was recrystallized from isooctane. The a,a-diphenyl-a(l-isopropyl-3-azetidinyl)acetonitrile weighed 142 g. (56#) and melted at 93-95 C.

Analysis: Calcd. for C20fk2lJ2: C,82.72; H,7.64; Ν,-9.65 : C,82-72; Η,7·73; Ν,9·55 Found - 5· Preparation 2 g,a-Diphenyl-fl!-(l-methyl-3-azetidinyl)acetonitrile.

A mixture of 4.0 g. (0.11 mole) of sodium amide, 21 g. (0.11 mole) of diphenylacetonitrile and 300 ml. of toluene was stirred at reflux for 4 hours in a nitrogen atmosphere. The heat was removed and an equimolar amount of 3-chloro-l-methylazetidine in toluene was added at a rate which maintained refluxing. The reaction mixture was refluxed an additional 4 hours, allowed to stand overnight at room temperature, washed with water and extracted with dilute hydrochloric acid.' The aqueous acid extract was made basic with dilute sodium hydroxide, the base insoluble oil extracted with isopropyl ether, the ether extract dried over sodium sulfate and concentrated. The residual solid was recrystallized from ligroin to give 6.7 g. (27$) of product, m.p. 113~115°C.

Analysis: Calcd. for CieH1BNa: C,82.4l; H,5-92,- N,10.68 Found : c,82.31; Η,6·9δ; Ν,ΙΟ-51 Preparation 3 In the manner of the preceding discussion and in accord with Preparations 1 and 2 starting with the appropriate 1-hydrocarbon-3-azetidinol and diphenylacetonitrile, the following a, 0£,α-4ΐρΉεηγ1-α-(l-ethyl-3-azetidinyl)acetonitrile from l-ethyl-3-azetidinol and diphenylacetonitrile; aja-diphenyl-#-(1-pfopyl-3-azetidinyl)acetonitrile from l-propyl-3-azetidinol and diphenylacetonitrile; - 6 ί 4 8 4 Ί a,a-diphenyl-a-( I-butyl-J-asetidinyl)acetonitrile from l-butyl-3-azetidinol and diphenylacetonitrile; a,a-diphenyl-a-( l-isobutyl-3-azetidinyl)acetonitrile from l-isobutyl-3-azetidinol and diphenylacetonitrile; a,a-diphenyl-a-(l-benzyl-jj-azetidinyl)acetonitrile from l-benzyl-J-azetidinol and diphenylacetonitrile; and a,a-diphenyl-o:-(l-phenethyl-J-azetidinyl)acetonitrile from l-phenethyl-3-azetidinol and diphenylacetonitrile.

“ Example 1 4,5-DiTiydro-?, 3-diphenyl-4-isopropylaminoinethylfuran2-(3h)one. a,a-Di.phenyl-a-( l-isopropyl-3-azetidinyl) acetonitrile (142 g.; 0.49 mole) was added to 500 g. of 70^ Sulfuric acid at 90-100°C.· The temperature was raised to 130°C. for 48 hours. The cooled mixture was poured onto ice and the cold mixture made basic by the addition of solid sodium hydroxide. The basic mixture was extracted with chloroform and the combined chloroform extracts dried over sodium sulfate and concentrated.

The residual material was crystallized from an 80$ isooctane 20$ isopropyl ether solution. The 4,5-dihydro-3,3~6iphenyI-4isopropylaminomethylfuran-2(3H}one weighed 105 U- (69-3$) and melted at 78-8O°C.

Analysis: Calcd. for C20Ha3NOa: C,77-64; H,7.49j N,4.53 Found : c,77-68; H,7-36; K,4.23 Example 2 In the manner of the preceding discussion and in accord with Example 1 starting with the appropriate a,a:-diphenyl-a(l-hydrocarbon-3-azetidinyl)acetonitrile and dilute sulfuric acid, the following 4,5-dihydro-3,3-diphenyl-4-hydrocarbylaminomethylfuran-2-(3H)ones are produced: 4.5- dihydro-3,3-6iphenyl-4-methylaminomethylfuran-2-(3H) one from g,g-diphenyl-a-( 1-methyl-3-azetidinyl) acetonitrile and dilute sulfuric acid; 4.5- dihydro-3,3-diphenyl~4-ethylaminomethylfuran-2-( 3H) one from g,Oi~diphehyl-*-(l~ethyl-3-azetidinyl) acetonitrile and 4 8 4 4 ς dilute sulfuric acid; 4.5- 4ihydro-3,3-diphenyl-4-propylaminometliylfuran-2-(3H) one from a,a-diphenyl-a-(l-propyl-3-azetidinyl)acetonitrile and dilute sulfuric acid; 4,5-dihydro-3J3_diplienyl-1l-isobutylaminomethylfuran-2-(3H) one from a,o'-diphenyl-a-(l-isobutyl-3-azetidinyl) acetonitrile and dilute sulfuric acid; 4.5- dihydro-3,3-diphenyl-4-ben2ylaminomethylfuran-2-( j5ff) one from a,a-diphenyl-a-(l-benzyl-3-azetidinyl)acetonitrile and dilute sulfuric acid; and 4.5- 4ihydro-3,3-diphenyl-4-phenethylaminomethylfuran-2(3H)one from a,a-diphenyl-o:-(l-phenethyl-3-azetidinyl)acetonitrile and dilute sulfuric acid.

Claims (7)

1. A compound having the formula: CeHg Cells -CHsNHR wherein R represents lower alkyl, lower cycloalkyl or phenyl lower alkyl.

2. 4 ,'5-Di’hydro-3,3-diphenyl-4-isopropylaminomethylfuran 2(3H)one.

3. A process for the preparation of a compound as claimed in Claim 1 or Claim 2 which comprises reacting an a,α-diphenyl-a-(l-hydrocarbyl-3-azetidinyl)acetonitrile wherein hydrocarbyl is lower alkyl, lower cycloalkyl or phenyl lower alkyl with dilute sulphuric acid.

4. A process as claimed in Claim 3 which is carried out with the application of heat.

5. A process as claimed in Claim 3 or Claim 4 wherein the dilute sulphuric acid is 70% by weight sulphuric acid.

6. A process as claimed in Claim 3, substantially as described in Example 1 or Example 2.

7. A compound as claimed in Claim 1 or Claim 2 which has been prepared by a process as claimed in any of Claims 3 to 6.