Improved process for the synthesis of alpha-((dialkylamino)substituted-methylene)-beta-oxo-(substituted) propanenitriles

Abstract: A novel process for producing a-[(dialkylamino)substituted-methylene]b-oxo-(substituted) propanenitriles of the formula: where R, R₁ and R₂ are defined in the specification by reacting a substituted isoxazole with a diaklylamide dimethylacetal is provided.

Description: BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION The invention relates to a process for the synthesis of α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile compounds and to novel substituted isoxazole compounds useful as intermediates in the process. 2. DESCRIPTION OF THE PRIOR ART The α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanitrile compounds are important intermediates for the preparation of therapeutic aryl and heteroaryl [7-(aryl and heteroaryl)pyrazolo(1,5-a)-pyrimidin-3-yl]methanone compounds which are useful as anxiolylic, antiepileptic, sedative-hypnotic and skeletal muscle relaxant agents. The aryl and heteroaryl [7-(aryl and hetroaryl)-pyrazolo [1,5-a] pyrimidin-3-yl]methanone compounds and uses for such compounds are described in U.S. 4,521,422. In U.S. 4,900,836, a series of reactions in which the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile compounds are utilized to produce the [7-(alkyl and hetroaryl)pyrazolo (1,5-a)-pyrimidin-3-yl]methanone compounds is described. This reference also describes the synthesis of the α-[(dialkylamino) substituted methylene]-β-oxo-(substituted) propanenitrile compounds via the reaction of a substituted acetonitrile with a dimethylformamide dimethylacetal. It has now been found that α-[(dialkylamino) substituted methylene]β-oxo-(substituted) propane nitrile compounds may be advantageously synthesized via reaction of a substituted isoxazole with a dialkylamide dimethylacetal. The use of substituted isoxazole compounds in the production of α-[(dialkylamino)substituted methylene]-β-oxo(substituted)propanenitrile compounds has not been taught nor suggested by the art. Certain substituted isoxazole compounds and their synthesis are known. For example, 5-(2,3,4,5-tetra-fluorophenyl)-isoxazole (Chem. Abst. Registry No. 110985-65-4), 5-(2,4-dichloro-5-fluorophenyl) isoxazole (Registry No. 103318-74-6), 5-(2,3,-dichloro-phenyl) isoxazole (Registry No. 76344-98-4), 5-(5-nitro-2-furyl)-isoxazole (Registry No. 32332-91-5), 5-(4-methylphenyl)-isoxazole (Registry No. 7064-35-9), 5-(m-chloro phenyl) isoxazole (Registry No. 7064-34-8), 5-(m-bromo phenyl) isoxazole (Registry No. 7064-33-7), 5-(p-chloro-phenyl) isoxazole (Registry No. 7064-32-6), 5-(p-bromo phenyl) isoxazole (Registry No. 7064-31-5), N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-2-5-isoxazolyl)-3-thiophenesulfonamide (Registry No. 103118-33-8), 3-hydroxy-4-(5-isoxazolyl)-2(5 H )-foranone (Registry No. 84-608-81-1) and 5-phenyl isoxazole (Registry No. 1006-67-3) are known. Other substituted isoxazole compounds including those claimed herein are not known. SUMMARY OF THE INVENTION The invention provides an improved process for the large scale production of α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanitrile compounds which may be represented by the following structural formula: wherein R is lower alkyl(C₁-C₃); R₁ is selected from the group consisting of phenyl; phenyl substituted by one of the group selected from halogen, nitro, alkyl(C₁-C₃) and alkoxy(C₁-C₃); phenyl di- or tri- substituted by methoxy, halogen and lower alkyl; phenyl substituted by one of the group consisting of dialkylamino(C₁-C₃), methylenedioxy, alkylthio(C₁-C₃), alkylsulfonyl(C₁-C₃), amino, alkanoyl(C₁-C₃)amino, trifluoromethyl and phenyl; thienyl; thienyl substituted by one or two of the group selected from halogen and alkyl(C₁-C₃); furanyl; furanyl substituted by one or two of the group selected from alkyl(C₁-C₃), naphthalenyl, pyrazinyl, and pyrrolyl; and R₂ is selected from the group consisting of hydrogen and lower alkyl(C₁-C₃). The improved process comprises reacting an R₁ substituted isoxazole having the formula wherein R₁ is as defined above with a dialkylamide dimethylacetal having the formula wherein R and R² are as defined above at a temperature from 50°C to 100°C and recovering the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile so produced. The invention also provides certain novel R₁ substituted isoxazole compounds. DESCRIPTION OF THE PREFERRED EMBODIMENTS The process and compounds of the present invention are described in the following reaction scheme I: In accordance with the above reaction scheme a 1-(cyclicsubstituted)ethanone (1), where R₁ is as described above, is reacted with dimethylformamide dimethyl acetal (2) for 15 hours at 50°-100°C. Evaporation and recrystallization gives the 3-dimethylamino-1-(substituted)-2-propen-1-one (3). The 3-dimethylamino-1-(substituted)-2-propen-1-one compounds (3) and their synthesis are described in greater detail in U.S. 4,178,449 (col 2 lines 44-54), U.S. 4,281,000 (col 2 lines 28-34), and U.S. 4,236,005 (col 2 lines 45-54). Related compounds are also known from EP-A-0 176 846 and EP-A-0 129 846. The 3-dimethylamino-1-(substituted)-2-propen-1-one (3) is reacted with hydroxylamine hydrochloride in absolute methanol for 2 hours at a temperature from 50° to 100°C. The reaction solution is evaporated, dissolved in methylene chloride and passed thru hydrous magnesium silicate. Concentration of the eluate gives the desired substituted isoxazole (5) which is reacted with a dialkylamide dimethylacetal (6) at a temperature from 50° to 100°C for 4 hours. The reaction solution is evaporated, dissolved in methylene chloride and passed thru hydrous magnesium silicate. On cooling and/or concentrating the methylene chloride solution, the desired α-[(dialkylamino)substituted methylene]-β-oxo-(substituted) propanenitrile (7) crystallizes. The formation of an oxazole with hydroxylamine hydrochloride departing from a chlorovinyl phenyl ketone is known from EP-A-0 168 737. As described in U.S. 4,900,836, the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitriles find utility as intermediates in the preparation of therapeutic aryl and heteroaryl[7-(aryl and heteroaryl)pyrazolo(1,5-a)pyrimidin-3-yl] methanones. As described in U.S. 4,521,422 the aryl and heteroaryl[7-(aryl and heteroaryl)pyrazolo(1,5-a) pyrimidin-3-yl]methanones are useful as anxiolylic, antiepileptic, sedative-hypnotic, and skeletal muscle relaxant agents. The above described process is an improvement over the procedure described in U.S. Pat. No. 4,900,836. The 1-(cyclicsubstituted)ethanones are readily available and inexpensive; the over all yields are higher; and the reaction work-ups are less labor and time intensive. The following non-limiting examples illustrate the process of the present invention as well as the preparation of the novel compounds isoxazole intermediates. Example 1 3-Dimethylamino-1-(3-thienyl)-2-propen-1-one A mixture of 48.4 g of 3-acetylthiophene and 75 ml of dimethylformamide dimethyl acetal, under nitrogen, is heated for 15 hours on a steam bath. The reaction is concentrated in vacuo and the residue crystallized from methylene chloride/hexane to give 60.55 g (87%) of the desired product, mp 89-90°C. Using the general procedure of Example 1, the following compounds of Example 2-26 shown in Table 1 are prepared. Example 27 A mixture of 58.1 g of (3-dimethylamino-1-(3-thienyl)-2-propen-1-one, 23.4 g of hydroxylamine hydrochloride and 250 ml of commercial absolute methanol is heated on a steam bath for 2 hours. The reaction is concentrated in vacuo , partitioned between methylene chloride and water and the organic layer dried over sodium sulfate. The methylene chloride is passed thru a short column of hydrous magnesium silicate and concentrated in vacuo to give 41.25 g (85%) of the desired product as a red-orange oil which solidified on standing. CI-MS: M/z 151(M⁺). Using the general procedure of Example 27, the following compounds of Example 28-52, shown in Table II are prepared. Example 53 α-[(Dimethylamino)methylene]-β-oxo-3-thiophenepropanenitrile A mixture of 41.2 g of 5-(3-thienyl)isoxazole and 36.0 g of dimethylformamide dimethylacetal, under nitrogen, is heated on a steam bath for 4 hours. The reaction is concentrated in vacuo to give a viscous oil which solidified. The residue is dissolved in methylene chloride and passed thru a short column of hydrous magnesium silicate. On cooling, 31.76 g of the desired product is obtained, mp 118-119°, CI-MS:m/z 206(M⁺). Concentrating in vacuo the methylene chloride gives an additional 20.2 g of product. (Total recovered 51.96 g, 92%). Using the general procedure of Example 53, the following compounds of Example 54-78, shown in Table III are prepared.

Claims: Claims for the following Contracting States : AT, BE, CH, LI, DE, DK, FR, GB, GR, IT, NL, SE A process for producing compounds of the formula: wherein R is lower alkyl(C₁-C₃); R₁ is selected from the group consisting of phenyl; phenyl substituted by one of the group selected from halogen, nitro, alkyl(C₁-C₃) and alkoxy(C₁-C₃); phenyl di- or tri- substituted by methoxy, halogen and lower alkyl; phenyl substituted by one of the group consisting of dialkylamino(C₁-C₃), methylenedioxy, alkylthio(C₁-C₃), alkylsulfonyl(C₁-C₃), amino, alkanoyl(C₁-C₃)amino, trifluoromethyl and phenyl; thienyl; thienyl substituted by one or two of the group selected from halogen and alkyl(C₁-C₃); furanyl; furanyl substituted by one or two of the group selected from alkyl(C₁-C₃), naphthalenyl, pyrazinyl and pyrrolyl; and R₂ is selected from the group consisting of hydrogen and lower alkyl(C₁-C₃); which comprises: reacting a substituted isoxazole having the formula with dialkylamide dimethylacetal having the formula at a temperature from 50 to 100°C and recovering the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile so produced. The process of Claim 1, wherein said substituted isoxazole is prepared by reacting a 3-dimethylamino-1-substituted-2-propen-1-one having the formula with hydroxylamine hydrochloride in absolute methanol at a temperature from 50°C to 100°C. The process of Claim 2 wherein said 3-dimethylamino-1-substituted 2-propen-1-one is prepared by reacting a 1-(cyclic substituted) ethanone having the formula with dimethylformamide dimethylacetal at a temperature of from 50°C to 100°C. The process of Claim 1, wherein α-[(dimethyl-amino)methylene]-β-oxo-3-thiophenepropanenitrile, 5-bromo-α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropanenitrile, α-[(dimethylamino)methylene]-5-methyl-β-oxo-2-furanpro-panenitrile, α-[(dimethylamino)methylene]-3-ethyl-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-4-nitro-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-β-oxo-tricyclo[3.3.1.1 3,7 ]decane-1-propanenitrile, α-[(dimethylamino)methylene]-β-oxo-4-biphenylpropanenitrile, 3,4-dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-3, 4-dimethyl-β-oxo-benzenepropanenitrile, 2, 4dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-2,6-difluoro-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene] -4-methyl-β-oxo-2-thiophene-propanenitrile, α-[(dimethylamino)methylene]-1-methyl-β-oxo-1 H -pyrrole-2 -propanenitrile,α-[(dimethylamino)methylene]-3-methyl-β-oxo-2-thiophene-propanenitrile,α-[(dimethylamino) methylene]-2,4-difluoro-β-oxo-benzenepropanenitrile or α-[(di-methylamino)methylene]-2,5-difluoro-β-oxo-benzenepropanenitrile is produced. A compound having the formula wherein R₁ is selected from the group consisting of 3-thienyl, 2-furanyl, 2-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2-thienyl, 2,4 difluorophenyl, 2,5 difluorophenyl. Claims for the following Contracting State : ES A process for producing compounds of the formula: wherein R is lower alkyl(C₁-C₃); R₁ is selected from the group consisting of phenyl; phenyl substituted by one of the group selected from halogen, nitro, alkyl(C₁-C₃) and alkoxy(C₁-C₃); phenyl di- or tri- substituted by methoxy, halogen and lower alkyl; phenyl substituted by one of the group consisting of dialkylamino(C₁-C₃), methylenedioxy, alkylthio(C₁-C₃), alkylsulfonyl(C₁-C₃), amino, alkanoyl(C₁-C₃)amino, trifluoromethyl and phenyl; thienyl; thienyl substituted by one or two of the group selected from halogen and alkyl(C₁-C₃); furanyl; furanyl substituted by one or two of the group selected from alkyl(C₁-C₃), naphthalenyl, pyrazinyl and pyrrolyl; and R₂ is selected from the group consisting of hydrogen and lower alkyl(C₁-C₃); which comprises: reacting a substituted isoxazole having the formula with dialkylamide dimethylacetal having the formula at a temperature from 50 to 100°C and recovering the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile so produced. The process of Claim 1, wherein said substituted isoxazole is prepared by reacting a 3-dimethylamino-1-substituted-2-propen-1-one having the formula with hydroxylamine hydrochloride in absolute methanol at a temperature from 50°C to 100°C. The process of Claim 2 wherein said 3-dimethylamino-1-substituted 2-propen-1-one is prepared by reacting a 1-(cyclic substituted) ethanone having the formula with dimethylformamide dimethylacetal at a temperature of from 50°C to 100°C. The process of Claim 1, wherein α-[(dimethyl-amino)methylene]-β-oxo-3-thiophenepropanenitrile, 5-bromo-α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropanenitrile, α-[(dimethylamino)methylene]-5-methyl-β-oxo-2-furanpro-panenitrile, α-[(dimethylamino)methylene]-3-ethyl-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-4-nitro-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-β-oxo-tricyclo[3.3.1.1 3,7 ]decane-1-propanenitrile, α-[(dimethylamino)methylene]-β-oxo-4-biphenylpropanenitrile, 3,4-dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-3, 4-dimethyl-β-oxo-benzenepropanenitrile, 2, 4dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene]-2,6-difluoro-β-oxo-benzenepropanenitrile, α-[(dimethylamino)methylene] -4-methyl-β-oxo-2-thiophene-propanenitrile, α-[(dimethylamino)methylene]-1-methyl-β-oxo-1 H -pyrrole-2 -propanenitrile,α-[(dimethylamino)methylene]-3-methyl-β-oxo-2-thiophene-propanenitrile,α-[(dimethylamino) methylene]-2,4-difluoro-β-oxo-benzenepropanenitrile or α-[(di-methylamino)methylene]-2,5-difluoro-β-oxo-benzenepropanenitrile is produced.

Inventors: CHURCH ROBERT F, DUSZA JOHN P, CHURCH, ROBERT F., DUSZA, JOHN P.
Applicants: AMERICAN CYANAMID CO, AMERICAN CYANAMID COMPANY
Application year: 1991
Main classification: C07C255
IPC codes: C07C255, C07D413, C07D333, C07C317, C07D207, C07C225, C07D261, C07D307, C07C253, C07C323, C07D241, C07C221