Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
  • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/21—Radicals derived from sulfur analogues of carbonic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

• This invention relates to new and useful N-cyano-N'-phenylcarboxamidines and to their chemical method of preparation. More particularly, the instant invention is concerned with use of the novel carboxamidine compounds as starting material for a one-step synthesis of antihypertensive agents such as the various 4-amino-2-(4-substituted piperazine-1-yl) quinazolines described in U.S. Patents 3,511,836; 3,669,968; 4,001,237;
• Hess U.S. Patent 3,935,213 describes a process for preparing quinazolines illustrated by formula (6) which involves the use of compounds of formulas (4) and (5) as set forth below.
• German Patent 2,261,739 (1974) (See Chem. Abs. 81, 84394q (1974)) discloses the following synthesis of quinazolin-2,4-diones:
• this invention is concerned with a new process for the preparation of antihypertensive quinazolines generally typified by formula I
• the instant process invol ves a one-step conversion of novel piperazinyl substi tuted N-cyano-N ' -phenylcarboxamidines to formula I quinazol ine products .
• one aspect of the instant invention is concerned with a process for preparing quinazol ine compound of formula I
• n is equal to 2 or 3;
• A is hydrogen or lower alkoxy of 1 to 4 carbon atoms inclusive;
• B and C are independently selected from the group consisting of lower alkoxy of 1 to 4 carbon atoms inclusive;
• R a is lower alkyl of 1 to 6 carbon atoms inclusive
• R b is selected from the group consisting of hydrogen, amino, lower alkyl of 1 to 4 carbon atoms inclusive and NHCO 2
• R c in which R c is lower alkyl of 1 to 4 carbon atoms inclusive
• R d and R e are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 6 carbon atoms inclusive, lower alkoxy of 1 to 6 carbon atoms inclusive, and lower alkylthio of 1 to 6 carbon atoms inclusive
• the compound of formula II employed is 4-(5-methylthio- 1,3,4-oxadiazole-2-carbonyl)piperazine-1-[N-cyano-N'- (3,4-dimethoxyphenyl)]carboxamidane;
• the cyclization process is carried out by treating the compound of formula II with phosphorus trichloride or phosphorus pentachloride in a solvent amount of phosphorus oxychloride;
• the cyclization process is carried out by treating the compound of formula II with phosphorus tribromide or phosphorus pentabromide in a solvent amount of phosphorus oxybromide;
• the cyclization process is carried out by treating the compound of formula. II with hydrogen chloride in phosphorus oxychloride;
• the cyclization process is carried out by treating the compound of formula II with a lewis acid catalyst;
• the cyclization process is carried out at a temperature of 25-125o;
• the cyclization process is carried out at a temperature of 70-100°;
• Preferred groups of compounds contemplated within the class of cyanocarboxamidines of formula II are those wherein:
• the A, B and C substituted phenyl radical is 3,4- dimethoxyphenyl, n is 2, or 3 and R 1 is selected from the group consisting of methyl, cyclopentyl, 2-furoyl, 5-methylthio-1,3,4-oxadiazole-2-carbonyl, 2-methyl-2-hydroxypropoxycarbonyl;
• the A, B and C substituted phenyl radical is 2,3,4- trimethoxyphenyl, n is 2 or 3 and R 1 is selected from the group consisting of methyl, cyclopentyl, 2-furoyl, 5-methylthio-1,3,4-oxadiazole-2-carbonyl, 2-methyl-2-hydroxypropoxycarbonyl.
• cycloalkyl as used herein includes cycloalkyl radicals containing 3 to 8 ring carbon atoms inclusive and encompasses such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• methylcycloalkyl refers to the aforementioned cycloalkyl radicals containing from 3 to 8 ring carbons inclusive having a methyl substituent and encompasses such groups as 1-methycyclopropyl, 1-methylcyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 1-methylcyclohexyl, 2-methylcycloheptyl, 4-methylcyclohexyl, and the like.
• cycloalkenyl it is intended to refer to those having from 4 to 8 ring carbon atoms inclusive containing a single ring carbon-carbon double bond encompassing such groups as 1-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, and the like.
• lower alkyl and “lower alkoxy”, as used herein, it is meant that the carbon chain which comprises these groups include both straight and branched carbon radicals of the designated number of carbon atoms inclusive.
• Exemplary of carbon chain radicals have 1 to 4 carbon atoms inclusive are methyl, ethyl, propyl, isopropyl, 1 -methy!propyl, 2-methylpropyl, and tert -butyl.
• Conversion of formula II carboxamidines to quinazolines of formula I is carried out by treating the formula II carboxamidines with cyclizing reagents such as phosphorus trichloride or phosphorus pentachloride in a solvent amount of phosphorus oxychloride.
• cyclizing reagents such as phosphorus trichloride or phosphorus pentachloride in a solvent amount of phosphorus oxychloride.
• Other phosphorus hal ides and phosphorus oxyhalides such as phosphorus tribromide and phosphorus pentabromide in a solvent amount phosphorus oxybromide may be employed.
• Ring closure of the carboxamidines of formula II to the quinazoline compounds of formula I is acid catalyzed with reagents such as aqueous hydrochloric acid, hydrogen chloride in phosphorus oxychloride, trichloroacetic acid or Lewis acid catalyst such as ZnCl 2 , FeCl 3 , AlCl 3 , AlBr 3 , and the like.
• reagents such as aqueous hydrochloric acid, hydrogen chloride in phosphorus oxychloride, trichloroacetic acid or Lewis acid catalyst such as ZnCl 2 , FeCl 3 , AlCl 3 , AlBr 3 , and the like.
• solvent amount refers to a quantity of phosphorus oxychloride or phosphorus oxybromide sufficient to provide good mixing and handling characteristics with respect to the reaction mixtures. For this purpose, a ratio of from about 2 to 15 ml. of the phosphorus halide for each gram of the carboxamidine reactant of formula II is generally preferred.
• temperatures for carrying out the cyclization reaction range from about 25-125° with a particularly preferred temperature range of from about 70-100°.
• reaction time and conditions required for cyclization of the compounds of formula II and. formation of the compounds of formula I vary according to several factors such as temperatures and reaction times. For instance, at lower temperatures, long reaction periods are needed, while at higher temperatures, the cyclization reaction is completed in a shorter time. Reaction periods from about 0.5 to 24 hrs. can be used with a period of 1.0 to 3.0 hrs. preferred at a temperature in the range of about 70-100 .
• the cyano carbon acts as a carbonium ion forming a carbon-carbon bond with the benzene nucleus thereby establishing the quinazoline ring while the cyano nitrogen becomes the quinazoline 4-amino group.
• R-X alkylating reagent in which R is lower alkyl of 1 to 4 carbon atoms incl usive or an aryl derivati ve containi ng electron wi thdrawing groups (e.g. , 2,4-dinitrophenyl ) , X is halogen (e. g. , Cl, Br, and I) , l ower al kyl SO 4 of 1 to 4 carbon atoms inclusive, phenyl SO 3 , F 3 CSO 3 , and the l ike to provide a hydrohalide intermediate of formula IV
• Alkylation of urea and thiourea starting materials of formula III and subsequent reaction with cyanamide is normally carried out in a reaction inert organic solvent.
• Suitable solvents include dioxane, tetrahydrofuran, dimethyl sulfoxide, diethyl sulfoxide, and alkanol solvents such as methanol, ethanol , or isoamyl alcohol.
• the reaction can be conducted at temperatures varying within the range of from about 25 to 100°C. for a period of about 0.5 to 24 hrs.
• the formula III urea and thioureas are obtained by reacting appropriately substituted phenyl isocyanates and phenylisothiocyanates with N-substituted piperazines and homopiperazines in an inert reaction solvent such as ethanol.
• Required piperazine and homopiperazine starting material is obtained by conventional procedures; e.g. acylation of piperazine or homopiperazine with
• the carboxamidines of formula II are also valuable for their anti -ulcer properties, for instance, 4-(2-furoyl)piperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl)]- carboxamidine and 4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)- piperazine-1-[N-cyano-N'-3,4-dimethoxyphenyl]carboxamidine at a subcutaneous dose of 10 mg/kg and 3 mg/kg body weight, respectively, inhibit acid secretion in the pylorus ligated rat model of Shray, Gastroenterology, 5, 43 (1946).
• the chloroform extracts are washed with water, saturated brine solution and dried. Concentration of the dried solution affords a residual gum which when rubbed under cold toluene provides 4.46 g., (49% yield) of crystalline material, m.p. 155-158°. Recrystallization from toluene affords analytically pure 4-methylpiperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl)]-carboxamidine, m.p. 160-163°.
• Example 1(a) Following the procedure of Example 1(a) but employing an equimolar amount of N-(cyclopentylcarbonyl)piperazine in place of N-methylpiperazine, there is produced 4-(cyclopentylcarbonyl)- piperazine-1-(N-3,4-dimethoxyphenyl) carbothioamide. Reaction of the carbothioamide with methyl iodide and then with cyanamide according to the procedure of Example 1(b) affords 4-(cyclopentyl- carbonyl)piperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl]carboxamidine.
• Phosphorus pentachloride (0.31 g., 1.48 mmoles) is added with stirring to 10 ml. of phosphorus oxychloride followed in 5 min. by 4-methylpiperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl)]-carboxamidine of Example 1 (0.45 g., 1.48 mmoles).
• the reaction mixture is heated at 95-98° for a period of 2.5 hr. during which time a yellow gum forms and changes to a suspended solid by the end of the heating period.
• the reaction mixture is then cooled to 30° and excess phosphorus oxychloride removed under reduced pressure to provide a residual material which is treated cautiously with ice/ water.
• Hydrogen chloride gas is bubbled for a period of 8 min. into a cold, stirred mixture of 4-(2-furoyl)piperazine-1-[N-cyano-N'-(3, 4-dime thoxyphenyl)] carboxamidine of Example 2 (3.0 g., 7.82 mmoles) in 45 ml. of phosphorus oxychloride.
• the reaction mixture is stirred at 25-30° for 10 min. and then heated at 70-75° for a period of 75 mih. during which time a gummy solid separates.
• the reaction mixture is cooled to 30o , the excess phosphorus oxychloride removed under reduced pressure and residual material rubbed under ice/water to provide a solid.
• Hydrogen chloride gas is bubbled for a period of 4 min. into a cold, stirred mixture of 4-(5-methylthio-1,3,4-oxadiazole-2- carbonyl)piperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl)]carboxamidine of Example 3 (0.16 g., 0.37 mmoles) in 6 ml . of phosphorus oxychloride and the mixture then stirred at 25-30° for an additional 8 min. period and finally heated to 72-75 for a period of 75 min. during which time a pale yellow solid precipitates.
• novel N-cyano-N'-phenylcarboxamidine compounds of this invention are particularly valuable as intermediates in the preparation of antihypertensive 4-amino-2-(4-substituted-piperazine-1-yl)-quinazolines.
• the invention includes the method of preparation of the novel N-cyano-N'-phenylcarboxamidines as well as the one step synthesis of the aforesaid antihypertensive compounds utilizing the novel N-cyano-N'-phenylcarboxamidines of the invention.
• novel N-cyano-N'-phenyl carboxamidine compounds are also valuable in the treatment of ulcers.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Heterocyclic Compounds Containing Sulfur Atoms (AREA)
• Furan Compounds (AREA)

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• 1977
  • 1977-09-30 US US05/838,417 patent/US4138561A/en not_active Expired - Lifetime
• 1978
  • 1978-09-18 GB GB7906214A patent/GB2036001B/en not_active Expired
  • 1978-09-18 CH CH511879A patent/CH641172A5/de not_active IP Right Cessation
  • 1978-09-18 WO PCT/US1978/000083 patent/WO1979000166A1/en not_active Ceased
  • 1978-09-22 CA CA000311878A patent/CA1121816A/en not_active Expired
  • 1978-09-26 BE BE190708A patent/BE870763A/xx not_active IP Right Cessation
  • 1978-09-27 NL NL7809799A patent/NL7809799A/xx unknown
  • 1978-09-27 FR FR7827628A patent/FR2404633A1/fr active Granted
  • 1978-09-27 DK DK429378A patent/DK429378A/da not_active Application Discontinuation
  • 1978-09-29 IE IE1958/78A patent/IE47569B1/en unknown
  • 1978-09-29 JP JP11930778A patent/JPS5459292A/ja active Pending
  • 1978-09-29 IT IT51318/78A patent/IT1107496B/it active
• 1979
  • 1979-05-29 SE SE7904690A patent/SE7904690L/xx unknown

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