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United States Patent (19) 11 4,098,788 Crenshaw Et Al

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United States Patent (19) 11 4,098,788 Crenshaw Et Al United States Patent (19) 11 4,098,788 Crenshaw et al. 45 Jul. 4, 1978 54 PROCESS FOR PREPARING QUINAZOLINES OTHER PUBLICATIONS Elderfield, Heterocyclic Compounds, vol. 6, pp. 75 Inventors: Ronnie Ray Crenshaw, Dewitt; 328-358, pub. by Wiley & Sons, (1957). George Michael Luke, Lafayette; Richard Anthony Partyka, Primary Examiner-Paul M. Coughlan, Jr. Liverpool, all of N.Y. Attorney, Agent, or Firm-Robert H. Uloth 57 ABSTRACT 73 Assignee: Bristol-Myers Company, New York, 2-Halo-4-aminoquinazolines are produced by a two-step N.Y. process involving cyclization of 1-phenyl-3-cyanoureas or 1-phenyl-3-cyanothioureas in the presence of phos (21) Appl. No.: 807,941 phorus halides and phosphorus oxyhalides to provide a 22 Filed: Jun. 20, 1977 phosphoquinazoline intermediate which is hydrolyzed to the quinazoline. Exemplary of the process is the 51) Int. Cl.2 ............................................ CO7D 239/94 intramolecular cyclization of 1-(3,4-dimethoxyphenyl)- 52 U.S. C. .................. ... 544/293; 260/553 A 3-cyanourea in the presence of phosphorus pentachlo 58 Field of Search ..................... 260/251 Q, 256.4 Q ride and phosphorus oxychloride to a phosphoquinazo line intermediate which is subsequently hydrolyzed 56 References Cited with formic acid to 2-chloro-4-amino-6,7-dimethoxy U.S. PATENT DOCUMENTS quinazoline. The 2-halo-4-aminoquinazolines of the in stant process are particularly valuable as intermediates 2,517,824 8/1950 Appelquest ................... 260/256.4 Q in the preparation of 4-amino-2-(4-substituted-piperazin 3,511,836 5/1970 Hess .............................. 260/256.4 Q 3,669,968 6/1972 Hess .............................. 260/256.4 Q 1-yl)guinazolines useful in the treatment of cardiovascu 3,920,636 1 1/1975 Takahashi et al. ........... 260/256.4 Q lar disease, e.g. hypertension. 4,001,237 1/1977 Partyka et al. ............... 260/256.4 Q 4,001,238 1/1977 Partyka et al. ............... 260/256.4 Q 21 Claims, No Drawings 4,098,788 1. 2 DETAILED DESCRIPTION OF THE PROCESS FOR PREPARING QUINAZOLINES NVENTION FIELD OF THE INVENTION As indicated hereinabove, the instant invention is This invention is concerned with a new process for 5 concerned with a process for preparing compounds of the production of 2-halo-4-aminoquinazolines. These formula I chemical compounds are utilized as intermediates in the preparation of antihypertensive agents such as the vari (I) ous 4-amino-2-(4-substituted piperazin-1-yl)guinazolines 10 described in U.S. Pat. Nos. 3,511,836, 3,669,968, 4,001,237, 4,001,238 and the 2-(4-substituted homopiperazino)-4-amino-6,7-dimethoxyquinazolines of U.S. Pat. No. 3,920,636. 15 DESCRIPTION OF THE PRIOR ART wherein Hess U.S. Pat. No. 3,511,836 (patented May 12, 1970) X is halogen selected from the group consisting of discloses preparation of 2-chloro-4-aminoquinazolines chlorine and bromine; and by reaction of 2,4-dichloroquinoazlines with ammonia R1, R, and R are independently selected from the 20 group consisting of hydrogen, lower alkyl of 1 to 4 in a solvent such as tetrahydrofuran. carbon atoms inclusive and lower alkoxy of 1 to 4 Hess U.S. Pat. No. 3,669,968 (patented June 13, 1972) carbon atoms inclusive describes a process for preparing 2-halo-4-amino-6,7,8- which comprises the consecutive steps of trialkoxy-quinazoline by treating 2,4-dihalo-6,7,8-trialk (a) treating a compound of formula II oxyquinazolines with ammonia in a reaction-inert or 25 ganic solvent. R (II) Takahashi, et al. U.S. Pat. No. 3,920,636 (patented November 18, 1975) described preparation of 1-(4-sub Y stituted homopiperazino)-4-amino-6,7-dimethox R yguinazolines from 2-chloro-4-amino-6,7-dimethox 30 NH-C-NH-CN yguinazolines. R Partyka, et al. U.S. Pat. No. 4,001,237 and 4,001,238 (both patented January 4, 1977) employ 2-chloro-4- wherein R, R2 and Rare as above and Y is oxygen or amino-6,7-dimethoxyquinazoline as starting material in 35 sulfur with a mixture of phosphorus halides and phos the preparation of a series of 6,7-dimethoxy-4-amino-2- phorus oxyhalides selected from the group consisting of (piperazinyl)guinazolines in which the piperazinyl radi phosphorus trichloride or phosphorus pentachloride cal is incorporated as the amine fragment of oxazole, and phosphorus oxychloride, or phosphorus tribromide or phosphorus pentabromide and phosphorus oxybro isoxazole, thiazole, isothiazole and 1,2,4-oxadiazole am mide until the cyclization is essentially complete to ides. provide a quinazoline phosphoramide intermediate; SUMMARY OF THE INVENTION (b) hydrolyzing said intermediates to produce the compound of formula I. Broadly described, this invention is concerned with a Preferred embodiments of the foregoing process for new process for preparation of 2-halo-4-aminoquinazo 45 the preparation of compounds characterized by formula lines of formula I I are those wherein: in step (a) the compound of formula II is a cyanourea R NH, (I) wherein R, R2 and Rare as above and Y is oxy gen; Y N 50 in step (a) the compound of formula II is a cyanothi R ourea wherein R, R and Rare as above and Y is N eeX sulfur; in step (a) the compound of formula II is 1-(3,4-dime R thoxyphenyl)-3-cyanourea; 55 in step (a) the compound of formula II is 1-(2,3,4- wherein X is a halogen atom selected from the group trimethoxyphenyl)-3-cyanourea; consisting of chlorine and bromine; R, R are indepen in step (a) the compound of formula II is 1-(3,4-dime dently selected from the group consisting of hydrogen, thoxyphenyl)-3-cyanothiourea; lower alkyl and lower alkoxy radicals which involves in step (a) the compound of formula II is 1-(2,3,4- intramolecular cyclization of 1-phenyl-3-cyanoureas or 60 trimethoxyphenyl)-3-cyanothiourea; in step (a) a mixture of phosphorus pentachloride and 1-phenyl-3-cyanothioureas in the presence of a mixture phosphorus oxychloride is employed; of phosphorus trichloride or phosphorus pentachloride in step (a) a mixture of phosphorus pentabromide and and phosphorus oxychloride or a mixture of phosphorus phosphorus oxybromide is employed; tribromide or phosphorus pentabromide and phospho in step (a) the compound of formula II is treated with rus oxybromide to provide a quinazoline phosphorus a mixture of a molar equivalent of phosphorus intermediate that is subsequently hydrolyzed to the trichloride or phosphorus pentachloride and a sol 2-halo-4-aminoquinazoline of formula I. vent amount of phosphorus oxychloride; 4,098,788 3 in step (a), the compound of formula II is treated with a mixture of about a molar equivalent of phospho (VI) rus tribromide or phosphorus pentabromide and a CHO O solvent amount of phosphorus oxybromide; I step (a) is carried out with the aid of heat at a temper CHO O NH-C-NH-CN ature in the range of about 23-125; step (a) is carried out with the aid of heat at a temper CHO ature in the range of 85-95; with about a molar equivalent of a mixture of phospho step (a) is carried out at a temperature in the range of 10 rustrichloride or phosphorus pentachloride in a solvent 85-95 for a period of 2 to 3 hours; amount of phosphorus oxychloride until cyclization is in step (b), the phosphoramide intermediate is hydro essentially complete to provide a quinazoline phos lyzed under acidic conditions to provide a quinazo phoramide intermediate; line of formula I; (b) hydrolyzing said intermediate with formic acid to in step (b), the phosphoramide intermediate is hydro- 1 5 produce the formula V compound. lyzed with dilute alkali to provide a quinazoline of According to the general process of this invention, formula I; cyanoureas and cyanothioureas of formula II are intra in step (b) the phosphoramide intermediate is hydro molecularly cyclized to a phosphoquinazoline interme lyzed with formic acid to provide a quinazoline of diate which is then hydrolyzed to provide quinazoline formula I; 2O compounds characterized by formula I. Cyclization of a step (b) is carried out at a temperature in the range of formula II urea to the phosphoquinazoline intermediate 85-95; is conveniently carried out by reacting the urea with a step (b) is carried out at a temperature in the range of mixture of phosphorus trichloride orphosphorus penta 85-95 for a period of 5 to 15 minutes; chloride and phosphorus oxychloride. While the exact step (b) is carried out at a temperature in the range of 5 chemical identity of the cyclized organophosphorus 85-95 for a period of 5 to 15 minutes and then intermediate has not been unequivocally proved, it is cooled to a temperature in the range of 5-15'. believed to be a phosphoramido compound in which the Another preferred embodiment of the present inven 4-amino substituent of the 2-chloroquinazoline is incor tion is a process for the preparation of a quinazoline of 3 porated in the phosphoramide. Approximately equimo O lar portions of a mixture of phosphorus trichloride or formula III phosphorus pentachloride and the formula II urea with a convenient solvent amount of phosphorus oxychlo NH (III) ride relative to the amount of urea starting material are was employed. Commonly used temperatures for carrying CHO N 35 out the cyclization reaction range from about 25-125, and a particularly preferred temperature range is from CHO N 2-Cl about 85-95. As will be appreciated by those skilled in the art, the reaction time and conditions needed for the which comprises the consecutive steps of cyclization of the compounds of formula II vary ac (a) treating a cyanourea having formula IV 40 cording to several factors.
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