United States Patent 19 11 Patent Number: 5,675,006 Karimian Et Al

Home , Quinazosin, Tiodazosin, Trimazosin

USOO5675006A United States Patent 19 11 Patent Number: 5,675,006 Karimian et al. 45) Date of Patent: Oct. 7, 1997

54 METHODS OF MAKING UREAS AND O227451 7/1987 X GUANDINES, INCLUDING, TERAZOSN, 2231571 11/1990 European Pat. Off.. 235O101 4/1975 PRAZOSN, DOXAZOSN, TODAZOSN, 2321890 8/1975 TRIMAZOSIN, QUINAZOSIN, AND 24.57911 6/1975 BUNAZOSIN (EXEMPLARY OF 2 27.0068 9/1977 SUBSTITUTED QUINAZOLINE 27.07058 9/1977 COMPOUNDS), AND MEOBENTINE, AND 2725019 12/1977 BETHANDINE AND INTERMEDIATES 181743 12/1992 Hungary. THEREFOR 1156,973 8/1969 United Kingdom. 1390014 4/1975 United Kingdom. 75 Inventors: Khashayar Karimian; Keshava 1390015 4/1975 United Kingdom. Murthy; Darren Hall, all of Brantford, 2021108 5/1979 United Kingdom. Canada PCT/CA93/ 00355 8/1993 WIPO. (73) Assignee: Brantford Chemicals Inc., Brantford, OTHER PUBLICATIONS Canada Synthetic Communications, vol. 18, No. 5, May 1988, U.S. pp. 525-530, A.V.N. Reddy, et al.: “An Efficient Synthesis (21) Appl. No.: 453,818 of 3,4-dihydro-4-imino-2(1H)-quinazolines'. 22 Filed: May 30, 1995 Houben-Weyl: "Methoden der Organischen Chemie'. Band E4, 1983, pp. 352-364, published by Georg Thieme Verlag, Related U.S. Application Data Stuttgart, DE. Houben-Weyl: "Methoden der Organischen Chemie', Band 62) Division of Ser. No. 4,114, Jan. 13, 1993, abandoned. E4, 1983, pp. 608–619, published by Georg Thieme Verlag, 30 Foreign Application Priority Data Stuttgart, DE. Althius.T.H. and Hess, H.J., “Synthesis and Identification of Aug. 31, 1992 CA Canada ...... 2077252 the Major Metabolites of Prazosin Formed in Dog and Rat', (51) Int. Cl' ...... CO7D 403/00; CO7D 403/02 Journal of Medicinal Chemistry vol. 20, p. 146 (1977). 52 U.S. Cl...... 544/283; 544/284; 544,285: Reiter, J. and Pongo, L, "On Triazoles. V12), Synthesis of 544/286; 544/287: 544/288; 544/289; 544,290; 1-and 2-R-3-R.R-Amino-5-amino-1,2,4-triazoles", 544,291; 544/292; 544/293; 514/259; 514/260 Journal of Heterocyclic Chemistry, vol. 23, p. 401 (1986). (58) Field of Search ...... 544,283-293 Curd, F.H.S., Landquist, J.K. and Rose, F.L., "Synthetic Antimalarials, Part XXXII. 2-p-Chloroanilino-4-3-di (56) References Cited ethylaminoethylaminoquinazolines containing Various Sub stituents in the Quinazoline Nucleus”,Journal of the Chemi U.S. PATENT DOCUMENTS cal Society, p. 1759 (1948). 3,511,836 5/1970 Maxwell et al...... 514/259 3,949,089 4/1976 Pfizer ...... 514,259 Primary Examiner-Matthew V. Grumbling 4,026,894 5/1977 Winn et al...... 514/259 Attorney, Agent, or Firm-Ivor M. Hughes; Neil H. Hughes; 4,138,561 2/1979 Crenshaw et al. 514/259 Marcelo K. Sarkis 4,251,532 2/1981 Roteman ...... 514/259 57 ABSTRACT FOREIGN PATENT DOCUMENTS Novel methods for the synthesis of substituted ureas and 105683 6/1979 Canada. guanidines including Terazosin, Prazosin, Doxazosin, 10577.54 7/1979 TiodaZosin, Trimazosin, Quinasin and Bunazosin 1081229 7/980 (exemplary of 2-amino substituted Quinazolines), Meoben 1390015 4/1975 tine and Bethanidine and novel intermediates suitable for 1464583 2/977 2041932 9/1980 use in such methods of synthesis are taught. 0.03441 2/1981 O227450 7/1987 20 Claims, No Drawings 5,675,006 1. 2 METHODS OF MAKNG UREAS AND -continued GUANDINES, INCLUDING, TERAZOSEN, PRAZOSEN, DOXAZOSIN, TODAZOSIN, OOAZOSN H Me Me 1 N - N TRIMAZOSN, QUINAZOSIN, AND BUNAZOSN (EXEMPLARY OF 2 SUBSTITUTED QUINAZOLINE s- a sci, COMPOUNDS), AND MEOBENTINE, AND BETHANDINE AND INTERMEDIATES TRMAZOSN OMe Me Me 1 O THEREFOR 10 This application is a divisional of application Ser. No. ar. 08/004,114 filed Jan. 13, 1993 now abandoned. QUINAZOSIN H Me Me 1 FIELD OF INVENTION R-1s 5 BUNAZOSN H Me Me 2 O This invention relates to novel processes of making ureas for example N-monosubstituted, N-N-disubstituted, N,N-N'- trisubstituted, N,N-N", N'-tetrasubstituted ureas and -N-n. guanidines and derivatives thereof. A number of such com Thus they include the following cyclized guanidines of general formula 2. pounds comprise 2-amino-substituted quinazolines (such as 20 terazosin, prazosin, tiodazosin, bunazosin, quinazosin and N 2 trimazosin and doxazosin) and other guanidines (such as Meobentine and Bethanidine) which are known medica ments known to reduce blood pressure in hyperactive sub jects. 25 This invention also relates to a number of novel interme diates (including novel ureas and novel guanidines) that may be used in the synthesis of for example the 2-amino substituted quinazolines and guanidines and the methods of the synthesis thereof. 30 Some of these novel intermediates that are guanidines may also be useful as accelerators in the manufacture of rubber and as activators for thiazole accelerators. 35 BACKGROUND OF THE INVENTION A number of medicines are guanidines. These guanidines include cyclized guanidines of the general formula 1. Thus they include the following cyclized guanidines of general formula 2.

R1O N N- ~ 45 The following compounds are exemplary:

R 2 1. PRAZOSN NH N W COMPOUND R R. R. in R 50 /N- A.Y PRAZOSN H Me Me 1 / V HCO N N 1N/ O

N HCO e 55 NH TERAZOSN H Me Me 1 2. TERAZOSN O N DOXAZOSN. H. Me Me 1 O HCO N N&Y.) 1N/ O O

N HC 65 5,675,006 3 4 -continued -continued 3. DOXAZOSIN MEOBENTINE; O

N/N1 1N/ N O O HCO N O wherein Me is CH (methyl).

10 The prior art preparations of cyclized and uncylized HCO 1 guanidines for example of Terazosin (R=tetrahydrofuryl), NH2 Prazosin (R=furyl), Doxazosin (R=1,4-benzodioxan-2- 4. TRIMAZOSIN yl), and Meobentine (R-4-methoxybenzyl, R=H, R= methyl, R=H, R=CH) are discussed below. CH3 15 Compounds of general formula 2 have been prepared by HCO ". N. N/> 1N/ , 'Y'YeoO CH3 a number of approaches which may be classified into five general methods. N In method 1, a 4-amino-6,7-dimethoxy quinazoline that is HCO 1 20 substituted at C-2 position with a good leaving group X, is NH2 condensed with a properamine. Up to nine steps are used to synthesize the 4-amino-6,7-dimethoxy quinazoline, starting 5. QUINAZOSIN from veratraldehyde J. Chem. Soc. 1759, (1948) and J. /N1 N N1N Med. Chem. 20, 146, (1977). H3CO N N 1N/ METHOD 1 N HCO al R1O N X R3 NH2 +H-N - G N 6. BUNAZOSIN R2 12 R4 / N NH MeO N N- N-1N1 35 * RO N N- N N N-1 R4 MeO 1. N RO 1. NH2 NH 7. TODAZOSIN X Reference N - N Cl Fr. Pat. 2321890 Fr. Pat. 235O101 Cat Pat. 1057754 45 Can Pat. 1081229 Ger Pat. 2707O68 Ger Pat. 2725019 Eurr Pat, OO34471. U.S. Pat. 4251532 U.S. Pat. 4026894 50 Brit Pat. 1156973 Brit Pat. 2021108 SCH Ger Pat. 2707068 Brit Pat, 1156,973 Brit Pat. 2021108 These guanidines also include uncyclized guanidines of the SOalkyl Brit Pat. 2021108 general formula 3. 55 N1 R's Those fine chemical manufacturers synthesizing prazosin, R terazosin, and doxazosin for the most part use this process R'll 1' or a modification thereof. The major shortcoming of this R1 NR, method (method 1) is the low yields (between about 5 and BETHANDINE; 25%) which may be ascribed to the large number of steps involved. In method 2, a 34-dimethoxyaniline that is substituted at 65 the C-6 position with a nitrile, amide or amidine group is condensed with an amine that is N-substituted with an appropriate functional group, Y. 5,675,006 5 6 Eur. Pat. 0034471). The reported yields starting from the thioether is 63%. However, the thioether itself is difficult to METHOD 2- manufacture. RO NH2 R3 M 5 - METHOD 4 - +Y-N N - G H RC Z. R4 RO N. SR

RO N N *3 N1 N - HN * - G N1 N. 10 Rio NC N N R R RO e H /* NH RO N N C-6(Z) Y Reference 15 N Rs NC CN CN Brit Pat. 1390014 R.O. Brit Pat. 1390015 Eur Pat OO34471 CN HN-C=NH Brit Pat. 1156,973 CN HN-C=NH Brit Pat. 1156.973 20 R (C1 instead of NH at RO N / C-1 position) N CN H-N=C-O-Alkyl Ger Pat. 24.57911 S- \ CN H-N=C-S-Alkyl Ger Pat. 24.57911 R O-C-NH, CN Ger Pat. 24.57911 RO 2 HN=C-NH, CN Ger Pat. 24.57911 25 NH The processes taught by German Patent 2457911 propose the use of highly toxic cyanogen bromide. The yields of the In method 5, 2-chloro-4-amionquinazoline is initially processes are poor at best and thus not attractive for com- condensed with piperazine and the resulting amine is reacted mercial production. with an acid chloride to afford the desired product (Brit. Pat. In method 3,3,4-dimethoxy-6-cyanoaniline is converted 1156973). to its corresponding isothiocyanate using thiophosgene. This is then condensed with a proper amine. The resulting thio urea is then S-alkylated (e.g. methyl iodide). High tempera ture reflux in the presence of ammonium chloride results in 35 the insertion of the amine group, followed by ring closure to afford Terazosin (Bel. Pat. PCT/F1820.0034, Eur. Pat. 0034471). However thiophosgene is extremely toxic and its use is not practical on commercial scale due to high cost and limited availability.

METHOD 3

M R3 N H M RO NH RO NCS N RO N N - G R4 NNS R RO CN RO CN RO CN

R3 R3

RO1. N n/ RO1. N s/ CHSH + N Y, (N Cl sas Y, N RO e RO CN Me

In method 4, N-cyano-N-(3,4-dimethoxyphenyl)-5- methylisothiourea (see J. Heterocycl. Chem. 23, 401 (1986) or Hungarian Pat. 181743) is condensed with a properamine to afford a carboxamidine which upon heating at high temperature affords the desired product (Can. Pat. 2015066, 5,675,006 7 8

METHOD 5 RO N Cl / \ R1O N. + HN NH -> SS N R2O 12 \ / R2O 2 -" NH NH / \ O R= O PRAZOSN sa

R1O N N O

C.Y.O TERAZOSN R2O 2 s SNJ R O O DOXAZOSIN NH O

As in method i, this process also fails to provide good by alkylation of the resulting thiourea generally affords low yields, because of the number of steps involved in the overall yields and therefore suffers from the same disadvan preparation of the 2-chloroquinazoline starting material. 25 tages described in the methods 2 and 3 (vide supra). These methods suffer from various other shortcomings. It is therefore an object of this invention to provide For example, the use of 2-chloro-4-amino-6,7- improved more efficient methods for the synthesis of com dimethoxyquinazoline (method 1 and 5) is prohibitive due to pounds such as ureas and guanidines for example cyclized the fact its synthesis involves nine steps from veratraldehyde guanidines such as 2-amino substituted quinazolines of and the overall yield is approximately 5-25% F. H. S. Curd 30 et. al., J. Chem. Soc. 1759 (1948) and J.Med. Chem. 20, 146 general formula 1 (e.g. Terazosin, Prazosin, Doxazosin, (1977). Tiodazosin, Trimazosin, Quinasin and Bunazosin) and for Activation of the amine group (method 2) requires the use example uncyclized guanidines such as those of general of highly toxic cyanogen bromide (Y=CN), followed by formula 3 (e.g. Meobentine and bethanidine). further modification of the activating group (Y=HN It is a further object of the invention to provide such C=NH. HN=C-O-Alkyl). Use of ammonium 35 improved more efficient processes which produce the thiocyanate, followed by alkylation of sulfur, will result in desired compounds for example guanidines and ureas and in Y=HN=C-S-Alkyl. Nevertheless, the yields are gener higher yields than in the prior art. ally low (ca. 40%). In method 3, although the reported yield It is still a further object of the invention to provide such of prazosin is high (ca. 68%), high toxicity and limited compounds for example quinazolines of very high purity commercial availability of thiophosgene renders the method (therefore having the desired efficacy). unattractive. In method 4, the overall yield starting from It is still further object of this invention to provide N-cyano N'-((3,4-dimethoxyphenyl)-S-methyl-isothiourea (manufacture) novel intermediates including ureas and is reported to be ca. 63%. Nevertheless, the requirement of guanidines suitable for use to synthesize other guanidines this isothiourea as starting material the preparation of which for example 2-amino-substituted quinazolines including being very difficult and inefficient, renders the method 45 Terazosin, Prazosin, and Doxazosin and other guanidines for unattractive. example meobentine and Bethanidine. Compounds of general formula 3 are synthesized using Further and other objects of the invention will be realized S-alkylated thiourea and the corresponding amine. The by those skilled in the art from the following summary of the synthesis of Meobentine has been reported is U.S. Pat. No. invention and detailed description of the embodiments 3,949,089 as described below: 50 thereof.

HCS NH2 SUMMARY OF THE INVENTION -G According to one aspect of the invention a method of manufacture of compounds such as ureas and guanidines OMe 55 including cyclized guanidines for example 2-amino CH substituted quinazolines compounds (for example Terazosin, N1 Prazosin, Doxazosin, Tiodazosin, Trimazosin, Quinasin and l NHMe Bunazosin) and for example uncylized guanidines such as H meobentine and Bethanidine are provided, comprising: (a) (i) adding oxygen or a hetero radical containing H3CO oxygen to an intermediate compound for example by WIa;MEOBENTINE adding a carbonyl (c) to an amine in one embodiment in a form of converting an amine to its corresponding The use of thiophosgene to manufacture thiourea is lim 65 lica O ited due to its high toxicity and commercial unavailability. (ii) starting with an intermediate compound containing Use of ammonium thiocyanate on the other hand followed oxygen for example containing a carbonyl group in 5,675,006 9 10 some embodiments connected to an amine or forming the oxygen of the urea reacts with the electrophile (EP) part of a urea, to become a good leaving group that can be displaced and (b) carrying out in any order (i) or (ii) of this by a nucleophile for example such as ammonia or an subparagraph (b) amine; (i) react the oxygen for example the oxygen of a carbonyl, 5 (d) replacing the reaction product between the oxygen and with a suitable electrophile (EP) in which the combi EP (leaving group) of (c) by NH or an amine to nation of the oxygen-electrophile (O-EP) becomes a provide for example unsymmetrically substituted good leaving group that can be and is subsequently guanidines; displaced by for example a nucleophile (such as for (e) optionally, and if required closing the resulting sub example ammonia or an amine) and 10 stituted guanidine to provide 2-amino-substituted (ii) adding a desired radical to the results of subparagraph quinazolines such as Terazosin, Prazosin, and Dox (a) or b (i) if step (i) of subparagraph (b) is carried out aZosin. before this step (ii), and In this way, greater yields and high purity of known products can be achieved, for example steps (a) and (b) of (c) optionally, and if required, closing a ring to form for 15 example a 2-amino-substituted quinazoline. the immediately previous process being both converted in Other guanidines including quinazolines may also be very high yields of 85-95%. Furthermore compounds of the manufactured according to the invention as would be under invention may be conveniently prepared by a "one pot" stood by persons skilled in the art. synthesis, starting from the substituted urea (b). According to another aspect of the invention the desired According to another aspect of the invention, such a radical is ammonia or an amine radical. method may comprise; In this way, greater yields and higher purity in the a) taking a known intermediate and converting it to a urea; manufacture of known products can be achieved. Further b) adding a suitable electrophile (EP) to react with the more compounds of the invention may be conveniently oxygen of the urea to yield a reaction product as a prepared by a "one pot” synthesis. leaving group susceptible to replacement by an amine; EP is preferably POCl. EP may also comprise: PCls. 25 c) replacing the leaving group of (b) with an amine; POs, tosyl chloride (CH, SOCl)-TsCl- and in some instances mesyl chloride (CH, SOCl)-MsCl d) closing a ring if required to produce a desired com Thus according to another aspect of the invention, such a pound. method comprises; In accordance with another aspect of the invention, such a) taking a known intermediate and adding oxygen or a 30 a method may comprise; hetero radical containing oxygen to it for example by e) taking a known intermediate and converting it to a urea; adding a carbonyl (c) to an amine; f) adding a suitable electrophile (EP) to react with the b) adding a desired radical to the results of (a); oxygen of the urea to yield a reaction product as a c) adding a suitable electrophile (EP) to react with the leaving group susceptible to replacement by an amine; oxygen to yield a reaction product (O-EP) which is a 35 g) displacing the leaving group of the reaction product of leaving group susceptible to replacement by a nucleo (f) with an amine; phile such as ammonia or an amine; h) closing the ring if required to produce a desired compound. d) replacing the reaction product (leaving group) of (c) The salts of the guanidines may also be produced for with NH or an amine group; example Terazosin hydrochloride and terazosin hydrochlo e) closing a ring if required to produce a desired com ride dihydrate and Doxazosin Mesylate. pound. In accordance with another aspect of the invention, exem In accordance with another aspect of the invention, such plary novel processes of the manufacture of guanidine a method may comprise; compounds are disclosed. In one method, guanidine com f) taking an intermediate compound carrying oxygen (for 45 pounds are synthesized starting for example from 34 example the results of subparagraph (a) of the previous dimethoxyanthranilonitrile I and the corresponding amine paragraph) and adding a suitable electrophile (EP) to III. The initial reactants are all available and are easily react with the intermediate at the site of the oxygen to manufactured as would be understood by persons skilled in yield a reaction product therebetween as a leaving the art. group susceptible to replacement by a nucleophile such 50 In an exemplary method, an amine I (nitrile) is converted to its corresponding urea II in high yields (85-90%) with as ammonia or amine; sodium cyanate. The resulting urea is then condensed with g) replacing the reaction product (O-EP) (leaving group) a properamine DIN-(tetrahydro-2-furoyl)piperazine in the of (f) with NH or ammonia group; case of Terazosin, N-(2-furoyl) piperazine in the case of h) optionally adding a radical if desired before or after Prazosin, N-(1,4-Benzodioxan-2-carbonyl)piperazine in the carrying out either or both of steps (f) and (g); 55 case of Doxazosin, Methylthiooxadiazale carbonyl pipera i) closing a ring if required to produce a desired com zine in the case of Tiodazosin, 2,2-dimethyl-2-hydroxyethyl pound. ester piperazine in the case of Trimazosin, propene carbonyl According to another aspect of the invention a method of piperazine in the case of Quinazosin and butyroyl diazo manufacture of substituted ureas and guanidines including cycloheptane (a 7-membered dinitrogen radical) in the case 2-amino-substituted quinazoline compounds (for example 60 of bunazosin in refluxing pyridine to afford IV (85-95% yield). The intermediate IV is then reacted with an appro Terazosin, Prazosin and Doxazosin) is provided comprising; priate electrophile (e.g. POCl, PCls, tosyl chloride, phos (a) converting an amine to its corresponding urea; phorous pentoxide), resulting in the conversion of the oxy substituting the NH group of the substituted urea of (a) gen of the urea into a good leaving group (V). Addition of by an amine; 65 ammonia (e.g. ammonia gas or ammonium carbonate) will (c) reacting the resulting substituted urea with a suitable then displace the activated oxygen function, forming the electrophile (EP) to yield a reaction product in which corresponding guanidine VL. Quinazoline ring system VII is 5,675,006 11 12 then formed by the attack of the amino group of the guanidine on the nitrile. This is a very facile reaction and in fact intermediate VI was not isolated. The following reaction scheme thus presents itself:

R R H RO NH RO N NH + H-N=C=O - G DCI a-2 RO CN R2O CN

R3 R (a1n N1 RO N N ~ st-n EP o P = 3. RO CN EP POs, TsCl y ". R3 R (1) n- R

R1O 's-as ~ RO NH - G RO CN RO

W VI wherein-O-EP is the reaction of the urea oxygen and EP, -continued and is a leaving group substitutable by-NH2 or an amine. 40 In this scheme R may be hydrogen or lower alkoxy (for COMPOUND R. R. R. n R example methoxy), R and R may be lower alkyl (for DOKAZOSN H Me Me 1 O example methyl), n is a number selected from 1 and 2 and R may be selected from unsubstituted or substituted furoyl (for example furoyl or tetrahydrofuroyl), benzodioxanyl 45 carbonyl (for example 1,4-benzodioxan-2-yl carbonyl), s O C lower alkylthiooxadiazole carbonyl (for example methylth O iooxadiazole carbonyl), dialkyl hydroxy alkyl ester (for example 2,2-dimethyl hydroxy ethyl ester), alkene (for TODAZOSN H. Me 1 N-N example propene) and alkyroyl (for example butyroyl). 50 7 W The following chart identifies combinations of substitu st- O Ys, ents for identified Medicines: TRMAZOSN OMe Me Me 1 O 55 COMPOUND R. R. R. n. R so-n- OH PRAZOSN H Me Me 1 o1NMe

O QUINAZOSIN H Me Me 1 O N ERAZOSN H Me Me 1 BUNAZOSN H Me Me 2 O O O 65 5,675,006 13 14 Thus the following is specifically included: -continued NH (...), TETRAZOSN + H-N=C=O-Se O o RO CN O D. DOXAZOSIN O H R1O N NH2 10

R2 O CN O The radical R and R-C may be substituted by other radicals as is apparent from examination of the substituents T 15 for R. Usual work up of the reaction mixture results in the isolation of the desired product. Compounds II (including IT), IV (including IV"), V (including V") and VI (including VT) are novel and the processes of their manufacture are also novel. T H RO N N In the case of Meobentine and Bethanidine, urea Ia, for \ \ 25 example, dimethyl urea, is reacted with Electrophile (EP) to produce (Ia). Condensation of benzylamine (Ia) with IIa R2 CN -N R3 affords Meobentine and Bethanidine. IV O EP=POCl, PCls, POs, TsCl EP 30 an. EP H3 NichEPEPOCl,preferably G Ia RO N N wherein-O-EP is the reaction of the urea oxygen and EP st 35 and is a leaving group substitutable by -NH2 or ammonia R2DCI CN EPN \ s R3' EP R v" O1 wherein -O-EP is the reaction of the NH urea oxygen and EP, and is a leaving loss NHCH ReH, OMe G group substitutable by -NH2 or ammonia IIa Ia

45 HN HCN, NHCH R2 REOMe, MEOBENTINE R-H; BETHANDINE

RO Compounds IIa are new and the processes of their manu facture are also novel,

In another method, for example the urea nitrile II is initially activated with an electrophile (EP) such as POCl, PCls, etc. (see above) to form intermediate VIII in which the oxygen function of the urea reacted with the EP becomes a good leaving group. Displacement of the oxygen by a proper amine III and subsequent work-up results in the isolation of the desired quinazoline VII (for example terazosin). Com 65 pounds II, VI and VIII are novel. Preferably EP is PCOl. The following reaction scheme presents itself: 5,675,006 15 16

R H R RO N NH H N EP R1O N. NH O - B Se n O RO2 CN RO cN YEP EP =POCl, PCls, P.O.s, TsCl W wherein O-EP is the reaction of the urea oxygen and EP, and is a leaving group substitutable by -NH2 or amonia yi v HN N-R

I R3 R 1. N Y RO N N. N ~ RO Nst N ~ N C NH R a RO CN W NH WI wherein R R R2 R are selected from H Me Me 1 / \

O O H Me Me 1.

O O H Me Me 1. O * O C O H Me Me 1. N - N O 7 > O SCH

OMe Me Me 1. O

lso-N- OH o1N Me 5,675, 006 17 18 Thus the following is specifically included: -continued R1O N N H N NH2 s O

NO +EP-G RO \\ O CN NH

W" 10 R1O N-" O (The tetrahydrofuryl radical may be substituted by furyl or . N EP 1,4-benzodioxan-2-yl to produce Prazosin and Doxazosin, VIII 15 respectively. The tetrahydrofuryl radical, tetrahydrofuroyl wherein-O-EP is the reaction of the radical, and tetrahydrofuroyl piperazine radical may also be urea oxygen and EP, and is a leaving group substitutable by -NH2 or ammonia substituted by the other radicals for example those for R..)

/ In another method, for example the amine III is converted 20 to its corresponding urea DX with cyanic acid. Again the N \ O oxygen function of the urea is converted to a good leaving . group using an electrophile (EP) such as POCl, PCls, etc. to form X. Displacement of the activated oxygen by the " 25 amine function of I and subsequent work-up results in the isolation of the desired quinazoline VII, which may be N converted to its pharmaceutically acceptable salts (for 's O NH 2. example the hydrochloride or mesylate salt). The following CN 30 reaction scheme presents itself: WI

y V O NH y M HN N-R3+H-N=C=O-G )-N N-R3-G )-N N-R3 \ ? HN M / EP-O N / X X wherein-O-EP is the reaction of the urea oxygen and EP, and is a leaving group substitutable by -NH2 or ammonia R RO NH EP = POCl, PCls, POs, MsCL, TsCl R CN I R3 R3 R 1. N 1 R 1. N / R1O N N- N ~ RO NN N ~ N C- NH R al R CN VII NH VI

wherein R R R2 i R are selected from 5,675,006 19 20 -continued H Me Me 1. / \

O O H Me Me 1

O O H Me Me 1 --CC

OMe Me Me O

lso-N- OH o1N Me H Me Me 1. N

and H Me Me 2 O -N- Me

35 Compounds DX, X and VI are novel and processes of their Thus the following is included: manufacture are also novel.

I EP-POCl3, POs, PCs DX." MsCl, TsCl EP

R1O NH

HN N R1O N. N. RO CN N-NH, \ \ - NEP\ R2 CN O X" wherein -O-EP is the reaction of the urea oxygen and EP, and is a leaving group substitutable by -NH2 or ammonia 5,675,006 22 -continued RO N N N N RO a \ \ O O NH VII"

RO N N N N RO e \ \ i O X NHHCl2.H2O

(Once again the tetrahydrofuryl radical may be replaced -continued by furyl or 14-benzodioxan-2-yl). The tetrahydrofuryl radi H IV" cal and the tetrahydrofuroyl radicals may also be substituted 20 R1O N as is apparent. Compounds VI", DX" and X" are novel and the processes R2 CN 1. \\ O of their manufacture are also novel. Thus according to another aspect of the invention, com 25 pounds of the formula R3 V R ( N1 R O R H N II / N-C-N RO N - / N 30 O R R R CN are provided wherein "N- DX" R is selected from hydrogen, R is selected from 35 hydrogen, and a substituted phenyl radical substituted \\ O by at least one of alkoxy (for example methoxy) and cyano, and R and R are each selected from hydrogen, (provided R. O y; V DX and Rare not hydrogen when RandR are hydrogen) or may with the nitrogen be connected together to form )-N N-R a closed ring preferably containing at least a second HN M M nitrogen, (preferably being a 6-membered or According to another aspect of the invention compounds 7-membered ring), the closed ring being substituted by of the formula substituted carbonyl for example R carbonyl (wherein 45 R is selected from furyl, tetrahydrofuryl, 1.4- / benzodioxan-2-yl, alkylthiooxadiazole for example NC-N methylthiooxadiazole and alkyl (for example propyl), / dialkyl hydroxy alkyl ester for example, 2,2-dimethyl R R 2-hydroxy-ethyl ester, and alkene (for example 50 propene). are provided, wherein: Exemplary of such compounds are II, DT, IV, IV". DX and DX" EP is an electrophile and together with the oxygen forms Set out below: a leaving group wherein-O-EP is the reaction of the 55 urea oxygen and EP, and is leaving group substitutable H by -NH2 or ammonia (preferably substitutable by RO N NH NH2 or an amine) (preferably EP being selected from POCl, PO, PCls, mesyl chloride and tosyl chloride), O R is selected from hydrogen, alkyl (for example methyl) R CN and a substituted phenyl radical substituted by at least R one of alkoxy (for example methoxy) and cyano, and H RandR are each selected from hydrogen, lower alkyl R1O N NH (for example methyl) a substituted phenyl radical sub O stituted by at least one alkoxy (for example methoxy) R CN 65 and cyano or may with the nitrogen be connected together to form a closed ring preferably containing at least a second nitrogen, (preferably being a 5,675,006 23 24 6-membered or 7-membered ring), the closed ring Exemplary of such compounds are compounds V, VT and being substituted by R-carbonyl (wherein R is selected VI" set out below: from for example furyl, tetrahydrofuryl, 1,4- benzodioxan-2-yl, akylthiooxadiazole, for example RO N N WT methylthiooxadiazole, alkyl for example propyl, dialkyl hydroxy alkyl ester for example 2,2-dimethyl st O 2-hydroxy-ethyl ester and alkene (for example NH \\ propene). Exemplary of such compounds are V, V, IIa, R CN R3 VIII, VII, X and X" set out below: where Raris, furyl, 10 tetrahydrofuryl, or R1O N N v *n n 1,4-benzodioxan-2-yl s O R3 w RO CN YEP l R3 R (a1n N1 RO N. N. ~ R3 w N R (1. NY NH RO N N ~ RO CN N RO N N VI" R CN o, EP 20 N. EP a. RO CN NH \\ O O o1

es NHCH 25 H WT Additionally compounds VII and XI are of higher purity RO NSl" than prior art compounds and contain for example residues O n of II, IV, V, VI, VII, IX or X. R CN EP 30 R W R H H RO N NH RO NSl" O O R CN n EP 35 R CN R3 IV N- X R H (1. N1 NEPN \ . O RO N ~ O R CN NH y; \ X R3 w R (1. N1 )-N N-R 45 EP-O \ / RO N.N. N. ~ wherein - O EP is the reaction of the urea oxygen and EP, and O is a leaving group substitutable by NH or ammonia RO CN n EP According to another aspect of the invention compounds 50 R3 WI of formula R (1. N1 NH R R1O N. N. ~ / st NECN NH M 55 RO CN R R R WI H are provided wherein R is selected from a substituted phenyl being substituted by a radical selected from at least RO NSl" one of alkoxy (for example methoxy) and cyano and R. R. 60 together with the Nitrogen, form a closed ring preferably RO O CN O n EP containing a second nitrogen (preferably being a 6-7 mem bered ring), the closed ring being substituted by furoyl, O y \ X tetrahydrofuroyl, 14-benzodioxan-2-yl carbonyl, methylth )-N N-R iooxadiazole carbonyl, dialkyl hydroxy alkyl ester (for 65 example 2, 2-dimethyl-2-hydroxy-ethyl ester), alkene (for example propene), alkoyl (for example butyroyl) 5,675,006 25 26 -continued -continued NH y V X RO VI )- N N-R EP-O \ A 5 R wherein the appropriate substituents are selected dependent on the medicine for example see the chart below:

COMPOUND R R. R. n R 10 PRAZOSIN H Me Me 1 / \

O O 15 TERAZOSN H Me Me 1

O O 20 DOXAZOSN H Me Me O

OX"

s O C 25 O TODAZOSN. H. Me Me 1 N - N wherein-O-EP is the reaction of the urea oxygen and EP, o, 14 ya and is a leaving group substitutable by -NH or ammonia. O SCH 30 Where the medicine is Prazosin the residues II, IV", V", VT", VIIT, DX" and/or X" may be: TRMAZOSN OMe Me Me 1 O H I l Me RO N NH o1N OH 35 Me O QUINAZOSIN H Me Me 1 R DCCCN N H IV" RO N N BUNAZOSN H Me Me 2 -N-n.O DOC N \, O The combinations of these residues with VII and XI are also new providing a product of higher purity. Thus for 45 R1O N N wn example for Terazosin, the residues IT, IV", V", VI", VIII, X" and/or X" are follows: R DONCN NEP \ .NA y H T O RO N.N. 50 R1O N N VII." O R CN RODCCN CN 2 \ NA. y H IV." O 55 RO N H WT RO N NH R CN n O r R cN YEP H.N. N. DX." RO NN N w" N. R cN na EPN \ i O 65 5,675,006 27 28 -continued -continued N X" R3 R ( N1 H 5 R1O N ~ O wherein-O-EP is the reaction of the urea oxygen and EP, R CN and is a leaving group substitutable by -NH2 or ammonia. R3 R (s N1 Where the medicine is doxazosin the residues II, IV, V, 10 VT, VIT, DX and/or X may be:

H T RO N NH 15 O R CN H IV RO N R2O CN 1. \\ -, R1O N N w N 25 R2O CN NEPN \ re,. RO N N VE

35 EP-O M / wherein-O-EP is the reaction of the urea oxygen and EP, NH and is a leaving group substitutable by -NH2 or ammonia wherein for the medicine: "N N X (a) TIODAZOSIN R is H O \ \ O R is Methyl s R is Methyl HN N X n is 1. 45 and R is

N - N

(b) TRIMAZOSIN and wherein-O-EP is the reaction of the urea oxygen and R is methoxy (OMe) EP, and is a leaving group substitutable by -NH or 55 R is Methyl ammonia. R is Methyl In respect of the medicines Tiodazosin, Trimazosin, and R is Quinasin and Bunazosin, the residues are II, IV, V,VI,VIII, DX and/or X

R H RO N NH O 65 (c) QUINAZOSIN RO CN R is hydrogen R is Methyl 5,675,006 29 30 R is Methyl Hmmr (CDC) d5.60 (bs, 2H, NH,); 4.32 (t, J=7.0 Hz, and R is 1H, CH, C-2 (tetrahydrofuroyl)); 3.80 (t, J-6.0 Hz, 2H, CH, C-5 (tetrahydrofuroyl));3.70-2.80 (m, 8H, CH's (C-2, C-3, C-5, C-6 (piperazinyl))); 2.39-149 (m, 4H, CH's (C-3, C-4 X-1s (tetrahydrofuroyl)). EXAMPLE 3 (d) BUNAZOSIN R is hydrogen 3,4-dimethoxy-6-4-(2-tetrahydrofuroyl)piperazine R is Methyl 10 1-ylcarbamidol benzonitrile (TV) R is Methyl 3,4-Dimethoxy-6-cyanoaniline-1-ylformamide (2.75 g, and R is 12.5 mmol) (II) and 4-(2-tetrahydrofuroyl) piperazine (2.56 g, 13.9 mmol) (III) are suspended in 25 mL dry pyridine and O the mixture is refluxed for 3 hours. The solvent is then 15 vacuum distilled to a minimum volume and then azeotroped -N- with small portions of water. The final aqueous solution is extracted with six portions (20 mL) of ethyl acetate. The Where the medicine is Meobentine or Bethanidine, the organic layer is concentrated and applied to a silica gel residue includes IIa. column (25 cmx2.5 cm). It is then eluted with ethyl acetate initially and the polarity is gradually increased with ethanol to a final solvent ratio of 80:20. Fractions containing the product (TLC: 80:20 ethylacetate:methanol, R=0.5) are combined and the solvent evaporated. The pure product is NHCH crystallized from a small volume of ethyl acetate as light 25 yellow needles (4.27 g. 85% yield). Thus the combinations of the above medicines with at "H nmr (CDC) d 7.35 (s, 1H, ArH, C-2); 7.10 (bs, 1H, least one of the associated residues is new and provides NH; 6.85 (s, 1H, ArH, C-5); 4.58 (t, J-7.0 Hz, 1H, CH, C-2 medicine having a very high purity. (tetrahydrofuroyl)); 3.89 (s. 3H, OCH); 3.80 (s, 3H, The invention will now be illustrated with respect to the OCH); 4.11-3.18 (m. 10H, CH's (C-2, C-3, C-5, C-6 following exemplary methods of manufacture. (piperazinyl), C-5 (tetrahydrofuroyl))); 2.22-149 (m, 4H, CH's (C-3, C-4 (tetrahydrofuroyl))). DETALED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION EXAMPLE 4 EXAMPLE 1. 35 3,4-dimethoxy-6-4-(2-tetrahydrofuroyl)piperazine 3,4-Dimethoxy-6-cyanoaniline-1-ylformamide (II) 1-ylcarbamidobenzonitrile(IV) 3,4-Dimethoxyanthranilonitrile (300 g, 1.69 mol) is 3,4-Dimethoxy-6-cyanoaniline-1-ylformamide (2.75 g, taken in glacial acetic acid (1500 mL) and cooled to +5°C. 12.5 mmol) (II) and 4-(2-tetrahydrofuroyl)piperazine (2.56 To this solution is added a suspension of sodium cyanate g, 13.9 mmol) (III) are suspended in 25 mL dry dimethyl (160.5g, 2.46 mol in 750 mL of deionized water) in 100 mL formamide and the mixture is refluxed for 3 hours. The portions over a thirty minute period. Acetone (6000 mL) is solvent is then vacuum distilled to a minimum volume and added and the mixture is maintained at +5° C. for an then azeotroped with small portions of water. The final additional 30 minutes. The product is filtered and the cake is aqueous solution is extracted with six portions (20 mL) of washed with acetone (2x150 mL) (293/7 grams, 79% yield). 45 ethyl acetate. The organic layer is concentrated and applied "H nmr (DMSO-d) d 8.19 (bs, 1H, NH); 748 (s, 1H, to a silica gel column (25 cmx2.5 cm). It is then eluted with C-5); 6.98 (s, 1H, C-2); 6.12 (bs, 2H, NH); 3.65 (s, 3H, ethyl acetate initially and the polarity is gradually increased OCH); 3.60 (s, 3H, OCH). with ethanol to a final solvent ratio of 80:20. Fractions EXAMPLE 2 containing the product (TLC: 80:20 ethylacetate:methanol, 50 R=0.5) are combined and the solvent evaporated. The pure 4-(2-tetrahydrofuroyl)piperazine-1-ylformamide product is crystallized from a small volume of ethyl acetate (DX) as light yellow needles (2.85 g, 60% yield). 4-(2-Tetrahydrofuroyl)piperazine (33.25 g, 180.7 mmol) 'nmr (CDC) d7.35 (s, 1H, ArH, C-2); 7.10 (bs, 1H, NH; (III) is dissolved in 165 mL water. 5N Hydrochloric acid 6.85 (s, 1H, ArH, C-5); 4.58 (t, J-7.0 Hz, 1H, CH, C-2 (34.5 mL) is added and the suspension is heated to 70° C. 55 (tetrahydrofuroyl)); 3.89 (s. 3H, OCH); 3.80 (s, 3H, with stirring. Sodium cyanate (13.1 g, 201.15 mmol) is OCH); 4.11-3.18 (m. 10H, CH's (C-2, C-3, C-5, C-6 added in small portion to the stirring solution and heating is (piperazinyl), C-5 (tetrahydrofuroyl))); 2.22-1.49 (m, 4H. continued for an additional 2 hours. The reaction mixture is CH's (C-3, C-4 (tetrahydrofuroyl))). concentrated under reduced pressure to yield a thick oil. Chloroform (100 mL) is added to the off and the solution is EXAMPLE 5 heated to reflux. The hot solution is filtered and the filtrate 3,4-dimethoxy-6-4-(2-tetrahydrofuroyl)piperazine is dried over NaSO. The dried solution is concentrated 1-ylcarbamidobenzonitrile (IV) under reduced pressure to a thick yellow oil. Ether (50 mL) is added to the oil and white crystals precipitated out. The (3,4-Dimethoxy-6-cyanoaniline-1-ylformamide (2.75 g. productisfiltered, washed with ether (25 mL) and dried. The 65 12.5 mmol) (II) and 4-(2-tetrahydrofuroyl)piperazine (2.56 product is used without further purification (33.8 g., 82.3% g, 13.9 mmol) (III) are suspended in 25 mL dry dichloro yield). ethane and the mixture is refluxed for 3 hours. 5,675,006 31 32 Water (30 mL) is added and the mixture is stirred at room added and the resulting solution is heated to 80° C. and temperature for 15 minutes. The layers are separated and the maintained for thirty minutes. The reaction mixture is aqueous phase is further extracted with five portions of removed from the heat and allowed to cool to room tem dichloroethane (20 mL). The organic layer is concentrated perature. Compound V is the result, Anhydrous, NH gas and applied to a silica gel column (25 cmx2.5 cm). It is then is moderately purged through the reaction mixture and the eluted with ethyl acetate initially and the polarity is gradu internal temperature is allowed to rise independently to a ally increased with ethanol to a final solventratio of 80:20. maximum temperature (70° C.-80° C). When the internal Fractions containing the product (TLC: 80:20 temperature drops below the previously attained maximum ethylacetate:methanol, R=0.5) are combined and the solvent temperature, the reaction mixture is slowly heated to 100° C. evaporated. The pure product is crystallized from a small 10 (alternatively (NH)CO can be used as a source of volume of ethyl acetate as light yellow needles (1.18 g. 25% ammonia). The reaction mixture is cooled to 60° C. and then yield). vacuum distilled to a minimum volume. The residual pyri *H nmr (CDC) d 7.35 (s, 1H, ArH, C-2); 7.10 (bs, 1H, dine is azeotroped off with small amounts of water. Water NH; 6.85 (s. 1H, ArH, C-5); 4.58 (t, J-7.0 Hz, 1H, CH, C-2 (10 mL) and n-butanol (30 mL) are added to the aqueous (tetrahydrofuroyl)); 3.89 (s, 3H, OCH); 3.80 (s, 3H, 15 solution and the mixture is heated to 60° C. the Warm OCH); 4.11-3.18 (m, 10H, CH's (C-2, C-3, C-5, C-6 mixture is basified to pH-100 with dropwise addition of (piperazinyl), C-5 (tetrahydrofuroyl))); 2.22-1.49 (m, 4H, 10% NaOH. The layers are separated and the aqueous phase CH's (C-3, C-4 (tetrahydrofuroyl))). is further extracted with three portions (20 mL) of n-butanol. The organic extractions are combined and filtered through a EXAMPLE 6 20 bed of celite. The filtrate is dried over NaSO concentrated under reduced pressure and applied to a silica gel column 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino (35 cmx5 cm). It is then eluted initially with ethyl acetate 6,7-dimethoxyquinazoline (VII) and the polarity is gradually increased with ethanol to a final The reaction mixture of Example 3 is cooled to 20° C. solvent ratio of 80:20. Fractions containing the product (after the three hour reflux). POCl (2.11 g, 13.75 mmol) is 25 (TLC: 80:20 ethyl acetate:methanol, R=0.37) are combined added and the resulting solution is heated to 70° C. and and concentrated under reduced pressure. The pure product maintained for thirty minutes. The reaction mixture is is crystallized from a minimum volume of ethyl acetate as removed from the heat and allowed to cool to room white crystals (2.78 g, 59% yield). temperature. Compound V is the result). Anhydrous, NH "H nmr (CDC1,) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H. gas is moderately purged through the reaction mixture and NH); 4.82-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 the internal temperature is allowed to rise independently to (s, 3H, OCH); 3.90 (s, 3H, OCH): 4.10-3.42 (m. 10H, CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 a maximum temperature (70° C-80° C). When the internal (tetrahydrofuroyl))): 2.39-1.75 (m, 4H, CH's (C-3, C-4 temperature drops below the previously attained maximum (tetrahydrofuroyl))). temperature, the reaction mixture is slowly heated to 100°C. 35 (alternatively (NH), CO can be used as a source of EXAMPLE 8 ammonia). The reaction mixture is cooled to 60° C. and then vacuum distilled to a minimum volume. The residual pyri 2-4-(2-Tetrahydrofuroylpiperazine-1-yl)-4-amino-6, dine is azeotroped off with small amounts of water. Water 7-dimethoxyquinazoline (VII) (10 mL) and n-butanol (30 mL) are added to the aqueous The reaction mixture of Example 3 is cooled to 20° C. solution and the mixture is heated to 60° C. The warm (after the three hour reflux). POs (2.66 g, 18.75 mmol) is mixture is basified to pH-10.0 with dropwise addition of added and the resulting solution is heated to 80° C. and 10% NaOH. The layers are separated and the aqueous phase maintained for thirty minutes. The reaction mixture is is further extracted with three portions (20 mL) of n-butanol. removed from the heat and allowed to cool to room The organic extractions are combined and filtered through a 45 temperature.Compound V is the result). Anhydrous, NH bed of celite. The filtrate is dried over NaSO, concentrated gas is moderately purged through the reaction mixture and under reduced pressure and applied to a silica gel column the internal temperature is allowed to rise independently to (35 cmx5 cm). It is then eluted initially with ethyl acetate a maximum temperature (70° C-80° C). When the internal and the polarity is gradually increased with ethanol to a final temperature drops below the previously attained maximum solvent ratio of 80:20. Fractions containing the product 50 temperature, the reaction mixture is slowly heated to 100° C. (TLC: 80:20 ethyl acetate:methanol, R=0.37) are combined (alternatively (NH)2CO can be used as a source of and concentrated under reduced pressure. The pure product ammonia). The reaction mixture is cooled to 60° C. and the is crystallized from a minimum volume of ethyl acetate as vacuum distilled to a minimum volume. The residual pyri white crystals (3.02 g. 67% yield). dine is azeotroped off with small amounts of water. Water "H nmr (CDC) d 6.98 (s, 1H, ArH. C-5); 5.52 (bs, 2H, 55 (10 mL) and n-butanol (30 mL) are added to the aqueous NH); 4.82-4.50 (m. 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 solution and the mixture is heated to 60° C. The warm (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, mixture is basified to pH-10.0 with dropwise of 10% NaOH. CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 The layers are separated and the aqueous phase is further (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 extracted with three portions (20 mL) of n-butanol. The (tetrahydrofuroyl))). organic extracts are combined and filtered through a bed of celite. The filtrate is dried over NaSO concentrated under EXAMPLE 7 reduced pressure and applied to a silica gel column (35 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino cmX5 cm). It is then eluted initially with ethyl acetate and 6,7-dimethoxyquinazoline (VII) the polariyy is gradually increased with ethanol to a final 65 solvent ratio of 80:20. Fractions containing the product The reaction mixture of Example 3 is cooled to 20° C. (TLC: 80:20 ethyl acetate:methanol, R=0.37) are combined (after the three hour reflux). PCls (3.90 g, 18.75 mmol) is and concentrated under reduced pressure. The pure product 5,675,006 33 34 is crystallized from a minimum volume of ethyl acetate as aqueous solution and with vigorous stirring the mixture is white crystals (0.71 g, 15% yield). basified to pH=10 with dropwise addition of 10% NaOH. "H nmr (CDC) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, The layers are separated and the aqueous phase is further NH); 4.82-4.50 (m. 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 extracted with four portions (10 mL) of chloroform. The (s, 3H, OCH); 3.90 (s, 3H, OCH,); 4.10-3.42 (m, 10H, organic extracts are combined and filtered through a bed of CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 celite. The filtrate is dried over NaSO, concentrated under (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 reduced pressure and applied to a silica gel column (25 (tetrahydrofuroyl))). cmx2.5 cm). It is then eluted initially with ethyl acetate and the polarity is gradually increased with ethanol to a final EXAMPLE 9 10 solvent ratio of 80:20. Fractions containing the product (TLC: 80:20 ethylacetate:methanol, R=0.37) are combined 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl-4-amino and concentrated under reduced pressure. The pure product 6,7-dimethoxyquinazoline (VII) is crystallized from a minimum volume of ethyl accetate as white crystals (0.77 g, 20% yield). The reaction mixture of Example 3 is cooled to 20° C. (after the three hour reflux). P-toluenesulfonyl chloride (3.57 15 *H nmr (CDC) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, g, 18.75 mmol) is added and the resulting solution is heated NH); 4.82-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 to reflux and maintained for ninety minutes. The reaction (s. 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, mixture is removed from the heat and allowed to cool to CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 room temperature. Compound V is the result, Anhydrous (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 NH gas is moderately purged through the reaction mixture (tetrahydrofuroyl))). and the internal temperature is allowed to rise independently to a maximum temperature (70° C.-80° C). When the EXAMPLE 11 internal temperature drops below the previously attained 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino maximum temperature, the reaction mixture is slowly heated 25 6,7-dimethoxyquinazoline (VII) to 100° C. (alternatively (NH)CO can be used as a source of ammonia). The reaction mixture is cooled to 60° C. and Under an inert atmosphere (N) and anhydrous conditions the vacuum distilled to a minimum volume. The residual 3,4-dimethoxy-6-cyanoanaline-1-ylformamide (2.21 g, 10 pyridine is azeotroped off with small amounts of water. mmol) is suspended in dry pyridine (10 mL). With vigorous Water (10 mL) and n-butanol (30 mL) are added to the stirring PCls (2.50 g, 12 mmol) is added and the solution is aqueous solution and the mixture is heated to 60° C. The heated to 60° C. and maintained for fifteen minutes. 4-(2- warm mixture is basified to pH-10.0 with dropwise addition Tetrahydrofuroyl)piperazine (2.20 g, 12 mmol is added and of 10% NaOH. The layers are separated and the aqueous the reaction mixture is brought to reflux and maintained for phase is further extracted with three portions (20 mL) of two hours. Compound V was produced but not isolated. n-butanol. The organic extracts are combined and filtered 35 The solvent is vacuum distilled off to a minimum volume through a bed of celite. The filtrate is dried over NaSO and the residual pyridine is azeotroped off with small concentrated under reduced pressure and applied to a silica portions of water. Water is added to the aqueous mixture to gel column (35 cmx5 cm). It is then eluted initially with bring the reaction volume to 30 mL. Chloroform (30 mL) is ethyl acetate and the polarity is gradually increased with then added to the aqueous solution and with vigorous ethanol to a final solventratio of 80:20. Fractions containing stirring the mixture is basified to pH=10 with drowise the product (TLC:80:20 ethyl acetate:methanol, R=037) addition of 10% NaOH. The layers are separated and the are combined and concentrated under reduced pressure. The aqueous phase is further extracted with four portions (10 pure product is crystallized from a minimum volume of mL) of chloroform. The organic extracts are combined and ethyl acetate as white crystals (0.23 g5% yield). filtered through a bed of celite. The filtrate is dried over "H nmr (CDC) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, 45 NaSO, concentrated under reduced pressure and applied to NH); 4.82-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 a silica gel column (25 cmx2.5 cm). It is then eluted initially (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, with ethyl acetate and the polarity is gradually increased CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 with ethanol to a final solvent ratio of 80:20. Fractions (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 containing the product (TLC: 80:20 ethyl acetate:methanol, (tetrahydrofuroyl))). 50 R=0.37) are combined and concentrated under reduced pressure. The pure product is crystallized from a minimum EXAMPLE 10 volume of ethyl acetate as white crystals (0.60 g, 16% yield). 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino "H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, 6,7-dimethoxyquinazoline (VII) NH); 4.82-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 55 (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, Under an inert atmosphere (N) and anhydrous conditions CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 3,4-dimethoxy-6-cyanoanaline-1-ylformamide (2.21 g, 10 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 mmol) is suspended in dry pyridine (10 mL). With vigorous (tetrahydrofuroyl))). stirring POC (1.9 g, 12 mmol) is added and the solution is heated to 60° C. and maintained for fifteen minutes. 4-(2- EXAMPLE 2 Tetrahydrofuroyl)piperazine (2.20 g, 12 mmol) is added and 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino the reaction mixture is brought to reflux and maintained for two hours. Compound V is produced but not isolated). The 6,7-dimethoxyquinazoline (VTI) solventis distilled off to a minimum volume and the residual 3,4-Dimethoxy-6-cyanoanaline-1-ylformamide (2.21 g, pyridine is azeotroped off with small portions of water. 65 10 mmol) is suspended in dry pyridine (10 mL) and with Water is added to the aqueous mixture to bring the reaction stirring p-toluenesulfonyl chloride (2.5 g. 13 mmol) is added volume to 30 mL. Chloroform (30 mL) is then added to the portionwise. The reaction mixture is heated on a water bath 5,675,006 35 36 (60° C.) until complete dissolution is achieved 4-(2- heated until total dissolution is achieved. Triethylamine (2.0 Tetrahydrofuroyl)piperazine (2.20 g, 12 mmol) is added and g, 20 mmol) is added and the solution is stirred for 5 the mixture is brought to reflux and maintained for two minutes. P-toluenesulfonyl chloride (3.92 g. 20 mmol) is hours. The solvent is vacuum distilled off to a minimum added and the reaction mixture is heated to reflux and volume and the residual pyridine is azeotroped off with maintained for 3 hours. Compound X is produced. 3,4- Small portions of water. Water is added to the aqueous Dimethoxyanthrallinonitrile (1.78 g, 10 mmol) is added and mixture to bring the reaction volume to 30 mL. Chloroform reflux is continued for an additional 24 hours. Compound (30 mL) is then added to the aqueous solution and with VI is the result). Water (30 mL) is added and with vigorous vigorous stirring the mixture is basified to pH=10 with stirring the mixture is basified to pH=10 with dropwise dropwise addition of 10% NaOH. The layers are separated O addition of 10% NaOH. The layers are separated and the and the aqueous phase is further extracted with four portions aqueous phase is further extracted with four portions (10 (10 mL) of chloroform. The organic extracts are combined mL) of dichloroethane. The organic extracts are combined and filtered through a bed of celite. The filtrate is dried over and filtered through a bed of celite. The filtrate is dried over NaSO, concentrated under reduced pressure and applied to NaSO, concentrated under reduced pressure and applied to a silica gel column (25 cmx2.5 cm). It is then eluted initially 15 a silica gel column (25 cmx2.5 cm). It is then eluted initially with ethyl acetate and the polarity is gradually increased with ethyl acetate and the polarity is gradually increased with ethanol to a final solvent ratio of 80:20. Fractions with ethanol to a final solvent ratio of 80:20. Fractions containing the product (TIC: 80:20 ethyl acetate:methanol, containing the product (TLC: 80:20 ethyl acetate:methanol, R=0.37) are combined and concentrated under reduced R=0.37) are combined and concentrated under reduced pressure. The pure product is crystallized from a minimum 20 pressure. The pure product is crystallized from a minimum volume of ethyl acetate as white crystals (0.53 g. 14% yield). volume of ethylacetate as white crystals (0.76g, 20% yield). "H nmr (CDC) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, "H nmr (CDCl) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, NH); 4.82-4.50 (m. 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 NH); 4.82-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)), 3.98 (s, 3H, OCH); 3.90 (s, 3H, OCH,); 4.10-3.42 (m, 10H, (s, 3H, OCH); 3.90 (s, 3H, OCH.); 4.10-3.42 (m. 10H, CH2's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 25 CH2's (C-2, C-3, C-5. C-6 (piperazinyl), C-5 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 (tetrahydrofuroyl))), 2.39-1.75 (m. 4H. CH's (C-3, C-4 (tetrahydrofuroyl))). (tetrahydrofuroyl))). EXAMPLE 13 EXAMPLE 1.5 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino 6,7-dimethoxyquinazoline (VII) 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl-4-amino 3.4-dimethoxy-6-cyanoanaline-1-ylformamide (2.21 g, 6,7-dimethoxyquinazoline (VII) 10 mmol) is suspended in dry dichloroethane (10 mL) and Amixture of 3,4-dimethoxyanthranilonitrile (7.91 g, 44.5 triethylamine (2.0g, 20 mmol) is added and the suspension mmol), 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide is stirred for 10 minutes. P-toluenesulfonyl chloride (2.5 g. 35 (10.1 g, 44.5 mmol) and P.O. (32.0 g, 225 mmol) in dry 13 mmol) is added portionwise and the reaction mixture is pyridine (50 mL) is refluxed with stirring for 2.5 hours. The heated to reflux and maintained for one hour, The mixture is reaction mixture is then allowed to cool to room temperature allowed to cool to room temperature and 4-(2- over a 1 hour period and then poured into a vessel containing Tetrahydrofuroyl)piperazine (2.20 g, 12 mmol) is added and sodium bicarbonate (60 g). The reaction vessel is then the mixture is brought to reflux and maintained for two washed with four portions of water (50 mL) which are hours. Water (30 mL) is added and with vigorous stirring the combined with bicarbonate mixture. The mixture is stirred mixture is basified to pH:10 with dropwise addition of 10% for 30 minutes and filtered. The filtrate is then extracted with NaOH. The layers are separated and the aqueous phase is four portions of chloroform (100 ml). The organic layers are further extracted with four portions (10 mL) of dichloroet combined, dried over NaSO and concentrated under hane. The organic extracts are combined and filtered through 45 reduced pressure. The orange oil obtained is applied to a a bed of celite. The filtrate is dried over NaSO, concen silica gel column (25 cmx2.5 cm) and is eluted initially with trated under reduced pressure and applied to a silica gel ethyl acetate and the polarity is gradually increased with column (25 cmx2.5 cm). It is then eluted initially with ethyl ethanol to a final solventratio of 80:20. Fractions containing acetate and the polarity is gradually increased with ethanol 50 the product (TLC: 80:20 ethyl acetate: methanol, R=0.37) to a final solvent ratio of 80:20. Fractions containing the are combined and concentrated underreduced pressure. The product (TLC: 80:20 ethyl acetate:methanol, R:0.37) are pure product is crystallized from a minimum volume of combined and concentrated under reduced pressure. The ethyl acetate as white crystals (2.05 g, 12% yield). pure product is crystallized from a minimum volume of "H nmr (CDC) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, ethyl acetate as white crystals (0.38 g, 10% yield), 55 NH); 4.82-4.50 (m. 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 "H nmr (CDC) d 6.98 (s. 1H, ArH, C-5); 5.52 (bs, 2H, (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, NH); 4.82-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 (s, 3H, OCH): 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 CH,2's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 (tetrahydrofuroyl))). (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 (tetrahydrofuroyl))). EXAMPLE 16 EXAMPLE 14 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino 2-4-(2-Tetrahydrofuroylpiperazine)-1yl)-4-amino-6, 6,7-dimethoxyquinazoline (VII) 7-dimethoxyquinazoline (VII) 65 A mixture of 3,4-dimethoxy-6-cyanoaniline-1- 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g. ylformamide (10.6 g., 48 mmol) (II), 4-(2-tetrahydrofuroyl) 10 mmol) is suspended in dichloroethane (15 mL) and piperazine (8.8 g., 48 mmol) (III) and POs (36 g. 250 mmol) 5,675,006 37 38 in dry pyridine (100 mL) is refluxed with stirring for 4 hours. Dimethoxyanthranilonitrile (1.78 g, 10 mmol) is added and The reaction mixture is then allowed to cool to room the mixture is brought to reflux and maintained for three temperature over a 1 hour period and then poured into a hours. The solvent is vacuum distilled off to a minimum vessel containing sodium bicarbonate (60 g). The reaction volume and the residual pyridine is azeotroped off with vessel is then washed with four portions of water (50 mL) small portions of water. Water is added to the aqueous which are combined with bicarbonate mixture. The mixture mixture to bring the reaction volume to 30 mL. Chloroform is stirred for 30 minutes and filtered. The filtrate is then (30 mL) is then added to the aqueous solution and with extracted with four portions of chloroform (100 ml). The vigorous stirring the mixture is basified to pH=10 with organic layers are combined, dried over NaSO and con dropwise addition of 10% NaOH. The layers are separated centrated under reduced pressure. The orange of obtained is and the aqueous phase is further extracted with four portions applied to a silica gel column (25 cmx2.5 cm) and is eluted (10 mL) of chloroform. The organic extracts are combined initially with ethyl acetate and the polarity is gradually and filtered through a bed of celite. The filtrate is dried over increased with ethanol to a final solvent ratio of 80:20. Na2SO, concentrated underreduced pressure and applied to Fractions containing the product (TLC: 80:20 ethyl acetate: a silica gel column (25 cmx2.5 cm). It is then eluted initially methanol, R0.37) are combined and concentrated under 15 with ethyl acetate and the polarity is gradually increased reduced pressure. The pure product is crystallized from a with ethanol to a final solvent ratio of 80:20. Fractions minimum volume of ethyl acetate as white crystals (1.85g. containing the product (TLC: 80:20 ethyl acetate:methanol, 10% yield). R=0.37) are combined and concentrated under reduced "H nmr (CDC) d 6.98 (s. 1H, ArH, C-5); 5.52 (bs, 2H, pressure. The pure product is crystallized from a minimum NH); 4.82-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 volume of ethyl acetate as white crystals (0.26g, 7% yield). (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m. 10H, "H nmr (CDCl3) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 NH); 4.82-4.50 (m, 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.1.0-3.42 (m, 10H, (tetrahydrofuroyl))). CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 (tetrahydrofuroyl))): 2.39-1.75 (m, 4H, CH's (C-3, C-4 EXAMPLE 17 (tetrahydrofuroyl))), 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino EXAMPLE 19 6,7-dimethoxyquinazoline (VTI) 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g. 2-4-(2-Tetrahydrofuroylpiperazine-1-yl)-4-amino 10 mmol) is suspended in dichloroethane (15 mL) and 6,7-dimethoxyquinazoline (VII) heated until total dissolution is achieved. Triethylamine (2.0 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g, g, 20 mmolis added and the solution is stirred for 5 minutes. 10 mmol) is suspended in dichloroethane (15 mL) and with Methanesulfonyl chloride (2.29 g, 20 mmol) is added and 35 stirring POCl (1.8 g., 12 mmol) is added and the reaction the reaction mixture is heated to reflux and maintained for 1 mixture is stirred for an additional ten minutes. 3,4- hour. 3,4-Dimethoxyanthranilonitrile (1.78 g, 10 mmol is Dimethoxyanthranilonitrile (1.78 g. 10 mmol) is added and added and reflux is continued for an additional 24 hours. the mixture is brought to reflux and maintained for 24 hours. Water (30 mL) is added and with vigorous stirring the Water (30 mL) is added and with vigorous stirring the mixture is basified to pH:10 with dropwise addition of 10% mixture is basified to pH:10 with dropwise addition of 10% NaOH. The layers are separated and the aqueous phase is NaOH. The layers are separated and the aqueous phase is further extracted with four portions (10 mL) of dichloroet further extracted with four portions (10 mL) of dichloroet hane. The organic extractions are combined and filtered hane. The organic extracts are combined and filtered through through a bed of celite. The filtrate is dried over NaSO, a bed of celite. The filtrate is dried over NaSO, concen concentrated under reduced pressure and applied to a silica trated under reduced pressure and applied to a silica gel gel column (25 cmx2.5 cm). It is then eluted initially with 45 column (25 cmx2.5 cm). It is then eluted initially with ethyl ethyl acetate and the polarity is gradually increased with acetate and the polarity is gradually increased with ethanol ethanol to a final solventratio of 80:20. Fractions containing to a final solvent ratio of 80:20. Fractions containing the the product (TLC: 80:20 ethyl acetate:methanol, R=0.37) product (TLC: 80:20 ethyl acetate:methanol, R=0.45) are are combined and concentrated underreduced pressure. The combined and concentrated under reduced pressure. The pure product is crystallized from a minimum volume of 50 pure product is crystallized from a minimum volume of ethyl acetate as white crystals (0.83 g, 22% yield). ethyl acetate as white crystals (0.30 g, 8% yield); *H nmr (CDC1) d 6.98 (s, 1H, ArH, C-5); 5.52 (bs, 2H, *H nmr (CDC) d 6.98 (s, 1H. ArH, C-5); 5.52 (bs, 2H, NH); 4.82-4.50 (m. 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 NH); 4.82-4.50 (m. 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 (s, 3H, OCH): 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, 55 (s, 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, CH2's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 CH2's (C-2. C-3, C-5, C-6 (piperazinyl), C-5 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 (tetrahydrofuroyl))). (tetrahydrofuroyl))). EXAMPLE 18 EXAMPLE 2.0 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino 6,7-dimethoxyquinazoline (VII) 6,7-dimethoxyquinazoline (VII) 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g, 4-(2-Tetrahyrofuroyl)piperazine-1-yl-formamide (2.27 g, 10 mmol) is suspended in dry pyridine (10 mL) and with 65 10 mmol) is suspended in dichloroethane (15 mL) and with stirring POCl (1.8 g. 12 mmol) is added and the reaction stirring, triethylamine (1.2 g, 12 mmol) is added and the mixture is stirred for an additional ten minutes. 3,4- reaction mixture is stirred for 15 minutes. POCl (1.8 g. 12 5,675,006 39 mmol) is added and the mixture is heated to reflux and maintained for ten minutes. The reaction is cooled to room temperature and 3,4-dimethoxyanthranilonitrile (1.78 g. 10 1. - mmol) is added and the mixture is brought to reflux and maintained for 24 hours. Water (30 mL) is added and with 5 su vigorous stirring the mixture is basified to pH=10 with dropwise addition of 10% NaOH. The layers are separated and the aqueous phase is further extracted with four portions and when Y is H, compound (VIII) is reacted with com (10 mL) of dichloroethane. The organic extracts are com pound (III) of the formula bined and filtered through a bed of celite. The filtrate is dried 10 over NaSO, concentrated under reduced pressure and applied to a silica gel column (25 cmx2.5 cm). It is then (1. N1 R3 eluted initially with ethyl acetate and the polarity is gradu HN su ally increased with ethanol to a final solvent ratio of 80:20. 15 Fractions containing the product (TLC : 80:20 ethyl acetate:methanol, R=0.37) are combined and concontrated and when NY is (ii), compound (VIII) is reacted with NH. under reduced pressure. The pure product is crystallized 2. The process of claim 1 wherein NY is (ii) and the from a minimum volume of ethyl acetate as white crystals reaction comprises reacting: (0.35 g, 9.2% yield). 20 "H nmr (CDC) d 6.98 (s, 1H, ArH. C-5); 5.52 (bs, 2H. intermediate (V) of the formula NH); 4.82-4.50 (m. 1H, CH, C-2 (tetrahydrofuroyl)); 3.98 (s. 3H, OCH); 3.90 (s, 3H, OCH); 4.10-3.42 (m, 10H, R w CH's (C-2, C-3, C-5, C-6 (piperazinyl), C-5 R 1 - (tetrahydrofuroyl))); 2.39-1.75 (m, 4H, CH's (C-3, C-4 25 (tetrahydrofuroyl))). RO N.N N. ~ O EXAMPLE 21 RO cNYEP 2-4-(2-Tetrahydrofuroylpiperazine)-1-yl)-4-amino 30 in the presence of NH to give compound (VI) of the 6,7-dimethoxyquinazoline Hydrochloride Dihydrate formula (XI) R WI Terazosin free base (VII.3.87 g. 10 mmol) was suspended R (1. N1 in 20 mL hot isopropanol and concentrated hydrochloric 35 RO1. N. N. ~ acid (5 mL) was added. A solution was obtained which was s concentrated to dryness under reduced pressure. Isopropanol (20 mL) was then added and the resulting suspension was RO CN brought to reflux and then cooled to room temperature. The slurry was filtered and washed with a small volume of 40 3. The process of claim2 further comprising closingaring isopropanol. Yield 4.1 g (90% yield), mp. 271-273. in: As many changes can be made to the examples without compound (VI) of the formula departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of R3 W the invention and not in a limiting sense. 45 R (1) NY The embodiments of the invention in which an exclusive RO1. NN- N ~ property or privilege is claimed are as follows: NH 1.The process of reacting compound (VIII) of the formula 50 R CN R W H to give compound (VTI) of the formula RO NNe' R3 VI O a 55 R (1. N1 R cN EP R1O N N- ~ to give compound (VI) of the formula N R e R3 WI R (1. N1 60 NH RO N N ~ 4. The process of claim 2 or 3 further comprising reacting N. compound (VI) or compound (VII) thereof to produce a NH medicine selected from the group consisting of Terazosin, R CN 6s Prazosin, Doxazosin, Tiodazosin, Trimazosin, Quinazosin or wherein Y is (i) hydrogen or wherein NY is (ii) a compound Bunazosin. of the formula 5. A process comprising reacting: 5,675,006 41 42 compound (V) of the formula 12. The process of claim 11 wherein R is furyl further comprising reacting compound (VT) to produce Prazosin. RO N N y 13. The process of claim 11 wherein R is 14 S1 N benzodioxan-2-yl, further comprising reacting compound OS \ Y O 5 (VII) to produce Doxazosin. R CN EP ---, 14. The process of claim 1 whereinY is Hand the reaction in the presence of NH to give compound (VT) of the comprises reacting: formula intermediate (VDI) of the formula 10 R VI RO NN N W H NH R2 CN \ \ l. R DCI N-NO 15 RO CNYEP wherein O-EP is a leaving group substitutable by -NH2 or an amine and wherein EP is selected from the to give compound (VI) of the formula group consisting of POCL, PCls, P.O., TsCl and wherein R is tetrahydrofury, furyl or 1-4-benzodioxan I 2-yl. 6. The process of claim 5 wherein R is tetrahydrofuryl 2O HN N-R further comprising reacting compound (VT) to produce \-/ Terazosin or a form thereof. to give compound (VI) of the formula 7. The process of claim 5 wherein R is furyl further comprising reacting compound (VT) to produce Prazosin. 25 R3. WT 8. The process of claim 5 wherein R is 14-benzodioxan 2-yl, further comprising reacting compound (VT) to produce R (1 n Doxazosin. RO N. N. ~ 9. The process of claim 5 where R is tetrahydrofuryl N further comprising closing the ring in: NH compound (VI") of the formula 30 R CN 15. The process of claim 14 further comprising closing a RO N N VI" ring in: S1 N compound (VI) of the formula NH \ \ O 35 R W R CN O 3 R (1. N1 RO N N ~ to give compound (VII") of the formula N 40 NH RO N N VII" R CN N- \\ O to give compound (VTI) of the formula CCC. N O R3 VII 45 R (1. N1 10. The process of claim 9 further comprising reacting RO N N- ~ pound (VII") to produce Terazosin hydrochloride dihy N 11. A process comprising closing a ring in: 50 R al compound (VT) of the formula NH 16. The process of claim 14 or 15 further comprising R1O s N WT reacting compound (VI) or compound (VTI) thereof to N- \ O 55 produce a medicine selected from Terazosin, Prazosin, NH 1. Doxazosin, Tiodazosin, Trimazosin, Quinazosin or RO CN R Bunazosin. to give compound (VIT) of the formula 7. tE. 15 further comprisinga reactinging:

RO N N VT 60 H T N \ \ O RO NN NH R a R O NH RO CN 65 wherein R is selected from furyl and 14-benzodioxan in the presence of EP to give the intermediate (VIIT) of 2-yl. the formula 5,675,006 43 with compound (III") formula H RO NSl" HN III" O 5 R2 CN n EP \ \ -- R wherein O-EP is a leaving group substitutable by to give compound (VI") of the formula -NH2 or an amine. 18. The process of claim 17 further comprising reacting R1O N N VI compound (VIII) to produce a compound selected from Terazosin, Terazosin hydrochloride dihydrate, Prazosin or Doxazosin. wherein O-EP is a leaving group substitutable by 19. The process of claim 14 comprising: 15 -NH and where R and R are methyl and R is reacting compound (VIT) of the formula selected from furyl, tetrahydrofuryl and 1,4- benzodioxan-2-yl. H WTT 20. The process of claim 19 further comprising reacting R1O N. NH compound (VI") to produce a product selected from

DCI naO Terazosin,Doxazosin. Terazosin hydrochloride dihydrate. Prazosin or R2 cNYEP