Methods of making ureas and guanidines including, terazosin, prazosin, doxazosin, tiodazosin, trimazosin, quinazosin and bunazosin (exemplary of 2-substituted quinazoline compounds), and meobentine, and bethanidine and intermediates therefor

• US 6,080,860 A
• Filed: 09/29/1997
• Issued: 06/27/2000
• Est. Priority Date: 08/31/1992
• Status: Expired due to Fees

• Current Assignee: Apotex Pharmachem India PVT Limited (Apotex Holdings Incorporated)
• Original Assignee: Brantford Chemicals, Inc.
• Inventors: Karimian, Khashayar, Murthy, Keshava, Hall, Darren
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/939,414
• Time in Patent Office: 1,002 Days
• Field of Search: 558/385, 558/386, 558/413, 558/417, 540/575, 544/284, 544/291, 544/367, 544/374, 544/377
• US Class Current: 544/291
• CPC Class Codes: C07D 271/113 with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 295/215 Radicals derived from nitrogen analogues of carbonic acid
• CPC Class Codes: C07D 307/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 319/20 with substituents attached to the hetero ring
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

Novel methods for the synthesis of substituted ureas and guanidines including Terazosin, Prazosin, Doxazosin, Tiodazosin, Trimazosin, Quinasin and Bunazosin (exemplary of 2-amino substituted Quinazolines), Meobentine and Bethanidine and novel intermediates suitable for use in such methods of synthesis are taught.

Claims

1. A compound of the formula:

##STR79## wherein R_a is hydrogen, R_b is selected from the group consisting of hydrogen and a 2-cyano-4,5-dialkoxy phenyl group optionally substituted in the 6-position by an alkoxy group, and R_c and R_d are each hydrogen, provided R_c and R_d are not hydrogen when R_a and R_b are hydrogen, or R_c and R_d together with the nitrogen to which they are attached form a 6- or 7-membered closed ring optionally containing a second nitrogen, the closed ring being substituted on the optional second nitrogen by a member selected from the group consisting of unsubstituted or substituted furoyl, benzodioxanyl carbonyl, alkylthiooxadiazole carbonyl, hydroxy alkoxy carbonyl alkenyl and alkyroyl.

2. A compound of claim 1 of the formula:

II ##STR80## wherein R is selected from the group consisting of hydrogen and alkoxy and R₁ and R₂ are each alkyl.

3. A compound of claim 1 of the formula:

IV" ##STR81## wherein R₁ and R₂ are each alkyl.

4. A compound of claim 1 of the formula:

IV"" ##STR82## wherein R₁ and R₂ are each alkyl.

5. A compound of claim 1 of the formula IV:

##STR83## wherein R, R₁, R₂ n and R₃ are selected from the chart as follows;

space="preserve" listing-type="tabular">______________________________________ R R.sub.1 R.sub.2 n R.sub.3 ______________________________________ H Me Me 1 #STR84## - H Me Me 1 #STR85## - H Me Me 1 #STR86## - H Me Me 1 #STR87## - OMe Me Me 1 #STR88## - H Me Me 1 #STR89## - H Me Me 2 ##STR90## ______________________________________

6. A compound of the formula:

##STR91## wherein --O--EP is the reaction product of the urea oxygen and an electrophile, EP and forms a leaving group substitutable by --NH₂ or a primary or secondary amino group wherein EP is selected from POCl₃, PCl₅, P₂ O₅, mesyl chloride and tosyl chloride, wherein R_b is selected from the group consisting of hydrogen, alkyl and a group 2-cyano-4,5-dialkoxy phenyl group optionally substituted in the 6-position by an alkoxy group and wherein R_c and R_d are each selected from the group consisting of hydrogen, provided R_c and R_d are not hydrogen when R_b is hydrogen, and lower alkyl or R_c and R_d together with the nitrogen to which they are attached form a closed heterocyclic ring optionally containing a second nitrogen, the closed heterocyclic ring being substituted on the optional second nitrogen by a member selected from the group consisting of unsubstituted or substituted furoyl, benzodioxanyl carbonyl, lower alkylthiooxadiazole carbonyl, hydroxy alkoxy carbonyl, alkenyl and alkyroyl.

7. A compound of claim 6 of the formula V" ##STR92## wherein -O-EP is the reaction product of the urea oxygen and an electrophile, EP, and is a leaving group substitutable by NH₂ or a primary or secondary amino group and wherein R₁ and R₂ are each alkyl.

8. A compound of claim 6 of the formula V"" ##STR93## wherein --O--EP is the reaction product of the urea oxygen and an electrophile, EP, and is a leaving group substitutable by --NH₂ or a primary or secondary amino group and wherein R₁ and R₂ are each alkyl.

9. A compound of claim 6 of the formula V ##STR94## wherein --O--EP is the reaction product of the urea oxygen and an electrophile, EP, EP and is a leaving group substitutable by --NH₂ or a primary or secondary amino group

and wherein R, R₁, R₂, n and R₃ are selected from the chart as follows:

space="preserve" listing-type="tabular">______________________________________ R R.sub.1 R.sub.2 n R.sub.3 ______________________________________ H Me Me 1 #STR95## - H Me Me 1 #STR96## - H Me Me 1 #STR97## - H Me Me 1 #STR98## - OMe Me Me 1 #STR99## - H Me Me 1 #STR100## - H Me Me 2 ##STR101## ______________________________________

10. A process comprising:

##STR102## with a compound of the formula H-N═

C═

O to give compound (II) of the formula ##STR103## wherein R is selected from hydrogen and alkoxy and R₁ and R₂ are each alkyl.

11. A process comprising:

refluxing compound (II) of the formula ##STR104## in the presence of Pyridine and compound (III) of the formula ##STR105## to give compound (IV) of the formula ##STR106## wherein R, R₁, R₂, n and R, are defined in the chart as follows;

space="preserve" listing-type="tabular">______________________________________ R R.sub.1 R.sub.2 n R.sub.3 ______________________________________ H Me Me 1 #STR107## - H Me Me 1 #STR108## - H Me Me 1 #STR109## - H Me Me 1 #STR110## - OMe Me Me 1 #STR111## - H Me Me 1 #STR112## - H Me Me 2 ##STR113## ______________________________________

12. The process comprising:

reacting compound (IV) of the formula ##STR114## in the presence of an electrophile, EP, wherein EP is selected from the group consisting of POCl₃, P₂ O₅, PCl₅ and TsCl, to give compound (V) of the formula ##STR115## wherein --O--EP is the reaction product of the urea oxygen and EP and is a leaving group substitutable by --NH₂ or a primary or secondary amino group and wherein R. R₁, R₂, n and R₃ are defined in the chart as follows;

space="preserve" listing-type="tabular">______________________________________ R R.sub.1 R.sub.2 n R.sub.3 ______________________________________ H Me Me 1 #STR116## - H Me Me 1 #STR117## - H Me Me 1 #STR118## - H Me Me 1 #STR119## - OMe Me Me 1 #STR120## - H Me Me 1 #STR121## - H Me Me 2 ##STR122## ______________________________________