USOO59 19931A United States Patent (19) 11 Patent Number: 5,919,931 Murthy et al. (45) Date of Patent: Jul. 6, 1999

54 PROCESS FOR THE MANUFACTURE OF where R is: INTERMEDIATES SUITABLE TO MAKE DOXAZOSIN, TERAZOSIN, PRAZOSIN, TODAZOSIN AND RELATED ANTHYPERTENSIVE MEDICINES O (Intermediate for Doxazosin) 75 Inventors: K. S. Keshava Murthy; Gamini Weeratunga; Tianhao Zhou, Bhaskar O Reddy Guntoori, all of Brantford, Canada 73 Assignee: Brantford Chemicals Inc., Brantford, O (Intermediate for Terazosin) Canada 21 Appl. No.: 08/627,454 22 Filed: Apr. 4, 1996 O (Intermediate for Prazosin) 51) Int. Cl...... C07D 405/06; CO7D 413/06 52 U.S. Cl...... 544/367; 544/374; 544/377; N N 544/379; 544/284; 544/291 58 Field of Search ...... 544/367,374 ls (Intermediate for Tiodazosin) 544/377, 379,284, 291 O SCH 56) References Cited U.S. PATENT DOCUMENTS compriSing reacting: 4,001.238 1/1977 Partyka et al...... 544/284

4,026,894 5/1977 Winn et al...... 544/291 4,046,762 9/1977 Manghisi et al...... 544/377 I 4,188,390 2/1980 Campbell ...... 544/291 O Suitable 4,287.341 9/1981 Hess et al...... 544/285 v with M V Solvent 5,675,006 10/1997 Karimian et al...... 544/293 HN NH - e R OR N / A FOREIGN PATENT DOCUMENTS 2O77252 3/1994 Canada. 217 1997 9/1986 United Kingdom. Primary Examiner Emily Bernhardt Attorney, Agent, or Firm-Ivor M. Hughes; Neil H. Hughes; Marcelo K. Sarkis 57 ABSTRACT wherein R may be selected from H, Methyl, Ethyl and A process is provided for the manufacture of: Suitable lower alkyl groups, C, H2 (where n is from 3 to 5) or any other Suitable group and thereafter if desired converting the resultant product to a Salt thereof.

HN N R 14 Claims, No Drawings 5,919,931 1 PROCESS FOR THE MANUFACTURE OF INTERMEDIATES SUITABLE TO MAKE Formula 1A DOXAZOSIN, TERAZOSIN, PRAZOSIN, TODAZOSIN AND RELATED ANTHYPERTENSIVE MEDICINES MeO N N N R FIELD OF INVENTION

MeO 1O This invention relates to a new process of making mono N-Acyl piperazines from piperazine which are useful inter mediates for the manufacture of Doxazosin, Terazosin, PraZosin, TiodaZosin and related antihypertensive medi cines. 15 where

BACKGROUND OF THE INVENTION

A number of antihypertensive medicines are the chemical entities containing N,N'-Substituted piperazines having one nitrogen acylated and the other linked to cyclized 25 the medicine in Formula 1A is Doxazosin. Guanidines of the general Formula 1. where

Formula 1 O MeO A w ls ( Nn N N R 2N. 35 MeO the medicine in Formula 1A is Terazosin. where

40 R = | Suitable substituents for R may be those listed below:

45 the medicine in Formula 1A is Prazosin. OC*- where N-N 50 R= us ls O SCH,

the medicine in Formula 1A is Tiodazosin. 55 The following compounds are thus presented:

N-N Doxazosin ---. 60 M V O MeO N N N O

MeO A number of antihypertensive medicines are the chemical 65 entities of Formula 1 wherein the methoxy substituents are at the 6 and 7 positions as shown below in Formula 1A: 5,919,931 3 4 -continued Terazosin Scheme 2 O O v M O 5 MeO N N N | O S1 V / MeO NH NH2 / \ | N - HN N R -e- MeO 2 1O MeO CN NH O Prazosin

O 15 MeO NH N N R A V O MeO N N N S1 N / | MeO CN O N MeO 2 2O NH MeO N N N R

Todazosin s V N O MeO 2 25 A V O SCH3 NH2 MeO s N N N-N 2 N See Canadian Patent Application No. 2,077,252. MeO 3O Both of the above methods use an N-Acyl piperazine as NH one of the active components. The N-Acyl piperazines of general Formula 2 have been prepared by a number of The compounds of general Formula 1 have been prepared methods which may be classified into one general method. by a number of approaches. One of the important approaches 35 They all involve coupling reactions between an activated is that (Scheme 1) a 4-amino-6,7-dialkoxy quinazoline, acid derivative A and piperazine (Scheme 3). Substituted at C-9 position with a good leaving group X, is condensed with N-Acylated piperazines (see for example Formula 2 U.S. Pat. Nos. 4,093.726, 4,112,097 and 4,188,390, EP 0028 40 473 Oct. 16, 1980; J. Med Chem. 1987, 30, 49–57 and references therein).

Scheme 1 45 O R may be selected from MeO N X e Sr/- NH \lN R-> N V / O MeO 2 50

NH2 O s O

/ \l ss O s MeO N N N R S1 \ / N MeO 2

60 O s NH2

N - N Another approach (Scheme 2) involves the condensation of a urea derivative with N-Acylated piperazines and 65 -k N > SCH etc. cyclization of the resultant urea derivatives with appropriate reagents to give the required products. 5,919,931 6

O O Scheme 3 O w (Y = - HN NH He 5 N-O or N - O R Y

O O

- / \ -- - / \l R Scheme 3). For example, Succinimido ester is prepared \ / \ / conventionally by reacting the free acid with N-Hydroxy B Succinimide in presence of a dehydrating agent dicyclohexylcarbodiimide, which is highly toxic, corrosive and expensive (Review; Synthesis, 1981,333 and references 15 cited therein). This is the same with mixed anhydrides Y is lsO O Y= O OR

O-N O ls OR where R may be pivaloyl or isobutyl, Scheme 3). It is therefore an object of this invention to provide a Simple, new and efficient proceSS for the Synthesis of mono 25 N-Acyl piperazine derivatives which are useful and impor tant intermediates used to manufacture quinazolines of gen eral Formula 1 (e.g. Doxazosin, Terazosin, Prazosin, or other activating groups. TiodaZosin, etc.). These activated acid derivatives (A) are generally pre It is a further object of the invention to provide an pared from corresponding acids or normal esterS Such as improved, efficient and higher yielding process than those methyl, ethyl or other lower alkyl esters. Most of the taught in the prior art. processes taught by patents use acid chlorides (Y=Cl, It is still a further object of this invention to provide novel Scheme 3) as activated acid derivatives (U.S. Pat. No. methods of preparing mono-N-Acyl piperazines including 4,188,390, Feb. 12, 1980; Canadian Patent No. 1,088,059, 35 intermediates for Doxazosin, TeraZosin, PraZOsin and other Oct. 21, 1980; U.S. Pat. No. 4,287,341, Sep. 1, 1981; EP antihypertensive medicines having an N-Acyl piperazine Patent 0,028,473 Al, Oct. 16, 1980; U.K. Patent GB 2,171, unit embodied in them. 997A, Sep. 10, 1986). These patents explain the preparation Further and other objects of the invention will be realized of piperazine derivatives Starts from normal esters. These by those skilled in the art from the following summary of esters are hydrolyzed using alkali to give acids, which are 40 invention and detailed description of embodiments thereof. converted to acid chloride using SOCl (thionyl chloride) or SUMMARY OF THE INVENTION chemical equivalents of it. These acid chlorides react with piperazine in the presence of mineral acids, which involves According to one aspect of the invention, a process of tedious working up procedures, pH adjustment, and extrac 45 manufacture of tions in order to obtain acceptable yields (U.S. Pat. No. 4,287,371, Sep. 1, 1981; Canadian Patent No. 1,088,059, Oct. 21, 1980; U.S. Pat. No. 4,188,390, Feb. 12, 1980; EP l patent No. 0,028,473 Al, Oct. 16, 1980; J. Med. Chem. 1977, HN N R 20, 146-149; J. Med. Chem. 1987, 30, 49–57). These 50 reactions involve corrosive reagents Such as Thionyl chlo ride or oxalyl chloride and one or more equivalents of concentrated mineral acids (Hydrochloric acid, Hydrobro is provided where R is: mic acid, etc.) The mineral acids are used to protect one of 55 the two nitrogens of piperazine to avoid diacylated product (B, in Scheme 3). In Canadian Letters Patent No. 1,057,754, in order to prepare the N-(Tetrahydro-2-furoyl) piperazine, O the patentee hydrogenates the N-(2-furoyl) piperazine (used (Intermediate for Doxazosin) to produce praZOsin whose process of manufacture is taught 60 in the prior art). O Other methods, not quite commonly used, employ Suc cinimido and pthalimido esters as activating groups (U.S. O (Intermediate for Terazosin) Pat. No. 4,188,390, Feb. 12, 1980). These procedures are 65 also not industrially viable as they involve expensive reagents and a number of Steps 5,919,931 7 8 -continued the starting materials (methyl propionate) has been used in 12.5 equivalents exceSS and the reaction was carried out under reflux (boiling point of methyl propionate 79 C.) in (Intermediate for Prazosin) the absence of any other solvent in order to achieve 30% maximum total yields. In another reaction with ethyl-2- hydroxy propionate, they heated reactants together without N-N using any solvent for 150 hours to get 32% yield of required amide. ls (Intermediate for Tiodazosin) In another reported case (Eur. J. Med. Chem. 1989, 24, O SCH 233-240), the Scientists reported amidation reaction using 6.67 eq of piperazine and a methyl ester compound. The reaction was done at reflux temperatures in MeOH for 16 hours and the yields were only 26%. as follows: The above two examples show how difficult and unat tractive this direct amidation procedure is. However, by 15 Scheme 4 proper manipulation of the reaction conditions and by O choosing the right Solvent System, Applicants provided unexpectedly, a reaction that provides the desired mono 1. -- HN NH Solvent acylated-piperazines, which reaction is very efficient and R OR1 V M A high yielding. The operating procedures of this reaction are very Simple and do not use any activating groups and external reagents except for corresponding Starting materials and an inert aromatic hydrocarbon Solvent System. The procedure is Scalable for industrial purposes and also make it environmentally friendly as it does not use hazardous and 25 corrosive materials or reagents. Applicants have found that the Suitable Solvents are R may be selected from (H, Methyl, Ethyl and other Xylene and toluene and that the appropriate reaction condi Suitable lower alkyl groups, for example, C. H. (where n tions preferably involve the use in the reaction of between is from 3 to 5)). about 1.5 to about 2.5 equivalents, preferably about 2 The Starting materials are known and may be made by equivalents, of piperazine, with one equivalent of appropri methods known to perSons skilled in the art or may be ate acid or ester (one equivalent of each provides less than purchased where available. This invention provides a new, optimal yields and results in diacyl products at reflux Simple and efficient one-step procedure for producing mono temperature of the Solvent used). N-acylated piperazine derivatives using unactivated lower Xylenes (which are preferred) have a reflux temperature alkyl (for example, methyl, ethyl, and the like) esters and/or 35 of about 142 C., present as mixed isomers or one isomer. acids. Toluene has a reflux temperature of about 110° C. If xylenes The use of these compounds employed in Applicants and toluene are mixed, the reflux temperature of the mixture invention does not involve: is between the two. 1. The use of corrosive reagents Such as thionyl chloride Thus according to another aspect of the invention a and oxalyl chloride to prepare the activated acids in the 40 process is provided comprising reacting: form of acid chlorides which involve in their prepara tion at least one extra Step and Sometimes two extra (1Equivalent) (2 Equivalents) StepS and use of concentrated mineral acids in the coupling reaction between the acid chloride and the O piperazine (U.S. Pat. No. 4,188,390, Feb. 12, 1980; 45 Canadian Patent No. 1,088,059, Oct. 21, 1990; J. Med. O OR" HN NH Chem, 1987, 30, 49–57; J. Med Chem., 1977, 20, with W 146-149; U.S. Pat. No. 4,287,341, Sep. 1, 1981; EP O Patent No. 0,028,473 Al, Oct. 16, 1980) and wherein R" may be Hand ethyl piperazine 2. The use of imido esters and mixed anhydrides (U.S. 50 solvent Pat. No. 4,188,390, February 1980; Review: Synthesis, Xylene 1981, 333 and references cited therein) as activating O groups, which are difficult to make and industrially not toluene viable as they involve the use of expensive and highly reflux toxic dehydrating reagents Such as dicyclohexylcarbo 55 diimide. To produce The present invention provides direct mono amidation of unactivated esters and acids with piperazine (Scheme 4) without using any activating reagents. Although direct ami dation using amines and unactivated esters and acids is 60 documented in the literature, amidation of piperazines poses problems as they have two nitrogens of equal reactivity, which can lead to diacylation product. This is often the case. For example, in Collection Czechoslovak Chem. Commun. Intermediate for Doxazosin 1985, 50, 1201-1211, authors reported amidation reactions 65 of piperazine with methyl propionate and ethyl-2-hydroxy According to another aspect of the invention, the follow propionate. In the reaction with methyl propionate, one of ing proceSS is also provided: 5,919,931 9 10 -continued (1 Equivalent) (2 Equivalents)

OR" - HN wNH -xylenes or toluene - O N NH HCl O \ / refluxA O piperazine OCS ) methyl tetrahydro-2-furanoate ()

O N NHCI N NH O \ / OCr' ) O 15 Intermediate for Terazosin A Suspension of piperazine (165.5g, 1.92 mol) in Xylenes (1000 mL) was added to the ethyl ester (200 g, 0.961 mol). R" is selected from H and Methyl The mixture was heated to reflux for 26.5 hours. Then the According to another aspect of the invention, the follow reaction mixture was washed by brine (500 mL). The ing proceSS is also provided: organic layer and the aqueous layer were separated and the aqueous layer was extracted with ethyl acetate (3x500 mL). (1 Equivalent) (2 Equivalents) The organic layers were combined and concentrated. Then isopropanol (1000 mL) was added, followed by concen w Xylenes or toluene OR" - HN NH -- He 25 trated HCI (960 mL, 1.15 mol). The slurry like mixture was O reflux stirred at 0° C. for 20 minutes. The precipitate was filtered and dried under vacuum for 24 hours to give 209.4 g of O piperazine product (77% yield). R" is selected from Hand Methyl Example 2 Preparation of N-(1,4-Benzodioxane-2-Carbonyl) O y1 NV /NH Piperazine Hydrochloride 35 O Intermediate for Terazosin O These reactions can be carried out in Xylene (mixture of OC OH + isomers) or toluene as Solvent using piperazine at reflux O temperatures. The optimal amount of piperazine used is 2 40 equivalents with respect to Starting material. These amounts \, xylene may however be varied over a broad range. The products can HN NH-> be worked up directly or as the Salt form using 1.1 equivalent of concentrated hydrochloric acid. The pure Salts can be precipitated in isopropanol at room temperature or at 0° C. 45 Other Solvent mixtures also can be used for precipitation. This invention will now be illustrated with respect to the O N NH-C- following detailed description of embodiments of the inven tion. 50 OC?'

Example 1 O N NHCI 55 OCr' ) Preparation of N-(1,4-Benzodioxane-2-Carbonyl) Piperazine Hydrochloride To a suspension of piperazine (23.90 g, 0.278 mol) in 60 xylenes (125 mL) was added the acid (25 g, 0.139 mol) O portionwise, under reflux conditions. The reaction mixture O was refluxed for 75 hours and brine (150 mL) was added. OEt w xylene The organic layer was separated and the aqueous layer was HN NH --> extracted with ethyl acetate (3x100 mL). The organic layers 65 were combined and concentrated. Then isopropanol (125 O mL) was added followed by concentrated HCl (9.70 mL, 0.0967 mol). The slurry like mixture was stirred at 0°C. to 5,919,931 11 12 -5 C. for 30 minutes. The precipitate was filtered and dried -continued under vacuum to give 20.0 g product (50% yield). Example 3 Preparation of N-(Tetrahydrofuran-2-Carbonyl) Piperazine To a suspension of piperazine (69.68 g., 0.8091 mol) in xylenes (100 mL) was added (50.00 g, 0.3965 mol) of methyl 2-furoate. The formed reaction mixture was refluxed xylene for 18 hours. The unreacted piperazine was filtered and the OMe HN NH--- filtrate was concentrated under Vacuum to give 47.0 g O \ / (0.2608 mol) of required product (64% yield). AS many changes can be made to the embodiments 15 without departing from the Scope of the invention, it is intended that all material herein be interpreted as illustrative N NH of the invention. O \ / The embodiments of the invention in which an exclusive property or privilege is claimed are as follows: 1. A process for the manufacture of:

To a Suspension of piperazine (66.2 g, 0.768 mol) in xylenes (500 mL) was added methyl tetrahydro 2-furanoate l HN N R (50.0g, 0.384 mol) and the resulting reaction mixture was 25 refluxed for 28 hours. The reaction was cooled to 0 C. for 1.5 hours and filtered. The filtrate was concentrated in vacuo to yield 56.1 g of the expected product (79% yield). where R is: Example 4 O Preparation of N-(Tetrahydrofuran-2-Carbonyl) Piperazine OC (Intermediate for Doxazosin) 35 O

A v xylene OH- HN NH--> O \ / O (Intermediate for Terazosin) 40

O (Intermediate for Prazosin) N NH O \ / 45 N-N ls (Intermediate for Tiodazosin) O SCH A Suspension of piperazine (7.23g, 0.084 mol) in Xylenes (50 mL) was added tetrahydro 2-furanoic acid (4.85g., 0.042 50 mol). The mixture was heated to reflux for 28 hours. The consisting essentially of reacting: reaction mixture was cooled to room temperature and fil tered. The filtrate was concentrated to give 3.53 g of product (46% yield). a solvent selected 55 from the group O consisting of Example 5 with A V xylenes and toluene HN NH -> R OR1 \ / A Preparation of N-2-Furoyl Piperazine 60

\, xylenes OMe HN NH--- / \ O \ / \ / 65 wherein Said reaction occurs in the presence of a Solvent Selected from the group consisting of Xylenes and toluene, 5,919,931 13 14 and wherein R is Selected from the group consisting of H, 7. The process of claim 1 of reacting: Methyl, Ethyl, propyl, butyl and pentyl and thereafter if desired converting the resultant product to a Salt thereof, (1 Equivalent) (2 Equivalents) wherein between about 1.5 to about 2.5 equivalents of piperazine are reacted with each equivalent of Compound I. 5 OR" + / V O HN NH - A - V / reflux 2. The process of claim 1 wherein about 2 equivalents of O piperazine are reacted with each equivalent of Compound I. piperazine 1O 3. The process of claim 1 or 2 wherein the solvent is / V XVlene. N NH y O \ / 15 4. The process of claim 1 or 2 wherein the solvent is O toluene. wherein R" may be selected from H and Methyl. 5. The process of claim 1 of reacting: 2O 8. The process according to claim 1 of preparing N-(1,4- Benzodioxane-2-Carbonyl) Piperazine Hydrochloride by (1 Equivalent) (2 Equivalents) reacting:

O O O 25 OR" W M O HN NH OEt with v W O O piperazine 3O

HN NH --- 35 \ / to produce O

O O A \ HCI N NH-> O / V 40 \ / OC N NH O O O

45 O A V N NH2Cl. and thereafter reflux, OCSO wherein R" may be selected from H and ethyl. 50 6. The process of claim 1 of reacting: 9. The process according to claim 1 of producing N-(1, 4-Benzodioxane-2-Carbonyl) Piperazine Hydrochloride by (1 Equivalent) (2 Equivalents) reacting:

v V 55 O OR" - O HN NH - - O \ / reflux OH O methyl tetrahydro-2-furanoate piperazine 60 O

N NH O \ / O 65 HN NH --- wherein R" may be selected from H and Methyl. 5,919,931 15 16 -continued 11. The process according to claim 1 of producing N-(Tetrahydrofuran-2-Carbonyl) Piperazine by reacting:

OH- HN NH --> O \ / A

1O N NH O N NHCI O \ / OCr O 15 10. The process according to claim 1 of producing 12. The process according to claim 1 of producing N-2- N-(Tetrahydrofuran-2-Carbonyl) Piperazine by reacting: Furoyl Piperazine by reacting: / V OMe - HN NH --> OMe O \ / A

25 N NH. O \ / HN NH --A

13. The process of claim 1, 3 or 4 wherein the solvent is N NH Xylene. O \ / 14. The process of claim 1, 3 or 4 wherein the solvent is toluene. 35