CA2028953A1 - Process for the preparation of quinazoline derivatives - Google Patents

Process for the preparation of quinazoline derivatives

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Publication number
CA2028953A1
CA2028953A1 CA002028953A CA2028953A CA2028953A1 CA 2028953 A1 CA2028953 A1 CA 2028953A1 CA 002028953 A CA002028953 A CA 002028953A CA 2028953 A CA2028953 A CA 2028953A CA 2028953 A1 CA2028953 A1 CA 2028953A1
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Prior art keywords
general formula
process according
lower alkyl
reaction
comprises carrying
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CA002028953A
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French (fr)
Inventor
Jozsef Reiter
Laszlo Pongo
Frigyes Gorgenyi
Marton Fekete
Margit Csorgo
Ilona Sztuhar
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Egis Pharmaceuticals PLC
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Egis Pharmaceuticals PLC
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Priority claimed from HU193189A external-priority patent/HU203342B/en
Priority claimed from HU193089A external-priority patent/HU203333B/en
Application filed by Egis Pharmaceuticals PLC filed Critical Egis Pharmaceuticals PLC
Publication of CA2028953A1 publication Critical patent/CA2028953A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

PROCESS FOR THE PREPARATION OF QUINAZOLINE DERIVATIVES

Abstract The invention relates to a process for the preparation of quinazoline derivatives of the general Formula I
(I) [wherein R1 and R2 may be the same or different and stand for hydrogen or lower alkyl or together form an ethylene (-CH2-CH2-) or trimethylene (-CH2-CH2--CH2-) group; and n is the integer number 2 or 37 and pharmaceutically acceptable acid addition salts thereof, which comprises a) reacting an isothiourea derivative of the general Formula III

(III) [wherein R stands for lower alkyl or phenyl-lower alkyl, where the phenyl ring of the latter group may be optionally substituted by one or more lower alkyl group(s) and/or halogen atom(s)] with an amine of the general Formula IV, (IV) (wherein R1, R2 and n are as stated above) at a temperature between 150 °C and 280 °C; or b) cyclising a compound of the general Formula II
(II) (wherein R1, R2 and n are as stated above) optionally in the presence of a catalyst;
and, if desired, converting a compound of the general Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.

Description

PROCESS FOR THE PREPARATION OF QUINAZOLINE DERIVATIVES

This invention relates to a new process for the prepara-tion of quinazoline derivatives, new intermediates useful in the said process and also to a process for the prepara-tion of the said new intermediates.
According to an aspect of the present invention there is provided a process for the preparation of quinazoline derivatives of the general Formula I

N1~2 H3 C O ~ N ( I ) H3CO~N N~ ,N--CO~

/wherein Rl and R2 may be the same or different and stand for hydrogen or lower alkyl or together form an ethylene (-CH2-CH2-) or trimethylene (-CH2-CH2--CH2-) group; and n is the integer number 2 or 37 and pharmaceutically acceptable acid addition salts thereof.
The general Formula I comprises all isomers and tautomers and the present invention encompasses a process for the pre-A 4637-62 PT/Gi ' paration of all isomers and tautomers of the compounds of the general Formula I.
The compounds of the general Formula I are known pharmaceutical active ingredients useful as antihypertensive agents due to their ~l-receptor blocking activity.
The compounds of the general Formula I may be prepared either by reacting 4-amino-6,7-dimethoxy-2-chloro-quinazoline of the Formula IX

~13cO ~ ~ ~ (IX) N'~2 with an amine of the general Formula IV

r~ R2 ~IV) H ~CH2)n CC ~ o~

(wherein Rl, R2 and n are as stated above) or by reacting the compound of the Formula IX with the corresponding diamine to yield a compound of the general Formula V

',~` ' ''' .. . - ~ .
'. ' ' , ' ' .

r~1 n2 113 C 0 ~, N ~,N ~ Nl`l ( v llj CO ~N

(wherein Rl, R2 and n are as stated above) and subjecting the compound thus obtained to acylation (West-German patent No. 2,646,186; Belgian patents Nos. 879,730 and 873,909 and French patent No. 2,468,595).
The disadvan$age of the above methods is that the starting material of the Formula IX is rather difficultly available and can be prepared from veratrum aldehyde by means of a seven-step synthesis and some of the steps of the said synthesis can be accomplished only with very low yields L J. Med. Chem. 20, 146 (1977)7.
It is the object of the present invention to provide a process for the preparation of the compounds of the general Formula I, which eliminates the above drawbacks of the known procedures.
According to an aspect of the present invention there is provided a process for the preparation of compounds of the general Formula I (wherein Rl, R2 and n are as stated above) and pharmaceutically acceptable acid addition salts thereof which comprises a) reacting an isothiourea derivative of the general Formula III

... ,.. _ . .. . - -:: ~

.:' . ~ ' -,. .

N
lil H 3 C O ~ ~ ~ ` N (Ill) / wherein R stands for lower alkyl or phenyl-lower alkyl, where the phenyl ring of the latter group may be optionally substituted by one or more lower alkyl group(s) and/or halogen atom(s)7 with an amine of the general Formula IV (wherein Rl, R2 and n are as stated above) at a temperature between 150 C and 2ao c; or b) cyclising a compound of the general Formula II

N

H3C0 ~ ; \(C~2) (wherein Rl, R2 and n are as stated above) optionally in the presence of a catalyst;
and, if desired, converting a compound of the general Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.
The present invention is based on the surprising recogni-;

tion that the compounds of the general Formula I can be readily prepared by thermal or catalytic cyclisation of the new compounds of the general Formula II, never disclosed in prior art.
It was unexpected that the ring closure of the compound Formula II could be carried out without any complications since it has long been known from the technical literature that tetrahydrofuran derivatives are, in contradistinction to furan derivatives, very instable.
Thus, for example, tetrahydrofuran itself explodes while forming a peroxide (Rein, Angewandte Chemie 52, 120 [1950]). The tetrahydrofuran carboxylic chloride explodes even while standing (Beilsteins Handbuch der organischen Chemie, Vol. 18/5, EIII/IV, p. 3828 and, resp., Mooradian et al., J. Am. Chem. Soc. 71, 3372 (1949~ as cited therein).
Owing to the above circumstances, in order to avoid the risk of dangerous explosions even the tetrahydrofuran carboxylic amides have been prepared in a roundabout way, by amidating tetrahydrofuran carboxylic esters prepared by subsequent hydrogenation (Corrodi et al., Helv. Chim. Acta 40, 2454 tl957]).
Based on the above facts, it is really surprising that the cyanoguanidine derivatives of general Formula (II), which are tetrahydrofuran carboxylic amides and are used as starting materials in the process of the present invention, have proven to be stable even at higher temperatures, thereby rendering them suitable for preparing the corresonding compounds of general Formula (I).
The term "lower alkyl" used throughout the specification relates to straight or branched chain saturated hydrocarbon groups comprising 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl etc.). The term "phenyl-lower alkyl" relates to lower alkyl groups as defined above substituted by a phenyl .

- 5a-group (e.g. b~nzyl, ~-phenyl-ethyl etc.). The term "halogen" encompasses the fluorine, chlorine, bromine and iodine atoms and is preferably fluorine, chlorine or bromine.
5The new starting materials of the general Formula II can be prepared by reacting an isothiourea derivative of the general Formula III and an amine of the general Formula IV and can be either isolated or directly cyclised into the desired quinazoline derivative of the general Formula I in situ without isolation.
The starting materials of the general Formula III
are known compounds [J. Heterocycl. Chem. 23, 401 (1986)]
or can be prepared in an analogous manner to the process disclosed in Hungarian patent No. 181,743.
15The starting materials of the general Formula IV
are known amines disclosed in prior art (DOS No. 2,646,186;
Belgian patents Nos. 873,909 and 879,730 and French patent No. 2,468,595).
According to process a) an isothiourea derivative of the general Formula III is reacted with an acylated amine of the general Formula IV in an inert organic solvent which has a boiling point above 150 C. It is preferred to use dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfolane, dimethylene glycol dimethyl ether, diethylene glycol di-ethyl ether, diphenyl ether, nitrobenzene, dichlorobenZene or tetrahydronaphthalene as solvent. According to a particular-ly preferred form of realization of process a) the reaction of the compounds of the general Formula III and IV is carried out in dimethylene glycol dimethyl ether or dimethyl formamideat a temperature between 150 C and 220 C, particularly preferably at 160-180 C. It is preferred to use as starting material a compound of the general Formula III wherein R
stands for methyl.

According to process b) a compound of the general Formula II is converted into the desired quinazoline derivative of the general Formula I by ring-closure. The cyclization reaction is accomplished either by heating (thermal cyclization) or in the presence of a suitable catalyst.
Thermal cyclization of the compounds of the general Formula II may be carried out in the absence or presence of a solvent. As reaction medium an inert solvent having a boiling point of 150-280 C - preferably boiling between 150 C and 220 C - may be used. It is thus preferred to use as reaction medium a solvent which has a boiling point above 150 C, particularly dimethyl formamide, dimethyl acet-.. : .-:

,.

amide. N-methyl-pyrrolidone, hexamethyl-phosphoric triamide, dimethyl sulfoxide, sulfolane, dimethylene glycol dimethyl ether, diethylene glycol diethyl ether, diphenyl ether, nitrobenzene, dichlorobenzene, tetrahydronaphthalene etc.
It is particularly preferable to work in dimethylene glycol dimethyl ether or dimethyl formamide as reaction medium.
Cyclisation of the compounds of the general Formula II
may also be accomplished in a solvent in the presence of a catalyst at a temperature between 25 C and 130 C, prefer-ably at 70-100 C. Phosphorous oxychloride may preferably act as solvent while as catalyst preferably phosphorous trichloride, phosphorous pentachloride, phosphorous tri-bromide or a Lewis acid may be used. As Lewis acid prefer-ably aluminium chloride, boron trifluoride, boron tri-fluoride etherate, zinc chloride, stannous chloride etc.
may be applied. ûne may particularly advantageously work in phosphorous oxychloride as solvent, in the presence of phosphorous trichloride as catalyst.
The compounds of the general Formula I can be isolated from the reaction mixture by methods known per se.
The compounds of the general Formula I can be converted into the pharmaceutically acceptable acid addition salts by methods known per se. Thus the compound of the general Formula I can be reacted in a solvent with the correspond-ing inorganic or organic acid (e.g. hydrogen chloride,hydrogen bromide, sulfuric acid, maleic acid, fumaric acid etc.).
According to a particularly preferred form of realiza-.

tinn nf the present in~en-tion a compound of the general Formula I is prepared, wherein Rl stands for methyl, R2 is hydrogen and n = 3, by use of the corresponding star-t-ing materials of the general Formulae II, III and IV, wherein Rl, R2 and n are as stated above.
According to an other particularly preferred form of realization of the process of the present invention a compound of the general Formula I is prepared wherein Rl and R2 form togeth~r an ethylene group (-CH2-CH2-) and n = 2, by use of the corresponding starting materials of the general Formulae II, III and IV, wherein Rl, R2 and n are as stated above.
According to a further aspect of the present invention there are provided new N-cyano-carboxamidine derivatives of the general Formula II (wherein Rl, R2 and n are as stated above).
According to a still further aspect of the present invention there is provided a process for the preparation of the new inteimediates of the general Formula II which comprises reac-ting an isothiourea derivative of the general Formula III /wherein R stands for lower alkyl or phenyl-lower alkyl whereby -the phenyl ring of the latter group may be optionally substi-tuted by one or more lower alkyl group(s) and/or halogen atom(s)7 wi-th an amine of the general Formula IV (wherein Rl, R2 and n are as stated above) at a temperature not exceeding 130 C.
The reaction is carried out in an i.nert solven-t, pre-ferably an alcohol or a polar aprotic solvent. It is particularly preferred to accornplish the reac-tion ln isopropanol or dimethyl formamide as solvent. The reactlon is carried out at a temperature not exceeding 130 C, prefer-ably at a temperature between 25 C and 130 C.
The compounds of the general Formula II can be isolated from the reaction mixture by methods known per se, advantayeously by evaporating the solvent and subjecting the residue to crystallization.
The advantage of the present invention is that the iO desired compounds of the general Formula I can be prepared from readily available starting materials by a simple easily feasible economical method and in highly pure form.
Further details of -the present invention are -to be found in the followiny Examples without limiting the scope of protection -to the said Examples.
_ample 1 4-(2-Tetrahydro-furo~l)~iperazine-l-/N-cyano-N'-(3,4--dime-thoxyphenyl?7-carboxamidine A solution of 25.1 9 (0.1 mole) of N-cyano-N'-(3,4-di-methoxyphenyl)-S-methyl-isothiourea and 27.6 g (0.15 mole) of N-(tetrahydro-2-furoyl)-piperazine in 150 ml of iso-propanol is heated -to boiling for 2 hours. The reaction mixture is cooled, the isopropanol is removed and the residual crude product (38.2 9) is recrystallized from ethanol.
Thus 35.7 9 of the desired compound are obtained, yield 92%, mp.: 182-184 C.

Example 2 4-(2-Tetrahydro-furoyl)-homopiperazine-l-/ N-cyano-N'--N'-(3,4-dimethoxYphenyl)7-carboxamidine One proceeds as described in Example l except that N-(tetrahydro-2-furoyl)~ipe-razine is replaced by 19.8 9 (0.1 mole) of N-(tetrahydro-2-furoyl)-homopiperazine and as solvent instead of the isopropanol 50 ml of dimethyl formamide are used. The reaction mixture is stirred at 120 C for 5 hours, then cooled and 200 ml of water are added. The precipitated crystalline product is filtered, washed twice with 50 ml of water each and recrystallized from ethanol. Thus 32.0 9 of the desired compound are obtained, yield 80%. Mp.: 166--168 C.

Example 3 N-(3,4-Dimethoxy-phenyl)-N-methyl-N-/ 3-(tetrahydro-2--furoyl-amino)-propyl7-N'-cYano-guanidine One proceeds as described in Example l except that N-(tetrahydro-2-furoyl)-piperazine is replaced by 27.9 9 (0.15 mole) of tetrahydro-N-L 3-(methylamino)propyl7-2--furane-carboxamide. The reaction mixture is stirred at 60 C
for 8 hours. Thus 24.7 9 of the desired compound are obtained, yield 63.5 %, mp.: 160-163 C.
Example 4 2-L 4-(Tetrahydro-2-furoyl)-piperazine7-4-amino-6,7-di-methoxy-quinazoline hydrochloride A solution of 19.4 9 (0.05 mole) of 4-(2-tetrahydro-2--furoyl)-piperazine-l-L N-cyano-N'-(3,4-dimethoxy-phenyl7-carboxamidine and 40 ml of diethylene glycol diethyl ether -~ :

is stirred at 180 C for half an hour. The reaction mixture is cooled whereupon 100 ml of dichloromethane are ardded and the pH of the mixture is adjusted to 3-4 by adding an ispropanolic hydrosen chloride solution under intensive stirring and cooling with icecold water. During acidifica-tion the precipitation of crystals begins. The nixture is stirred at 0-5 C for a further hour, the precipitated product is filtered and crystallized from isopropanol.
Thus 15.6 9 of the desired compound are obtained, yield lû 73.5 %, mp.: 277-279 C.
Example 5 2-/ 4-(Tetrahydro-2-furoyl)-piperazinyl7-4-amino-6,7--dimethoxy-quinazoline hydrochloride One proceeds as described in Example 4 except that as solvent 40 ml of dimethyl formamide are used and the reaction mixture is heated to boiliny at 154 C for one hour and a half. After cooling 200 ml of water are added, the pre-cipitated product is filtered, washed twice with 100 ml of water each, suspended in 100 ml of methanol and the pH of the mixture is adjusted to }-4 by adding isopropanol contain-ing hydrogen chloride. The precipitated crys-tals are filtered and recrystallized from isopropanol. Thus 11.5 9 of the desired compound are obtained, yield 54.2 %.
Example 6 2-/ 4-(Tetrahydro-2-furoyl)-piperazinyl7-4-amino-6~7 dimethoxy-quinazolir,e hydrochloride ûne proceeds as described in Example 4 except that in place of diethylene glycol diethyl ether 30 ml of sulfolane are used as solvent. rhe reaction mixture is stirred at 280 C for a quarter of an hour.Thus 12.29 9 of the desired compound are obtained, yield 57.5 %.
Example 7 N-/ 3-/ (4-Amino-6,7-dimethoxy-2-quanizolinyl)-methyl-amino7-propvl7-tetrahydro-2-furane-carboxamide hvdro-chloride 4.1 9 ~0.03 rnole) of phosphorous trichloride are added to 40 ml of phosphorous oxychloride under cooling and stirr-ing whereupon the mixture is stirred for 10 minutes and thereafter 11.7 9 (0.03 mole) of N-(3,4-dimethoxy-phenyl)--N-methyl-N-/ 3-(tetrahydro-2-furoylamino)-propyl7-N-cyano--guanidine are added. The temperature is slowly raised to 70 C and the reaction mixture is kept at this temperature for 2.5 hours. The excess of phosphorous oxychloride is evaporated in vacuo. To the residue slowly icecold water is added. The precipitated crude product is recrystallized from ethanol. Thus 9.6 9 of the desired compound are obtained, yield 75%, mp.: 223-225 C.
Example 8 N-/ 3-/ (4-Amino-6,7-dimethoxy-2-quinazolinyl)-methvl-amino7-proeyl7-tetrahvdro-2-furane-carboxamide hvdro-chloride One proceedsas described in Example 7 except that in 25 place of phosphorous trichloride 6.2 9 (0.03 mole) of phosphorous pentachloride are used and the reaction mixture is stirred at 25 C for 3 hours. Thus 8.5 9 of the desired compound are obtained, yield 66.4 %.

Example 9 N-/ 3-/ (4-Amino-6,7-dimethoxy-2-quinazolinvl)-methYl-am-ino7-propv17-tetrahydro-2-furane-carboxamide hYdro-chloride One proceeds as described in Exa~mple 7 except that in place of phosphorous trichloride 8.1 9 (0.03 mole) of phosphorous tribromide are used and the reaction mixture is stirred at 180 C for half an hour. Thus 7.8 9 of the desired comoound are obtained, yield 61%.
~ 10 Example 10 ; ~ N-/ 3-/ (4-Amln:o-6,7-dimethoxY-2-quinazolinyl)-meth amino7-erop ~ tetrah~dro-2-furane-carboxamide hYdro-chloride One proceeds as described in Example 7 except that the mixture is saturated by introducing gaseous hydrogen chloride.
The reaction mixture is stirred at first at 25-30 C for 15 ; minutes and flnally at 70-75 C for an hour. Thus 8.5 9 of the desired compound are obtained, yield 66.4 %.
Example 11 2-/ 4-(Tetrahvdro-2-furoyl)-piperazinvl7-4-amino-6,7--dimethoxy-quinazoline hydrochloride A solution`of 25.1 9 (0.1 mole) of N-cyano-N'-(3,4-di-methoxy-phenyl)-S-methyl-isothiourea and 27.6 9 (0.15 mole) of N-(tetrahydro-2-furoyl)-piperazine in 50 ml of dimethyl formamide is heated to boiling at 155-160 C for 5 hours. The reaction mixture is cooled, 200 ml of water are added, the precipitated product is filtered, washed twice with 100 ml of water each, suspended in 100 ml of methanol and the pH

.
- , ., :
, , . . .
' , .. ; : ' , ~ '-.

- ~

of the suspension is adjusted to 3-4 by adding isopropanol containing hydrogen chloride. The precipitated crystals are filtered off and recrystallized from isopropanol. Thus 19.5 9 of the desired compound are obtained, yield 46%, mp.: 277--279 C.
Example 12 2-/ 4-(Tetrahydro-2-furoyl)-piperazinvl7-4-amino-6,7--dimethoxy-quinazoline hvdrochloride One proceeds as described in Example 11 except that in place of dimethyl formamide 100 ml of diethylene glycol diethyl ether are used as solvent, and the reaction mixture is heated to boiling at 180 C for 2 hours. After cooling 100 ml of dichloroethane are added and the pH of the mixture is adjusted to 3-4 by adding isopropanol contain-ing hydrogen chloride under cooling with icecold water andvigorous stirring. The mixture is stirred at 0-5 C for an hour, the precipitated product is filtered and re-crystallized from isopropanol. Thus 20.8 9 of the desired compound are obtained, yield 49%, mp.: 277-279 C.

~ . . . .
.
:
. .
' ,.

Claims (19)

1. A process for the preparation of quinazoline derivatives of the general Formula I
(I) [wherein Rl and R2 may be the same or different and stand for hydrogen or lower alkyl or together form an ethylene (-CH2-CH2-) or trimethylene (-CH2-CH2--CH2-) group; and n is the integer number 2 or 37 and pharmaceutically acceptable acid addition salts there-of, which c ompr ise s a) reacting an isothiourea derivative of the general Formula III
(III) [wherein R stands for lower alkyl or phenyl-lower alkyl, where the phenyl ring of the latter group may be optionally substituted by one or more lower alkyl group(s) and/or halogen atom(s)] with an amine of the general Formula IV
(IV) (wherein R1, R2 and n are as stated above) at a temperature between 150°C and 280°C; or b) cyclising a compound of the general Formula II

(II) (wherein R1, R2 and n are as stated above) optionally in the presence of a catalyst;
and, if desired, converting a compound of the general Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.
2. Process according to Claim 1a), which comprises carrying out the reaction in a solvent which has a boiling point above 150 °C, preferably in di-methyl formamide, dimethyl acetamide or sulfolane.
3. Process according to Claim 1a), which comprises carrying out the process at a temperature between 150 °C and 220 °C.
4. Process according to Claim 1b), which comprises carrying out the reaction at a temperature between 150 °C and 280 °C, preferably at 150-220 °C.
5. Process according to Claim lb) or 4, which comprises carrying out the reaction in the absence of a solvent.
6. Process according to Claim lb) or 4, which comprises carrying out the reaction in the presence of a solvent.
7. Process according to Claim lb, which comprises carrying out the reaction in the presence of a catalyst.
8. Process according to Claim 7, which comprises carrying out the reaction at a temperature between 25 °C and 130 °C, preferably at 70-100 °C.
9. Process according to any of Claims 7 and 8, which comprises using phosphorous oxychloride as solvent and phosphorous trichloride, phosphorous tribromide or a Lewis acid as catalyst.
10. Process according to any of Claims 1-9 for the preparation of a compound of the general Formula I, where-in R1 stands for methyl; R2 is hydrogen and n = 3, which comprises using as starting materials compounds of the general Formula II, III and IV, in which R1, R2 and n are as stated in the preamble of this Claim.
11. Process according to any of Claims 1-9 for the preparation of a compound of the general Formula I, where-in R1 and R2 together form an ethylene group (-CH2-CH2-) and n = 2, which comprises using as starting material compounds of the general Formulae II, III and IV, in which R1, R2 and n have the same meaning as stated in the preamble of this Claim.
12. Compounds of the general Formula I, whenever prepared by a process according to any of Claims 1-11.
13. A process as substantially described herein with particular reference to the Examples.
14. Compounds of the general Formula II
[wherein R1 and R2 independently may be the same or different and stand for hydrogen or lower alkyl or together form an ethylene - (-CH2-CH2-) or trimethylene (-CH2-CH2-CH2-) group; and n is the integer number 2 or 3].
15. Process for the preparation of compounds of the general Formula II (wherein R1, R2 and n are as stated in Claim 14), which comprises reacting an isothiourea derivative of the general Formula III [wherein R stands for lower alkyl or phenyl-lower alkyl, where the phenyl ring of the latter group may be optionally substituted by one or more lower alkyl group(s) and/or halogen atom(s)]
with an amine of the general Formula IV (wherein R1, R2 and n are as stated above) at a temperature not exceeding 130 °C.
16. Process according to Claim 15, which comprise s carrying out the reaction in an alcohol or a polar aprotic solvent.
17. Process according to Claim 16, which comprises carrying out the reaction in isopropanol.
18. Process according to Claim 16, which comprises carrying out the reaction in dimethyl formamide.
19. Process according to any of Claims 15-18, which comprises carrying out the reaction at a temperature between 25 °C and 130 °C.
CA002028953A 1989-04-21 1990-04-20 Process for the preparation of quinazoline derivatives Abandoned CA2028953A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
HU1931/89 1989-04-21
HU193189A HU203342B (en) 1989-04-21 1989-04-21 Process for producing quinazoline deivatives
HU193089A HU203333B (en) 1989-04-21 1989-04-21 Process for producing n-cyano-carboxamidine derivatives
HU1930/89 1989-04-21

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CA2077252C (en) * 1992-08-31 2001-04-10 Khashayar Karimian Methods of making ureas and guanidines, and intermediates therefor
ES2096518B1 (en) * 1994-03-28 1997-12-01 Grupo Farmaceutico Almirall S NEW RINGS.
WO2008015525A2 (en) * 2006-07-31 2008-02-07 Orchid Chemicals & Pharmaceuticals Limited An improved process for the preparation of alfuzosin hydrochloride
WO2008152514A2 (en) 2007-05-04 2008-12-18 Actavis Group Ptc Ehf Process for the preparation of alfuzosin and salts thereof
WO2009016387A2 (en) 2007-08-02 2009-02-05 Cipla Limited Process for the preparation of alfuzosin hydrochloride

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US4026894A (en) * 1975-10-14 1977-05-31 Abbott Laboratories Antihypertensive agents
US4044135A (en) * 1975-10-14 1977-08-23 Abbott Laboratories Antihypertensive agents
GB1591490A (en) * 1977-08-04 1981-06-24 Abbott Lab 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride dihydrate
US4138561A (en) * 1977-09-30 1979-02-06 Bristol-Myers Company Cyanocarboxamidines and quinazoline process
FI56836C (en) * 1977-10-25 1980-04-10 Fermion Oy 4-SUBSTITUTES OF PIPERAZIN-1- (N-ARYL-N'-CYANO) -CARBOXIMIDAMIDER BUTTER OF THE BREAST PREPARATION WITH PHARMACOLOGICAL PROPERTIES 6,7-DIMETOXY-ELLER 6,7,8-TRIMETOXY-2-AMINO -SUBSTITUERADE-Piperazine-1-YL) -KINAZOLINER
FI57751C (en) * 1977-10-25 1980-10-10 Fermion Oy PROCEDURE FOR THE FRAMSTATION OF 6,7-DIMETOXY-ELLER 6,7,8-TRIMETOXY-4-AMINO-2- (4-SUBSTITUTES-PIPERAZIN-1-YL) -KINAZOLINE WITH BLODTRYCKSSAKANDE NETKAN
FR2421888A1 (en) * 1978-02-06 1979-11-02 Synthelabo ALKYLENE DIAMINE AMIDES AND THEIR APPLICATION IN THERAPEUTICS
FI59800C (en) * 1979-01-10 1981-10-12 Fermion Oy PROCEDURE FOR THE FRAMSTATION OF 6,7-DIMETOXY-4-AMINO-2- (4- (FURO-2-YL) -PIPERASIN-1-YL) -QUINAZOLINE
FI67699C (en) * 1979-01-31 1985-05-10 Orion Yhtymae Oy PROCEDURE FOR THE FRAMSTATION OF AV 6,7-DIMETOXY-4-AMINO-2- (4- (2-FUROYL) -1-PIPERAZINYL) QUINAZOLINE HYDROCHLORIDE WITH BLODTRYCKSSAENKANDE VERKAN
ATE32074T1 (en) * 1983-11-22 1988-02-15 Heumann Ludwig & Co Gmbh PROCESS FOR THE PREPARATION OF 4-AMINO-6,7DIMETHOXY-2-(4-(FURO-2-YL)-PIPERAZINE-1-YL)QUINAZOLINE AND ITS PHYSIOLOGICALLY ACCEPTABLE SALTS.

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YU70890A (en) 1992-05-28
JPH02292282A (en) 1990-12-03
ATA93190A (en) 1994-01-15
IT1241128B (en) 1993-12-29
PL162976B1 (en) 1994-01-31
DK99090A (en) 1990-10-22
DK99090D0 (en) 1990-04-20
IT9020092A0 (en) 1990-04-20
RU1838309C (en) 1993-08-30
SE9001402L (en) 1990-10-22
CA2015066A1 (en) 1990-10-21
KR900016194A (en) 1990-11-12
ES2019826A6 (en) 1991-07-01
CH681300A5 (en) 1993-02-26
GR900100294A (en) 1991-09-27
SE9001402D0 (en) 1990-04-20
BG91821A (en) 1993-12-24
GB2231571A (en) 1990-11-21
GB9008941D0 (en) 1990-06-20
AT398075B (en) 1994-09-26
FI902002A7 (en) 1990-10-22
PL284860A1 (en) 1991-03-11
FI902002A0 (en) 1990-04-20
IT9020092A1 (en) 1991-10-20
GB2231571B (en) 1992-09-16

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