CS202069B2 - Method of preparing 2-/4-substituted piperazine-1-yl/-4-amino-6,7-dimethoxyquinazolines - Google Patents

Abstract

Compounds of the formula <IMAGE> or of a hydrochloric or hydrobromic acid addition salt thereof, in which R1 is hydrogen or methoxy, and R2 denotes benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl having 2 to 5 carbon atoms or (2-hydroxyalkoxy)carbonyl having 4 or 5 carbon atoms, are prepared in accordance with a novel process. Initially, a 2-chloro-6,7-dimethoxyquinazoline or a 2-bromo-6,7-dimethoxyquinazoline, whose amino group situated in the 4 position is substituted, is reacted, in an inert organic solvent and at 50-200 DEG C, with a corresponding piperazine. In a second reaction step, the substituents of the amino group are removed by hydrogenolysis. The compounds which are obtained can be used as agents for lowering blood pressure.

Description

^{(54) P} b ^of US toasted ² - (4-substituted ^p i ^p erazin-1-7-4 - ^^ - 6, ⁷ and -dimethoxychinazolinů

The present invention relates to a novel process for the preparation of substituted aminoohhnazoline derivatives. The final products prepared by the process of the present invention are known compounds of value. their ability to lower blood pressure in hypertensive mammals. More specifically, these hypotensive compounds are certain 2- (4-substituted-piperazio-1-yl) -4-amino-6,7-dimethoxyquinazoline and 2- (4-substituted piprrazio-1-yl) -4- amioo-6,7 8-trimethoxyquinazoline as claimed in U.S. Patent Nos. 3,517,836 and 3,669,968.

U.S. Patent No. 3,511,836 claims certain procedures for the preparation of 2- (4-substituted piperazin-1-yl) 4-a _and mino-6,7-dimethoxyquinazoles, for example by the reaction of 2-chloro-4-amino-6,7- dimeehosxyhnazoline with the corresponding 1-substituted-piperazine piperazine by reacting 2- (4-substituted piperazio-1-yl) -4-chloro-66, -diethylhexyquinazsine with ammonia or alkylation, alkanoylation, aroylation or alkoxylation of SO-piperazinyl-4-aarnino dimethoxyquinazoline. U.S. Pat. No. 3,669,968 discloses the preparation of 2- (4-substttoovaných -piperazin-1-yЗ). 4A) and r ^ _am no-6, .7, 8-trimethsxyGciinazolinů chlsr reacting 2-4-amio-6,7 8-Trimethoxyxyquinazoline with 4'-substituted piperazine.

U.S. Patent No. 3,935,213 claims the preparation of 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines and the corresponding 6.7 _{L of} 8-trimrhoxychioazolines by a process comprising either 1) reacting the appropriate 4,5-dimethoxy substituted. or 3,4,5-trimethoxy-substituted 2-amino-broonitrile with certain 1,4-disubstituted piperazines; or 2) reacting the appropriate 4,5-dimethoxy- or 3,4,5-? 2-Aminobenzamidine with the same 1,4-disubstituted piperazines.

2020'69

Compounds of formulas: СНзО ^ VV ¹ CH ₃ O NHCH2CH3H3 а СНэО nhch ₂ c ₆ h _p

wherein Ϊ is hydrogen, alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, alkenoyl of 2 to 7 carbon atoms, allyl, propargyl, 2-methallyl, phenyl, benzyl, benzoyl, chlorobenzoyl bromobenzoyl, trifluoromethyl, methoxyphenyl methylphenyl, methylbenzoyl, trifluoromethylbenzoyl, furoyl, benzofuroyl, thenoyl, pyridinecarbonyl, 3,4,5-trimethoxybenzoyl, alkoxycarbonyl of 1 to 6 carbon atoms in alkoxy and alkenyloxycarbonyl of 3 to 6 carbon atoms in alkenyloxy are disclosed in U.S. Pat. 3,511,836.

However, the other intermediates used in the process of the present invention are novel.

The present invention provides a process for the preparation of compounds of formula (I):

NHa wherein is hydrogen or methoxy and

R ₂ is alkenyl of 3-5 carbon atoms, benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl having 2 to 5 carbon atoms, alkenyloxycarbonyl having 4-5 carbon atoms or (2-hydroxyalkoxy) carbonyl having 4-5 carbon atoms, or their hydrochlorides or hydrobromides, characterized in that one mole of the compound of formula (II),

(II) wherein R is as defined above and X is chlorine or bromine Rg is hydrogen and R6 is -COOCRCgRRg, -CORg, -COCFg, -CHO or COORg, Rg is. a hydrogen atom, a chlorine atom, a bromine atom, a methoxyl group or a nitro group, and R8 is a C1-C4 alkyl group or the -C8H4R8 group is reacted with one to two moles of the second reactant of formula III (III).

where Rg. m is as defined above in an inert organic solvent at a temperature of from 50 to 200 ° C. . .

A particularly preferred temperature range is from 80 to 130 ° C.

When the process of the present invention is carried out with a compound of formula II wherein R 8 is hydrogen and R 6 is -COOCH 8 -COR 8 · -COCF 6, -CHO or COO 1 R 8, wherein R 8 and R 8 are as defined above, directly prepare the desired compound or a hydrochloride or hydrobromide thereof. In the latter case, p. preferably, reacting the compound of formula II with two two-second reaction components of formula III.

While the process of the present invention is useful for the preparation of the known hypotensive agents of formula I, it is particularly useful for the preparation of two particularly valuable compounds of formula I, namely 2- [4- (2-furoyl) piperazin-1-yl] -4-amint-6. »7-dimethtxychinazolinu and ² - [4- ^(2-hydroxy-2 - meth ^H lppo ^of ху -1 ^^ ^- ^^^ · ^-) -?! ^^^ ^0-1-yl]] -4 -a ^m i ⁿ o-6,7

8-trimethethoxyquinazoline, known as prazosin atrimazosin. 2- (4- (2-methylprop-2-enyloxycarbonyl) piperazio-1 H-4-aeine-6,7,8-trimethoxyquinazolio is a valuable starting ether for the preparation of trimazosin [US Patent No. 3,669,968 ). Prazosin and trimazosin have, according to a recent publication, a therapeutic effect in humans [Cohen, Journal of Clinical Pharmm (Dogy, J_0, 408 (1970), De Guúa, et al., Curent Therapeutic Research, 15, 339 (1973) //). .

The reaction of the compounds of formulas II and III is carried out in a suitable inert organic solvent.

A suitable solvent is one which sufficiently dissolves the reaction components and does not adversely affect the reactants or reaction products. Examples of these solvents. ^ alkanes, such as isopropanol, butanol, isobutanol, ^and isoamУ JLT ⁰ Heo, 2-meehyl-pentanol and 3,3-dieethe - 1-buUιjnot, glycols such as eteylθnglykol and dieteyl ^e ogPyttl, glykoleteery as ethyl-leoglycol moietyee ether, diethyl-leoglycol, e-ether, 1,2-. dimethoxyethane and diete.ylθogPytoldimthe-lther, tertiary amides such as NN-dimethylformamide, N, N and N-diethylacetmid _{meehe-lУ-rolidtn)} dimeethysulfoxid and pyridine. While the reaction can be carried out over a wide temperature range, a temperature of 50 to 200 ° C is preferred. A particularly preferred temperature range is from 80 to 130 ° C. The time required to complete the reaction depends on several factors, such as the reaction temperature, the reactivity of the respective starting materials, and the concentration of the reactants. At lower temperatures a longer reaction time is required, while at higher temperatures the reaction is completed within a shorter time. In general, a period of from 15 minutes to 50 hours is sufficient.

In certain cases, the reaction of a compound of Formula II with a compound of Formula III forms an intermediate of Formula IV, which is then further reacted to give the desired compound of Formula I. The preparation of compounds of the present invention can be carried out by any of two methods is shown in the following reaction scheme:

CH ₃ O ' ^x ^ * ^x ^ * ^N

NHj (I)

The process of the present invention is:. performed according to method B.

Compounds of formulas II and III used as reaction components in the process of the present invention are those wherein X is a chlorine or bromine atom, and particularly preferred are compounds wherein X is a chlorine atom, R1 is hydrogen or metho1, R8 is alkenyl (C pěti-C,) benzoyl, fumyl, thienylcarbonyl, (C alk-C alk alk) alkenylcarbonyl, (C až-C alkeny) alkenylcarbonyl, or (C--C 2-2-hydroxyalkyloxy) carbonyl R je is hydrogen · and Rj R — is a hydrogen, chlorine, bromine, methane, methoixyl or nitro group, and Rg is an alkyl of one to four atoms or -C -CH ^Rj

When a compound of formula II wherein R 6 is hydrogen or methyl, R is hydrogen and R ₄ is -COOCH 8 C 9 HHR 3 -COR 8, -COCF 6, -CHO or -COOR 9, where R ₈ is hydrogen; and R 8 are as defined above, reacted with 1-substituted piperazene of formula III in the process of the present invention, then the reaction proceeds directly to give the desired compound of formula I as shown in Method B of the above scheme. Thus, for a compound of formula II, a 1-substituted piperazine of formula III reacts both at the 2-position of the quinazoline of formula II to cleave the halogen atom (X = Cl or Br) and to cleave the R 1 group when R 1 is hydrogen and R 1 is one of the above of said carbonyl-containing groups. This gives a compound of formula I in one step.

While method B is carried out using conventional molar ratios of the compound of formula II to the compound of formula III from 1: 1 to, 1: 3 or below, it is preferable to react the compound of formula II with the compound of formula III in a 1: 1 molar ratio. 2, for reasons of efficiency and economics.

When the process of the present invention is carried out according to Method B, the desired product of formula (I) is readily isolated by standard methods, either in the form of the hydrochloride (if X is chlorine), hydride (if X is bromine) or the free base . For example, if the compound of formula II, wherein X is especially chlorine, is reacted with two moles of the compound of formula III, then the hydrochloride obtained is isolated by filtration of the reaction mixture and washing the product. If it is necessary to obtain the product of the compound of formula I in the form of the free base, the reaction mixture is treated with an excess of an aqueous solution of a strongly alkaline reagent such as sodium hydroxide at the end of the reaction. potassium hydroxide or sodium carbonate and the free base are extracted with a water-immiscible solvent such as chloroform, carbon tetrachloride, 1,2-dichloroethane or benzene. The product can then be obtained, for example, by evaporation of the solvent and further purification.

While the intermediates of formula II, wherein R 1 is hydrogen, is hydrogen and is benzyl, are disclosed in U.S. Patent No. 3,511,836, and the same patent discloses intermediates of formula IV with the same meanings for R, R 4 and R 4. and R _2, as mentioned above. certain remaining compounds of formulas II and IV are novel.

The above-described intermediates of formulas II are prepared from the corresponding 2,4-dihalo-6,7-dimethoxyquinazoline or 2,4-halo-6,7,8-trimethoxyquinazoline wherein the halogen atom is a chlorine or bromine atom. The preparation of these dihalogen compounds has already been described in U.S. Patent Nos. 3,511,836 and 3,669,968, and in Cirdir et al., J. Chem. Soc. (London) 777 (1947) and J. Chem. Soc. 1759 (1948).

The following examples illustrate the invention in greater detail.

Example·

4-erzzoyazin-2-chloro-6,7-dimethoxyquinazzlin

In a 100 ml three-necked round-bottomed flask equipped with a reflux condenser, a thermometer and a drying tube were placed 32 ml of anhydrous tetralofuran, 10 ml of anhydrous N, N-dimethylformamide, 6.48 g (0.025 mol) of 2,4-dihsr-6,7-. dimethoquinoline azoline (prepared according to the method of Curd et al., J. Chem. Soc. 1759 (1948), 3.03 g (0.025 mol) of benzamide and 2.4 g (0.50 · mol) of 50% w / w sodium hydride, The resulting mixture was heated to boiling for 24 hours, cooled to mL temperature, filtered, washed with tetrafluoroform to give 6.0 g (66%) of the sodium salt of the title compound, mp 315 ° C. C.

After suspending 1.0 g of the sodium salt in 20 ml of water, the mixture is treated with 2 N hydrochloric acid to pH 3-4, stirred for 15 minutes at 20-25 ° C, filtered and dried overnight. 0.67 g of the title compound is obtained, m.p. 235-240 ° C. Crystallization from isoamyl alcohol has a melting point of 236-238 ° C. The nmr spectrum shows bands at Me 342 and 344.

Example 2 .alpha.-Acetylamino-hlC11-6-6,7-memoxyxycinazon

6.48 g (0.025 mol) was added to a 100 mL reaction vessel. _{2,4-dichllr-6>} 7-dimethlxychinazolinu, 1.5 g (0.025 mol) of acetamide, 32 ml of anhydrous Ν, Ν-dimethylformamide and 2.4 g (0.050 mol) of 50% sodium hydride. After warming to 40 ° C, an exothermic reaction is initiated and the temperature rapidly rises to 120 ° C with considerable foaming. During the exothermic reaction, the reaction mixture first turns purple and then red. The mixture was then cooled to 90 ° C. and kept at this temperature for two hours. After cooling to room temperature, the mixture is poured into 150 ml of water, washed with two 100 ml portions of chloroform and the aqueous phase adjusted to pH 2 by addition of concentrated hydrochloric acid. The precipitated product is filtered off, dried and yielded in 86% yield. title compound, mp 275 ° C. On chromatography on a thin layer of silica gel in a network of ethyl acetate, diethylamine 95: 5 is evident. only one spot. The spectral spectrum exhibits a mooecular ion at M / e 281.

Example 1 a d 3

4-Ethoxycarbonylamino-2-chloro-6, d-dimethoxyquinazoline

2-, 4-dichloro-6,7-dimethoxyquinazoline (6.48 g, 0.025 mol), 32 ml tetaahydoifuraou, ethylcarbamate (2.23 g, 0.025 mol) and 50% sodium hydride (2.4 g, 0.050 mol) The reaction mixture is refluxed for two hours, then 70 ml of methanol are slowly added and the mixture is heated to 60 ° C and filtered while hot. The filtrate is concentrated to a thick suspension, the solid is filtered off, washed with 5 ml of chloroform to give 5.4 g (70%) of the title compound. A sample crystallized from tetrahydrofuran / hexane (2: 3) melted at 212 ° C.

Calcd for C 50 N 4 N 3 O 4 Cl: 50.09% C, 4.53% H, 13.48% N; Found: C 49.95%, H 4.4%, N 13.54%.

Example 4.

2- [4- (2-Furoyl) -piperazin-1-yl] -O-m: Li-4-methyl-7-dimethylamino-C

In a 50 ml flask equipped with stirrer, reflux condenser, drying oven. 160 is added. mg. (0,6-mol) 4-benzo-ylamino-4-oxo-1,7-dimethoxyquinazoline prepared according to the procedure of Example 1, 244.2 mg (1.32 mmol) of 1 - (- furoll) piproazine and 4 ml of islamrlalcohol. The resulting mixture was heated at 100 ° C for 4 hours, then cooled to room temperature for 4 hours, and the precipitate was filtered off, dried to give 60 mg of crude product. The product was identified as 2o [ ₍ 4- (fluoro) P) peparazin-1-o40aO-amino-6d 7-aminochloroquinoline chrominophthaline on a thin layer (ethyl acetate / ethyl acetate 90:10). silica gel column.

(1.3 cm x 22.9 cm eluting with a mixture of benzene, acetone, formic acid and water (100: 100: 20: 5 -.

(v / v) to give 35 mg of m.p. 275 ° C.

If the above procedure was repeated using the above solvent instead of isoamyl alcohol and the reaction was performed using the temperature and time indicated in the table, the title compound was obtained in an analogous manner.

Solvent Reaction temperature ° C Reaction time hours 2-butanol 50 50 2-m-1: 1 80 18 2ooeehyУ --- prealtaool 130 2 diet-hyl! 200 0.25

Example 5

24-4- (г ^ Лгоу) ^{piazroo0oLyl-a,} 40-m-iIhi6o-sixth, 7memchOУ] drchinahoOin (prazos ^)

4-Hydroxy-4-chloro-2-chloro-7,4-dimethyl-polycholine (2.0 g, 0.0064 ooOI) and 23 mL of isolaoyl alcohol were mixed in a year flask. A solution 1o (-ofuolyl) piproaziiu (2.54 g, 0.014 mol) in 18 mL ^г lalklholu Islam and the mixture was heated for 4 hours at 130 ° C., Solids were Vyyгáieoé oddilt ^ her flex isoamylalcohol, followed οΙοΙ with 100 ml of 10% aqueous. sodium hydroxide solution. An equal volume of chloroform was added and the mixture was stirred for 15 minutes. The organic phase is filtered off, concentrated to about 25 ml and 50 ml of trtralyfrofuran are added. The solids were filtered off and then further purified by silica gel column chromatography (2.5 cm x 45.7 cm), eluting preferably with ethyl acetate and then with methanol. The fraction 1b of the title compound was combined and evaporated to dryness. The residue is taken up in 10 ml of chloroform, hexane is added until turbid, the mixture is stirred for 15 minutes and the crystals are discarded.

When the above reaction was carried out at 80 ° C for 18 hours, the results remained unchanged.

Annlýsa for C! T ^ ₂ ^^ H, _O-4 '' calculated: 59.51% C, 5.52% H, 18.26% N; found: C, 59.25; H, 5.46; N, 18.40.

The product was further characterized by thin layer chromatography and compared to an authentic sample of prazosin.

Claims (7)

SUBJECT OF THE INVENTION 1. A process for preparing 2- (4-substttuovaných pipeaazin-1-yl) -4-aminO66,7 · -diteethoxychinazolinů- formula I _ь '•' ΫγγΟ- · ' NH} where ' R 1 is hydrogen or meehoxyl and R 8 is C 3 -C 5 alkenyl, benzoyl, iuroyl, thienylcarbonyl, C 2 -C 5 alkoxycarbonyl, C 4 -C 5 alkenyloxycarbonyl or C 4 -C 5 (2-hydroxyalkoxy) carbonyl or hydrochlorides thereof or hydrobromides, characterized in that one mole of the first reactant of formula (II) wherein R 1 is as defined above, X is chlorine or bromine R 1 is hydrogen and R4 is -COOCH8CcH4, -COR8, -COCF1, -CHO or -COOR8, R4 is hydrogen, chlorine or bromine, mehe / l, methoxy or nitro; and R₈ is alkyl of 1-4 carbon atoms or -C ^ R ^ H, is reacted with one to two moles of a second reactant of the formula III hn_ NR @ ₂ (III) wherein R is as defined above, in an inert organic solvent at a temperature of from 50 to 200 ° C. 2. Process according to claim 1, characterized in that the reaction is carried out at a temperature of from 80 to 130 ° C. 3. Process according to claim 1 or 2, characterized in that one mole of the first reactant of the formula II is reacted with two moles of the second reactant of the formula III to form the final product of the formula I. 4. Process according to claims 1-3, characterized in that as the starting compounds of the formulas II а III wherein R is hydrogen, R ₂ is a 2-furoyl а X, R₁ and R are as defined above . 5. Process according to claims 1-4, characterized in that as the starting compounds of the formulas II а III, wherein _R] is methoxy, R ₂ is 2-methyl-2-hydroxypropyl-1-yloxycarbonyl а X, R and R1 are as defined above. 6. Process according to claims 1-4, characterized in that as the starting compounds of the formulas II а III wherein R₁ is methoxy, R ₂ is 2-methylprop-2-nitrophenyloxycarbonyl and X, R ^ and R ^ are as defined above. 7. A process according to any one of claims 1 to 6, wherein the starting material is a compound of formula (II) wherein X is chlorine and R1 and R2 are as defined above.