KR820001835B1 - Process for preparing 4-aminozpiperidonoquina-zoline derivatives - Google Patents

Abstract

Title compds. [I; R = lower alkyl; X = 3-, 4-(CH2)nCONR1R2-R1R2, or -O(CH2)nCONR1R2(R1 = H, C1-6 alkyl; R2 = H, C1-6 alkyl, ph, substituted alkyl; R1R2 = 1,2,3,4-tetrahydroisoquinolyl) useful as anti-hypertensiv agent, were prepd. by reaction of quinazoline(II; Q = eliminating group) and piperidine(III) in the presence of inactive solvent. Thus, 1.2 g II (R = Me; Q = Cl), 1.01 g III(X = CONHC4Hg) and 2.52 ml Et3N was added and heated for 24 hr followed by filteration and recrystallization to give 0.57 g I(m.p., 263-264≰C).

Description

Method for preparing 4-amino-2-piperidinoquinazoline derivative

The present invention relates to 4-amino-2-piperidinoquinazoline derivatives useful as cardiovascular modulators, in particular hypertensive agents, and to methods for preparing pharmaceutically acceptable acid addition salts thereof.

The novel compound according to the present invention is represented by the following general formula (I).

In the above formula,

R is a lower alkyl group;

X is a group represented by the following general formula-(CH ₂ ) _n CONR ⁱ R ² or -O (CH ₂ ) _n CONR ⁱ R ² attached to the 3- or 4- position of the piperidino group,

n is 0 or 1;

R ⁱ is hydrogen or a C ₁ -C ₆ alkyl group;

R ² is C ₁ -C ₆ alkyl; Phenyl; Or phenyl, (which in the end, R ² oxygen atoms separated by at least two carbon atoms from the nitrogen atom attached to the R ² position), hydroxy or C ₁ -C ₆ alkyl group substituted by a C ₁ -C ₆ alkoxy Or R ¹ and R ² together with the nitrogen atom to which they are attached form a 1,2,3,4-tetrahydro isoquinolyl group.

In the present specification, the alkyl group and the alkoxy group are preferably up to 6 carbon atoms, and the term phenyl group is optionally substituted with 1 or 2 substituents selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and halogen. Mean phenyl group.

Pharmaceutically acceptable acid addition salts are those produced from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, and belonging to such acid addition salts include hydrochloride, bromate, sulfate or sulfite, phosphate or Acid phosphates, acetates, maleates, fumarates, lactates, tartarates, citrates, gluconates, saccharides, or P-toluenesulfonates. Compounds according to the invention having one or two asymmetric centers exist as one or more pairs of enantiomers, and these pairs or individual isomers can be separated using physical methods such as fractional crystallization of appropriate salts. The present invention includes those in which the isolated pairs and mixtures thereof are in the form of racemic mixtures or isolated d- and 1-optical active isomers.

Among the compounds having the same general formula as the compound (I) according to the present invention, preferred are compounds having the following substituents in this formula. In other words

R is a methyl group;

X is attached to the 4-position of the piperidino group and is represented by the following formula.

(A) -CONR ¹ R ²

R ¹ is hydrogen, a methyl group or an ethyl group;

R ² is a C ₁ -C ₆ alkyl group; Phenyl group; Or a C ₁ -C ₄ alkyl group substituted with a phenyl group, a hydroxy group or a C ₁ or C ₂ alkoxy group or R ¹ and R ² together with the nitrogen atom to which they are attached form a 1,2,3,4-tetrahydroisoquinolyl group.

(B) -CH ₂ CONHR ²

R ² here is a C ₁ -C ₆ alkyl group.

(C) -O (CH ₂ ) _n CONH (C ₁ -C ₆ ) alkyl

Where n is 0 or 1.

Among the compounds having the general formula (I), most preferred are those in which R is a methyl group, X is in the 4-position and has the following groups.

-CONHC ₂ H ₅

-CONH (CH ₂ ) ₃ CH ₃

-CONH Benzyl

-CH ₂ CONH (CH ₂ ) ₂ CH ₃

According to the method of the present invention, the compound is prepared by heating a quinazoline represented by the following general formula (II) with piperidine represented by the following general formula (III) in an inert organic solvent for about 48 hours.

In the above formula,

R is as defined in the general formula (I) above;

Q is an easily leaving group such as chloro, bromo, iodo, lower alkoxy, (lower alkyl) thio or (lower alkyl) sulfonyl groups, and the like.

Wherein X is as defined in the general formula (I).

This reaction typically proceeds in the presence of an excess of a reagent represented by the general formula (III) and a tertiary organic amine such as triethylamine, but is not essential. In a typical reaction, the reactants are heated under reflux for about 48 hours in an inert organic solvent such as n-butanol and the product is separated and purified by conventional methods. The reaction mixture is cooled, the solvent is evaporated in vacuo and the resulting solid is shaken with chloroform and water. After filtration the solid (or salt) is recrystallized in a suitable solvent such as ethanol or purified by chromatography.

Intermediates, such as formula (II), are known compounds and employ methods analogous to conventional methods when preparing them.

Intermediates such as general formula (III) are prepared using conventional methods as known compounds, for example, can be prepared through the following reaction route.

(end)

Instead of acid chlorides, acid bromide, active esters or mixed anhydrides can be used.

(I)

Starting materials 1-benzyloxycarbonylpiperidine-3- or 4-carboxylates are described in J. Org. Prepared in a manner similar to that found in Chem., Vol. 31, 2957 (1966).

(All)

(la)

(hemp)

(bar)

The acid chlorides and esters of scheme (bar) are prepared by conventional methods from the corresponding free acids. Pyridine acid with n = 1 is a known compound and prepared by a method similar to the conventional method. A pyridine compound with n = 2 is also prepared from the corresponding alcohol according to the following conventional method.

(four)

When preparing acid addition salts, the crude product is prepared by dissolving the crude product in a small amount of a solvent such as chloroform and reacting this solution with a suitable acid solution in a suitable solvent such as a hydrogen chloride ether solution. The precipitate of the resulting acid addition salt is filtered off and separated, if necessary, by recrystallization from a solvent of isopropanol / methanol.

The hypotensive action of the compound prepared by the present method showed that the hypotensive ability was shown when orally administered at a dose of 5 mg / kg to rats with autologous symptoms and dogs with renal hypertension.

Compounds prepared by this method may be administered alone, but are usually administered in admixture with appropriately selected pharmaceutical carriers, taking into account the route of administration and standard pharmaceutical practice. For example, it can be administered orally in the form of tablets containing excipients such as starch or lactose, in capsules alone or in admixture with excipients, or as elixirs or suspensions containing flavors or pigments. They can also be injected parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral administration, it is best to use it in the form of a sterile liquid made from an isotonic solution containing a solute such as salt or glucose.

정도의 량으로 하여 투여한다. 따라서 성인 환자의 경우에 있어서 경구투여량을 정제 또는 캅셀로 만들어 투여하는데 이중에 본 발명에 의한 활성화합물을 약 0.25 내지 25mg 함유시킨다. 치료대상되는 환자의 체중과 건강상태 및 특수한 투여경로에 따라 반드시 투여량을 변환시켜야 한다.The present compound can be used to treat hypertension by administering a unit dose orally or parenterally to a human, and also orally administered about 0.5 to 50 mg once or three times a day for adult patients (70 kg body weight). Intravenous injection is about 1 for the dose

It is administered in an amount of about. Therefore, in the case of adult patients, oral dosages are made into tablets or capsules, which contain about 0.25 to 25 mg of the active compound according to the present invention. Dosages must be converted according to the weight and health of the patient being treated and the particular route of administration.

The present invention will be described in detail according to the embodiment. All temperatures shown in the examples are degrees Celsius (° C.).

Example 1

Preparation of 4-amino-6,7-dimethoxy-2- [4- (N-n-butylcarbamoyl) piperidino] -quinazolinhydrochloride

4-amino-2-chloro-6,7-dimethoxyquinazolin (1.2 g), 4- (Nn-butylcarbamoyl) piperidine (1.01 g) and triethylamine (2.52 ml) were added to n-butanol ( 105 ml) and heated at reflux for 24 hours, then the mixture was cooled to evaporate the solvent and the remaining solid was shaken by addition of chloroform and water. The solid product was collected by filtration and recrystallized twice from ethanol to obtain the target compound (0.57 g) (melting point: 263 to 264 °).

Calcd for C ₂₀ H ₂₉ N ₅ O ₃ HCl,%

Found: C 56.8; H 7.4; N 16.5

Calculated Value: C 56.7; H 7.1; N 16.5

Example 2-18

In the same manner as in Example 1, 4-amino-2-chloro-6,7-dimethoxyquinazoline and appropriately substituted piperidine were prepared as starting materials, and the following quinazoline was prepared as shown in the following table. Separate into each form. In Examples 9 and 16, the product was purified by chromatography.

The following manufacturing methods are all manufactured at the Celsius temperature (° C.), and are examples of preparing the starting materials used in the previous examples.

Preparation Example (A)

Preparation of 4- (N-phenylcarbamoyl) piperidine

4- (N-phenylcarbamoyl) piperidine (75.0 g) [Chem. Abs. Prepared according to the method in 2013h (1958), hydrogenated using platinum oxide as a catalyst under acetic acid (800 ml) under a condition of 50 p.s.i / 30 ° C. The catalyst is filtered off and the solution removed is evaporated and the residue is made caustic to pH 12 with sodium hydroxide, extracted with chloroform and the organic extract is discarded. The aqueous layer is evaporated to dryness and the residue is separated with chloroform and filtered to evaporate to afford the target compound (17.0 g) having a melting point of 121 to 127 ° C. Its hydrochloride (melting point; 231-233 ° C.) is prepared from free base and hydrogen chloride in isopropanol and recrystallized in isopropanol / ethyl acetate.

Anal for C ₁₂ H ₂₆ N ₂ OHCl,%

Found: C 60.1; H 7.2; N 11.7

Calculated value: C 59.9; H 7.1; N 11.6

Preparation Example (B)

Preparation of 4- (N-n-butylcarbamoyl) piperidine

A mixture of isonicolin oil (100.0 g) and toluene (600 ml) and n-butylamine (51.6 g) was added to the mixture for more than 1 hour at 0 ° C. overnight and then heated for 30 minutes in a steam bath. Add. The aqueous layer is separated, basified to pH 12 with sodium hydroxide, and extracted twice with ethyl acetate. The mixture of organic extracts was dried (using magnesium sulfate) and the evaporated residue (36.0 g) was dissolved in acetic acid (400 ml) and hydrogenated at 50 psi / 30 in the presence of platinum oxide. The catalyst was separated by filtration and evaporated to dryness. The residue was basified to pH 12 (using sodium carbonate) and extracted with chloroform. Evaporation of the dried chloroform extract (using sodium sulfate) afforded 18.7 g of the target compound having a melting point of 75 to 79 ° C. Oxalate is prepared from free base and oxalic acid in isopropanol and recrystallized in isopropanol / ethyl acetate to obtain a melting point of 143 to 144 ° C.

Analytical value for C ₁₀ H ₂₀ N ₂ O • C ₂ H ₂ O ₄ ,%

Found: C 52.9; H 8.0; N 10.3

Calculated value: C 52.5; H 8.1; N 10.2

Preparation Example (c)

Preparation of 4- (N-2,4-dichlorobenzylcarbamoyl) piperidine

1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride (4.6 g) [J. Org. Chem. Vol. 31, No. 2957 (1966), was added to a solution of chloroform (25 ml), and 2,4-dichlorobenzylamine (3.87 g) and triethylamine (2.2 g) were dissolved in chloroform (100 ml). Completely added dropwise into the cooled solution (ice water cooling), the solution was left at room temperature for 1 hour, washed with water, dried (using sodium sulfate) and evaporated. The resulting solid residue is crystallized in toluene / ethanol to give 1-benzyloxycarbonyl-4- (N-2,4-dichlorobenzylcarbamoyl) piperidine (7.04 g) having a melting point of 144 to 145 ° C.

Anal for C ₂₁ H ₂₂ N ₂ O ₃ Cl ₂ ,%

Found: C 60.0; H 5.2; N 6.8

Calculated value: C 59.9; H 5.3; N 6.7

The above product (6.5 g) was added to acetic acid (25 ml) and the solution cooled by stirring (ice water cooling) was gradually treated using a solution saturated with hydrogen bromide in acetic acid (25 ml). After the precipitate was formed, the reaction mixture was stirred at 20 ° C. for 1 hour, followed by addition of dry ether (100 ml), and the resulting solid was taken and washed with ether to give 4- (N-2,4-dichlorobenzylcarbamoyl) piperidine. Bromate (3.4 g, melting point: 171-173 ° C.) was obtained, and the infrared structure and the analysis by nuclear magnetic resonance confirmed the same structure. This product was used in Example 5 without further purification.

Preparation Example (D)

4- (N-2-methoxybenzylcarbamoyl) piperidine

1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2-methoxybenzylamine as starting materials were prepared in the same manner as in Preparation Example (c), to obtain the target compound having a melting point of 139 to 140 ° C. .

Calcd for C ₁₄ H ₂₀ N ₂ O ₂ ,%

Found: C 67.3; H 8.1; N 11.0

Calculated value: C 67.7; H 8.1; N 11.3

Preparation Example (E)

Preparation of 4- (N-methyl-N-benzylcarbamoyl) piperidine

Using the 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and N-methylbenzylamine as starting materials, the target compound was prepared in the same manner as in Production Example (c), and used directly in Example 10. Characteristic of this intermediate is hydrochloride, which has a melting point of 175 to 176 캜.

Anal for C ₁₄ H ₂₀ N ₂ OHCl,%

Found: C 62.4; H 7.7; N 10.1

Calculated value: C 62.6; H 7.9; N 10.4

Preparation Example (F)

Preparation of 4- (1,2,3,4-tetrahydroisoquinol-2-ylcarbonyl) piperidine

Example 1 This compound was prepared in the same manner as in Preparation Example (c), using 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 1,2,3,4-tetrahydroisoquinolon as starting materials. Use directly on 13. The intermediate material is characterized by a hydrochloride having a melting point of 245 to 247 ° C.

Anal for C ₁₄ H ₂₀ N ₂ OHCl,%

Found: C 63.6; H 7.6; N 9.9

Calculated value: C 64.2; H 7.6; N 10.0

Preparation Example (G)

Preparation of 4- [N- (2-methoxyethyl) carbamoyl piperidine

1-benzyloxycarbonyl-4- [N- (2-methoxyethyl) carbamoyl] piperidine (5.76 g) [analysis value (%): C 63.9; H 7.5; N 8.4, calcd for C 63.7; H 7.6; N 8.8; In Preparation Example (c), using toluene instead of chloroform and using 2-methoxyethylamine and 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride as starting materials in the same manner as in Preparation Example (c) Prepared] is added to ethanol (75 ml) and hydrogenated under conditions of 50 psi / 50 ° on a catalyst coated with 5% platinum on charcoal. The catalyst is separated by filtration and the filtrate is evaporated to obtain the target compound of the present oily phase, which solidifies when left standing. Infrared analysis and nuclear magnetic resonance analysis showed that the structure is the same. This compound is used in Example 7 without further purification.

Recipe (H)

Preparation of 4- [N- (2-hydroxyethyl) carbamoyl] piperidine

1-benzyloxycarbonyl-4- [N- (2-hydroxyethyl) carbamoyl] -piperidine (6.24 g) [melting point: 107-108 ° C., analytical value (%): found: C 62.8; H 7.2; N 9.0, calcd: C 62.7; H 7.2; N 9.1; This compound was prepared in the same manner as in Preparation Example (c), using 2-hydroxyethylamine and 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride as starting materials. Hydrogenated to obtain the target compound, which was confirmed to have the same structure by infrared analysis and nuclear magnetic resonance analysis. This product is used in Example 6 without purification.

Preparation Example (I)

Preparation of 4- [N- (α-methylbenzyl) carbamoyl] piperidine

1-benzyloxycarbonyl-4- [N- (α-methylbenzyl) carbamoyl] piperidine (5.5 g) [melting point: 136 °; the compound contains α-methylbenzylamine and 1-benzyloxycarbonylpiperi Prepared according to the method of Preparation (c) using din-4-carboxylic acid chloride as a starting material. Found (%): found: C 72.2; H 7.1; N 7.5, calcd for C ₂₂ H ₂₆ N ₂ O ₃ : C 72.1; H 7.2; N 7.7] was hydrogenated as in Preparation Example (G) and used in Example 11 without purification of the crude product.

Preparation Example (J)

Preparation of 4- (N-ethylcarbamoyloxy) piperidine

A mixture of 1-benzyl-4-piperidinol (293.4 g), ethyl isocyanate (120 g) and 1,2-dichloroethane (1467 ml) was heated and stirred for 7 hours with reflux. 10.9 g of isocyanyl ethyl was added again, and the mixture was heated to reflux for 6 hours. After cooling, the mixture was allowed to stand at room temperature for 36 hours to prevent the reaction from being completed. Then, 33 g of ethyl isocyanate was added again and heating was continued for 6 hours under reflux conditions. After cooling the mixture and adding water (2000 ml) and stirring for 1 hour 30 minutes, the organic layer was separated and washed with saturated sodium hydrogen carbonate solution (2000 ml) and water (2000 ml). The aqueous layer was mixed and extracted with dichloroethane (150 ml), the organic layer was dried (magnesium sulfate) and then evaporated in vacuo and stirred in hexane to break off the crude product. After cooling, the mixture is filtered to give 1-benzyl-4- (N-ethylcarbamoyloxy) piperidine (354.4 g, melting point: 96 to 98 ° C).

This product (118 g) is added to industrial methylated spirit (826 ml) and then hydrogenated on a catalyst (12 g) coated with 5% platinum on charcoal until hydrogen aspiration is absent under conditions of 50 ° C / 50 psi. The residue obtained by evaporation of the filtrate from which the catalyst was separated by filtration was recrystallized in a mixture of hexane (450 ml) and ethyl acetate (112 ml) to obtain the target compound (208.1 g, molten 85 to 87 ° C).

Preparation Example (K)

(1) 2- (1-benzylpiperidine-4-oxy) acetic acid, hydrochloride

Stir with 1-benzyl-4-hydroxy piperidine (10 g) in dry dimethylformamide (50 ml) and 50% dispersion in sodium hydride (5 g) mineral oil in dry dimethylformamide (50 ml). Suspension is added dropwise under nitrogen atmosphere. The suspension is stirred at 20 ° C. for 4 hours and then a solution of 2-chloroacetic acid (4.95 g) in dimethylformamide (50 ml) is equally divided into two portions and slowly added at two hour intervals. The resulting thick slurry is stirred at 20 ° C. for 24 hours. Isopropanol (75 ml) is added and the slurry is acidified to pH 6 with 2N hydrochloric acid and concentrated in vacuo. The residue of the aqueous layer was adjusted to pH 10 using sodium hydroxide solution, extracted 100 ml at a time using chloroform, and extracted three times. Extract it (100 ml x 3 times). Discard the organic extract, concentrate the aqueous layer to about half the volume and evaporate the filtrate under vacuum to obtain the target compound (3 g). This compound was confirmed by nuclear magnetic resonance.

(2) N-n-butyl-2- (piperidine-4-oxy) acetamide, hydrochloride

2- (1-benzylpiperidine-4-oxy) acetic acid, hydrochloride (7.0 g) and thionyl chloride (5 ml) were added to dry chloroform (100 ml) under heating under reflux for 2 hours 30 minutes. The acid chloride produced by evaporation of the solvent was dissolved in chloroform (50 ml), and n-butylamine (5 ml) was added dropwise to chloroform (50 ml) with stirring at 0 ° C. The solution is stirred at 0 ° C. for 4 hours and left overnight at room temperature. The chloroform solution is first washed with water (50 ml × 3 times), followed by 2N-sodium hydroxide solution (50 ml × 3 times), followed by 2N hydrochloric acid solution (50 ml × 3 times). The acidic aqueous solution is basified to pH 12 and extracted with chloroform (100 ml × 3 times). The chloroform extract is dried, the solvent is evaporated in vacuo, the residue is added in ether and treated with ethereal hydrogen chloride to take up the resulting solid. It is washed with ether and dried to give N-n-butyl-2- (1-benzylpiperidine-4-oxy) acetamide, hydrochloride. This compound was confirmed by nuclear magnetic resonance spectroscopy. This product (3 g) was hydrogenated under 50 ° / 50 psi on a catalyst (engelhardt special debenzylation catalyst) coated with 5% platinum on charcoal to a solution added in ethanol (100 ml). The residue obtained by filtration separation of the catalyst and vacuum evaporation of the solvent was triturated with ether and the white solid was filtered to afford the target compound (1.7 g). This is recrystallized in isopropanol / diethyl ether and then recrystallized with ethyl acetate to obtain the target compound having a melting point of 145 to 146 ° C.

_{C 11 H 22 N 2 O 2} · HCl for the analysis value,%

Found: C 52.3; H 9.2; N 10.9

Calculated value: C 52.7; H 9.3; N 11.2

Preparation Example (L)

Preparation of IV-ethyl-2- (piperidine-4-oxy) acetamide

2- (1-benzylpiperidine-4-oxy) acetic acid and hydrochloride prepared in the same manner as in Production Example K (1) were converted to methyl esters of this compound by refluxing in methanol and concentrated hydrochloric acid. Methyl (10 g) and ethylamine (50 ml) of 2- (1-benzylpiperidine-4-oxy) acetate are heated together with 3A molecular sieve at 120 ° in a bomb for 6 hours. The residue obtained by vacuum evaporation of the solvent is triturated with ether and the filtrate is evaporated to give N-ethyl-2- (1-benzylpiperidine-4-oxy) acetamide oil (7.7 g). This product (7.0 g) is added to ethinol (150 ml) and hydrogenated at 50 ° C./50 psi on a charcoal coated with charcoal 5% platinum (Engelhardt special debenzylation catalyst). The catalyst was filtered off and the filtrate isolated was evaporated and the residue was dissolved in toluene and evaporated in vacuo to give N-ethyl-2- (piperidine-4-oxy) acetamide (4.8 g) as oil. This compound is dissolved in ether, treated with ethereal hydrogen chloride, converted to hydrochloride, recrystallized in methanol / ether and then recrystallized in isopropanol to give the target compound having a melting point of 172 to 173.

Anal for C ₉ H ₁₈ N ₂ O ₂ HCl,%

Found: C 48.8; H 8.8; N 12.4

Calculated value: C 48.5; H 8.6; N 12.6

Preparation Example (M)

Preparation of 3- (N-n-butylcarbamoyl) piperidine

Nn-butylnicotinamide (7.0 g) was added to acetic acid (100 ml) under hydrogenation at 50 ° C and 50 psi on platinum oxide, and the resulting filtrate was evaporated from the catalyst. The resulting residue was treated with toluene. Vacuum evaporate. The residue was added to chloroform (50 ml), washed with sodium hydrogen carbonate (50 ml x 3 times), the organic layer was separated and dried (using sodium sulfate) and the solvent was evaporated in vacuo to give 3- (Nn-butylcarbamoyl) piperidine ( 3.8 g). This compound was added to chloroform and treated with a solution of oxalic acid added to ether to convert it into oxalate. Obtain the desired compound.

Analytical value for C ₁₀ H ₂₀ N ₂ O • C ₂ H ₂ O ₄ ,%

Found: C 52.9; H 8.4; N 10.0

Calculated value: C 52.5; H 8.1; N 10.2

Preparation Example (N)

Preparation of 4- [N- (2,4-dimethoxybenzyl) carbamoyl] piperidine

1-benzyloxycarbonyl-4- [N according to the same method as Preparation Example (C) using 2,4-dimethoxybenzylamine and 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride as starting materials. Prepare (-, 2,4-dimethoxybenzylcarbamoyl] piperidine The product is confirmed by nuclear magnetic resonance analysis The addition of this product (7.6 g) in ethanol is carried out on a catalyst coated with 5% platinum on charcoal. After hydrogenation under conditions of ° / 50 psi, the catalyst was filtered off and the filtrate was evaporated in vacuo to afford 4- [N- (2,4-dimethoxybenzyl) carbamoyl] piperidine (5.0 g) in the solid state. This compound was added to chloroform, treated with ethereal hydrogen chloride, converted to hydrochloride, and recrystallized in isopropanol to obtain the target compound having a melting point of 222 to 224 캜.

Calcd for C ₁₅ H ₂₂ N ₂ O ₃ HCl,%

Found: C 57.4; H 7.5; N 8.9

Calculated value: C 57.2; H 7.4; N 8.9

It should be noted here that the substituted piperidine intermediates used in Examples 3,8 and 9 and 4-amino-2-chloro-6,7-dimethoxyquinazolin are known compounds. In addition, the preparation of the piperidine intermediate used in Example 14 is described in Preparation Example 21 of British Patent Application No. 26202 (1978), which is currently co-filed by the inventors.

Claims (1)

4 represented by the following general formula (I), characterized in that a quinazoline represented by the following general formula (II) is heated in a piperidine represented by the following general formula (III) with an inert organic solvent for about 48 hours. -A method for preparing amino-2-piperidino quinazoline derivatives or pharmaceutically acceptable acid addition salts thereof.

In the above formula, R is a lower alkyl group; X is a group represented by the following general formula,-(CH ₂ ) _n CONR ¹ R ² or -O (CH ₂ ) _n CONR ¹ R ² , attached to the 3- or 4- position of the piperidino group, in R ¹ is hydrogen or a C ₁ -C ₆ alkyl group; R is C ₁ -C ₆ alkyl; Phenyl; Or phenyl, (which in the end, R ² is an oxygen atom from a nitrogen atom attached to the R ² apart by at least two carbon atom position) hydroxy or C ₁ -C ₆ alkyl group substituted by a C ₁ -C ₆ alkoxy Or R ¹ and R ² together with the nitrogen atom to which they are attached form a 1,2,3,4-tetrahydro isoquinolyl group.

In the above formula, R is as defined in the general formula (I) above; Q is a leaving group which is easy to detach.

In the above formula, X is as defined in the said general formula (I).