KR820001847B1 - Process for preparing 4-amino-2-piperidiono quinazoline derivatives - Google Patents

Abstract

The title compds. (I; R = lower alkyl; X= -(CH2)nCONR1R2 or -OCH(Ph)CONR1R2; n = 0, 1 or 2; R1 = H or C1-6 alkyl; R2 = C1-6 alkyl, ph, C3-7 cycloalkyl, or ph substituted C1-6 alkyl) useful as antihypertensives, e.g., at 1-50 mg/day orally, were prepd. by reaction of II and R1R2NH in the presence of inert org. solvent for 10hr. Thus, 2.0g 4-amino-2-(4-carboxypiperidino-6,7-dimethoxyquinazoline was refluxed with 2.0g N,H'-carbonyldiimidazole in BuOH to give 2.0g 4-amino-6,7-dimethoxy-2-[4-(N-phenethylcarbamoyl) piperidino quinazoline hydrochloride.

Description

Method for preparing 4-amino-2-piperidinoquinazoline derivative

The present invention relates to a method for preparing cardiovascular modulators, especially 4-amino-2-piperidinoquinazolin derivatives which are therapeutic agents for hypertension and 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,

로 표시되는 기로서, 여기에서X is-(CH ₂ ) _n CONR ¹ R ² or

Which is represented by

n is 0, 1 or 2

R ¹ is hydrogen or a C ₁ -C ₆ alkyl group,

R ² is C ₁ -C ₆ alkyl, phenyl, C ₃ -C ₇ cycloalkyl, or phenyl, C ₃ -C ₇ cycloalkyl, halogen, hydroxy, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxycarbonyl, phenoxy or —NR ³ R ⁴ (R ³ and R ⁴ are each hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkanoyl oil) Or a C ₁ -C ₆ alkyl group substituted with a C ₁ -C ₆ alkylsulfonyl group (wherein R ² , oxygen, nitrogen, or a halogen atom is replaced by at least two carbon atoms from a nitrogen atom to which R ² is attached) Or R ¹ and R ² together with the nitrogen atom to which they are attached form a morpholino group in which one or two C ₁ -C ₆ alkyl groups are optionally substituted, or one or two at any position on the benzene ring A C ₁ -C ₆ alkoxy group forms a substituted 1, 2, 3, 4-tetrahydroisoquinolyl group.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine, and an alkyl group, an alkoxy group, an alkanoyl group, an alkenyl group or an alkynyl group has up to 6 carbon atoms and generally up to 4 Refers to a straight or branched chain.

Further according to the present disclosure [-OCH (phenyl) CONR ¹ R ^2], including the "phenyl and phenoxy" is not C ₁ -C ₆ alkyl, C ₁ -C ₆ 1 of the alkoxy group and a halogen or two substituents Is a phenyl group or phenoxy substituted at any position.

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 Acidic phosphates, acetates, maleates, fumarates, lactates, titrates, 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 each isomer can be separated using physical methods such as fractional crystallization of appropriate salts.

The present invention encompasses the separated pairs and mixtures thereof in the form of racemic mixtures or separated d- and 1-active isomers.

이외의 다른 것일 수도 있고 R²역시 C₂-C₆알케닐기, C₂-C₆알키닐기 또는 C₂-C₆알콕시카보닐기로서 치환된 저급알킬기 이외의 다른 것일수도 있다.In one aspect, X is

It may be other than and R ² may be other than a lower alkyl group substituted as a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, or a C ₂ -C ₆ alkoxycarbonyl group.

Among the compounds according to the present invention, those having the following general formulas (I) are those compounds having the following substituents in this formula.

R is a methyl group;

X is a group represented by the following formula.

(A) -CONR ¹ R ²

From here,

R ¹ is hydrogen, methyl or ethyl;

-C=CH, (C₁또는 C₂알콕시) 카르보닐, 페녹시, -N(CH₃)₂, -NHCOCH₃, -NHSO₂CH₃또는 할로겐으로 치환된 C₁-C₄알킬기(단 R²에 있어서 산소, 질소 또는 할로겐원자는 R²가 붙어있는 질소원자로부터 최소한 2개의 탄소원자에 의해 떨어져 위치함)이거나 R¹와 R²는 이들이 붙어있는 질소원자와 함께 벤젠환 상의 임의의 위치에 1 또는 2개의 메톡시가 치환된 모르폴리노기 또는 1, 2, 3, 4-테트라히드로 이소퀴놀릴기를 형성한다.R ² is C ₁ -C ₆ alkyl; Phenyl; C ₃ -C ₆ cycloalkyl; Or phenyl, C ₃ -C ₆ cyclo alkyl, hydroxy, C ₁ or C ₂ alkoxy, —CH = CH ₂ ,

C ₁ -C ₄ alkyl group substituted with —C═CH, (C ₁ or C ₂ alkoxy) carbonyl, phenoxy, —N (CH ₃ ) ₂ , —NHCOCH ₃ , —NHSO ₂ CH ₃ or halogen in the ^two oxygen, nitrogen or halogen atom, at least in conjunction spaced apart by a carbon atom), or R ¹ and R ² it may be any position on the benzene ring with the nitrogen atom to which they are attached from a nitrogen atom attached to the R ² One or two methoxys form a substituted morpholino group or a 1, 2, 3, 4-tetrahydro isoquinolyl group.

(B) -CH ₂ CONHR ²

Where R ² is C ₁ -C ₆ alkyl, benzyl, cycloalkyl-methyl or a -CH ₂ CH = CH _2.

(C) -CH ₂ CH ₂ CONHR ²

Wherein R ² is C ₁ -C ₆ alkyl or benzyl.

Wherein R ² is C ₁ -C ₆ alkyl, benzyl or cyclopropylmethyl.

The best among compounds having the general formula (I) is a compound in which R is a methyl group and X is a group as follows.

According to the process of the present invention, the compound according to the present invention of general formula (I) is a compound of the general formula (II) or an acylating agent thereof for the amine of general formula (V) Prepared by reacting an acid chloride or bromide of formula (II), an "active" ester, a mixed anhydride or imidazolide in an inert organic solvent at a temperature of 50 to 100 ° C. for about 10 hours.

In the above formula,

R, R ¹ and R ² are as defined in the general formula (I). If using free form (II), the reaction should be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. Acid chlorides and bromide oxides are prepared according to conventional methods of reacting free acids with thionyl chloride or thionyl bromide, respectively.

Examples of active esters are succinimido esters and phthalimido esters. These conventional methods use free acid in the presence of tilsu, such as dicyclohexyl carbodiimide, in the presence of N-hydroxysuccinimide or N-hydroxy. It is prepared according to the method of reacting with phthalimide.

Mixed anhydrides that can be suitably used have the following general formula.

(R and n are as described above)

To prepare them, conventional methods are used, i.e., prepared by reacting alkanoyl chloride (e.g. pivaloyl chloride) with free acid in the presence of a base such as triethylamine.

The general formula of imidazolide is as follows.

(R and n are as described above.) In preparing this compound, conventional methods are used, i.e., reaction of N, N'-carbonyldiimidazole with free acid (IV) in a suitable solvent such as diethylformamide. To make it.

As a representative method, N, N'-carbonyldiimidazole is added to a solution of free acid (IV) in a suitable solvent such as dimethyl-formamide at a temperature of 50 to 100 ° C in the presence of a molecular sieve, and at this temperature for 2 to 4 hours. After stirring, the amine having the general formula of R ¹ R ² NH is added and the solution is held at this temperature for about 10 hours. After cooling, the molecular sieve is filtered off and washed with chloroform. The chloroform wash and the filtrate are mixed, washed with water, dried and evaporated in vacuo to afford the crude product which is then purified by conventional methods.

R ² is hydroxy-substituted lower alkyl is an R ² is lower alkenyl Al produced by the method described above - can be prepared by hydration by a known method of a sign of a compound corresponding to the substituted lower alkyl reaction. Acid addition salts are prepared by dissolving the crude product in a suitable solvent, such as a small amount of chloroform, and reacting this solution with a solution of the appropriate acid in a suitable solvent, such as a hydrogen chloride solution. The resulting precipitate is separated by filtration as acid addition salt, which is separated by recrystallization from a solvent of isopropanol / methanol as necessary.

When preparing the free acid having general formula (II), it is manufactured by making piperidine, 4-amino-6, and 7-di (lower alkoxy) -2-chloroquinazolin react appropriately substituted by a well-known method.

The blood pressure lowering action of the compound according to the present invention can be seen that the ability to lower blood pressure when administered orally at a dose of 5mg / kg in rats with autologous symptoms and dogs with renal hypertension symptoms for hypertension.

The compounds according to the invention 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 of an isotonic solution containing a solute such as salt or glucose.

The compound can be administered orally or parenterally to humans to treat hypertension, and about 0.5 to 50 mg per day orally administered to adult patients (70 kg body weight). Intravenous injection should be administered in an amount of about 1 / 5-1 / 10 of the daily oral dose. Therefore, in adult patients, oral dosages are administered in tablets or capsules, of which about 0.25-25 mg of the active compound of the present invention is contained. Dosages must be varied according to the weight and health of the patient being treated and the specific route of administration.

The present invention will be described in detail according to the embodiment.

All temperatures shown in the examples are in degrees Celsius (° C).

Example 1

Preparation of 4-amino-6, 7-dimethoxy-2- [4- (N-phenethylcarbamoyl) piperidino] quinazoline hydrochloride

N, N'-carbonyldiimidazole (2.0 g) was added to 4-amino-2- (4-carboxypiperidino-6, 7-dimethoxyquinazoline (2.0) in dimethylformamide (100 ml) in the presence of 3A molecular sieve. g) was added to the dissolved solution at 70 ° C. and stirred at this temperature for 2 hours, then 2-phenylethylamine (1.0 g) was added and the reaction proceeded for another 5 hours at 70 ° C. The reaction mixture was allowed to stand at room temperature overnight. After standing, the mixture was stirred for 3 hours at 70 ° C. and cooled, the molecular sieves were removed by filtration and washed well with chloroform The mixed solution of the filtrate and the floroform was washed with water and dried (on Na ₂ SO ₄ ). The resulting residue is dissolved in a minimum volume of chloroform, treated with etheric hydrogen chloride, the resulting solid is taken up, washed with ether and crystallized in isopropanol / methanol to give 0.81 g of the target compound. (Melting point: 284 to 285 ° C).

C ₂₄ H ₂₉ N ₅ O _3. Analytical values for HCI,%;

Found: C61.0 H6.5 N14.5

Calculation: C61.1 H6.4 N14.8

Examples 2-25

The following compounds were prepared in the same manner as in Example 1, using carboxyquinazoline, N, N′-carbonyl-diimidazole, and an appropriate amine represented by the general formula R ¹ R ² NH as starting materials. In Examples 2 to 4, 7, 9 to 12, 16 and 22 to 25, the crude product is purified by chromatography by eluting with silica on a mixture of chloroform and methanol.

Example 26

Preparation of 4-amino-2- [4- (N-allylcarbamoyl) piperidino] -6,7-dimethoxyquinazoline hydrochloride

4-amino-2- [4-carboxypiperidino] -6, 7-dimethoxy-quinazolin (2.3 g), dicyclohexylcarbodiimide (DCCD) (1.4 g) and N-hydroxysuccinimide (NHS) (0.8 g) was added to dry dimethylformamide (DMF), stirred at 60 ° C. for 2 hours, then allylamine (0.4 g) was added and heating continued at 60 ° C. for 6 hours. 5N hydrochloric acid (50ml) was added to the cooled mixture, followed by separation by shaking with chloroform (50ml). The aqueous layer is made basic to pH12 with 5N sodium hydroxide solution and extracted twice with 50 ml each time using chloroform. The chloroform-extract is dried (with magnesium sulfate) and then evaporated in vacuo to give a yellow gummy material (1.4 g). It is dissolved in a small amount of isopropanol and treated slightly in excess with dry hydrogen chloride gas. The above product was recrystallized from a mixture of ethyl acetate-methanol to obtain the target compound (0.6 g) (melting point: 277 °).

Found: C54.9 H5.5 N16.9

Calculated Value: C54.6 H5.6 N 16.8

[Examples 27 to 37]

Piperidinoquinazoline containing carboxy, N-hydroxysuccinimide, dicyclo hexylcarbodiimide, and an amine represented by the general formula R ¹ R ² NH as starting materials, To prepare a compound such as

Example 38

4-amino-6, 7-dimethoxy-2- [4- (N- {2-methyl-hydroxypropyl)}-carbamoyl) piperidino] quinazoline hydrochloride monohydrate

4-amino-6,7-dimethoxy-2--2- [4- (N- [2-methylallyl} -carbamoyl) piperidino] quinazolin (2.0 g) in 50% aqueous sulfuric acid solution (100 ml) The dissolved solution is allowed to stand at room temperature for 24 hours, then cooled with ice water and basified to pH 8.0 by addition of concentrated ammonia (specific gravity 0.880). Then evaporated to dryness, the residue was suspended in hot ethanol (200 ml), filtered and the filtrate was concentrated in vacuo to give a white solid (1.6 g). This solid is dissolved in methanol (10 ml) and treated with a slight excess of etheric hydrochloric acid. The resulting solid was recrystallized from ethyl acetate / methanol distillation to obtain the target compound (0.6 g). (Melting gum: 232 to 234 ° C)

C ₂₀ H ₂₉ N ₅ O ₄ ∙ Analytical value for HCI.H ₂ O,%

Found: C52.4 H6.8 N15.1

Calculated Value: C52.5 H7.0 N15.3

Example 39

Preparation of 4-amino-2- [4-(-N-n-butyl-carbamoylketyl) piperidino] -6,7-dimethoxyquinazoline hydrocollide

4-amino-2- [4-carboxymethylpiperidino] -6, 7-dimethoxyquinazolin (3.0 g), N, N'-dicyclo hexylcarbodiimide (1.83 g) and N-hydroxy succine Mead (1.04 g) is added to dimethylformamide (50 ml) and stirred at 70 ° C. for 2 hours, then n-butylamine (10 ml) is added and the solution is stirred at 50 ° C. for 4 hours. The filtered solution was filtered and the filtrate was treated with hydrochloric acid solution (5N, 50ml), and then extracted three times with 50ml at a time using chloroform. The chloroform extract is dried (using sodium sulfate) and the solvent is evaporated in vacuo to dissolve the oily substance in hydrochloric acid (10 ml, 2N) and shaken with ethyl acetate. The aqueous layer is separated, adjusted to ph11 with sodium hydroxide solution, and extracted with chloroform. Dry the (3 × 20 ml) chloroform extract and evaporate the solvent in vacuo. The residue is treated with dioxane and the filtered filtrate is evaporated in vacuo, and the resulting product is eluted with chloroform on silica (100 g), followed by chromatography with chloroform / methanol (30: 1). Fractions containing this product are combined and concentrated to convert the residue in fluoroform into hydrochloride by treating with ethereal hydrogen chloride. This is recrystallized in methanol / dioxane to obtain the target compound (0.25 g). (Melting point: 238-239 ° C.).

Found: C56.5 H7.3 N15.4

Calculated Value: C56.4 H7.4 N15.7

Example 40

Preparation of 4-amino-6, 7-dimethoxy-2- [4- (N- [2, 2-dimethylpropyl] -carbamoylmethyl) piperidino] quinazoline hydrochloride

4-amino-2- [4- (carboxymethyl) piperidino] -6, 7-dimethoxy quinazoline (3.0 g), N, N ',-dicyclohexylcarbodiimide (1.83 g) and N- Hydroxysuccinimide (1.04 g) is added to dimethylformamide, stirred at 70 ° C. for 2 hours 30 minutes, then 2, 2-dimethylpropylamine (0.78 g) is added and the mixture is stirred at 50 ° C. for 4 hours. After cooling the solution, the filtrate was concentrated in vacuo. The residue is dissolved in chloroform and extracted with sodium hydrogen carbonate solution. The resulting organic layer is dried (using sodium sulfate) and the solvent is evaporated in vacuo. The residue is eluted with chloroform on silica (120 g) and then chromatographed by eluting with chloroform / methanol (20: 1). Fractions containing product are combined and concentrated and the residue in chloroform is converted to hydrochloride by treatment with ethereal hydrogen chloride. This solid was recrystallized in methanol / dioxane to obtain the target compound (0.45 g) (melting point; 228 to 231 ° C).

Found: C57.3 H7.8 N15.3

Calculated Value: C57.3 H7.7 N15.2

Example 41

4-Amino-6, 7-dimethoxy-2- [4- (N-n-propylcarbamoyl) piperidino] quinazoline hydrochloride

It is prepared from 4-amino-2- (4-carboxypiperidino) -6, 7-dimethoxyquinazolin and n-propylamine using the same method as the previous example, but purification by chromatography is not performed. The hydrocoolide hemihydrate is recrystallized in methanol / isopropanol and then recrystallized with ethanol to give the target compound having a melting point of 263 to 264 ° C.

Found: C54.4 H6.6 N16.8

Calculated Value: C54.5 H7.0 N16.7

The temperature in the following preparation examples all represent degrees Celsius (° C.), and these preparation examples are examples of preparing starting materials used in the above-described examples.

Production Example (A)

Preparation of 4-amino-2- (4-carboxypiperidino) -6, 7-dimethoxyquinazoline monohydrate

The desired compound was prepared as in Example 1 using 4-amino-2-chloro-6, 7-dimethoxyquinazolin and 4-carboxypiperidine as starting materials in the presence of triethylamine (melting point: 295 ° C.).

C ₁₆ H ₂₀ N ₄ O ₄ Analytical values for H ₂ O,%

Found: C54.9 H6.0 N16.1

Calculation: 54.8 6.416.0

Production Example (B)

Preparation of 4-amino-2- (4-carboxymethylpiperidino) -6, 7-dimethoxyquinazoline hydrochloride

Triethylamine (20 ml) 4-amino-2-chloro 6, 7-dimethoxyquinazoline (17.3 g) and piperidine-4-acetic acid hydrochloride (12.0 g) in n-butanol (500 ml) were added under reflux. Stir for 20 hours. The mixture was cooled to 0-4 ° C., the solid product was separated, slurried with acetone (100 ml), filtered, slurried with chloroform (100 ml), filtered and washed with ether to obtain the desired compound ( 19.0 g), which is recrystallized in acetic acid to obtain the target compound having a melting point of 250 to 252 캜.

C ₁₇ H ₂₂ N ₄ O ₄ ㆍ HCI analysis,%

Found: C53.1 H6.4 N14.2

Calculated Value: C53.3 H6.1 N14.6

Recipe (C)

Preparation of 4-amino-2- [4- (2-carboxyethyl) piperidino] -6, 7-dimethoxy quinazoline hydrochloride

A solution of 4-amino-2-chloro-6, 7-dimethoxyquinazolin (24.9 g) and 3- (4-piperidinyl) propionate (20 g) in n-butanol (1000 ml) was added under reflux. Stir for hours. The hot suspension is filtered to discard the insolubles. The filtrate is cooled in ice water to give a precipitated solid precipitate and the filtrate is evaporated in vacuo. The evaporated residue and the precipitated solid were mixed and crystallized in isopropanol to give 4-amino-2- [4- (2- {n-butoxycarbonyl} ethyl) piperidino] -6, 7-dimethoxyquinazolin, Hydrochloride (27.0 g) is obtained (melting point: 250 to 252 ° C).

C ₂₂ H ₃₂ N ₄ O ₄ Analytical values for HCI,%

Found: C58.0 H7.3 N12.5

Calculated Value: C58.3 H7.3 N12.4

A solution of this n-butyl ester (20 g) in methanol (50 ml) and 5N-sodium hydroxide solution (50 ml) is heated under reflux for 4 hours. The aqueous residue from which the organic solvent is evaporated is acidified with 2N hydrochloric acid and then cooled. The precipitated solid is taken, dried, slurried with ether and filtered to give the desired compound, which is recrystallized in water and then recrystallized in dimethyl formamide to obtain the target compound having a melting point of 238 to 241 ° C.

C ₁₈ H ₂₄ N ₄ O ₄ Analytical values for HCI,%

Found: C54.2 H6.3 N14.3

Calculated Value: C54.5 H6.4 N14.1

Preparation Example (D)

(1) Preparation of 2- (1-acetyl-piperidine-4-oxy) phenyl ethyl acetate

A mixture of N-acetyl-4-hydroxypiperidine (27.5 g) in dry dimethylformamide (100 ml) was dispersed in sodium hydride (25 g, in mineral oil) in dimethyl formamide (150 ml) and dimethoxyethane (10 ml). 50% dispersion) is slowly added to the stirred dispersed suspension and stirred at room temperature for 3 hours. Subsequently, the mixture to which 2-bromo phenylacetic acid (45 g) was added to dimethylformamide (250 ml) was slowly added while cooling in ice water. The mixture is stirred again at room temperature for 20 hours, then isopropanol is added and the solvent is evaporated in vacuo.

The evaporation residue is taken up in water, acidified to pH1 with 2N-hydrochloric acid and extracted four times with chloroform (300 ml). The mixed chloroform extracts are washed with water and brine, dried (using magnesium sulfate), and then evaporated in vacuo. The evaporation residue is dissolved with nitric acid (9 ml) in anhydrous ethanol (450 ml) and heated at reflux for 8 hours. After cooling, the solution is carefully neutralized with an aqueous sodium carbonate solution and the organic solvent is evaporated in vacuo. The aqueous residue is adjusted to pH 10 with sodium carbonate solution and extracted twice with chloroform. The mixed chloroform extracts are dried (using magnesium sulfate) and then evaporated in vacuo. The residue is distilled to obtain the target compound (37.2 g) having a melting point of 190 to 194 ° C / 0.18 mm.

Calcd for C ₁₇ H ₂₃ NO ₄ ,%

Found: C66.4 H7.8 N4.5

Calculation: C66.9 H7.6 N4.6

(2) Preparation of 2- [piperidine-4-oxy] -phenylacetic acid hydrochloride

A solution of ethyl 2- [1-acetylpiperidine-4-oxy] phenyl acetate (10.0 g) in methanol (50 ml) and sodium hydroxide solution (30 ml, 5N) were heated under reflux for 5 hours. The organic solvent is evaporated in vacuo and the aqueous residue is acidified to pH 2 with hydrochloric acid solution and filtered. The filtrate is evaporated in vacuo, treated with toluene and evaporated in vacuo to treat the remaining residue with isopropanol (50 ml) and filtered to wash the remaining solid with isopropanol. The filtrate is mixed with the washings and the solvent is evaporated in vacuo. The evaporated residue is triturated with acetone, taken to a white solid and crystallized in isopropanol to give the title compound (5.05 g).

(Melting point: 180 to 182 °)

C ₁₃ H ₁₇ NO ₃ ㆍ HCI analysis,%

Found: C57.4 H6.8 N5.5

Calculated Value: C57.5 H6.7 N5.2

(3) Preparation of 4-amino- [4- (1-carboxy-1-phenyl-methoxy) piperidino] -6,7-dimethoxyquinazoline

Triethylamine (5 ml), 4-amino-2-chloro-6, 7-dimethoxyquinazoline (4.8 g) and 2- (piperidine-4-oxy) phenylacetic acid hydrochloride in n-butanol (100 ml) (4.9 g) was added and heated to reflux for 20 hours. The mixture is cooled and the precipitated solid is taken off and washed with ether. The solid (0.7 g) obtained by recrystallization in acetic acid was washed with ether to give 4-amino-2- [4- (1-carboxy-1-phenyl-methoxy) piperidino] -6, 7-dimethoxy. Quinazolin, acetate (0.56 g, melting point: 271 to 274 °) is obtained.

C ₂₃ H ₂₆ N ₄ O _5. Analytical values for CH ₃ CO ₂ H,%

Found: C60.0 H6.0 N11.3

Calculated Value: C60.2 H6.1 N11.2

The remaining product is slurried as hot isopropanol and filtered and the remaining solid is washed with isopropanol and ether to give the desired compound (6.46 g).

Production Example (E)

Mono-N- (methanesulfonyl) ethylenediamine preparation

A solution in which methanesulfonyl chloride (16.8 g) was added to dry chloroform (25 ml), and triethylamine (15 g) and mono-N-acetyletalendiami (15 g) were dissolved and stirred in dry chloroform (25 ml). Drop wise and stirred at room temperature for 60 hours. The reaction mixture is extracted, washed with water (50 ml × 3) and the combined aqueous fractions are shaken with chloroform and separated. The aqueous component is evaporated in vacuo and the residue is added in methanol (100 ml) and concentrated hydrochloric acid (50 ml) and heated with reflux for 12 hours. The solvent is evaporated in vacuo and then treated with methanol while remaining. The insoluble solid is filtered off and the filtrate is treated with chloroform while refluxing the residue which is evaporated in vacuo. Decantation of the solvent left semi-solid N-monomethanesulfonylethylenediamine and hydrochloride, which contained triethylamine hydrochloride. The product is used to prepare the compound of Example 18 without further purification. The amines used in the above examples are known compounds except for the amines used in Example 18.

Claims (1)

The amine of the general formula (V) is reacted with a functional equivalent thereof of the following general formula (II) or an acylating agent in an inert organic solvent at a temperature of 50 to 100 ° C. for about 10 hours to give 4 of the general formula (I) A method for preparing amino-2-piperidinoquinazoline derivatives or pharmaceutically acceptable acid addition salts thereof.

In the above formula, R is a lower alkyl group; X is a group represented by-(CH ₂ ) _n CONR ¹ R ² or -OCH (phenyl) CONR ¹ R ² , where n is 0, 1 or 2; R ¹ is hydrogen or a C ₁ -C ₆ alkyl group; R ² is C ₁ -C ₆ alkyl; Phenyl; C ₃ -C ₇ cyclo alkyl; Or phenyl, C ₃ -C ₇ cycloalkyl, halogen, hydroxy, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkoxycarbonyl, phenoxy or -NR ³ R ⁴ a C ₁ -C ₆ substituted by (R ³ and R ⁴ each represents a hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkanoyl or C ₁ -C ₆ alkylsulfonyl) alkyl (where, in the R ² oxygen, nitrogen, or a halogen atom are also spaced apart by at least two carbon atoms from the nitrogen atom attached to R ²⁾ or R ¹ and R ² is 1 or together with the atom to which they are attached two C ₁ -C ₆ alkyl group is optionally substituted by morpholinyl group, or form a or in any position of the benzene ring with one or two C ₁ -C ₆ alkoxy groups substituted with 1, 2, 3, 4-tetrahydroisoquinoline To form a quinolyl group.

In the above formula R is as defined above. R ¹ R ² NH (Ⅴ) (R ¹ and R ² are as defined above.)