DD148720A5 - PROCESS FOR THE PREPARATION OF 4-AMINO-2-PIPERIDINOCHINAZOLINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel 4-amino-2-piperidinoquinazoline derivatives, in particular of derivatives having a substituted alkoxy group in the 4-position of the piperidine ring. The new compounds are useful as regulators of the cardiovascular system and particularly for the treatment of hypertension. A preferred compound is 4-amino-6,7-dimethoxy-2- & 4- (2-ethoxy-1-phenylethoxy) piperidino! Quinazoline hydrochloride. To prepare this compound, 4-amino-2-chloro-6,7-dimethoxyquinazoline is dissolved in butanol together with 4- (2-ethoxy-1-phenylethoxy) -piperidine and heated under reflux.

Description

Process for the preparation of 4-amino-2-piperidinoquine

zoli derivatives

Application of the invention:

The invention relates to a process for the preparation of novel derivatives of 4-amino-2-piperidinoquinazoline, in particular of derivatives having a substituted alkoxy group in the 4-position of the piperidine ring. Such compounds are useful as regulators of the cardiovascular system and particularly for the treatment of hypertension.

Characteristic of the known technical solutions: The compounds according to the invention are new.

Object of the invention:

The aim of the invention is to provide a process for the preparation of compounds of general formula I, wherein R is C ₁ -C ₄ -alkyl, benzyl or (CyCg-CycloalkyDmethyl, R ^{1 is} C ₁ -C ₄ -AIlIyI,

X -CH ₉ UHp-, substituted by a phenyl group and optionally by one or two methyl groups, and ρ

R is hydrogen, C 1 -C 4 -alkyl or phenyl, optionally substituted by one or two substituents

tents of the group C ₁ -C ₄ -alkyl, C ₁ -C ₄ -

Halogen, CP- ,, -COHR ³ R ⁴ and SO ₉ FR ³ R ⁴ , wherein R and

4

 Each R is hydrogen or C 1 -C 4 alkyl,

and for the preparation of the pharmaceutically acceptable acid addition salts thereof.

Pharmaceutically acceptable acid addition salts are those which form with acids which form non-toxic acid addition salts and contain pharmaceutically acceptable anions such as the hydrochloride, hydrobromide. Sulphate or bisulphate, phosphate or acid phosphate, acetate, haleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate or p-toluenesulphonate.

The compounds of the invention containing one or more centers of asymmetry exist as one or more pairs of enantiomers, and such pairs or individual enantiomers may be separable by physical methods, e.g. by fractional crystallisation of suitable salts. The invention encompasses the separated pairs as well as their mixtures as racemic mixtures or as separate d- and 1-optically active isomeric forms.

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"Halogen" means fluoro, chloro, "bromo or iodo. Cy and C, alkyl and alkoxy groups may be straight chain or branched chain.

In one aspect of the invention, R is C 1 -C 4

R is preferably CH ^, C ₂ H ^, benzyl or cyclopropyl

methyl

 R is preferably CHo.

p - ^

R is preferably H, methyl, ethyl or phenyl. X is preferably -CH (phenyl) CH ₂ -, -CH ₂ CH ₂ (phenyl) - or -CH ₂ (CH ₃ ) (phenyl) -.

The preferred individual compounds are those of Examples 1 and 3.

g of the essence of the invention;

The compounds are prepared according to the invention in the following ways:

(l) The compounds according to the invention in which R is C 1 -C 4 -alkyl or benzyl can be prepared according to Scheme A:

1 2

R, R, R and X are as defined above, and Q represents a readily leaving group such as chlorine, bromine, iodine, (OjL-4-alkylthio or (C 1 -C 4) alkydsulfonyl.

Q is preferably Cl or Br.

In a typical procedure, the reaction components are heated together, e.g. to a temperature of 70 to 130 C, preferably under reflux in an inert organic solvent, e.g. n-butanol, for up to about

- 5 -. 218 7 6

and, if necessary, recrystallizing the resulting fold to purity, Of course, the product of route (1) is naturally in the form of an acid addition salt.

The antihypertensive activity of the compounds of this invention is demonstrated by their ability to lower the blood pressure of conscious, spontaneously hypertensive rats and conscious, renal hypertensive dogs when dosed orally at doses up to 5 mg / kg.

The compounds of the invention may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected in consideration of the intended route of administration and standard pharmaceutical practice.

For example, they may be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They can be injected parenterally, e.g. intramuscular, intravenous or subcutaneous. For parenteral administration, they are best used in the form of a sterile γ / aqueous solution which may contain other solutes, e.g. enough salts or glucose to make the solution isotonic. Thus, the invention provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable acid addition salt together with a pharmaceutically acceptable diluent or carrier.

48 h. The product can be isolated and cleaned according to conventional procedures.

The intermediates of formulas (II) and (III) are either known compounds or can be prepared analogously to conventional procedures. The preparation of many intermediates of formula (III) is illustrated in the methods of preparation described below,

(2) The compounds in which R is C 1 -C 4 -alkyl or (C 0 -C 6 -cycloalkyl) -ethyl can be prepared according to Reaction Scheme B:

The hydrogenation can be carried out according to conventional procedures, e.g. by hydrogenating the compound of formula (IA) in a suitable solvent, e.g. Ethanol, over a Pd / C catalyst, typically at room temperature and about 1.05 bar (15 psi) for a few hours.

The hydroxy compound (IV) may then be reacted with the compound of the formula RQ in a suitable solvent, e.g. Dimethylformamide, in the presence of a base, e.g. Sodium hydroxide, and be reacted under a nitrogen atmosphere. In general, long reaction times, e.g. up to 24 hours, necessary. The product can be isolated and cleaned according to conventional procedures.

The starting materials of the formula (IA) can be prepared by the above route (1).

(3) The pharmaceutically acceptable acid addition salts of the compounds of formula (I) may be prepared by conventional procedures, e.g. by mixing the free

- 5 -

6 - 2 187

The compounds of the invention may be administered to humans for the treatment of hypertension, either orally or parenterally, and may be administered orally at doses approximately in the range of 1 to 50 mg per day for an average adult patient (70 kg) in a single dose or up to 3 divided doses become. Intravenous doses will be approximately 1/5 to 1/10 of the oral daily dose. Thus, unitized doses in tablet or capsule form for an average adult patient will generally range from 1 to 50 mg of the active compound. Variations necessarily occur depending on the weight and condition of the treatment and the particular route of administration, as known to those skilled in the art.

The invention further provides for the treatment of an animal, including humans, with hypertension to which the animal is administered an antihypertensive amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof or a pharmaceutical composition as defined above.

Example of use;

The following examples illustrate the invention:

example 1

Preparation of 4-amino-6,7-dimethoxy-2 - / - (2-ethoxy-1-phenylethoxy) -piperidino-quinazoline hydrochloride (Scheme C)

2.6 g of 4-amino-2-chloro-6,7-dimethoxyquinoline and 3.0 g of 4- (2-ethoxy-1-phenylethoxy) piperidine in 100 ml of n-butanol were refluxed for 22 hours. The solution was then cooled, filtered and the filtrate concentrated in vacuo,

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The residue was triturated with diethyl ether and recrystallized twice from isopropanol to give 2.0 g of 4-amino-6,7-dimethoxy-2-4- (2-ethoxy-1-phenylethoxy) -piperidinoquinoline hydrochloride, mp 229 to 230 °, to give.

Analysis; % i ₄ O ₄ . HCl: C 61, O; H 6 , 9; IT 11, 5; Found .: C 61, 4; H 6 ,8th; N 11, 5th Calc .: for Cp ^ H ^ N Example 2

Preparation of 4-amino-6,7-dimethoxy-2- / 4- (2-phenoxy-1-phenylethoxy) -piperidino-quinazoline hydrochloride hydrate (Scheme D):

1 »44 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 2.0 g of 4- (2-phenoxy-1-phenylethoxy) piperidine in 100 ml of n-butanol were refluxed for 20 hours. The solvent was then removed in vacuo, the residue triturated in ether and crystallized from isopropanol. The pesticide was partitioned between chloroform and aqueous sodium bicarbonate solution, the chloroform extract dried over MgSO _4, and the solvent evaporated in vacuo. The residue was chromatographed on 100 g of silica eluted with chloroforni then chloroform / methanol (20: L). Product-containing fractions were combined, the solvent was evaporated in vacuo and the residue was converted to the hydrochloride by treating a chloroform solution with ethereal hydrochloric acid.

The solid hydrochloride was collected and recrystallized from isopropanol to give 0.85 g of 4-amino-6,7-dimethoxy-2- / 4- (2-phenoxy-1-phenylethoxy) piperidine-quinazoline hydrochloride hydrate, mp 202-204 °, to surrender.

- 8th -. 218 7 6 9

Analysis, % i

Found: C 62.8; H 6.1; IJ 10.0;

Calc .: for C ₂₉ K ₃₂ Ii ₄ O ₄ - HCl. H ₂ O: C, 62.8; H 6.4; N 10.1.

Examples 3 to 6

The following compounds were prepared similarly to the previous examples starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and the appropriate piperidine, the product of Example 3 would be similar to Example 1 and the products of Examples 4, 5 and 6 would be similar Example 2, but the product of Example 5 was not converted to the hydrochloride.

Formula (IV)

example r5 H R ² isolated form and size ( ⁰ C) Analysis, 5 (theoretically in C H 6.3 6.3 Brackets) N vj H H Hydrochloride 241-243 59.7 (59.9 6.7 6.8 12.0 12.2) 4 CH ₃ C ₂ H ₅ Hydrochloride 234-235 ° 61.3 (61.4 6.8 7.1 11.0 11.5) VJL CH- H free base, monohydrate, 146-148 ° 63.0 (63.1 7.0 7.0 12.2 12.3) 6 C ₂ H ₅ Hydrochloride 231-233 61.9 (62.1 11,1 11,1)

Beis piel_ 7.

Preparation of 4-amino-6-cyclopropylmethoxy-2- / 4- (2-ethoxy-1-phen-ethylethoxy; piperi-din27-7-methoxy-quinazoline, D (+) tartrate

0.75 g of 4-amino-2 - / - (2-ethoxy-1-phenylethoxy) -piperidine p7-6-hydroxy-7-methoxyquinazoline hydrochloride in 50 ml of dimethylformamide and 1 ml of 5 H sodium hydroxide solution were added at room temperature under a nitrogen atmosphere 40 stirred in the dark. 0.27 g of cyclopropylmethylbromide were then added and the solution was stirred under Ii _{2 for} 20 h. 5 mg of potassium iodide, then another 0.27 g of cyclopropylmethylbromide were added and stirring was continued for 2 h at room temperature. The solvent was removed under reduced pressure and the residue was taken up in 50 ml of water, basified to pH 12 with 2N sodium hydroxide and extracted extracted 100 ml of chloroform three times. The combined chloroform layers were dried (over ifepSO.) And the solvent removed in vacuo to yield a semi-solid. The product was chromatographed on 7 g of silica eluting with chloroform. Product containing fractions were combined and the solvent removed in vacuo. The residue was converted to the tartrate by treating a chloroform solution with a solution of D (+) tartaric acid in ether. The resulting pest was filtered off, washed with ether and dried under reduced pressure to give 115 mg of 4-amino-6-cyclopropylmethoxy-2- / 4- (2-ethoxy-1-phenylethoxy) -piperidino-7-methoxyquinazoline, D (+). tartrate,

M.p. 142-145 °, to yield.

Analysis, %:

Found: C 59.8; H 6.5; N 8,9

Calcd. for C ₂₈ H ₃₆ Ii ₄ O ₄₄ C ₄ HgO ₆ : C 59.8; H 6.6; N 8,7.

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Example 8

Preparation of 4-ethoxy) piperidino7-7-methoxyquinazoline hydroiodide

The title compound was prepared similar to Example 7, starting from 4-amino-2- / 4- (2-ethoxy-1-phenylethoxy) piperidine, 7-hydroxy-7-methoxyquinazoline and ethyl iodide in the presence of sodium hydroxide, and had a mp . from

227 - 228 O AV ^HI: C 52 1; H 5, 8th; N 9 4 Analysis, C 52 5; H 5, 9; N 9 4th Found .: for _C26 H, example 9

Preparation of 4-amino-6-benzyloxy-2- / 4- (2-ethoxy-1-phenylethoxy) -piperidino-7-7-methoxyquinazoline hydrochloride

0.72 g of 4-amino-6-benzyloxy-2-chloro-7-methoxyquinazoline (J.Med.Chem. 1977, 20, 14, 7 and 0.57 g of 4 - (2-ethoxy-1-phenylethoxy) piperidine 50 ml of n-butanol was refluxed for 30 hours The solvent was removed in vacuo and the residue was triturated with ether to give a solid, which was recrystallized from isopropanol / diisopropyl ether to give 740 mg of 4-amino-6-benzyloxy-2 . - / 4- (2-ethoxy-1-phenyläthoxy) piperidino7-7-me thoxychinazolin hydrochloride to yield a sample recrystallized from ethanol had mp 238-240 ° analysis%:..:

Found: C 65.5; H 6.5; Έ 10.0

Calcd. for C ₃₁ H ₃₆ N ₄ O ₄ -HCl: C, 65.9; H 6.6; N 9.9.

The following preparations illustrate the preparation of certain starting materials.

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Preparation A Preparation of 4- (2-hydroxyphenethyloxy) piperidine

5.0 g of 1-acetyl-4-hydroxy-piperidine in 50 ml of tetrahydrofuran (THP) was added to a stirred suspension of sodium hydride (1.84 g, 50% dispersion in mineral oil) in 25 ml of THP under a nitrogen atmosphere. When foaming ceased, 4.6 g of styrene oxide in 25 ml of THP was added, then the reaction mixture was diluted with 25 ml of dimethylformamide (DMP) and stirred at 60 ^° C. for 18 hours. After addition of isopropanol to the cooled solution, the solvent was removed in vacuo, the residue treated with water, adjusted to pH 4 with 2N hydrochloric acid, and extracted with chloroform. The chloroform extract was dried (via HapSO.) And the solvent was evaporated in vacuo to give N ~ acetyl-4 ~ (2-hydroxyphenethyloxy) piperidine. This product in 50 ml of ethanol and 100 ml of 5N sodium hydroxide solution was refluxed for 3 hours. The solvent was then removed in vacuo, the residue taken up in water, extracted with chloroform, dried and the solvent removed in vacuo. The product in chloroform was converted to the hydrochloride by treatment with ethereal hydrochloric acid and evaporation of the solvent.

The residue was taken up in methanol, treated with ether, the precipitate separated and recrystallized from isopropanol to give 0.6 g of 4- (2-hydroxyphenethyloxy) -piperidine hydrochloride, m.p. 174-175 ⁰ C, m.p. Analysis, %: Found: calc. For C ^ H ₁₉ NO ₂ * HCl:

C 60 ,1; H 7, 8th; N 5, 2 C 60 , 6; H 7, 8th; N 5, 4th

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Production B

Preparation of 4- (2-ethoxyphenethyloxy) piperidine

8.0 g of N-acetyl-4- (2-hydroxyphenethyloxy) piperidine, prepared according to A, and 0.3 g of 1,2-dimethoxyethane in 50 ml of dry DIsIP were added to a stirred suspension of sodium hydride (2.96 g, 50 % dispersion in mineral oil) in 50 ml of dry DLIP. The suspension was 3> 5 h at room temperature and stirred at 0 to 5 ⁰ C cooled, then a solution of 9.6 g of ethyl iodide in 25 ml DIJF was added dropwise. The mixture was allowed to warm to room temperature (20 ^° C.) and was then stirred for 2 hours at room temperature. 75 ml of isopropanol were added, the solvent removed in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried and the solvent removed in vacuo to give 5.2 g of N-acetyl-4-bis (2-ethoxyphenethyloxy) piperidine.

This product in 50 ml of ethanol and 50 ml of 5N sodium hydroxide solution was refluxed for 3.5 hours. The organic solvent was removed in vacuo and the aqueous residue extracted with chloroform. The organic extract was dried (over ITa ₂ SO.), Concentrated in vacuo, then the residue was partitioned between 2N hydrochloric acid solution and ether. The v / aqueous phase was then basified with sodium carbonate solution and extracted with chloroform. The chloroform extract was dried (over Na ₂ SO ₄ ), the solvent was evaporated in vacuo, then the residue was taken up in ether and converted into the oxalate. Recrystallization from isopropanol yielded 1.6 g of 4- (2-ethoxy-phenethyloxy) -piperidine-oxalate. M.p. 136-137 ⁰ C. analysis, %:

Found: C 60.3; H 7.4; N 4.1

Calc. for C ₁₅ H ₂₃ ITO ₂ ^ C ₂ H ₂ O ₄ : C 60.2; H 7.4; N 4.1.

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Production C

Preparation of 4- (2-ethoxy-1-phenylethoxy) piperidine (Scheme E)

(i) egg - (1-acetyl-4-piperidinoxy) phenylacetic acid ethyl ester

27.5. g of N-acetyl-4-hydroxy-piperidine in 100 ml of dry DLDP was added slowly to a stirred suspension of sodium hydride (25 g * 50% dispersion in mineral oil) in 150 ml of DM3? and 10 ml of 1,2-dimethoxyethane.

The suspension was stirred for 3 h at room temperature. 45 g of o-chlorophenylacetic acid in 250 ml of DMF were then added slowly with ice / water cooling. The mixture was stirred at room temperature for 20 h, then isopropanol was added and the solvent removed in vacuo. The residue was taken up in water, acidified to pH 1 with 2N hydrochloric acid and extracted four times with 300 ml of chloroform. The combined chloroform extracts were washed with water and brine, dried (over LiSO 4) and the solvent removed in vacuo. The residue in 450 ml of anhydrous ethanol containing 9 ml of concentrated sulfuric acid was refluxed for 8 hours. The cooled solution was carefully neutralized with aqueous sodium carbonate solution and the organic solvent removed in vacuo. The aqueous residue was adjusted to pH 10 with sodium carbonate solution and extracted twice with chloroform. The combined chloroform extracts were dried (over MgSO 4) and evaporated in vacuo. Distillation of the residue afforded 37.2 g of oC- (N-acetyl-4-piperidinoxy) phenylacetic acid ethyl ester, bp 190-194 ° C / 0.18 mm. Analysis, %:

Found: C 66.4; H 7,8; N 4,5

for C ₁₇ H ₂₃ IIO ₄ :. C 66.9; H 7.6; Ή 4,6.

218 7 6

(ii) N-acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine

3.24 g of lithium borohydride was added portionwise to a solution of 11.2 g of cC - (H-acetyl-4-piperidinoxy) phenylacetic acid ethyl ester in 200 ml of dry THP. When the hydrogen evolution had dried, the reaction mixture was refluxed for 4 hours. Water was added to the cooled solution, the solvent was removed in vacuo, then the residue was taken up in 200 ml of chloroform and washed with dilute hydrochloric acid, water and Slaz solution. The chloroform extract was dried (over MgSO4) and the solvent removed in vacuo. Thin-layer chromatographic analysis of the product showed that the reduction was incomplete, therefore the product was treated in 100 ml of THP with an additional amount (3.24 g) of lithium borohydride and heated at reflux for 4 hours. The reaction mixture was treated as above to give 9-5 g of N-acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine as an oil, which solidified on standing

 A sample, crystallized from ether, had a mp

from 92 - 94 ⁰ C Analysis, %: ßet, calcd for C ₁₅ H ₂₁ NO ₃ :

(iii) 4 ~ (2-ethoxy-1-phenylethoxy) piperidine

This compound was prepared similarly to Preparation B starting from N-acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine (prepared as described in Section (ii) and ethyl iodide, followed by basic hydrolysis of the N-acetyl group Oxalate, m.p. 137-139 ⁰ C analysis, %:

Found: C 59.9; H 7.4; N 4.0

Calc. for C ₁₅ H ₂₃ NO ₂ -C ₂ H ₂ O ₄ : C 60.2; H 7.4; U 4.1.

C 68 1; H 8th, 1; If 5, 7 C 68 4; H 8th, 1; N 5, Third

2 1876

Production D

4- (2-phenoxy-1-phenyläthoxy) piperidine

5.25 g of N-acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine (prepared according to C (ii), 4.2 g of diethyl azodicarboxylate, 6.3 g of triphenylphosphine and 2.25 g of phenol in 100 ml of dry ( Tetrahydrofuran was stirred for 2 h at 0 ^° C. and then left at room temperature for 48 h, the solvent was removed under reduced pressure, the residue was taken up in 50 ml of diethyl ether and refluxed overnight, the precipitated by-products were filtered off and the filtrate was evaporated The residue was taken up in ether, set aside for cooling and the precipitate was filtered off, concentrated to dryness, and the residue was refluxed in 50 ml of methanol and 30 ml of 5N sodium hydroxide solution for 5 hours was stripped off in vacuo, the aqueous residue was acidified to pH 3 with 2N hydrochloric acid and extracted twice with ether, whereupon the organic extracts were discarded. The aqueous phase was adjusted to pH 12 with sodium hydroxide solution, extracted with (three times 100 ml) ether, the ether extracts combined, dried (over MgSO 4) and the solvent removed in vacuo to give 3.55 g of 4- (2-phenoxy-1 -phenylethoxy) -piperidine as an oil. A sample was transferred to the oxalate, which was recrystallized from isopropanol and had a mp of 170-172 ⁰ C. Analysis,%:

found: C 64.9; H 6.6; N 3.8

calcd for ^c -j9 ^H ₂ 3 ^K0 2 ^#C 2 ^H 2 ⁰ 4 ^{: C 65} » ^{1; H 6>5; Ή 3} ' ⁶ *

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Production E

Preparation of 4- (2-hydroxy-2-phenyl-n-propoxy) piperidine (Scheme P)

(i) N-acetyl-4- (2-phenylallyloxy) piperidine

13.6 g of N-acetyl-4-hydroxypiperidine in 50 ml DIvIP were added dropwise to a stirred suspension of sodium hydride (10 g, 50% dispersion in mineral oil) in 50 ml DLIP under nitrogen. The mixture was stirred at room temperature for 3 hours, then 20 g of γ- (bromomethyl) styrene in 50 ml of DMP was added dropwise. The mixture was stirred at room temperature for 4 h, then diluted with water and extracted with (three times 200 ml) chloroform. The combined chloroform extracts were dried (over Na 2 SO 4), evaporated in vacuo and distilled to give 25 g of N-acetyl-4- (2-phenylallyloxy) piperidine, b.p. 170-180 ° C / 0.3 mm with one of these Structure to give corresponding NMR spectrum.

(ii) 4- (2-hydroxy-2-phenyl-n-propoxy) piperidine

4.0 g of N-acetyl-4- (2-phenylallyloxy) piperidine in 60 ml of dry THP was added dropwise to a stirred solution of 6.35 g of mercury (II) acetate in 60 ml of water, and the solution was allowed to stand at room temperature for 1 hour touched. 40 ml of 3N sodium hydroxide solution and 0.75 g of sodium borohydride in 40 ml of 3 N sodium hydroxide solution were then added dropwise to the stirred solution at 0 ^° C. The gray suspension was stirred for 1 h at 0 ⁰ C, glacial acetic acid was added until pH 6, then the suspension was filtered and the Piltrat with (three times 150 ml) chloroform. The combined chloroform extracts were dried (over Na ₂ SO 4) and concentrated in vacuo to give 2.1 g of N-acetyl-4- (2-hydroxy-2-phenyl-n-propoxy) piperidine. This product in 30 ml of methanol and 20 ml of 5N sodium hydroxide solution was refluxed for 4 hours. The

- * 9 - 2187

organic solvents were evaporated and the aqueous solution extracted with (three times 20 ml) chloroform, dried (over Ua ₉ SO.) And the Lösungsmitte3. evaporated in vacuo to give 1.8 g of 4- (2-hydroxy-2-phenyl-n-propoxy) piperidine as an oil. A sample was characterized as the oxalate, which was recrystallized from ethyl acetate and a mp of 132 - 134 ⁰ C had.

Analysis, %:

get: C 58.8; H 7.1; N 4.8

calcd. for C ₁₄ H ₂₁ ITO ₂₄ C ₂ H ₂ O ₄ : C 59.1; H 7.1; N. 4,3.

Production P

Preparation of 4- (2-ethoxy-2-phenyl-n-propoxy) piperidine

7.0 g of N-acetyl-4- (2-phenylallyloxy) piperidine (prepared according to E) in 10 ml of ethanol were added to a stirred suspension of 9.2 g of mercury (II) acetate in 50 ml of ethanol at room temperature. The Gemisch.wurde stirred for 1 h at room temperature, then cooled to 0 ⁰ C. 20 ml of 5N sodium hydroxide solution, then 1.03 g of sodium borohydride in 20 ml of 5N sodium hydroxide solution were added to a stirred suspension and after 10 minutes glacial acetic acid was added to pH6. The suspension was filtered, the filtrate concentrated and the residue partitioned between chloroform and water. The organic layer was dried (over Na ₂ SO ₄ ) and the solvent removed in vacuo. Gas-liquid chromatography (GLC) analysis of the product indicated incomplete conversion of the desired product, therefore, the oxy-carburization procedure was repeated as above to give 7.4 g of a GLC 84 % pure N-acetyl-4- (2-ethoxy). 2-phenyl-propoxy) piperidines. The product in 100 ml of ethanol and 30 ml of sodium hydroxide solution was refluxed for 11 hours. The organic solvent was evaporated and the aqueous solution extracted with (3 x 30 ml) chloroform. The combined chloroform extracts were (over Na ₂ SO.) Ge

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dried and the solvent removed in vacuo to give 3.8 g of 4- (2-ethoxy-2-phenyl-n-propoxy) piperidine as an oil. A sample was converted into the oxalate, the twice from ethyl acetate, then recrystallized from acetone to a mp of 126 -. 127 ⁰ C had. Analysis, %:

found: .C 60.4; H 7.6; N 4.1

Calcd for C ₁₆ H ₂₅ MyC ₂ H ₂ O ₄ MAH ₂ O:. C 60.4; H 7.3; N 3.9.

Production G

Preparation of 4-amino-2- / 4- (2-ethoxy-1-phenylethoxy) -piperidine-J-O-hydroxy-1-methoxyquinazoline hydrochloride hydrate

0.9 g of 4-amino-6-benzyloxy-2- / 4- (2-ethoxy-1-phenylethoxy) -piperidino / --methoxy-quinazoline hydrochloride in 150 ml of dry ethanol was added over 5 % Pd / C at room temperature and 1.05 bar (15 psi) for 2 hours. The catalyst was filtered off and the filtrate concentrated to dryness in vacuo. The residue was triturated with ether to yield 0.55 g of a white pesticide. A sample (200 mg) was recrystallized from isopropanol to give 71 mg of 4-amino-2- / 4- (2-ethoxy-1-phenylethoxy) -piperidino_7-6-hydroxy-7-methoxyquinazoline hydrochloride hydrate, mp 141 144 ⁰ C analysis, %%

Found: C, 58; H 6.5; N 11.5

Calcd. for C ₂₄ H ₃₀ N ₄ O ^ HCl'H ₂ O: C, 58.5; H 6.8; N 11.4.

3. Method according to item 2, characterized in that each of R and R ^{1 is} CH ₃ , X is -CH (phenyl) CH ₂ -,

R ^{2 is} C ₂ H ₅ and Q is Cl.

4. Method according to item 2, characterized in that each of R and R ^{1 is} CH ₃ , X is -CH ₂ CH (phenyl) -,

R ^{2 is} H and Q is Cl.

For this .... JLSeiien formulas

K ¹ O RO

/ V

p'per / dtn © of the fetus / ct ·

C f O /

O-X-

HA / \ -O -X -

CH ₃ O CH ₃ O

C

OV

CJE)

f. ν

-X-OQ

fa) (HZ)

Scheme A

PhCIJ

Hycfr / e-rung

I \ -o -γ_

is a departing one

yorzugsh / eise CC, Sr or

X -

Scheme B

Scheme C

/ VH.

scheme

rs /

OCHCH ₁ OC ₂ H ₅

ElOH, H ^

A / a H

S.

0 -CHCH ₂ OH

Scheme E

Oh t M "

OCH ₁ C

Scheme F

Claims (2)

Invention claim: A process for preparing a 4-amino-2-piperidinoquinazoline derivative of the formula (I) wherein R is (C ₁ -C ₄ ) alkyl, benzyl or / Tc ₃ -C ₆ ) cycloalkylmethyl, R ¹ (C ¹ -C ₄ ) ) Alkyl; X is -CHpCH ₂ , substituted by a phenyl group or optionally by 1 or 2 methyl groups; and R is hydrogen, (C ₁ -C -alkyl, unsubstituted phenyl or by one or two of (C ₁ -C ₄ ) -alkyl, (C ₁ -C 6) -alkoxy, halogen, CP ₃ , -COM ³ R ⁴ "and V ^ wherein each of B? and R ⁴ Y / oxygen or (C ₁ -C) alkyl, selected substituents being substituted phenyl; or a pharmaceutically-acceptable acid addition salt thereof, characterized in that a quinazoline of formula (II),? / orin R and R are as defined above and Q is a leaving group such as chlorine, bromine, iodine, / Tc ₁ -C,) -Alkyl27thio or / Tc ₁ -C,) -alkyl-27sulfonyl, is reacted with a piperidine of formula (III) wherein X and R are as defined above, and then, if desired (i) converting a compound of formula (I) in which R is benzyl into a compound of formula (I) in which RY / oxygen is hydrogenated, followed by conversion of the compound in which RY / acid is , in a compound of formula (I) wherein R is (C ₁ -C 6) alkyl or C ₁ -C 6 cycloalkyl-methyl, by reacting with a compound of formula RQ in which R is C ₁ -C ) -Alkyl or / Tc ^ -C ^ -cycloalkyl / methyl and Q is a readily leaving group follows; and or (ii) converting the product of formula (I) into a pharmaceutically acceptable acid addition salt by reaction with a non-toxic acid. 218769 2. A process according to item 1, characterized in that R is CH.sup.-, CgHj-j is benzyl or cyclopropylmethyl, R is CH.sub.o; R ^{2 is} H, methyl, ethyl or phenyl; and X is -CH (phenyl) CH ₂ -, -CH ₂ CH (phenyl) - or -CH ₂ C (CH ₃ ) (phenyl) -.