NO800230L - PROCEDURE FOR THE PREPARATION OF CHINAZOLINE DERIVATIVES - Google Patents

Description

The invention relates to the production of therapeutically active compounds which are new derivatives of 4-amino-2-piperidino-quinazoline, and more particularly to the production of derivatives with a substituted alkoxy group in the 4-position of the piperidino ring. Such compounds are useful as regulators of the cardiovascular system and particularly in the treatment of hypertension...

The new compounds produced according to the invention are

those with the general formula:

r1°->^v^^ /N\ V°- x- or2

Y

RO ]f

m2

wherein R is C₁-C₁ alkyl, benzyl or (C₁-C₁ cycloalkyl)-methyl, R is C₁-C₂ alkyl,

X is -CH2CH2- substituted with a phenyl group and optionally with 1 or 2 methyl groups, and R" is hydrogen, C-^-C^alkyl, or phenyl

which is optionally substituted with one or more substituents such as C1-C. alkyl, C--C. alkoxy, halogen, CF.,, 34 34 3 4 ■

-CONR R and -SO 2 NR R wherein R and R are each hydrogen

■or C₁-C₁ alkyl, as well as pharmaceutically acceptable acid addition salts thereof.

Pharmaceutically acceptable acid addition salts are those formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloride. hydrobromide, sulphate or bisulphate, phosphate or.acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate,.

gluconate, saccharate or paratoluenesulfonate salts.

The compounds produced contain one or more asymmetric centers and will exist as one or more pairs of enantiomers, and such pairs or individual enantiomers can be separated using physical methods, for example fractional crystallization of suitable salts. The invention includes separated pairs as well as mixtures thereof, as well as racemic mixtures or separated d- and 1- optically active isomeric forms.

By "halogen" is meant fluorine, chlorine, bromine or iodine.

Ca and alkyl and alkoxy groups can be branched or unbranched. According to a feature of the invention, R is C 1 -C 4 alkyl. R is preferably CH 3 , C 2 H 1 -, benzyl or cyclopropylmethyl. R 2 is preferably CH 2 R 2 is preferably H, methyl, ethyl or phenyl. X is preferably

-CH(phenyl)CH2-, -CH2CH(phenyl)- or -CH2C(CH3)(phenyl)-.

The preferred single compounds are those according to examples 1 and 3.

The compounds according to the invention can be prepared according to the following routes: (1)

Compounds in which R is C-^-C^alkyl or benzyl can be prepared according to the following scheme:

12

R, R , R and X have the definitions given above and Q means an easily leaving group such as chlorine, bromine, iodine, (C 1 -C 4 alkyl)thio or (C 1 -C 4 alkyl)sulfonyl. Q is preferred

show Cl or Br.

In a typical preparation, the reactants are heated, for example at a temperature in the range 70 - 130°C, preferably under reflux, in an inert organic solvent, such as n-butanol for periods of up to 48 h. The product obtained can be isolated and purified by conventional ways.

The starting compounds of formulas II and III are either known compounds or can be prepared by analogous known methods. Preparation of many of the starting products of formula III is shown later. (2) . Compounds in which R is -C₁ -C₁ alkyl or (C₁ -C₃ cycloalkyl)- methyl can. is produced according to the following reaction core:

Hydrogenation can be carried out in a conventional manner, for example by hydrogenating the compound of the formula (IA) in a suitable solvent such as ethanol over a Pd/C catalyst, typically at room temperature at a pressure of 1.05 kg/cm• ■ 2 for a few hours.

The hydroxy compound (IV) can then be reacted with a compound of formula RQ in a suitable solvent such as dimethylformamide in the presence of a base such as sodium hydroxide qg under a nitrogen atmosphere. In general, relatively long reaction times will be necessary, for example up to 24 h. The product can be isolated and purified using conventional methods.•

The starting materials with the formula (IA) can be prepared via the route (1) shown above.

(3)

The pharmaceutically acceptable acid addition salts of compounds. the deis with the formula (I) can be prepared in a conventional manner, for example by mixing the free base with the desired acid in a suitable solvent, such as isopropanol, and filtering and, if necessary, recrystallizing the thus obtained., salt. When. the product is prepared according to route (1) it will often be present in the form of an acid addition salt..

The antihypertensive activity of the compounds prepared

according to the invention is evidenced by their ability to lower the blood pressure of conscious, spontaneously hypertensive rats and conscious renally hypersensitive dogs when the compounds are administered orally in doses of up to 5 mg/kg.

The new compounds can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with consideration of the intended route of administration due to standard pharmaceutical practice.

For example, they can be administered orally in the form of tablets

containing excipients such as starch or lactose,

or in capsules either alone or in a mixture with excipients, or in the form of. elixirs or suspensions containing flavorings or colored ingredients. They can be injected parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other dissolved components, for example sufficient salt or glucose to make the solution isotonic.

The new compounds can be administered to humans for the treatment of hypertension either by oral or parenteral routes and can be administered orally at daily dose levels in the range of 1-50 mg/day for an average adult patient (70 kg) given as a single dose or up to 3 divided doses. Intravenous dose levels can be expected to be

about. — to -of the daily oral dose. Thus, for an average adult patient, the individual oral doses in tablet or capsule form will generally contain the active compound in an amount of 1 - 50 mg. Variations will necessarily occur depending on the patient's weight and condition and the particular administration route chosen, as will be known in the state of the art.

The following examples illustrate the invention.

EXAMPLE 1

Preparation of 4-amino-6,7-dimethoxy-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]quinazoline. hydrochloride

2.6 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 3.0 g of 4-(2-ethoxy-1-phenylethoxy)piperidine in 100 ml of n-butanol were heated under reflux for 22 h. The solution was then cooled, filtered and the filtrate evaporated under vacuum. The residue formed was triturated with diethyl ether and recrystallized twice

■times from isopropanol to give 4-amino-6,7-dimethoxy'-2-['4-(2-ethoxy-1-phenylethoxy) piperidino ] quinazoline hydrochloride (2.0 g), m.p. 229 -.230°C.'

Analysis-%:

Found; C, 61.0; H, 6.9; N, 11.5 Calculated for C25H32N4°4•HCl: C, 61.4; H, 6.8; N, 11.5

EXAMPLE 2

Preparation of 4-amino-6,7-idimethoxy-2-[4-(2-phenoxy-1-phenylethoxy)piperidino]quinazoline hydrochloride hydrate

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-butanebl were heated under reflux for 20 h. The solution was then evaporated under vacuum and the residue triturated with ether. and recrystallized from isopropanol. The solid was dissolved in an aqueous sodium carbonate solution and extracted with chloroform and the chloroform extract dried over MgSO4 and evaporated under vacuum. The residue was chromatographed on silica (100 g) and eluted with chloroform followed by a chloroform/methanol mixture (20:1). The fractions containing the desired product were combined and the solvent evaporated under vacuum and the residue converted to the hydrochloride salt by treatment of a chloroform solution with ethereal hydrogen chloride. The solid hydrochloride salt was collected and recrystallized from isopropanol to give 4-amino6-6,7-dimethoxy-2'-[4-(2-phenoxy-1-phenylethoxy)piperidino]quinazoline, hydrochloride hydrate, • (0.85 g ) m.p. 202 - 204°C.

Analysis-%:

Found: C, 62.8; H, 6.1; N, 10.0 Calculated for C2gH32N4O4. HC1. H 2 O: C, 62.8; H, 6.4; N., 10.1'

EXAMPLES 3.- 6

The following compounds were prepared in the same way as in the previous examples, from 4-amino-2-chloro-6,7-dimethoxy-quinazoline and the desired piperidine, i.e. the product according to example 3/ was prepared in the same way as in Example 1; and the products according to Examples 4, 5 and 6 were prepared in the same manner as in Example 2, but the product according to Example 5 was not converted to the hydrochloride salt.

EXAMPLE 7

Preparation of 4-amino-6-cyclopropylmethoxy-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]-7-methoxyquinazoline, D(+) tartrate

0.75 g of 4-amino-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]-6-hydroxy-7-methoxyquinazoline hydrochloride in 50 ml of dimethylformamide and 1 ml of 5N sodium hydroxide solution was stirred at room temperature under an atmosphere of nitrogen for 40 min. in the dark. Cyclopropyl methyl bromide (0.27 g) was then added and the solution stirred under a nitrogen atmosphere for 20 h. 5 mg of potassium iodide followed by a further 0.27 g of cyclopropyl methyl bromide was added and stirring continued for 2 h at room temperature. The solvent was evaporated under vacuum and the residue taken up in 50 ml of water and made alkaline to pH 12 with 2N sodium hydroxide solution and extracted with chloroform (3 x 100 ml). The combined chloroform extracts were dried over sodium sulfate and the solvent evaporated under vacuum to

give a semi-solid. The product was chromatographed on silica (7 g) and eluted with chloroform. The fractions containing the product were combined and the solvent evaporated under vacuum. The residue was converted to the tartrate salt by treating a chloroform solution with a solution of D( + ) tartaric acid in ether. The resulting solid was filtered, washed with ether and dried under reduced pressure to give 4-amino-6-cyclopropylmethoxy-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]-7-methoxyquinazoline, D(+) tartrate, (115 mg), m.p. 14 2 - 14 5°.

Analysis %:

Found: C, 59.8; H,'6.5; N, 8 , 9 Calculated for C^gt^ . C₂O: C, 59.8; H, 6.6; N, 8.7

EXAMPLE 8

Preparation of 4-amino-6-ethoxy-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]-7-methoxyquinazoline hydroiodide

The title compound was prepared in the same manner as 1 Example 7 starting from 4-amino-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]-6-hydroxy-7-methoxyquinazoline and ethyl iodide in the presence of sodium hydroxide and showed a melting point of 227 - 228°C.

Analysis. %:

Found: C, 52.1; H, 5.8; N, 9.4 Calculated for.C^H^^O^.HI: C, 52.5; H, 5.9; N, 9.4

EXAMPLE 9

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

0.72 g of 4-amino-6-benzyloxy-2-chloro-7-methoxyquinazoline'

[J. With. Chem. 1977 NOK 20. 146] and 0.57 g of 4-(2-ethoxy-l-phenylethoxy)piperldih in 50 ml of n-butanol was heated under reflux for: .30 h. , The solvent was evaporated under vacuum and the residue triturated with ether to to give a solid which was recrystallized from isopropanol/diisopropyl ether to give 4-amino-6-benzyloxy-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]-7-methoxyquinazoline hydrochloride (740 mg). A sample recrystallized from ethanol had a melting point of .238 - 240°C.

Analysis %:

Found: C, 6.5 .- 5 ; H, 6, 5; N, 10 , 0 Calculated for C31H36N404•HC1: C'65.9; H, 6.6; N>9.9

The following presentations show the preparation of certain of the starting compounds:

MANUFACTURE A

Preparation of 4-(2-hydroxyphenethyloxy) piperidine

5.0 g of N-acetyl-4-hydroxypiperidine in 50 ml of tetrahydrofuran (THF) was added to a stirred suspension of sodium hydride

(1.84. g, Nati 50%1 ig dispersion in mineral oil) in 25 ml . tetrahydrofuran (THF) under a nitrogen atmosphere. When the effervescence had subsided, 4.6 g of styrene oxide in 25 ml of THF were added

set and the reaction mixture diluted with 25 ml of dimethylformamide (DMF) and stirred at 60°C for 18 h. After addition of isopropanol to the cooled solution, the solvent was removed under vacuum and the residue treated with water, adjusted to pH 4 with 2N hydrochloric acid and extracted with chloroform. The chloroform extract was dried over sodium sulfate and the solvent evaporated under vacuum to give N-acetyl-4-(2-hydroxyphenethyloxy)piperidine. The product was taken up in 50 ml of ethanol and. 100 ml of 5N sodium hydroxide solution was heated under reflux for 3 h. The solvent was removed under vacuum and the residue taken up in water, extracted with chloroform, dried and the solvent evaporated under vacuum. The product in the chloroform solution was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride and the solution evaporated.

The residue was taken up in methanol, treated with ether and the precipitated solid separated and recrystallized from isopropanol to give 4-(2-hydroxyphenethyloxy)piperidine hydrochloride (0.6 g), m.p. 174 - 175°C.

Analysis % :

Thinned: C, 6 0.1; H, 7.8; N, 5.2 Calcd for C13H19N02.HC1: C, 60.6; H, 7.8; N, 5.4

MANUFACTURE B

Preparation of 4-(2-ethoxyphenethyloxy) piperidine

8.0 g of N-acetyl-4-(2-hydroxyphenethyloxy)piperidine prepared

according to preparation A and 0.3 g of 1,2-dimethoxyethane i

50 ml of dry DMF was added dropwise to a stirred suspension

of sodium hydride (2.96 g, 50% dispersion in mineral oil)

in 50 ml dry DMF. The suspension was stirred at room temperature

for 3.5 h, cooled to 0 - 5°C, after which a solution of 9.6 g of ethyl iodide in 25 ml of DMF was added dropwise. The temperature of the mixture was allowed to rise to room temperature (20°C) and then stirred at room temperature for 2 h. 7 5 ml of isopropanol was

the additive and solvent removed under vacuum and the residue partitioned between chloroform and water. The chloroform layer was dried and the solvent evaporated under vacuum to give 5.2. g N-acetyl-4-(2-ethoxyphenethyloxy)piperidine.

The product in 50 ml ethanol and 50 ml/5N sodium hydroxide solution was heated under reflux for 3.5 h. The organic solvent was removed under vacuum and the aqueous residue extracted with chloroform. ■ The organic extract was dried over sodium sulphate and evaporated under vacuum and the residue distributed between 2N hydrochloric acid solution and ether. The aqueous phase was made alkaline with a sodium carbonate solution and extracted with chloroform. The chloroform extract was dried over sodium sulfate and the solvent evaporated under vacuum, after which the residue was taken up in ether and converted to the oxalate salt. Recrystallization from isopropanol gave 4-(2-ethoxyphenethyloxy)piperidine oxalate salt (1.6 g), m.p. 136 - 137°C. • Analysis %: Found: C, 60.3; H, 7.4'; N, 4.1 Calculated for C15H23N02•C2H2°4: C'60'2'H'7'4; N,-4,l

MANUFACTURE C

Manufacturing. of 4-(2-ethoxy-l-phenylethoxyVpiperidine).

(i) α-(N-acetyl-4-piperidinoxy)phenyacetic acid, ethyl ester 27.5 g of M-acetyl-4-hydroxypiperidine in 100 ml of DMF was slowly added to a stirred suspension of sodium hydroxide (25 g, 50 %<4>ig dispersion in mineral oil) in 150 ml DMF and 10 ml 1,2-dimethoxyethane.

The suspension was stirred at room temperature for 3 h after which 45 g of α-bromophenylacetic acid in 250 ml DMF was slowly added under ice/water cooling, "The mixture was stirred at room temperature"

for 20 h, after which isopropanol was added and the solvent evaporated under vacuum. The residue was taken up in water, acidified to pH 1 with 2N hydrochloric acid and extracted 4 times with chloroform (300 ml). The combined chloroform extracts were washed with water and brine, dried over magnesium sulfate and the solvent evaporated under vacuum. The residue in 450 ml of anhydrous ethanol and 9 ml of concentrated sulfuric acid was heated under reflux for 8 h. The cooled solution was carefully neutralized with an aqueous sodium bicarbonate solution and the organic solvent evaporated

under vacuum. The aqueous residue was adjusted to pH 10 with a sodium carbonate solution and extracted twice with chloroform. The combined chloroform extracts were dried over magnesium sulfate and evaporated under vacuum. The distillation of the residue gave α-(N-acetyl-4-piperidinoxy)phenylacetic acid, ethyl ester (37.2 g). bp 190 - 194°C/0.18 mm Hg.

Assay %: .Found.: C, 66.4; H, 7.8> '' N, 4.5 Calcd for C17<H>23N04: C, 66.9; H, 7.6'; N, 4.6

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

3.24 g of lithium borohydride was added portionwise to 11.2 g of α-(N-acetyl-4-piperidinoxy)phenylacetic acid, ethyl ester in 200 ml of dry THF. When hydrogen evolution had subsided, the reaction mixture was heated under reflux for 4 h, after which water was added to the cooled solution and the solvent evaporated under vacuum and the residue taken up in 200 ml of chloroform and washed with dilute hydrochloric acid, water and sodium chloride solution. The chloroform extract was dried over magnesium sulfate and the solvent evaporated under vacuum. Analysis by thin layer chromatography of the product indicated that the reduction was incomplete and the product was therefore treated with an additional amount of lithium borohydride (3.24 g) in 100 ral THF and was heated under reflux for 4 h. - The reaction mixture was worked up as above to give 9 .5 g of N-acetyl-4-(2-hydroxy-1-phenylethoxy)piperidine in the form of a

oil that solidified on standing. A sample recrystallized from ether had a melting point of 92-94°C.

Analysis %:

Found: C, 68.1; H, 8.1; H, 5.7

Calculated for C₂H₂NCy: C, 68.4; H, 8.1; N, 5.3'

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

This compound was prepared in the same manner as in Preparation B using N-acetyl-4-(2-hydroxy-1-phenylethoxy)piperidine (prepared as indicated in part (ii) above) and ethyl iodide, followed by basic hydrolysis of the N-acetyl group. A sample was characterized in the form of the oxalate salt, m.p. 137 - 139°C.

Analysis % :

Found-: C, 59.9; H, 7.4; N, 4.0 Calculated for C1'5H23N02 " C2H2°4 : C, 60.2; H, 7.4; N, 4.1

MANUFACTURE D

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

5.25 g of N-acetyl-4-(2-hydroxy-1-phenylethoxy)piperidine (prepared as indicated in preparation C (ii)) and 4.2 g of diethyl azo-dicarboxylate, 6.3 g of triphenylphosphine and 2.25 g of phenol in 100 ml of dry tetrahydrofuran was stirred at 0°C for 2 h and then allowed to stand at room temperature for 48 h. The solvent was evaporated under vacuum and the residue taken up in 50 ml of diethyl ether at the reflux temperature and allowed to stand in a refrigerator overnight. Precipitated" by-products were removed - by filtration and the filtrate was evaporated to dryness. The residue was again taken up in ether and set aside for cooling and the precipitated solid was filtered off. The ether filtrate was evaporated to dryness and the residue was taken up in 50 ml of methanol and heated under reflux with 30 mL, 5N sodium hydroxide solution for 5 h.

The organic solvent was removed under vacuum and the aqueous residue acidified to pH 3 with 2N hydrochloric acid and extracted twice with ether and the organic extracts discarded. The aqueous phase was adjusted to pH 12 with a sodium hydroxide solution, extracted 3 times with 100 mL portions of ether and the ether extracts were combined, dried over magnesium sulfate and the solvent evaporated under vacuum to give 3.55 g of 4-(2-phenoxy-1- phenylethoxy)piperidine■

in the form of an oil. A sample was converted to the oxalate salt which was recrystallized from isopropanol and had a melting point of 170-172°C.

Analysis %:

Found: C, 6 4.9; E, 6.6; N, 3.8 Calculated for<C>19H23N02•<C>2H2°4: C'65'1; H'6'5; N'3.6

MANUFACTURE E

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

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

13.6 g of N-acetyl-4-hydroxypiperidine in 50 ml DMF was added dropwise to a stirred suspension of sodium hydride (10 g, 50% 1 µg dispersion in mineral oil) in 50 ml DMF under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 h, after which 20 g of α-(bromomethyl)styrene in 50 ml of DMF were added dropwise. The mixture was stirred at room temperature

for 4 h and then diluted with water and extracted with chloroform (3 x 200 ml). The combined chloroform extracts were

dried over sodium sulfate, evaporated under vacuum and distilled to give 25 g of N-acetyl-4-(2-phenylallyloxy)piperidine

bp 170 - 180°C/0.3 mm Hg with an n.m.r. spectrum consistent. with its structure.

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

4.0 g of N-acetyl-4-(2-phenylallyloxy)piperidine in 60 ml of dry THF was added dropwise to a stirred solution of 6.35 g of mercury (II) acetate in 60 ml of water and the solution stirred at room temperature for 1 h .A sodium hydroxide solution.

(40 mL, 3N) and 0.75 g of sodium borohydride in sodium hydroxide solution (40 mL, 3N) were added dropwise to the stirred solution at 0°C. The gray suspension was stirred at 0°C for 1 h after which glacial acetic acid was added to pH 6. The suspension was filtered and the filtrate extracted with chloroform (3 x 150 ml). The combined chloroform extracts were dried over sodium sulfate and evaporated in vacuo to give 2.1 g of N-acetyl-4-(2-hydroxy-2-phenyl-n-propoxy)piperidine. This compound in 30 ml of methanol and sodium hydroxide solution (20 ml, 5N) was heated under reflux for 4 h. The organic solvent was evaporated and the aqueous solution extracted with chloroform (3 x 20 ml), dried over

sodium sulfate and the solvent evaporated. under vacuum to give 8 g of 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine as an oil. A sample was characterized as the oxalate salt which was recrystallized from ethyl acetate and had a melting point of 132-134°C.

Analysis %:

Found: C, 58.8; H, 7.1; N, 4.8 Calculated for c14H2iN02•C2H2°4: C'59.1; H' 7'1; N, 4.3

MANUFACTURE F

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

7.0 g of N-acetyl-4-(2-phenylallyloxy)piperidine (prepared as

in preparation E) in 10 ml of ethanol was added to a stirred suspension of 9.2 g of mercury (II) acetate in 50 ml of ethanol at room temperature. The mixture was stirred at room temperature for 1 h and then cooled to 0°C. A sodium hydroxide solution (.20 mL, 5N) followed by sodium borohydride (1.03 g) in one sodium hydroxide solution (20 mL, 5N) was added to the stirred

suspension and after 10 min. glacial acetic acid was added to pH 6. The suspension was filtered and the filtrate concentrated and the residue partitioned between chloroform and water. The organic layers were dried over sodium sulfate and the solvent evaporated under vacuum. Gas-liquid chromatography (GLC) analysis of the product indicated incomplete conversion to the desired product<p>g^ox<y>m<e>rcuring process was repeated as above to give 7.4 g of N-acetyl-4-(2 -ethoxy-2-phenyl-n-propoxypiperidine with a purity of 84% determined by GLC. The product in 100 ml ethanol and a 30 ml sodium hydroxide solution was heated under reflux for 11 h. The organic solvent was evaporated and the aqueous solution extracted with chloroform (3 x 30 mL).The combined chloroform extracts were dried over sodium sulfate and the solvent evaporated in vacuo to give 3.8 g of 4-(2-ethoxy-2-phenyl-n-propoxy) piperidine as an oil A sample was converted to the oxalate salt which was recrystallized twice from ethyl acetate and then from acetone and showed a melting point of 126 - 127 o C■.

Assay %: Found: C, 60.4; 'H, 7.6; N,' 4.1 Calculated for C16H25N02•C2H2°4'IH2°: C' 60.4? H' 7'3? 'N'3.9

MANUFACTURE G

Preparation of 4-amino-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]-6-hydroxy-7-methoxyquinazoline, hydrochloride hydrate

0.9 g of 4-amino-6-benzyloxy-2-[4-(2-ethoxy-1-phenylethoxy)-piperidino]-7-methoxyquinazoline, hydrochloride in 150 ml of dry ethanol was hydrogenated over 5% Pd/C at room temperature and

•1.05 kp/cm 2 for 2 h. The catalyst was removed by filtration and the filtrate evaporated to dryness under vacuum. The residue-

was triturated with ether to give a white solid (0.55 g).

A sample (200 mg) was recrystallized from isopropanol to

to give 71 mg of 4-amino-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]-6-hydroxy-7-methoxyquinazoline, hydrochloride hydrate, m.p.

141.- 14 4°C.

Assay %: Found: C, 58.0; H, -6.5; N, 11.5 Calculated for C24H3Q<N>4<0>4.<H>C1.H20:C, 53.5; H, 6.8^N, 11.4

Claims (4)

1. Procedure for the preparation of a quinazoline with the formula wherein R is C 1 -C 4 alkyl, benzyl or (C 1 -C 8 cycloalkyl)methyl, R<1> is C1-C4 alkyl, X is -CH2 CH2 - substituted with a phenyl group and.éven- tuteled with 1 or 2 methyl groups, and . R 2 is hydrogen, C 1 -C 4 alkyl or f,en <yl> optionally substituted with one or two substituents such as 3 4 C,-C. alkyl, C 1 -C . alkoxy, halogen, CF-, -CONR R 3"'4 3 4 or -SC^NR"R in which R and R each mean hydrogen or C1~C4 alkyl, as well as a pharmaceutically acceptable acid addition salt thereof, characterized by . to convert a quinazoline. with the formula wherein R and R have the meanings given above and Q is a readily leaving group such as chlorine, bromine, iodine, (C 1 -C 4 alkyl)-thio or (C 1 -C 4 alkyl)sulfonyl, with a piperidine of the formula in which X and R 2 have the meanings given above and optionally followed by (i) converting a compound wherein R is a benzyl group into a compound wherein R is hydrogen by hydrogenation, followed by converting a compound wherein R is hydrogen into a compound of formula (I) wherein R is C -C^ alkyl or (C₁ -C₁ cycloalkyl)methyl by reaction with a compound with. the formula R.Q in which R is C-^-C^ alkyl or (C^-C 8 cyclo-alkyl) methyl and Q is a light leaving group, and or (ii) converting a compound of formula (I)N. to a pharmaceutically acceptable acid addition salt by reaction with a non-toxic acid. 2. Process according to claim 1, characterized in that R is CH 2 , C 2 H 2 - , benzyl or cyclopropylmethyl, R is CH 2 , R 2 is H, methyl, ethyl or phenyl, and X is -CH (phenyl) CH2-, -CH"2CH (phenyl) - or -CH2C (CH3)(phenyl)-. 3. Method according to claim 2, characterized 1 2 in that R and R are both CH3 , X is -CH(phenyl)CH2~ , R is C2H5 and Q is Cl. 4. Method according to claim 2, characterized in that R and R are both CH3 , X is -CH2CH(phenyl)-, R" is H and Q is Cl.-