NO783829L - PROCEDURES FOR THE PREPARATION OF NEW QUINAZOLINE DERIVATIVES - Google Patents

Description

Procedure for the production of new quinazoline derivatives.

The present invention relates to a method for the production of the new 4-amino-2-piperidino-quinazoline derivatives and especially derivatives with a substituted alkoxy group in the 4-position in the piperidino group. Such compounds are useful as regulators of the cardiovascular system, and especially in the treatment of hypertension.

The new compounds produced according to the invention are those with the general formula:

where "alk" represents an ethylene group optionally substituted by one or two lower alkyl groups, and R is hydrogen, lower alkyl, C₁-cycloalkyl, or a group of the formula

2 3

where R and R independently represent hydrogen,

4 5 lower alkyl, lower alkoxy, halogen, CF_, -CONR R 4 5 4 5

or -SC^NR R where R and R each independently represent hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts thereof.

In the present specification, "halogen" means fluorine, chlorine, bromine or iodine. The term "lower" applied to an alkyl or alkoxy group indicates that this group contains from 1-6 carbon atoms, preferably from 1-4 carbon atoms, and where such groups contain from 3-6 carbon atoms/ can therefore be straight or branched.

Pharmaceutically tolerable acid addition salts are those formed from acids that form non-toxic acid addition salts containing pharmaceutically tolerable anions, such as hydrochlorides, hydrobromides, sulphate or bisulphate, phosphate or the acid phosphate, acetate. the maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate or p-toluenesulfonate salts.

The compounds produced according to the invention contain one or more asymmetric centers which will exist as one or more pairs of enantiomers, and such pairs or individual isomers can be separated by physical methods, e.g. by fractional crystallization of suitable salts.

The invention includes the preparation of the separated pairs as well as mixtures thereof, and racemic mixtures or separated d-

and 1-optically active isomeric forms.

R is preferably methyl, CH3CH3

X is preferably -OCH2CH2OR, -OCH2-CH-OR or -0-CH2~C-OR

CH3

R"<*>" is preferably hydrogen, C 1 -C 4 alkyl, cyclopentyl, or phenyl, optionally substituted by lower alkyl, alkoxy, halogen, trifluoromethyl or carbamoyl. 1.1 a preferred group of the compounds is R"<*>" different from C1-C8 cycloalkyl and R and R are different from trifluoromethyl.

|The two preferred individual compounds are such oq qår i "(aal) kR " eer r C-CHH32, CH"2a-lko" g er R1 -Cer H2CHfe2n-olg. R 1 is C 2 H 5 and (b) R is CH 3 ,

According to the invention, the compounds can be prepared by several methods which include the following: 1) The compounds can be prepared by reacting a quinazoline with the formula

where Q represents a leaving group that is easily removed, such as chlorine, bromine, iodine, lower alkoxy, (lower alkyl)thio- or (lower alkyl)sulfonyl with a piperidine of the formula

Q is preferably chlorine or bromine.

The reaction is preferably carried out in the presence of a base such as triethylamine or excess reagent of the formula (III).

In a typical method, the reactants are heated together, e.g. at a temperature of 70 to 130°C, preferably under reflux in an inert organic solvent, e.g. n-butanol for a period of time up to approx. 48 hours. The product can be isolated and purified by conventional methods.

E.g. the product is preferably obtained in crude form By evaporating the reaction mixture in vacuo, and the crude product can be purified either by recrystallization from a suitable solvent or by transfer to e.g. the hydrochloride salt by reaction with hydrogen chloride in e.g. ethanol followed by recrystallization of the salt. In some cases, of course, the reaction product will be the hydrochloride salt. In some cases, the crude product can also be purified chromatographically, e.g. by making it basic and extracting with chloroform/evaporating the chloroform extracts and chromatographing the residues on e.g. neutral alumina in that product is eluted with chloroform or a mixture of chloroform and methanol. The eluted product can be purified by transfer to the hydrochloride salt, followed by recrystallization as above.

Intermediates with formula (II) are generally known compounds, or can be prepared by methods analogous to those previously known.

The intermediates of formula (III) are either known compounds or can be prepared by conventional methods, e.g. as follows:

b) The piperidines in which "alk" is an ethylene group substituted with one or two lower alkyl groups can also be prepared via the corresponding 1-acetyl-4-alkenoxypiperidines, e.g. as follows (R"1" can be hydrogen in this method): c) 4-(2-hydroxyethoxy)piperidine can be prepared by the previously described method: d) 4-(2-hydroxyalkyloxy)priperidines can also be prepared by the following conventional methods :

riu l..

[in which Prot. is a suitable N-protecting group, e.g. acetyl or benzyl, and can be removed by conventional methods in the final step, and R" is H or lower alkyl]

7 je) 4-(2-Alkoxyalkyloxy)piperidines can be prepared by reacting an N-protected 4-(2-hydroxyalkyloxy)piperidine compound by one of the above methods with an alkyl halide or mesylate in the presence of a strong base, e.g. .eg: (Prot. and R" are as stated above, R"<1>= H or lower alkyl) and f) 4-(2-aryloxyalkyloxy)piperidines can be prepared by: i) reaction of N-acetyl-4 -(2-hydroxyalkoxy)piperidine obtained as above with a suitable substituted with phenol in the presence of triphenyl phosphine and diethyl azodicarboxylate ("D.E.A.D." ). :

(R" and R'" are as above stated)

ii) 4-(2-aryloxyalkyloxy)piperidines can alternatively be prepared from an N-protected 4-(2-hydroxyalkyloxy)piperidine obtained as above and fluorobenzene or a substituted fluorobenzene in the presence of NaH and D.M.F.:

2) The pharmaceutically acceptable acid addition salts of a compound of formula (I) can be prepared by conventional methods, e.g. by mixing a free base with the correct amount of acid in a suitable solvent, e.g. isopropanol, filtration and, if necessary, recrystallization of the salt thus formed until it is pure. Often, of course, the product from method (I) will be in the form of an acid addition salt. The invention also includes the pharmaceutically acceptable bioprecursors of the compound of formula (I) and said salts thereof.

The term "pharmaceutical tolerable bioprecursor" requires some explanation. It is, of course, common practice in pharmaceutical chemistry to overcome these undesirable physical or chemical properties of a drug by transferring the drug into a chemical derivative which does not have the same undesirable property, but which, when administered to an animal or a human being, reverts to the starting drug. E.g. if the drug is not well absorbed when it is given to the animal or patient orally, it may be possible to transfer the drug in a chemical derivative that is well absorbed and which in the serum or tissues is returned to the starting drug. If again a drug is unstable in solution, it may be possible to produce a chemical derivative of the drug which is stable and which is administered in solution/but which is returned to the body to give the starting drug. The pharmaceutical chemist is well aware of the possibility of overcoming agricultural deficiencies in a drug by chemical modifications which are only temporary and are reversible after administration to an animal or patient.

For the purpose of this specification, the term "pharmaceutically acceptable bioprecursor" of a compound of formula (I) means a compound having a structural form which is different from the compound of formula (I) but which nevertheless after administration to an animal or human being is transferred in the patient's body to a compound of the formula (I).

The antihypertensive action of the compound according to the invention is demonstrated by its ability to lower blood pressure in proven spontaneous

hypertensive rats and proven renally hypertensive dogs when administered orally at doses up to 5 mg/kg.

The compound according to the invention can be given alone, but will generally be given mixed with a pharmaceutical carrier selected taking into account the intended route of administration and usual pharmaceutical practice. E.g. can be given orally in the form of tablets as contain such excipients as starch or lactose or capsules either alone or in a mixture with excipients, or in the form of electric acid or

suspensions containing flavoring or coloring matter. They can be injected in pairs, e.g. intramuscularly, intravenously or subcutaneously. For parenteral administration, it is preferably used in the form of a sterile aqueous solution which may contain other soluble substances, e.g. enough salts or glucose to make the solution isotonic.

Thus, the invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The compounds produced according to the invention can be given to humans for the treatment of hypertension either orally or parenterally and can be given orally in amounts approximately in the range of 1-20 mg/day for an average adult patient. (70 kg) given in a single dose or up to 3 divided doses. Intravenous dosage amounts would be expected to be approx. 1/5 -1/10 of the daily oral dose. For an average adult patient, individual oral dosages in tablet or capsule form will be approximately in the range from 5 - 100 mg of the active compound. Variations will necessarily occur depending on the weight and condition of the individual being treated and the particular route of administration chosen will be known to the person skilled in the art.

The invention now further provides a method for treating an animal comprising a human being with hypertension which comprises administering to the animal an antihypertensive amount of a compound of formula (I) or pharmaceutically acceptable acid addition salts thereof, or pharmaceutical compositions as defined above.

The following examples illustrate the invention:

in Example 1 | Preparation of 4- amino- 6, 7- dimethoxy- 2-[ 4-( 2- ethoxyethoxy) piperedino] quinazoline hydrochloride

4-Amino-chloro-6,7-dimethoxyquinazoline (4.3 g), 4-(2-ethoxyethoxy)piperidine (3.2 g) and triethylamine (10 ml) in N-butanol (400 ml) were heated at reflux overnight in a nitrogen atmosphere. The mixture was then cooled, evaporated in vacuo and the residue basified (aqueous Na 2 CH 3 ) and extracted 3 times with chloroform. The combined chloroform extracts were evaporated and the residue chromatographed on neutral alumina (150 g, grade 1, deactivated with 5 ml

water). Elution with chloroform gave the crude product (3.6 g) which was converted to the hydrochloride salt by treatment with hydrogen chloride in ethanol. The hydrochloride was then recrystallized from ethanol/isopropanol to give 4-amino-6,7-dimethoxy-2-[4-(2-ethoxyethoxy)piperidino]quinazoline hydrochloride (3.4 g), m.p. 219-220°C.

Found: C, 55.4; H, 7.2; N, 13.5 Calculated for<C>19H28N4°4"HCL: C'55-3'H 1N' 13-6

Example 2-7

The following quinazolines were prepared similarly to example 1 from 4-amino-2-chloro-6,7-dimethoxyquinazoline and the correspondingly substituted piperidine, and were isolated in the indicated form.

li

in I

The following small differences in the procedure from example 1 should be mentioned. In example 3, the product from the chromatographic purification was recrystallized directly without prior transfer to

a hydrochloride salt. In examples 5 and 7, silica gel was used for the chromatographic purification. In Example 6, the residue left after evaporation of the original reaction mixture was .

(which was a hydrochloride salt) recrystallized from dimethylformamide and then directly chromatographed on silica gel.

Example 8

4-amino-6,7-dimethoxy-2-[4-(2-methoxy-n-propoxy)piperidino]quinazoline hydrochloride.

4-amino-2-chloro-6,7-dimethoxyquinazoline (3.6 g), 4-(2-methoxy-n-propoxy)piperidine (3.0 g) and triethylamine (1.5 g) in n-butanol were heated under reflux for 30 hours. The solvent was evaporated in vacuo, the residue stirred with diethyl ether, the solid collected and recrystallized twice from isopropanol to give 4-amino-6,7-dimethoxy-2-[4-(2-methoxy-n-propoxy)piperidino]quinazoline hydrochloride (2.8 g), m.p. 239-241°C.

Found : C, 55.1; H, 7.2; N, 13.6Calculated for C19<H>28N404'HC1: C'55-2'H'7'1'N'13*6

Example 9-22

The following quinazolines were prepared similarly to Example

8 from 4-amino-2-chloro-6,7-dimethoxyquinazoline and the corresponding substituted piperidine and was isolated in the indicated form.

The following examples illustrate the preparation of certain of the starting materials used in the preceding examples:

Example A

Preparation of 4-(2-methoxyethoxy) piperidine

A solution of N-acetyl-4-hydroxypiperidine (30.5 g) in dimethylformamide (200 ml) was added dropwise to a stirred suspension of sodium hydride (11.26 g, 50% dispersion in mineral oil) in dimethylformamide (300 ml) under a nitrogen atmosphere. The reaction temperature was kept below 30°C by external cooling and, after the addition was complete, stirring was continued for a further 1 1/4 hours. A solution of 1-bromo-2-methoxyethane (32.6 g) in dimethylformamide (100 ml) was then added dropwise under external cooling and the resulting clear solution was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo, the residue partitioned between water and chloroform, the organic extracts dried (Na2SO^) and evaporated which gave a crude residue (16.1 g). The above aqueous phase was saturated with sodium chloride, further extracted with chloroform and the organic phase was dried (Na 2 SO 4 ) and evaporated to give a further residue (9.2 g). That residue was combined with the original residue and heated on a steam bath overnight with hydrochloric acid (243 mL, 2N). The reaction mixture was extracted with chloroform to remove residual mineral oil, the aqueous phase was concentrated, basified with sodium hydroxide;

(pH 12), and then re-extracted with chloroform.

The organic extracts were washed with brine, dried (Na 2 SO 4 and evaporated) to give 4-(2-methoxyethoxy)piperidine (8.3 g).

A sample of this product in ethyl acetate was transferred to the oxalate salt with the addition of ethereal oxalic acid followed by recrystallization from ethanol and the oxalate had a melting point of 86-88°C.

Analysis:

Found : C, 48.1; H, 7.6; N, 5.6. Calculated for CRH JO.-ICO.H),: C, 48.2; H, 7.7; N, 5.6

The following piperidine derivatives were prepared by methods in I similar to example A from N-acetyl-4-hydroxypiperidine and the corresponding bromide. Hydrolysis of the N-acetylated intermediates in Examples B and D was carried out using dilute sodium hydroxide instead of dilute hydrochloric acid.

Example E

Preparation of N-acetyl-4-allyloxypiperidine

A solution of N-acetyl-4-hydroxypiperidine (100 g) in dimethylformamide (250 ml) was added dropwise to sodium hydride (38 g, 50% mineral oil dispersion) under an atmosphere of nitrogen. The mixture was stirred for 2 hours, then allyl bromide (93 g) was slowly added while the reaction temperature was maintained at 25°C by external cooling. The mixture was then stirred at room temperature overnight, diluted with isopropanol (20 ml) and ether (500 ml), filtered and evaporated in vacuo. Distillation of the residue gave N-acetyl-4-allyloxypiperidine

1(108.8 g)/boiling point 128 C/2 mm., spectroscopically identified. IN

Example F

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

A solution of N-acetyl-4-allyloxypiperidine (6.4 g) in absolute ethanol (10 ml) was added dropwise to a stirred solution of mercuric acetate (11.5 g) in ethanol (50 ml) at room temperature. After 20 min. the mercuric acetate was dissolved and the mixture was stirred for a further 40 min. cooled in ice water and sodium hydroxide (20 ml, 5N) was then added." A yellow precipitate formed during the addition. A solution of sodium borohydride (1.3 g) in sodium hydroxide (20 mL, 5N) was then added, the mixture stirred for 10 min. and acetic acid added to bring the pH to 6. The mixture was filtered from precipitated mercury, the ethanol evaporated in vacuo, and the resulting aqueous phase extracted with chloroform.

The organic extracts were dried (Na 2 SO 4 ), evaporated in vacuo

and the resulting crude residue (7.5 g) taken up in ethanol (50 ml)'

and heated under reflux overnight with sodium hydroxide (20 mL, 5N) and water (20 mL). Most of the ethanol was then removed in vacuo, the aqueous layer extracted with ether, the extracts dried (Na 2 SO 4 ) and evaporated to give a residue (5 g). Thin layer chromatography indicated that incomplete hydrolysis of the acetyl function was present so the residue was treated with hydrochloric acid (20 mL, 2N) and heated on a steam bath for 10 hours. The mixture was then washed with ether, the aqueous phase made basic (Na 2 SO 3 ), extracted with ether and the organic extract dried (Na 2 SO 4 ) and evaporated to give a residue (4.3 g). Distillation of the residue gave 4-(2--ethoxy-n-propoxy) piperidine (3.0 g) bp 112-116°C/10 mm, from which the sesquioxalate salt was prepared by reaction of an ether solution of the piperidine with ethereal oxalic acid, followed by recrystallization from ethyl acetate and the oxalate had a m.p. at 68 - 70°C.

Analysis %:

Found C, 48.3; H, 7.5; N, 4.7 |Calculated for c10H21NO2*1 * 5(C02H)2:C'48-4'H, 7.5; N, 4.4

Example G

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

N-acetyl-4-allyloxypiperidine (18 g) in tetrahydrofuran (30 ml) was added dropwise to a stirred yellow suspension of mercuric acetate (34 g) in a mixture of water (120 ml) and tetrahydrofuran (120 ml).

--The suspension dissolved during the addition and the resulting clear solution was stirred at room temperature for 20 min., then sodium hydroxide (70 mL, 5N) was added simultaneously with

cooling of ice/water. The thus obtained intermediate was then reduced by adding sodium borohydride (2 g) in sodium hydroxide (40 ml, 5N) in which the excess hydride was cleaved after 10 min. with glacial acetic acid. The liquid phase was then decanted from, saturated

with sodium chloride, the organic phase separated and the remaining aqueous layer extracted 4 times with chloroform.

The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a colorless oil (23 g).

This oil was stirred with 5N sodium hydroxide at room temperature

for 16 hours and then at 100°C for two hours. The solution was then extracted with chloroform (4 times), the combined extracts dried (Na 2 SO 4 ) and evaporated in vacuo to give a crude crystalline product (16.1 g). This was taken up in methylene chloride, filtered/evaporated and the residue triturated with petroleum ether (b.p. 40 - 60°C) which gave 4-(2-hydroxy-n-propoxy)piperidine (11.0 g), m.p. 55-57°C. The oxalate salt thereof was prepared as example F and recrystallized from isopropanol, m.p. 104-105°C.

Analysis %:

Found C, 48.2; H, 7.7; N, 5.6 Calcd for <C>gH17N02.(C02H)2: C, 48.2; H, 7.7; N, 5.6

Example H

I [Preparation of N-acetyl-4-(2-methylallyloxy) piperidine

This compound was prepared in the same way as example E from ;

N-acetyl-4-hydroxypiperidine and 2-methylallyl chloride, and was distilled and used directly in the next step. It had a k.p. 128°C lmm Hg.

Example I

" Preparation of 4-(2-methoxy-2-methyl-n-propoxy) piperidine

This compound was prepared similarly to example F from N-acetyl-4-(2-methylallyloxy)piperidine and mercuric acetate/methanol. The compound was characterized as hemioxalate m.p. 208-210°C.

Analysis %:

Found: : C, 56.7; H, 9.5; N, 5.9 Calculated for C10H21<N>O2.1/2(CO2H)2:C, 56.9; H,.9.6; N, 6.0

Example J

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

This compound, m.p. 80 - 82°C, was prepared similarly to example G from N-acetyl-4-(2-methylallyloxy)piperidine and mercuric acetate in a mixture of water and tetrahydrofuran.

Analysis %:

Found : C, 62.2; H, 11.1; N, 8.3

Calcd for CgH^NC^: C, 62.4; H, 11.1; N, 8.1

Example K

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

This compound was prepared similarly to Example F out

from N-acetyl-4-(2-methylallyloxy)piperidine and mercuric acetate/

[ letanol followed by basic hydrolysis to remove the N-acetyl group.

I I

A sample was transferred to the hemi-oxalate salt which was recrystallized from ethyl acetate/methanol, m.p. 184-185°C.

Analysis %:

Found: C, 58.6; H, 9.7; N, 5.8 Calculated for C11H23N02 * 1//2C2H204: C'58'5; H'9'8'N'5-7

Example L

Preparation of 4-(2-isopropoxy, ethoxy) piperidine

This compound was prepared similarly to example A from N-acetyl-4-hydroxypiperidine and 1-bromo-2-isopropoxyethane. The compound was characterized by spectroscopic methods.

Example M

Preparation of 4-(2-methoxy-n-propoxy) piperidine

This compound was prepared similarly to example F from N-acetyl-4-allyloxypiperidine and mercuric acetate in methanol. To improve the transfer of the starting material into the product, the mercury acetate/methanol treatment was repeated twice to give N-acetyl-4-(2-methoxy-1-propoxy)piperidine which was hydrolyzed in sodium hydroxide and methanol solution to give 4-( 2- methoxy-1-propoxy) piperidine. A sample was characterized as the oxalate salt, m.p. 89-91°C.

Analysis %:

Found: C, 49.6; H, 7.9; N,5.3Calculated for CgH19N<0>2.<C>2<H>2<0>4: C, 50.2; H, 8.1; N, 5.3

Example N

in . Preparation of 4-(2-phenoxy-n-propoxy) piperidine j!

N-acetyl-4-(2-hydroxy-n-propoxy)piperidine (12 g) in dry DMF<I>'

(50 mL) was added dropwise to a stirred solution of sodium hydride (5.0 g, 50% dispersion in mineral oil) in DMF (50 mL) at 60-70°C under a nitrogen atmosphere. The suspension was stirred for 3 hours, and then fluorobenzene (6.4 g) in DMF (50 ml) was added dropwise and the suspension was stirred at 100°C for 50 hours. The cooled solution was treated with isopropanol (20 ml), then water (200 ml), extracted with petroleum ether (3 x 200 ml) and chloroform (3 x 200 ml). The combined chloroform extracts were dried (Na-2SO4) and the solvent evaporated in vacuo. The residue (9.0 g) in sodium hydroxide solution (20 mL, 5N) and methanol (20 mL) was heated under reflux for 5 hours to effect dissolution. The methanol was evaporated, the residue diluted with water, then extracted with chloroform (3 x 50 ml). The combined chloroform extracts were washed with 2N HCl (3 x 30 ml), the combined aqueous extracts basified to pH 12 with sodium hydroxide solution and extracted with chloroform (3 x 50 ml). The combined chloroform layers were dried (Na 2 SO 4 ), the solvent evaporated in vacuo, and the residue was triturated with ether and filtered. The filtrate was concentrated, then distilled to give 4-(2-phenoxy-n-propoxy)piperidine (0.5 g), m.p. 118-122°C/

0.3 mm, characterized by spectroscopy.

Example 0 I

4-(2-[2,6-dimethoxyphenoxy]ethoxy)piperidine

Methanesulfonyl chloride (23g) was added dropwise to a stirred solution of 2-[2,6-dimethoxyphenoxy]ethanol (20g) (J.Med.Chem. 1969, 12, 326) in pyridine (50ml). The solution was allowed to stand at room temperature for 60 hours and the solvent was then evaporated under reduced pressure. The residue was taken up in chloroform, washed with water, (3 x 100 ml) and sodium bicarbonate solution (5%, 3 x 100 ml), dried and the solvent evaporated.

The residue was triturated with n-hexane and the solid collected to give 2-[2,6-dimethoxyphenoxy]ethyl mesylate (11.3 g) which was characterized by spectroscopy.

N-acetyl-4-hydroxypiperidine (4.3 g) in DMF (50 mL) was added dropwise to a stirred solution of sodium hydride (3.0 g, 50% dispersion

in mineral oil) in DMF (50 mL) under a nitrogen atmosphere. After<I>j

with stirring at room temperature for 3 hours, 2-[2,6-dimethoxyphenoxy] ethyl mesylate (9.0 g) in DMF (50 ml) was added dropwise and stirred continuously for 20 hours at room temperature. The solvent was evaporated in vacuo and the residue taken up in water, extracted with chloroform (3 x 100 ml), the organic layer dried (Na 2 SO 4 ) and the solvent evaporated. The distillation gave N-acetyl-4-(2-[2,6-dimethoxyphenoxy]ethoxy)piperidine (6.0 g), m.p. 200°C/l mm Hg.

This product (6.0 g) in methanol (40 mL) and sodium hydroxide

solution (20 mL, 5N) was heated under reflux for 20 h. The methanol was evaporated under reduced pressure, the aqueous residue extracted with petroleum ether (3 x 30 ml) and ether (3 x 30 ml). The ether extract was dried (Na 2 SO 4 ) and the solvent was evaporated. The residue in ether was treated with ethereal hydrogen chloride and the precipitated solid recrystallized from isopropanol to give 4-(2-[2,6-dimethoxyphenoxy]ethoxy)piperidine hydrochloride

(1.4 g), m.p. 143-145°C.

Analysis %:

Found : C, 56.4; H, 7.6; N, 4.3 Calculated for C15H23N04•HC1: C'56-7; H>7-6?N'4-4

Example P

(A) Preparation of N-acetyl-4-(2,2-diethoxyethoxy)piperidine

N-acetyl-4-hydroxypiperidine (57.2 g) in dry DMF (250 mL) was

added dropwise to a stirred solution of sodium hydride (23.2 g, 50% dispersion in mineral oil) in dry DMF (200 mL) under a nitrogen atmosphere and external cooling in an ice/water bath. The suspension was allowed to warm to room temperature and was then stirred

5 hours. Bromoacetaldehyde diethyl acetal (94.7 g) was added slowly to the stirred reaction mixture under cooling and then the mixture was stirred at room temperature for 18 hours. An additional amount of sodium hydride (23.2 g) was added portionwise and stirring continued until foaming had ceased. An additional 100 ml of dry DMF was added and the mixture cooled in an ice/j

•water bath while a second batch of bromoacetaldehyde diethyl acetal (94.7 g)

<p>le slowly added. The mixture was stirred at room temperature for 3 hours and then isopropanol (150 ml) was added to decompose the excess sodium hydride. The suspension was filtered, the filtrate concentrated under reduced pressure, then the residue taken up in water and extracted into chloroform. The chloroform extract was dried (Na2SO4)/the solvent evaporated in vacuo and the residue distilled to give N-acetyl-4-(2,2-diethoxyethoxy)piperidine (61.5 g), m.p. 142-145°C/3 mm., characterized by n.m.r.

(B) Preparation of N-acetyl-4-(2-hydroxyethoxy)piperidine

N-acetyl-4-(2,2-diethoxyethoxy)piperidine (12 g) in 0.5N hydrochloric acid

(50 ml) was stirred overnight at room temperature. The solution was saturated with sodium chloride and extracted several times with chloroform (total 500 ml). The chloroform extract was dried (Na2SO4)

and the solvent evaporated in vacuo and with a bath temperature of 30°C. The resulting intermediate aldehyde (9.8 g) was reduced immediately with sodium borohydride (0.75 g) in ethanol (75 mL) at pH 6. After 3 hours of stirring at room temperature, the reduction was complete. Water was then added to the stirred solution and the organic solvent evaporated in vacuo. The residue was taken up in water (30 mL), extracted with chloroform (10 x 30 mL), the combined chloroform extracts dried (Na 2 SO 4 ) and the solvent evaporated in vacuo. The residue was taken up in water (70 ml) and washed with petroleum ether (2 x 10 ml). The aqueous phase was concentrated to give N-acetyl-4-(2-hydroxyethoxy)piperidine (6.9 g) which was characterized spectroscopically. A sample was distilled and had a boiling point of 139-140°C/0.3 mm.

Analysis %:

Found: C, 57.5; H, 9.1; N, 7.6

Calcd for C9H17N03: C, 57.8; H, 9.1; N, 7.5

(C) 4-(2-Cyclopentyloxyethoxy) piperidine

N-acetyl-4-(2-hydroxyethoxy)piperidine (5.0 g) in DMF (25 mL)

was added dropwise to a stirred suspension of sodium hydride (1.28 g, 50% dispersion in mineral oil) in dry DMF (50 mL) under a nitrogen atmosphere. After foaming had ceased, cyclopentyl mesylate (4.4 g) (tetrahedron 1972, _28, 2469) in DMF (10 ml) was added slowly and the mixture stirred at room temperature - for 40 hours. Additional amounts of sodium hydride (0.64 g) and then cyclopentyl mesylate (2.2 g) were added and the mixture stirred at 60°C for 7 hours and then room temperature for 64 hours. Isopropanol was added, the mixture filtered and the filtrate concentrated in vacuo. The residue in ethanol (30 ml) and 5N sodium hydroxide solution (30 ml) was heated under reflux for 3 hours. The ethanol was removed in vacuo, the residue diluted with water and extracted with chloroform. The chloroform extract was dried (Na 2 SO 3 ), the solvent evaporated in vacuo, then the residue treated in chloroform with ethereal hydrogen chloride. The solvent was decanted and the residue triturated with ether to give 4-(2-cyclopentyloxyethoxy)piperidine hydrochloride as a gum. The product contained some 4-(2-hydroxyethoxy) piperidine impurities but was used directly.

Example Q

Preparation of 4-(2-p-fluorophenoxyethoxy) piperidine

A solution of N-cetyl-4-(2-hydroxyethoxy)piperidine (5.0 g), trifonylphosphine (8.4 g), diethyl azodicarboxylate (5.6 g) and p-fluorophenol (3.36 g) in freshly distilled tetrahydrofuran (75 mL) was stirred in an ice bath for two hours and then allowed to stand at room temperature for 48 hours. The solvent was evaporated in vacuo, the residue taken up in chloroform and washed twice with IN sodium hydroxide solution and twice with water, dried (Na 2 SO 4 ) and the solvent evaporated in vacuo. The residue was taken up in the minimum volume of reflective ether and then set aside for cooling in a refrigerator. The precipitated solid was collected, the filtrate evaporated and the residue taken up in ether and set aside for cooling. The precipitated solid was again removed, the filtrate evaporated and the residue extra-hardened with refluxing petroleum ether (60-80°C, 5 x 100 ml). The solvent was evaporated in vacuo and the residue was heated under reflux for 5 hours in ethanol (50 ml ) as sodium hydroxide solution (50 mL), then neutralized with 2N hydrochloric acid and the organic solvent evaporated. The aqueous residue was acidified to pH 12 with 2N hydrochloric acid, extracted twice with ether. The aqueous phase was basified to pH 12 with 2N sodium hydroxide solution and then extracted with chloroform (3 x 100 ml).

The combined chloroform extracts were dried (Na 2 SO 4 ) and the solvent evaporated in vacuo to give 4-(2-p-fluorophenoxyethoxy) piperidine (1.3 g).

A sample of this product in chloroform was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride and had a m.p. 144 - 145°C.

Analysis %:

Found : C, 56.1; H, 6.8; N, 5.5 Calcd for C13HlgFN02.HC1: C, 56.6; H, 6.9; N, 5.1

Examples R - U

The following piperidine derivatives were prepared by a similar method as in example Q from N-acetyl-4-(2-hydroxyetosky)piperidine and the corresponding phenol.

Example V

Preparation of 4-[2-(4-piperidyloxy)ethoxy]benzamide

N-acetyl-4-(2-hydroxyethoxy)piperidine (1.0 g), 4-hydroxybenzamide (0.82 g), diethyl azodicarboxylate (1.12 g) and triphenylphosphine (1.68 g) in tetrahydrofuran (30 mL) was stirred at room temperature for 6 6 hours. The precipitated solid was collected and dried to give 4-[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide (0.72 g), m.p.

154 - 155°C.

Analysis %:

Found: C, 62.7; H, 7.1; N. 9.1 Calculated for C16H22N204: C'62'7'H'7'2'N'9.2

4[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide (4.3 g) in ethanol (60 mL), water (30 mL) and 2N hydrochloric acid (10 mL) was heated under reflux for 24 h and the solvent then evaporated in vacuo. The residue was taken up in water, extracted 3 times with chloroform, the aqueous phase adjusted to pH 12 with sodium carbonate solution and extracted 3 times with chloroform. Pooled chloroform extracts were discarded, the aqueous phase was saturated with sodium chloride, extracted with chloroform, the chloroform layer dried (Na 2 SO 4 ) and the solvent evaporated in vacuo to give 4-[2-(4-piperidyloxy)ethoxy]benzamide (0.36 g) . The aqueous phase was concentrated in vacuo and the remaining solid extracted with refluxing ethyl acetate (200 mL).

The solid was removed by filtration and the filtrate evaporated in vacuo which gave additional 4-[2-(4-piperidyloxy)ethoxy] benzamide (0.30 g) identical to that obtained above. A sample of this product in chloroform/methanol was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride, then recrystallized from ethyl acetate/isopropanol, m.p. 244 - 246°C and characterized spectroscopically.

Example W

I Preparation of 3-[2-(4-piperidyloxy]ethoxy)benzamide

N-acetyl-4-(2-hydroxyethoxy)piperidine (5.0 g), 3-hydroxybenzamide (4.4 g), diethyl azodicarboxylate (5.6 g) and triphenylphosphine (8.4 g) in dry tetrahydrofuran (100 ml) were stirred at 0°C for 2 hours and then at room temperature for 64 hours. The solvent was evaporated in vacuo, and the residue then treated with refluxing ether (3 x 100 ml) and the mother liquors decanted. ° The rest of the oil was taken up in chloroform and washed with dilute sodium hydroxide solution (40 ml) and water (40 ml). The chloroform layer was dried (MgSO 4 ) and the solvent then evaporated in vacuo. The residue was treated with ether (50 mL) and set aside in the freezer. The resulting solid was collected, slurried with ether (30 mL), filtered and the solid washed with ether (30 mL) to give 4-[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide (3.7 g) containing some triphenylphosphine oxide (about 25% according to n.m.r.).

The product in ethanol (48 ml), water (24 ml) and 2N hydrochloric acid (8 ml) was heated under reflux for 24 hours and the ethanol then evaporated in vacuo. The aqueous residue was extracted with ether (2 x 100 ml), then chloroform (100 ml), then the aqueous phase was adjusted to pH 12 with sodium hydroxide solution and extracted with chloroform (2 x 100 ml). The organic layer was dried (MgSO 4 ) and the solvent evaporated in vacuo to give 3-[2-(4-piperidyloxy)ethoxy]benzamide (0.55 g). The aqueous phase was saturated with sodium chloride and extracted with chloroform (3 x 100 ml). The combined chloroform extracts were dried (MgSO 4 ) and the solvent evaporated in vacuo which gave a further yield of 3-[2-(4-piperidyloxy)ethoxy]benzamide (0.26 g) identical to that obtained above. This sample was characterized as the hydrochloride salt by treating an ethanol solution with ethereal hydrogen chloride, m.p. 144 - 146°C.

Analysis %:

Found C, 56.0; H, 7.2; N, 9.2 Calculated for cl4H2o<N>2°3'<H>C1: C'55-9'H'1N' 9-3

Claims (3)

.1. Analogous procedure for the preparation of a compound of the formula: where R is lower alkyl, and X is a group with the formula -O-alk-OR <1> where "alk" represents an ethylene group optionally substituted with one or two lower alkyl groups, and R"<1>" is hydrogen, lower alkyl C., -Cg cycloalkyl, or a group of the formula wherein R 2 and R 3 each independently represent hydrogen, lower alkyl, lower alkoxy, halogen CF-., -CONR 4 R5 4 5 4 5 or -SC^NR R , where R and R each independently represent enters hydrogen or lower alkyl; and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting a compound with the formula where R is as defined above and Q is a reactive leaving group such as chlorine, bromine, iodine, lower alkoxy, lower alkylthio or lower alkylsulfonyl, with a piperidine of the formula where X is as above, optionally that the product of formula (I) is then transferred to a pharmaceutically tolerable acid addition salt by treatment with a non-toxic acid. 2. Method according to claim 1, characterized in that starting materials are used in which R is CH^ t X is CH3 CH3 -OCI^-CH^ OR <1> , -OCI^-CHOR <1> or -OCI^-C-OR <1> , and R 1 is H, C^- CH3 alkyl, cyclogentyl, phenyl optionally substituted with lower alkyl, lower alkoxy, halogen, trifluoromethyl or carbamoyl. 3. Process according to claim 1, characterized in that starting materials are used where R is CH_, "alk" is -CH2 CH2 -, and R 1 is C2 H5 or Cgl^ .