NO179580B - Intermediate for the preparation of optically pure aromatic amine compounds - Google Patents

Description

The present invention provides a compound which is useful for the preparation of aromatic derivatives substituted with an amino group and with various ester, amine or amide functions, as well as their enantiomers.

Application No. 90.4802 - from which the present application is divided - relates to a method for obtaining compounds that can be enantioselective and used therapeutically, and more particularly in pathological phenomena that infect the neurokinin system such as: pain (D. Regoli et al., Life Scuences, 1987, 40, 109-117), allergy and inflammation (J.E. Morlay et al., Live Sciences, 1987, 41, 527-544), circulatory failure (J. Losay et al., 1977, Substance P, Von Euler, U.S. and Pernow ed., 287-293, Raven Press, New York), gastrointestinal problems (D. Regoli et al., Trends Pharmacol. Sei.,

1985, 6, 481-484), respiratory problems (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50).

Endogenous ligands for neurokinin receptors have been described, such as substance P (SP), neurokinin A (NKA) (S.J. Bailey et al., 1983, Substance P, P. Skrabanck ed., 16-17 Boole Press, Dublin) and neurokinin B (NKB) (S.P. Watson, Life Sciences, 1983, 25, 797-808).

The neurokinin receptors have been recognized in numerous preparations and are currently classified as 3 types: NK1, NK2 and NK3. While most of the preparations that have been studied so far have several types of receptors, such as guinea pig ileum (NK, NK2 and NK3),

some of them have only one, such as dog carotid artery (NK1), rabbit pulmonary artery without endothelium (NK2) and rat portal vein (NK3) (D. Regoli et al., Trends Pharmacol. Sei., 1988,

9, 290-295 and Pharmacology, 1989, 38, 1-15).

A more accurate characterization of different receptors is made possible by the synthesis of selective antagonists. Thus, [Sar<9>, Met-(02)<11>] SP, [Nie<1>0]NKA4_10 and [Me Phe7]-NKB will present a selectivity respectively for the receptors NK1, NK2 and NK3 (cf. D. Regoli , 1988 and 1989 mentioned above).

In and with said application no. 90.4802, it was found that certain aminated aromatic compounds have interesting pharmacological properties, as they are antagonists against neurokinin receptors and are particularly useful for the treatment of any substance P pathology and neurokinin dependence.

Thus, the present invention relates to a compound for the production of a compound of formula (I) as mentioned in application no. 9 0.4802, namely an optically pure compound of formula (XXI*), and its salts with mineral acids or organic acids as stated in the characteristic of the claim.

This compound can be prepared by treating a compound with formula:

in a solvent such as dioxane, in an acidic environment, e.g. in the presence of hydrochloric acid, to obtain the amino acid of formula: which is esterified in an alkanol AlkOH, where Alk is an alkyl with from 1 to 4 carbon atoms, in an acidic environment, the corresponding ester is treated with formula: whereAlk, Q, Ar <1>, R° and m are as defined above, either with a functional derivative of an acid of formula: or with an iso(thio)cyanate of formula: Z and W being as defined above, to obtain the ester with the formula: which is then reduced to the corresponding alcohol with formula:

where m, Q, T, Ar<1>, R° and Z are as defined above, in optically pure form. These connections are new.

The alcohol (V*) can be converted into a methane sulfate derivative with the formula:

The compounds of formula (XVII*) are known and can be easily prepared by the method described by G. Helmchen et al., Angew. Chem. Int Ed. Eng., 1979, 1, 18, 65; according to the following form:

The following examples illustrate the invention.

Example 1

(+) N[4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride. SR 47050 A.

The optical rotation capability of the compound below is measured at 25°C.

A) N-(1-phenylethyl)-(3-(tert-butoxycarbonylaminomethyl)-3,4-dichlorobenzenepropanamide).

Step 1

In a three-necked flask of 2 litres, treated with nitrogen, 39.6 ml of diisopropylamine in solution in 200 ml of anhydrous THF are added. Cool to -60°C and add at this temperature in the following order:

17 6 ml of a 1.6 M solution of butyllithium in hexane,

50 g of 3,4-dichlorobenzeneacetonitrile in 300 ml of THF, so

39.4 ml tert-butyl bromoacetate in 100 ml THF.

It is allowed to return to a temperature of 0°C for 2.5 hours. The mixture is poured onto 3 liters of aqueous solution saturated with ammonium chloride. It is extracted twice with ether, dried over magnesium sulfate, and the solvents are evaporated. The oil obtained is chromatographed on 1 kg of silica H. Elution with a cyclohexane/ethyl acetate mixture: 95/5. 44.3 g of tert-butyl-jØ-3,4-cyanodichlorobenzenepropanoate is thus obtained.

sm.p. = 67°C.

Step 2

A mixture of 40 g of the product obtained above (step 1), 700 ml of absolute ethanol, 200 ml of concentrated ammonia (20%) and 3 spaces of Raney nickel is stirred under a hydrogen atmosphere for 5 hours. After filtering the catalyst and evaporating the solvents, 38.8 g of tert-butyl-jØ-3,4-aminomethyldichlorobenzenepropanoate are obtained in the form of an oil.

Step 3

A solution of 23.5 g of the product obtained above (step 2) in 150 ml of dichloromethane is cooled to -10°C. 250 ml of trifluoroacetic acid is added, then the temperature is allowed to rise to 20°C for 1.5 hours.

After removal of the solvents, 27 g of /3-3,4-aminomethyldichlorobenzenepropanoic acid trifluoroacetate are obtained in the form of an oil.

Step 4

To 27 g of the product obtained above (step 3) in solution in 150 ml of water, add 150 ml of dioxane, then 30 ml of triethylamine, then a solution of 23 g of di-tert-butyl dicarbonate in 50 ml of dioxane. It is heated at 100°C for 1 hour. Dioxane is removed under vacuum, and the resulting solution is washed with isopropyl ether. The aqueous phase is poured onto 1.5 liters of phosphate buffer solution pH = 2. After extraction with ether and drying on magnesium sulfate, the solvents are evaporated. The oil obtained is crystallized in isopropyl ether, which gives 20.3 g of /3-(tert-butoxycarbonylaminomethyl)-3,4-dichloro-benzenepropanoic acid.

Step 5

To 10 g of the product obtained above (step 4) in solution in 150 ml of dichloromethane is added in the following order:

- 8 ml triethylamine,

3.5 g of S(-)α-methylbenzylamine

14 g BOP (benzotriazolyl-N-oxytrisdimethylaminophosphonium hexafluorophosphate).

After stirring at room temperature for 1 hour, wash with water, then with a phosphate buffer solution pH = 2, then with an aqueous solution saturated with sodium bicarbonate. It is dried over magnesium sulfate, the solvents are removed under vacuum to obtain 12 g of [N-(1-phenylethyl)]/3(tert-butoxycarbonylaminomethyl)-(3,4-dichlorobenzene-propanamide.

B) Methyl ester of f3-(2,4-dichlorobenzoylaminomethyl)-3,4-dichloro-benzenepropanoic acid (+).

Step l

Separation of the diastereoisomers of [N-(1-phenylethyl)]/3-tert-butoxycarbonylaminomethyl-3,4-dichlorobenzenepropanamide.

The crude product is a mixture of two diastereoisomers. They are separable by thin-layer chromatography. It is separated in a preparative manner by means of chromatography on 400 g of silicon dioxide H by eluting with a mixture of toluene/ethyl acetate: 80/20. The least polar isomer comes out first, and 5.8 g is recovered.

sm.p. = 146-147°C.

[α]D = -43.6° (c=1 chloroform).

Step 2

A solution of 5 g of the product obtained above in 10 ml of dioxane and 50 ml of 6 N hydrochloric acid is heated under reflux overnight. After cooling the solution, wash with ether, then progressively neutralize the aqueous phase with solid sodium bicarbonate to pH = 7. A precipitate is thus obtained which is filtered, washed with water, with isopropanol, then with ether. After drying, 1.88 g of β-aminomethyl-3,4-dichlorobenzenepropanoic acid is obtained.

sm.p. = 202-204°C.

Step 3

To a suspension of 1.85 g of the product obtained above (step 2) in 20 ml of methanol cooled to -20°C under nitrogen, 1.10 ml of thionyl chloride is added, then the temperature is allowed to rise to 20°C. 2 hours later, 200 ml of ether is added, the product which has crystallized is filtered and washed with ether. After drying, 2.15 g of (-) methyl-^-aminomethyl-3,4-dichlorobenzene-propanoate are obtained.

sm.p. = 184-186°C.

[α]D = -4.3° ( c = 1 in methanol).

Step 4

To a solution of 2.0 g of the product obtained above (step 3) and 1.5 g of triethylamine in 20 ml of dichloromethane cooled to 0°C, a solution of 2,4-dichlorobenzoyl chloride (1.54 g) in 5 ml of dichloromethane. 5 minutes later, the solution is concentrated to dryness, water is added and extracted with ethyl acetate. The residue obtained is further crystallized in isopropyl ether. 2.72 g of (+)methyl-[3-(2,4-dichlorobenzoylaminoethyl)benzenepropanoate are thus obtained.

sm.p. = 105-107°C.

[a]D = + 26.6° (c = 1 in chloroform).

C) Methyl ester of (-)-0-(2,4-dichlorobenzoylaminomethyl)-3,4-dichloro-benzenepropanoic acid.

Step 1

By proceeding as described in example 1 B) step 1, the most polar isomer is recovered by eluting with a mixture of toluene/ethyl acetate: 80/20, then 60/40. Concentration of the fractions affords 5.4 g of [N-(1-phenylethyl)]/?-(tert-butoxycarbonylaminomethyl)-3,4-dichlorobenzenepropanamide.

sm.p. = 161-162°C.

[α]D = -18.4° (c = 1 in chloroform).

Step 2

By proceeding as described in example 1 b) step 2, /3-aminomethyl-3,4-dichlorobenzenepropanoic acid is prepared.

sm.p. = 202-204°C.

Step 3

By proceeding as described in example 1 B) step 3, ( + ) methyl β-aminomethyl-3,4-dichlorobenzenepropanoate is prepared.

sm.p. = 184-185°C.

[α]D = + 3.9° (c=1 methanol).

Step 4

By proceeding as described in example 1 B) step 4, one prepares (-) methyl-γS-(2,4-dichlorobenzoylaminomethyl-3,4-dichlorobenzenepropanoate).

sm.p. = 108-109°C.

[a]D = -21.1° (c = 1 in chloroform).

D) Reduction of the methyl esters of /3-(2, 4-dichlorobenzoylaminomethyl)-3,4-dichlorobenzenepropanoic acid (+) or (-).

A 0.5 M solution of calcium borohydride in THF is first prepared by stirring a suspension of sodium borohydride (0.1 mol) and calcium chloride (0.05 mol) in 100 ml of THF for 3 hours. 13 ml of this solution is then added to a solution of 2.5 g of the methyl ester of /3-(2,4-dichlorobenzoylaminomethyl)-3,4-dichlorobenzenepropanoic acid (+) or (-) in 20 ml of THF . It is left to stir overnight. The following day, the solution is cooled to 0°C, then hydrolysed with water, then with dilute hydrochloric acid. After extraction with ether, (+) or (-) alcohol is obtained, practically pure in the form of an oil.

E) Preparation of derivative mesylates: (+) or (-) (2,4-dichlorobenzoylaminomethyl)-T-3,4-dichlorobenzenepropanol methane sulfonate.

1.3 g of the alcohol obtained above is brought into solution in 30 ml of dichloromethane, then 0.5 ml of triethylamine and 0.3 ml of mesyl chloride are added to the solution which has been cooled to 0°C. The reaction mixture is stirred at 0°C for 45 minutes, washed three times with ice water, decanted, dried over magnesium sulfate and concentrated under vacuum.

The residue is chromatographed on silica gel, eluent: ethyl acetate/pentane 60/40. The pure fractions are concentrated under vacuum. In this way, a residue is obtained from the (+) ester which is recrystallized with isopropyl ether to obtain 1.1 g of (+) (2,4-dichlorobenzoylaminomethyl)-t-3,4-dichlorobenzenepropanol methanesulfonate.

sm.p. = 74-77°C

[a]D = + 21.2° (c = 1 in chloroform).

In this way, starting from the (-) ester by proceeding as above, (-) (2,4-dichlorobenzoylminomethyl)-t-3,4-dichlorobenzene-propanol methanesulfonate is obtained.

sm.p. = 72-76°C.

[a]D = -22.5° (c = 1 in chloroform).

F) Preparation of (+) N[4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride. SR 47050.

A. 0.6 g of (+) mesylate obtained above and 0.54 g of benzyl-4-piperidine are brought into solution in 1 ml of dimethylformamide, and the reaction mixture is heated at 60°C for 30 minutes. Water is added and extracted with ethyl acetate. The organic phase is concentrated under vacuum, and the residue is chromatographed on silica gel. Eluent: dichloromethane/methanol: 97/3.

The fractions of the pure product are concentrated under vacuum, the residue diluted in dichloromethane and addition of hydrochloric acid ether makes it possible to obtain the hydrochloride.

m = 0.5 g.

[a]D = + 14.0° (c = 1 in chloroform).

Example 2

N[4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride (-). SR 47051 A.

By proceeding in the same way as above (according to example 1 F)), but by using as starting product the (-) isomer of mesylate, SR 47051 A is obtained.

[a]D = -14.5° (c = 1 in chloroform).

Example 3

By proceeding as described in example 1 above, one produces:

N[4-(4-benzyl-1-piperidinyl)-2-(3,4-difluorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride (-). SR 47243 A.

[a]D = -8.5° (c = 1 in chloroform).

Example 4

By proceeding as described in example 1 above, one produces:

(+) N[4-(4-benzyl-1-piperidinyl)-2-(3,4-difluorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride. SR 47238 A.

[a]D = +7.3° (c = 1 in chloroform).

Example 5

(+) and (-) N[4-(4-benzyl-1-piperidinyl)-2-(3,4-dichloro-phenyl)butyl]4-fluoro-1-naphthalenecarboxamide hydrochloride.

Step 1

1-amino-2-(3,4-dichlorophenyl)-4-hydroxybutane.

150 ml of a solution saturated with hydrochloric acid ether is added to 149 g of 4-(2-tetrahydropyranyloxy)-2-(3,4-dichlorophenyl)-1-aminobutane in solution in 700 ml of methanol. The mixture is stirred for half an hour at room temperature, concentrated under vacuum, and the residue is taken up in 500 ml of water and washed with ether. The aqueous phase is made alkaline with a solution of sodium hydroxide and extracted twice with dichloromethane. The organic phases are dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is taken up in 400 ml of isopropyl ether, and the mixture is stirred for 1 hour at room temperature. The precipitate is filtered and washed with ether.

m = 98.2 g.

sm.p. = 90.91°C.

Step 2

The (+) enantiomer of 1-amino-2-(3,4-dichlorophenyl)-4-hydroxy-butane.

To 59.65 g of D(-) tartaric acid in solution in 2 liters of methanol heated under reflux is added 93 g of the racemic mixture, prepared above according to step 1, in solution in 300 ml of methanol. It is allowed to return to room temperature, the crystals are filtered, washed with methanol and dried under vacuum at 50 °C on P2O5.

m = 64, 8 g

[a]D = -5.2° (c = 1 in water).

It is then recrystallized in 2.96 liters of methanol, the crystals are filtered and washed in methanol and dried under vacuum at 50°C on P2O5.

m = 45.3 g

[or]D = -4.5° (c = 1 in water)

sm.p. = 201°C.

The D(-) tartaric acid is taken up in 250 ml of water, made alkaline with a concentrated solution of sodium hydroxide and extracted with 3 times 200 ml of dichloromethane, washed with a solution saturated with sodium chloride, decanted, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is taken up in isopropyl ether, the mixture is stirred for 1 hour at room temperature, the crystals are filtered and washed with isopropyl ether.

m = 24.7 g

[a]D = +9.0° (c = 1 in methanol)

sm.p. = 79.80°C.

The (-) enantiomer of 1-amino-2-(3,4-dichlorophenyl)-4-hydroxy-butane.

By proceeding as before and using L(+) tartaric acid, the (-) enantiomer is obtained.

[a]D = -9.2° (c = 1 in methanol)

sm.p. = 79-80°C.

Step 3

N[2-(3,4-dichlorophenyl)-4-mesyloxybutyl]4-fluoro-1-naphthalene-carboxamide (-) enantiomer).

4.45 g of 4-fluoronaphthoic acid chloride in solution in 50 ml of dichloromethane is added drop by drop at -60°C to a solution of 5 g of the product obtained before the (+) enantiomer in 100 ml of dichloromethane in the presence of 2.6 g of triethylamine. The mixture is stirred for 15 minutes at -60°C and the temperature is allowed to rise to -30°C. 2.5 g of triethylamine and 2.7 g of mesyl chloride are then added and allowed to return to room temperature. Wash with water, dry the organic phase over magnesium sulphate and concentrate under vacuum. The residue is chromatographed on silica gel, eluent: dichloromethane/methanol 99.5/0.5.

The pure fractions are concentrated under vacuum,

m = 8, 4 g

[α]D = -22.8° (c=1 methanol).

N-[2-(3,4-dichlorophenyl)-4-mesyloxybutyl]4-fluoro-1-naphthalene-carboxamide (+) enantiomer.

The (+) enantiomer is obtained by proceeding as described above in step 3, but by using the (-) enantiomer from step 2.

[α]D = +22.7° (c = 1 in methanol).

Step 4

N-[4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl]4-fluoro-1-naphthalenecarboxamide. (-) enantiomer SR 48225 A. 7 g of the (-) enantiomer obtained in step 3 and 5.02 g of 4-benzyl-piperidine are brought into solution in 15 ml of dimethylformamide and the reaction mixture is heated at 70°C for 2 hours. The mixture is poured onto water, extracted with ethyl acetate, the organic phases are washed with a solution saturated with sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel, eluent: dichloromethane/methanol 97/3.

The fractions of the product are concentrated under vacuum, the residue is diluted in dichloromethane, and the addition of hydrochloric acid ether makes it possible to obtain the hydrochloride.

m = 6.2 g

[α]D = -3 5.5° (c=1 methanol).

(+) enantiomer. SR 48226 A.

By proceeding in the same way as for the (-) enantiomer prepared above, but by using the (+) enantiomer obtained in step 3, one obtains the (+) enantiomer.

m = 7 g

[α]D=+36.0° (c = 1 in methanol).

Claims (1)

Compound, useful for the preparation of an optically pure compound of formula (I*): where: m is 2 or 3; the carbon atom bonded to Q and Ar may have a specific or (-) configuration, Ar and Ar<1> independently represent a thienyl group; a phenyl group, unsubstituted, mono- or disubstituted with a halogen atom, with C 1 -C 1 alkyl, with trifluoromethyl, with alkoxy, in which the alkyl is C 1 -C 1 , with hydroxyl, with methylenedioxy; an imidazolyl group; wherein Ar' can also be a benzothienyl group, unsubstituted or substituted by halogen; a naphthyl group, unsubstituted or substituted by halogen; a biphenyl group; an indolyl group, unsubstituted or substituted on the nitrogen with a benzyl group; X represents hydrogen; - X<1> represents hydrogen, a hydroxyl group or is united with X<11> below to form a carbon-carbon bond; or X and X<1> together form an oxo- or dialkylamino-alkyloxyimino group with the formula =N-0-(CH2) p-Am, where p is 2 or 3 and Am is a dialkylamino group, each alkyl can contain from 1 to 4 carbon atoms; Y represents a nitrogen atom or a group Z(X<*>') where X'' is hydrogen or together with X<1> forms a carbon-carbon bond; Q represents hydrogen, a C 1 -C 4 -alkyl group or an amino-alkyl group of the formula -(CH 2 )q-Am', where g is 2 or 3 and Am' is a piperidine, 4-benzylpiperidine or dialkylamino group, wherein each alkyl may contain from 1 to 4 carbon atoms; R represents hydrogen, a methyl group or a group (CH2)n-L, where n is an integer from 2 to 6 and L is hydrogen or an amino group, - T represents a group selected from W being an oxygen or sulfur atom, and Z represents either hydrogen or M or OM when T represents the group or M when T represents the group M represents hydrogen or straight or branched C 1 -C 6 alkyl; phenylalkyl in which the alkyl group comprises from 1 to 3 carbon atoms, unsubstituted, mono- or polysubstituted on the aromatic ring with halogen, hydroxy, alkoxy with from 1 to 4 carbon atoms, alkyl with from 1 to 4 carbon atoms; pyridylalkyl in which the alkyl group comprises from 1 to 3 carbon atoms; naphthylalkyl in which the alkyl group comprises from 1 to 3 carbon atoms; pyridylthioalkyl in which the alkyl group comprises from 1 to 3 carbon atoms; styryl; (1-methyl)-2-imidazolylthioalkyl in which the alkyl group comprises from 1 to 3 carbon atoms; 1-oxy-3-phenylindan-2-yl; an aromatic or heteroaromatic group, unsubstituted, mono- or polysubstituted; or one of their salts with inorganic or organic acids, characterized in that it has formula (XXI<*>): where: denotes that the carbon atom with this label has a particular (+) or (-) configuration; P is hydrogen or -SO 2 CH 3 ; m is 2 or 3; Ar<1>, Q, R°, T and Z are as stated above, - or one of its salts with mineral acids or organic acids.