HUT73189A - Process for producing amino- and amino-methyl-tetraline derivatives - Google Patents

Abstract

The present invention relates to a compound of formula (I) wherein A is a bond between -COOR 'and a tetralin ring, or a C1-C4 alkylene or C2C4 alkenylene group, R' is a C4-C4 alkyl group and n is a 0 or 1 with the proviso that when n is 0 and the group -A-COOR 'is in the 6 or 7 position, then A is other than a methylene group, and its salts and their N-protected derivatives. The compounds of formula (I) are useful for the preparation of pharmaceutical compounds.

Description

This invention relates to novel amino and aminomethyltetralin derivatives. The compounds are useful intermediates for the preparation of the corresponding phenylethanolamino or phenylethanolaminomethyl-tetralin derivatives.

According to the present invention, the compounds of the formula I and their salts and N-protected derivatives

THE represents a bond between -COOR 'and the tetralin ring, or C 1 -C 4 alkylene or C 2 C 4 alkenylene, R is C1-C4 alkyl, and n value is 0 or 1 -

with the proviso that when n is 0 and the group -A-COOR 'is in the 6 or 7 position, then A is other than methylene by

- for the preparation of compounds of formula I wherein A is a bond between -COOR 'and a tetraling ring, an aldehyde of formula II wherein P is a suitable amino protecting group introduced temporarily and P' is hydrogen or P and P 'are taken together to form a phthalimido group, then the free carboxyl group is esterified and optionally deprotected;

- reacting an aldehyde of formula (II) as defined above with 2- (trimethylsilyl) ethoxymethyl-triphenylphosphonium chloride to prepare compounds of formula (I) wherein A is methylene; The compound of formula (III) is reacted with tetraalkylammonium fluoride, then the resulting compound of formula (IV) is oxidized, the resulting free carboxyl group is esterified and optionally deprotected;

- preparing a compound of formula (I) wherein A is C2-C4 alkenylene, reacting a compound of formula (II) or (IV), as defined above, with a Wittig reagent that already contains a COOR 'group, and In this case, the protecting group is removed and the resulting compound is optionally reduced to form compounds of formula I wherein A is C2-C4 alkylene.

In the present invention, C 1 -C 4 alkyl, C 1 -C 4 alkylene groups denote monovalent and divalent groups and may be straight or branched C 1 -C 4 hydrocarbon groups. The C 1 -C 4 alkyl group is preferably methyl or ethyl, while the C 1 -C 4 alkylene group is preferably methylene, ethylene or propylene, which may be optionally substituted with a methyl group.

C2-C4 alkenylene is a divalent straight or branched C2-C4 hydrocarbon containing a double bond.

C2-C4-alkenylene is preferably vinylene or 1,3-propylene.

Tetralin is the abbreviation for 1,2,3,4-tetrahydronaphthalene.

Salts of the compounds of formula I according to the invention are addition salts with pharmaceutically acceptable mineral or organic acids such as hydrochlorides, hydrobromides, sulphates, hydrogen sulphates, dihydrogen phosphates, cyprates, maleate, tartrates, fumarates, gluconates, naphthalene sulfonates as well as addition salts which allow easy separation or crystallization of the compound of formula I such as picrates, oxalates or addition salts with optically active acids such as camphorsulfonic acid, mandelic acid or substituted almond acid.

Chiral centers may also be present on substituent A. Further stereoisomers are possible by means of chiral centers, and the process for the preparation thereof and the mixture of isomers are also within the scope of the present invention.

Preferred compounds of formula (I) are those wherein A-COOR 'is attached at the 6- or 7-position of the tetraling ring and A is a bond between -COOR' and a tetraling ring or has two or three carbon atoms. alkylene or C 2 -alkenylene.

Compounds of formula (I) may be prepared from compounds of formula (II) wherein P is an amino protecting group temporarily introduced and P 'is hydrogen or P and P' together with the nitrogen atom to which they are attached represent a phthalimido group or the like.

The general formula (I) which contains a bond at the A site between the group -COOR 'and the tetraling ring • · · · ·

Compounds of formula 5 may be prepared by oxidation of compounds of formula II, esterification of the free carboxyl group, and deprotection.

Compounds of formula (I) wherein A is methylene may be prepared by reacting compounds of formula (II) with 2- (trimethylsilyl) ethoxymethyl-triphenylphosphonium chloride, followed by the reaction of the intermediate of formula (III) with tetraalkyl. with ammonium fluoride followed by the procedure described above using the compounds of formula (IV) as starting material.

Reaction of the aldehydes of formula (II) or (IV) with Wittig compounds having the substituent -COOR 'followed by deprotection yields compounds of formula (I) wherein R is C2-C4 alkenylene and R and n are as defined and the resulting product is reduced to a double bond to give compounds of Formula I wherein A is C2-C4 alkylene.

Compounds of formula (I) wherein A is branched may be prepared from the compounds of formula (I) thus obtained by: protecting the amino group by mono- or dimethylation at the α-position relative to -COOR '; the ester is then hydrolyzed and the Arndt-Eistert reaction is carried out to give the next higher carbon homologue, the carboxyl group • · · · · <

• «· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 6 is esterified and in each case the amino protecting group is removed; the compounds may also be prepared from the aldehydes of formula IV by blocking the -CHO group (e.g., by preparing Schiff's base such as tert-butylimino derivative), by mono or dimethylation at the α-position of the -CHO group; cleavage and reaction with the appropriate Wittig compound, and optionally reducing the double bond.

The type of protecting group depends on the aldehyde of formula (II) used and the reaction conditions.

When the compound of formula (II) is used in a reaction in which there are no highly acidic reaction conditions, it is preferable to use a teralkoxycarbonyl group such as a t-butoxycarbonyl group (BOC) or a t-amyloxycarbonyl group (AOC), preferably a BOC protecting group is used. Cleavage of protecting groups can be accomplished by acid hydrolysis in the art, in particular using trifluoroacetic acid or an alcoholic hydrochloric acid solution.

The substituted or unsubstituted benzyloxycarbonyl groups can also be used as protecting groups, which are then removed by catalytic hydrogenation, preferably using a Pd / C catalyst.

When highly basic reaction conditions are used, the amino group is generally protected in the form of a phthalimido derivative which is terminated after the reaction by treatment with hydrazine or an appropriately substituted hydrazine derivative.

Protected with a protecting group when required by the reaction conditions

Alternatively, an aldehyde of formula (II) can be used and the protecting group is replaced by another group which is cleaved as described above.

One skilled in the art will recognize which protecting groups may be used under the various reaction conditions (e.g.

D. Barton and W.D. Ollis, Comprehensive Organic Chemistry, Vol. 5, pp. 323-331).

The oxidation of the aldehyde of formula (II) to convert the -CHO group to the carboxyl group is generally carried out at room temperature using Jones reagent, a solution of chromic anhydride in dilute sulfuric acid. The reaction is generally carried out by adding the Jones reagent to a solution of the starting aldehyde in acetone. The acid thus obtained is isolated in a known manner and esterified by treatment with C 1 -C 4 alkyl chloroformate in the presence of tertiary amine, which is also used to bind the acid formed during the reaction. The reaction is preferably carried out at -10 ° C to + 10 ° C in an aprotic solvent such as a halogenated hydrocarbon. The amino protecting group is then removed in the usual manner. For example, if a BOC group is used in a preferred embodiment, this can be removed by treating the alcoholic solution of the protected product with 4N alcoholic hydrochloric acid.

The conversion of the aldehyde (II) to the aldehyde (IV) is conveniently carried out with a solution of the aldehyde (II) in 2-trimethylsilyl-ethoxymethyl-triphenylphosphonium chloride and an alkali metal alcoholate in an aprotic organic solvent. . · · ··· ··· ·

- _ · · · · · ··· ··········

8, the solvent may be an alkyl or cyclic ether such as tetrahydrofuran or dimethoxyethane. The intermediate of formula (III) is isolated in a known manner and then treated with tetraalkylammonium fluoride in a polar aprotic organic solvent, preferably containing a small amount of water.

The aldehydes of formula (II) and (IV) are then prepared by W.S.

Wadsworth and W.D. Emmons [J. Amer. Chem. Soc., 1961, 83, 173338], whereby the compounds are reacted with a carboxymethylphosphonate of the formula (EtO) 2P (O) CH (R) -COOR '- in which R is as defined and R is hydrogen, methyl or ethyl in the presence of a strong base such as an alkali metal hydride in an aprotic organic solvent such as dimethoxyethane or tetrahydrofuran.

If the group -COOR 'is not directly attached to the carbon atom of the phosphonate, the appropriate Wittig's reagent is Ph3P = CH-A'-COOR', where A 'is a C 1 or C 2 alkylene group and R' is as defined above. usually in the presence of a strong base such as sodium hydride or n-butyllithium in an aprotic solvent such as alkyl or cyclic ether.

By the methods described, compounds of formula I can be prepared wherein A is C ₂ -C ₄ -alkenylene and R 'is as defined. If desired, these compounds can be converted to the corresponding compounds wherein A is C2-C4 alkylene by reduction of the double bond. The reduction is conveniently carried out by catalytic hydrogenation at room temperature, conventional

- 9 pressures using Pd / C as hydrogenation catalyst. When a benzyloxycarbonyl group or a substituted benzyloxycarbonyl group is used to protect the amino group, the protecting group can be removed in one step.

If desired, monocarbon or dimethylation of the carbon at the position relative to the alkoxycarbonyl group can be carried out by treating the compound of formula (I) thus obtained with a methyl halide, usually methyl iodide, in the presence of a strong base. The compound thus obtained can then be converted to the next higher carbon homologue by basic hydrolysis of the group -COOR 'under basic conditions by the Arndt-Eister reaction (Bér., 1935, 68, 200) to convert the acid to the corresponding acid chloride. this is treated with diazomethane and the resulting compound is hydrolyzed in the presence of Ag2O, the carboxyl group is esterified and finally the amino protecting group is removed.

Prior to the methylation reaction, the -CHO group in the starting aldehyde of formula (IV) must be protected either by conversion to a Schiff base such as a t-butylimino derivative or by a primary amine such as tert-butyl. by reaction with an amine. The methylation can then be carried out as described, the aldehyde is recovered by mild acid hydrolysis, and the -CHO group is oxidized to the carboxyl group and then esterified; or reacting the aldehyde with a compound of Wadsworth and Emmons and optionally reducing the double bond as described.

* ·. · · · ·. .

•. . ·. ··: ···.

·· ·· · ♦ · · a «

If desired, racemic mixtures of the compounds of formula (I) obtained may be resolved into the pure isomers by diastereoisomeric salts of optically active acids such as camphorsulfonic acid or optionally substituted mandelic acid.

The ester may be hydrolyzed and the racemic mixture resolved into pure optical isomers by formation of diastereoisomeric salts with optically active bases such as α-alkylbenzylamines, menthylamine.

If the amine of formula (I) contains an additional chiral center, the diastereoisomers and pure isomers may be isolated as described above.

The aldehyde of formula (II) can be prepared from the corresponding 2-amino or 2-aminomethyl-5- or -6- or -7- or -8-hydroxytetralin in a four step process by first protecting the amino group, reacting the amine with trifluoromethanesulfonic anhydride to give the N-protected 2-amino or 2-aminomethyl-5- or -6- or -7- or -8-trifluoromethanesulfonyloxy-tetralin the corresponding N-protected 2-amino- or 2-aminomethyl-5 or -6- or -7- or -8-vinyl tetralin with [CH3 (CH2) 3] 3SnCH = CH2 in the presence of tetrakis (triphenylphosphine) palladium and The vinyl derivative is oxidized with an alkali metal periodate in the presence of an OSO4 catalyst.

The starting compounds of 2-amino- or 2-aminomethyl-5- or -6- or -7- or -8-hydroxytetralin are known and can be prepared in a known manner to produce isomeric aldehydes of the same absolute configuration.

• · · · you «

11 The pure isomers of the aldehydes of formula II are preferred.

The following examples illustrate the invention. The solvents in parentheses after the melting point values indicate the crystallization solvent.

Example 1

2-Amino-7- (2-ethoxycarbone 1) -vinyl tetralin hydrochloride

a) 2- (tert-Butoxycarbonylamino) -7- (trifluoromethanesulfonyloxy) tetralin

A mixture of 2-tert-butoxycarbonylamino-7-hydroxytetralin (24 g, 0.09 mol) and pyridine (50 mL) was cooled to 0 ° C under nitrogen and trifluoromethanesulfonic anhydride (16, 4 ml, 0.10 mol). The reaction mixture was allowed to stand for 10 minutes at 0 ° C and then allowed to rise to room temperature. After 2.5 hours, the reaction mixture was poured into water and extracted with ethyl ether. The organic layer was washed with 1N hydrochloric acid, water, dried over sodium sulfate and concentrated in vacuo.

The resulting dark oily product was purified by column chromatography over silica gel using petroleum ether / ethyl acetate 9: 1 as eluent. 25 g of the title compound are obtained. M.p. 87-89 ° C.

b) 2- (tert-Butoxycarbonylamino) vinyl tetralin

The product obtained in step a) (25 g, 0.063 mol), anhydrous dioxane (280 ml), tributyl vinyltin (19.3 ml, 0.066 mol), lithium chloride (8.141 g), Pd (PI 13 P) 4 (1.483 g) and some crystals of 2,6-di-tert-butyl-4-methylphenol under nitrogen at reflux for 3 hours. ··· "

- 12, then cool to room temperature. To the reaction mixture was added pyridine (32 mL) and 1N tetrabutylammonium fluoride in tetrahydrofuran (90 mL). The reaction mixture was allowed to stand at room temperature for 16 hours, ethyl ether was added and filtered through celite. The organic solution was washed with water, 1N hydrochloric acid, water, dried over sodium sulfate and evaporated to dryness. The resulting oily product was purified by silica gel column chromatography (eluent: cyclohexane: ethyl acetate = 9: 1). 10 g of 2- (tert-butoxycarbonylamino) vinyl tetralin are obtained, m.p. 104-105 ° C (isopropyl ether).

c) 7-Formyl-2- (tert-butoxycarbonylamino) tetralin

The compound obtained in step b) (2.5 g, 0.009 mol), sodium periodate (6 g), 2.5% osmium tetroxide solution in terbutanol (3.3 ml), tetrahydrofuran 60 ml) and water (20 ml) were stirred under nitrogen for 3 days at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The resulting dark oily product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 95: 5). The residual oily product solidifies on standing and is crystallized from isopropyl ether. Yield: 1.7 g.

d) 2- (tert-Butoxycarbonylamino) -7- (2-ethoxycarbonyl) -

-vinyl-tetralin% sodium hydride (0.6 g, 0.024 mol), ethyl diethyl · ··· ··········································································· ··· · * »« ··

- A mixture of 13-phosphonoacetate (4.8 mL) and dimethoxyethane (50 mL) was stirred at room temperature under nitrogen for 1 hour then slowly added dropwise to the compound of step c (3.4 g) in dimethoxyethane (65 mL) ). The reaction mixture was allowed to stand at room temperature for 4 hours, water was added and the reaction mixture was extracted with ethyl ether. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. This gave a yellow oil (3.1 g) which was purified by silica gel column chromatography (eluent: cyclohexane: ethyl acetate = 9: 1, then 8: 2).

Yield: 2.7 g.

110-111 ° C (isopropyl ether)

e) 2-Amino-7- (2-ethoxycarbonyl) vinyl tetralin hydrochloride

A solution of the compound obtained in step d) (2.7 g, 0.0078 mol) in absolute ethanol (50 ml) was treated with 4N hydrochloric acid (33 ml) in absolute ethanol at room temperature for 5 hours.

The reaction mixture was then concentrated in vacuo and the residue dried in an oven to give the title compound (2.05 g), mp 184-186 ° C.

Example 2

2 Amino-7- (2-ethoxycarbonyl) ethyl-tetralin hydrochloride

a) 2- (tert-Butoxycarbonylamino) -7- (2-ethoxycarbonyl) ethyl tetralin

Example 1 (d) (2.6 g, 0.075 mol), absolute ethanol (60 ml) and 5% Pd / C ··· ···

- 14 (0.26 g) was added to the hydrogenation vessel. Hydrogenation was continued at room temperature under normal pressure for 2.5 hours, then the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. This gave 2.2 g of 2- (tert-butoxycarbonylamino) -7- (2-ethoxycarbonyl) ethyl tetralin.

Melting point: 110-111 ° C.

b) 2-Amino-7- (2-ethoxycarbonyl) ethyl tetralin hydrochloride

A mixture of the compound obtained in the previous step (a) (2.1 g, 0.006 mol), absolute ethanol (40 ml) and 4N hydrochloric acid in absolute ethanol (25 ml) was reacted at room temperature for 5 hours. The resulting reaction mixture was concentrated in vacuo and the resulting white solid was dried in an oven to give 1.7 g of the title compound. Mp 162-164 ° C.

. example

2-Amino-7- (ethoxycarbonyl) tetralin hydrochloride

a) 7- (ethoxycarbonyl) -2- (tert-butoxycarbonylamino) -

tetralin

Example 1 (c) (1.55)

g) and acetone (15 mL) at 20 ° C were added Jones reagent (chromic anhydride solution in fresh sulfuric acid) (8 mL). After 5.5 hours, isopropanol was added to the reaction mixture, which was filtered. The filtrate is concentrated in vacuo, the residue is taken up in water and the aqueous solution is made basic with sodium hydroxide. The reaction mixture was extracted with ethyl ether, acidified with hydrochloric acid and extracted twice with ethyl ether. The organic extracts were combined, washed with water, sodium sulfate ···· ···> -. <· · -: -. *. ·· ·· ·.

The mixture is dried over anhydrous and evaporated in vacuo. 1.5 g of a yellow solid are obtained.

A mixture of the product thus obtained, methylene chloride (20 ml) and triethylamine (0.79 ml) was cooled to 0 ° C, and ethyl chloroformate (0.55 ml, 0.0057 mol) was added followed by After 5 minutes, dimethylaminopyridine (0.32 g). The reaction mixture was left at 0 ° C for 30 minutes, then poured into water and methylene chloride was added. The organic layer was separated and washed successively with aqueous sodium bicarbonate solution, 1N hydrochloric acid and water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography (eluent; cyclohexane: ethyl acetate = 9: 1 then 8: 2). Yield: 0.52 g.

¹ H-NMR (80 MHz, CDCl ₃ ): δ = 7.6 (m, 2H), 7 (m, 1H), 4.25 (q, 2H), 4.4 (1H, -NH-) , 3.8 (m, 1H), 1.3 (m, 12H).

b) 2-Amino-7- (ethoxycarbonyl) tetralin hydrochloride

The compound obtained in the previous step a) (0.5 g,

0.0016 mol) of absolute ethanol (10 ml) and 4N hydrochloric acid in ethanol (7 ml) were reacted for 24 hours at room temperature. The reaction mixture was concentrated in vacuo and the resulting pale yellow oil was solidified by treatment with isopropanol. The resulting solid was collected by filtration to give 0.29 g of the title compound.

¹ H NMR (80 MHz, DMSO-d 6) δ = 8.4 (-H ₂ , HCl), 7.6 (m, 2H), 7.1 (m, 1H), 4.2 (q, 2H) ), 1.3 (t, 3H).

Example 4 (2R) -2-Amino-7- (2-ethoxylcarbonylvinyl) tetralin hydrochloride

a) (2R) -7-Hydroxy-2- (tert-butoxybabanylamino) tetralin (2R) -2-amino-7-hydroxytetralin (9.4 g, 0.058 mol) in triethylamine (39 (5 mL, 0.28 mol) in anhydrous dimethylformamide (100 mL) was cooled to 0 ° C. To the resulting reaction mixture was added di-tert-butyl dicarbonate (13.6 g, 0.063 mol) and the reaction mixture was allowed to stand at room temperature for 2 hours. The reaction mixture was poured into water (500 mL) and extracted with ethyl ether, washed with water, dried and evaporated to dryness. The product was purified by flash chromatography eluting with cyclohexane: ethyl acetate 7: 3. 12.7 g of the title compound are obtained.

[α] _D ²⁰ = + 69.3 ° (c = 1%, MeOH).

b) (2R) -2- (tert-Butoxycarbonylamino) -7- (trifluoromethanesulfonyl-oxy) tetralin

A mixture of the compound obtained in the previous step (a) (12.4 g, 0.047 mol) and pyridine (25 ml) was cooled to 0 ° C under nitrogen and trifluoromethanesulfonic anhydride (8.5 ml) was added over 25 minutes. 0.052 mol) while maintaining the temperature between 0 and 5 ° C. The resulting reaction mixture was stirred at room temperature for 2.5 hours and then poured into water (400 mL). The reaction mixture is extracted with ethyl ether, the organic phase is dried, filtered and evaporated to dryness. The residue was purified by flash chromatography eluting with 85:15 cyclohexane: ethyl acetate. The collected fractions were evaporated and the resulting oily product cooled.

Yield: 15 g.

Mp 52-55 ° C.

[α] _D ²⁰ = + 48.3 ° (c = 1%, MeOH)

c) (2R) -2- (tert-butoxycabanylamino) -7-vinyl tetralin

Work up as in Example 1, step b, starting from the product of the previous step b).

Yield: 7 g.

89-91 ° C (isopropyl ether).

[q] _d 20 _{= + 40} ° _{(c = 0j 3} CH ₂ Cl ₂ ).

d) (2R) -7-Formyl-2- (tert-butoxycarbonylamino) tetralin

Work up as in Example 1, step c, using the product of step c) as the starting material and purify by flash chromatography eluting with 7: 3 hexane: ethyl acetate.

Yield: 4.9 g.

98-100 ° C.

[α] _D ²⁰ = + 41.5 ° (C = 0.3%, CH ₂ Cl ₂ ).

e) (2R) -7- (2-Ethoxycarbonyl) vinyl-2- (tert-butoxycarbonylamino) tetralin

The title compound (3.3 g) was prepared according to Step d) of Example 1, using the product of Step d) as starting material.

Mp 107-108 ° C.

[of] _D ²⁰ = + 35.2 ° (C = 0.3%, CH ₂ Cl ₂ ) ·

f) (2R) -2-Amino-7- (2-ethoxycarbonyl) vinyl tetralin hydrochloride

The title compound was prepared as in Example 1, step e), starting from the compound of the preceding step e).

M.p. 204-206 ° C.

[α] _D ²⁰ = + 52.3 ° (c = 1%, MeOH).

Example 5 (2R) -2-Amino-7- (2-ethoxycarbonyl) ethyl tetralin hydrochloride

a) (2R) -7- (2-Ethoxycarbonyl) ethyl-2- (tert-butoxycarbonylamino) tetralin

The title compound (0.7 g) was prepared according to Example 2 (a), starting from the compound obtained in Example 4 (e) (0.75 g, 0.0021 mol).

101-102 ° C.

[α] _D ²⁰ = + 30.3 ° (c = 0.3%, CH ₂ Cl ₂ ).

b) (2R) -2-Amino-7- (2-ethoxycarbonyl) ethyl tetralin-

hydrochloride

The title compound (0.4 g) was prepared according to Example 2 (b), starting from the preceding compound.

(a) (0.6 g, 0.0017 mol). 175-178 ° C (acetone).

[of] _D ²⁰ = + 45.6 ° (c = 0.3%, CH ₂ C1 _2).

Example 6 (2S) -2-Amino-7- (2-ethoxycarbonyl) -vinyl-tetralin hydrochloride

The title compound (m.p. 200-203 ° C, after crystallization from acetone) was prepared according to Example 4 using (2S) -2-amino-7-hydroxytetralin as starting material, via the following intermediates.

a) (2S) -7-Hydroxy-2- (tert-butoxycarbonylamino) tetralin [α] _D ²⁰ = + 62.4 ° (c = 1%, MeOH)

b) (2S) -2- (tert-Butoxycarbonylamino) -7- (trifluoromethanesulfonyloxy) tetralin [α] _D ²⁰ ₌ -43.10 ( _C = 1%, MeOH)

c) (2S) -2- (tert-Butoxycarbonylamino) -7-vinyl tetralin M.p .: 90-92 ° C (isopropyl ether).

[α] ²⁰ = -38.1 ° (c = 0.3%, ch ₂ Cl ₂ ) ·

d) (2S) -7-Formyl-2- (tert-butoxycarbonylamino) tetralin M.p. 98-101 ° C.

[α] _D ²⁰ = -45.5 ° (c = 0.3%, CH ₂ Cl ₂ ).

e) (2S) -7- (2-ethoxycarbonyl) vinyl-2- (tert-butoxycarbonyl);

amino) tetralin

106-108 ° C (isopropyl ether).

[α] _D ²⁰ = -36.1 ° (c = 0.3%, CH ₂ Cl ₂ ).

Example 7 (2S) -2-Amino-7- (2-ethoxycarbonyl) ethyl tetrlinide hydrochloride

a) (2S) -7- (2-Ethoxycarbonyl) ethyl-2- (tert-butoxy)

carbonyl-amino) tetralin

The title compound was prepared according to Example 2 (a) using the compound of Example 4 as starting material.

M.p. 100-102 ° C (isopropyl ether). [Α] D ²⁰ = -30.7 ° (c = 0.3%, CH ₂ Cl ₂ ).

b) (2S) -2-Amino-7- (2-ethoxycarbonyl) ethyl tetralin hydrochloride

The title compound was prepared according to Example 2, step b, starting from the product of step a) above.

Yield: 60%.

178-180 ° C.

[α] _D ²⁰ = -44.8 ° (c = 0.3%, CH ₂ Cl ₂ ).

Example 8

2-Amino-7- (3-ethoxycarbonyl) allyl tetralin hydrochloride

a) 7- (Formylmethyl) -2- (tert-butoxycarbonylamino) tetralin

A mixture of potassium tert-butylate (1.1 g, 9.9 mmol) and anhydrous tetrahydrofuran (130 mL) was cooled to -60 ° C under nitrogen and then 2- (trimethylsilyl) ethoxymethyl-triphenyl- was added. phosphonium chloride (4.7 g, 10.8 mmol). The reaction mixture was allowed to stand at -60 ° C for 10 minutes and then allowed to rise with stirring for 10 minutes. A solution of the compound obtained in Example 1, step c (1 g, 3.6 mmol) in tetrahydrofuran (10 mL) is then added slowly dropwise. The resulting reaction mixture was stirred for 20 minutes then poured into ice / water (200 mL) and extracted with ethyl ether. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo. The rest

Purify by flash chromatography 21 eluting with 9: 1 cyclohexane: ethyl acetate. There was thus obtained a yellow oil (1.2 g) which was 2- (tert-butoxycarbonylamino) -7- {2- [2- (trimethylsilyl) ethoxy] vinyl} tetralin.

To a solution of the product (2.56 mmol) in acetonitrile (19.5 mL) and water (0.5 mL) was added 1.1 m tetrabutylammonium fluoride solution (20 mL) and the reaction mixture was heated to 80 ° C. warm for 30 minutes under nitrogen, then cool and pour into water (150 mL). The reaction mixture was extracted with ethyl ether, and the extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography eluting with 8: 2 cyclohexane / ethyl acetate. 100 mg of the title compound are obtained.

b) 7- (3-Ethoxycarbonyl) allyl-2- (tert-butoxycarbonyl)

amino) tetralin

The product was prepared according to Step d) of Example 1, starting from the product of Step a) above.

c) 2-Amino-7- (3-ethoxycarbonyl) allyl tetralin hydrochloride

The title compound was prepared according to Example 1, Step e), starting from the product of Step b) above.

Example 9

2-Amino-7- (3-ethoxycarbonyl) propyl-tetralin hydrochloride

a) 7- (3-Ethoxycarbonyl) propyl-2- (tert-butoxycarbonylamino) tetralin

The title compound is obtained in Example 2, Step a)

- 22, starting from Example 8

b).

b) 2-Axnino-7- (3-ethoxycarbonyl) -propyl-tetralin hydrochloride

The title compound was prepared according to Example 2, Step b, starting from the compound of Step a) above.

Example 10 (2R) -2-Amino-7- (ethoxycarbonyl) tetralin hydrochloride

a) (2R) -7- (Ethoxycarbonyl) -2- (tert-butoxycarbonyl)

-amino) -tetralin% NaClO2 (920 mg, 8.13 mmol) and NaHPO4 · 5H2O (730 mg, 5.3 mmol) in water (5 mL) are added (2R) -7 -formyl-2- (tert-butoxycarbonylamino) tetralin (200 mg, 0.73 mmol) [4. Prepared according to example dc) in a solution of tert-butanol (7 ml).

The reaction mixture was stirred vigorously at room temperature for 1 hour, adjusted to pH 3 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in a mixture of methylene chloride (10 mL) and triethylamine (0.11 mL) and the reaction mixture was cooled to 0 ° C and ethyl chloroformate (80 μΐ) was added slowly dropwise and after 5 min. dimethylaminopyridine (50 ng). The reaction mixture was left at 0 ° C for 1 hour, then poured into water and extracted with ethyl acetate. The organic layer was washed successively with 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography eluting with 75:25 cyclohexane / ethyl acetate. 200 mg of the title compound are obtained.

Mp 125-128 ° C.

b) (2R) -2-Amino-7- (ethoxycarbonyl) tetralin hydrochloride

A solution of 8.4 N hydrochloric acid in ethanol (7 mL) was added to a solution of the product of the previous step (a) (600 mg, 1.9 mmol) in ethanol (20 mL), and the reaction was allowed to stand at room temperature for 5 hours. simmer. The residue was taken up in trituration in hot acetone (10 mL), cooled and filtered to give 350 mg of the title compound. 185-188 ° C.

[α] _D ²⁰ = + 54.8 ° (c = 0.3%, MeOH).

Example 11 (2S) -2-Amino-7- (ethoxycarbonyl) tetralin hydrochloride

The title compound (m.p. 189-191 ° C, [α] ρ ² θ + 52.4 ° (c = 0.3%, MeOH)) was prepared according to Example 10, starting from (2S) - 7-Formyl-2- (tert-butoxycarbonylamino) tetralin (prepared according to Step d) of Example 6) via the following intermediate:

a) (2S) -7- (ethoxycarbonyl) -2- (tert-butoxycarbonyl)

amino) tetralin

124-125 ° C.

Example 12

2- (Aminomethyl) -7- (2-ethoxycarbonyl) vinyl tetralin hydrochloride

a) 2- (tert-Butoxycarbonylaminomethyl) -7- (trifluoromethanesulfonyloxy) tetralin

A mixture of 2- (tert-butoxycarbonylaminomethyl) -7-hydroxytetalin (15.9 g, 0.071 mol) (Step K of Preparation K of European Patent 436,435) and pyridine (45 ml). cooled to 0-5 ° C under nitrogen and trifluoromethanesulfonic anhydride (13 mL, 0.08 mol) was added over 30 min. The reaction mixture was allowed to warm to room temperature. After 4 hours, the reaction mixture was poured into ice / dilute hydrochloric acid and the weakly acidic mixture was extracted with ethyl acetate.

The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness.

The product was purified by flash chromatography (petroleum ether: ethyl acetate 9: 1). The resulting oily product solidified overnight at 4 ° C and was crystallized from petroleum ether (80 mL). 16.7 g of the title compound are obtained. 65-67 ° C.

b) 2- (tert-Butoxycarbonylaminomethyl) -7-vinyl tetralin

The compound obtained in the previous step (a) (500 mg, 1.22 mmol), anhydrous dioxane (5 mL), tributyl vinyl tin (0.5 mL, 1.7 mmol), lithium chloride (150 mg) ), Pd (ΡϊΐβΡ) 4 (30 mg) and some crystals of 2,6-di-tert-butyl-4-methylphenol were refluxed under nitrogen for 3 hours and then cooled to room temperature. To the reaction mixture was added ethyl ether and filtered through celite. The organic phase is washed, dried over sodium sulfate and vacuum dried.

· .. · · .. · .. ·

- Evaporate. The resulting oily product was purified by flash chromatography eluting with 95: 5 cyclohexane: ethyl acetate followed by crystallization from petroleum ether to give 0.2 g of 2- (tert-butoxycarbonylaminomethyl) -7-vinyl tetralin. we get.

98-100 ° C.

c) 7-Formyl-2- (tert-butoxycarbonylaminomethyl) tetralin

A 2.5% solution of osmium tetroxide in tert-butanol (2 ml) was added to the compound obtained in the preceding step (1.4 g, 0.0049 mol), sodium periodate (3.5 g), tetrahydrofuran. (40 mL) and water (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour, then poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The residual dark oily material was purified by chromatography, eluting with cyclohexane / ethyl acetate (6: 4),

The resulting oily residue solidifies after treatment with petroleum ether.

Yield: 0.65 g.

M.p. 92-94 ° C.

d) 2- (tert-Butoxycarbonylaminomethyl) -7- (2-ethoxycarbonyl) vinyl tetralin

Triethylphosphonoacetate (3.5 mL) was added over 20 minutes to a suspension of 60% sodium hydride (0.7 g, 0.175 mmol) in dimethoxyethane (30 mL) under nitrogen. The reaction mixture was stirred for 1 hour and then stirred

(2.5 g) in dimethoxyethane · · · · · · · · · · ·

- A solution of 26 (20 ml) in 10 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour, water (400 mL) was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography using cyclohexane / ethyl acetate 8: 2 as the eluent.

Yield: 2.8 g.

Mp 117-119 ° C (ethyl ether: ethyl acetate 7: 1).

e) 2- (Aminomethyl) -7- (2-ethoxycarbonyl) vinyl tetralin hydrochloride

A solution of the compound obtained in the preceding step (d) (0.7 g, 0.002 mol) in absolute ethanol (40 ml) was allowed to react with saturated ethanolic hydrogen chloride solution (10 ml) for 4 hours at room temperature.

The reaction mixture was concentrated in vacuo and the residue was crystallized from isopropanol to give the title compound (0.35 g).

Mp: 215-218 'C.

Example 13

2- (aminomethyl) -7- (2-ethoxycarbonyl) ethyl tetralin hydrochloride

a) 2- (tert-Butoxycarbonylaminomethyl) -7- (2-ethoxycarbonyl) ethyl tetralin

Example 12 (d) (1.45 g,

0.004 mol) of absolute ethanol (50 ml) and 5% Pd / C (0.15 g) were transferred to a hydrogenation vessel. Hydrogenation is carried out at room temperature under normal pressure for 3 hours • · * ···

After 27 minutes, the reaction mixture was filtered through celite, the filtrate was concentrated in vacuo and petroleum ether was added to the resulting oily substance to give, after filtration, 1.2 g of 2- (tert-butoxycarbonylaminomethyl) -7- (2-ethoxycarbonyl). ) to give ethyl tetralin.

69-71 ° C (petroleum ether: isopropyl ether 5: 3).

b) 2- (Aminomethyl) -7- (2-ethoxycarbonyl) ethyl tetralin hydrochloride

The compound obtained in the previous step a) (0.9 g,

0.0025 mole) of absolute ethanol (45 ml) and saturated ethanolic hydrogen chloride solution (15 ml) were reacted at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue was crystallized from isopropanol.

Yield: 0.54 g.

174-175 ° C.

Example 14

2- (aminomethyl) -7- (ethoxycarbonyl) tetralin hydrochloride% sodium chloride (1.8 g, 16 mmol) and NaH 2 PO 4 (1.6 g, 11.6 mmol) water (8 mL) was added to a solution of the product of Example 12, step (c) (500 mg, 1.73 mmol) in tert-butanol (25 mL). After stirring at room temperature for 1.5 hours, dilute hydrochloric acid was added until pH = 3. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in absolute ethanol (20 mL) and bubbled with hydrogen chloride at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo, made basic by the addition of ammonium hydroxide solution 28 and extracted with ethyl acetate. The organic phase is dried and concentrated in vacuo to give an oily residue which is dissolved in isopropanol and made basic with saturated isopropanolic hydrogen chloride solution. Filtration gave 0.2 g of the title compound.

op .: Mp 208-210 ° C. Example 15 2- (aminomethyl) -6- (ethoxycarbonyl) terephthalene hydrochloride a) 6-Hydroxy-2- (tert-butoxycarbonylaminomethyl) tetralin 2- (aminomethyl) -6-hydroxytetralin (Eur 436 435)

(23.7 g, 0.09 mol), dimethylformamide (185 ml) and triethylamine (90 ml) were cooled to 0 ° C. To the resulting reaction mixture was added di-tert-butyl dicarbonate (22.5 g, 0.10 mol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (1 L) and extracted three times with ethyl ether. The organic extracts were combined, washed with water, dried and evaporated to dryness. The residue was purified by chromatography, eluting with cyclohexane: ethyl acetate (7: 3).

Yield: 23 g.

Op .: 114 ° C. b) 2- (tert-Butoxycarbonylaminomethyl) -6- (trifluoromethanesulfonyloxy) tetralin The title compound was obtained according to Example 1 (a)

Prepared using the compound of the previous step a) as starting material and the product obtained

- 29 to use directly in the next step.

c) 2- (tert-Butoxycarbonylaminomethyl) -6-vinyl tetralin

The compound was prepared according to Example 1, step b, starting from the compound of the preceding step b).

M.p. 70 ° C.

d) 6-Formyl-2- (tert-butoxycarbonylaminomethyl) tetralin

The title compound was prepared according to Step c) of Example 1, starting from the compound of Step c) above. 115 DEG C. (isopropyl ether).

e) 2- (Aminomethyl) -6-ethoxycarbonyl-tetralin hydrochloride% NaClO2 (9 g, 0.08 mol) and NaHPO4 (8 g, 0.067 mol) in water (40 g). ml) is added to the previous one

b) (2.5 g, 0.0086 mol) in tert-butanol (120 ml).

The resulting reaction mixture was stirred at room temperature for 1 hour, adjusted to pH 3 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was dissolved in absolute ethanol (100 mL) and hydrogen chloride was bubbled through the resulting solution for 30 min. The solvent was evaporated, the residue was dissolved in water, and the aqueous solution was made basic by the addition of ammonium hydroxide, filtered and extracted with ethyl acetate. The organic layer was separated, dried and evaporated to dryness. The resulting free base is converted to the corresponding hydrochloride salt in isopropanol / ethyl ether. so the title compound ···· .... .. ,, ...

•. * · · · ».

· .. ··. ··· ··· · ·· · ».. ... '.

Op. ·. 200 'C.

Example 16

2- (aminomethyl) -6- (2-ethoxycarbonyl) ethyl tetralin hydrochloride

a) 6- (2-Ethoxycarbonyl) vinyl-2- (tert-butoxycarbonyl)

amino-methyl) tetralin

The title compound was prepared according to Example 1, step d, starting from the compound of Example 15, step d.

b) 6- (2-Ethoxycarbonyl) ethyl-2- (tert-butoxycarbonyl);

amino-methyl) tetralin

The compound obtained in the previous step a) is hydrogenated according to the example 2 a) to give the title compound.

Mp: 77 'C.

c) 2- (Aminomethyl) -6- (2-ethoxycarbonyl) ethyl tetralin hydrochloride

The title compound was prepared according to Example 2, step b, starting from the compound of step b) above.

Claims (2)

- 31 Claims A process for the preparation of a compound of formula (I): wherein THE is -COOR 'and a tetralin ring! bonding, C4 alkenylene, or C 1 -C 4 alkylene or C ₂ - R is C1-C4 alkyl, and n value is 0 or 1 with the proviso that when n is 0 and the group -A-COOR 'is in the 6 or 7 position, A is other than methylene - and their salts and N-protected derivatives, characterized in that - for the preparation of compounds of formula I wherein A is a bond between -COOR 'and a tetraling ring, an aldehyde of formula II wherein P is a suitable amino protecting group introduced temporarily and P' is hydrogen or P and P 'are taken together to form a phthalimido group, then the free carboxyl group is esterified and optionally deprotected; - reacting an aldehyde of formula (II) as defined above with 2- (trimethylsilyl) ethoxymethyl-triphenylphosphonium chloride to prepare compounds of formula (I) wherein A is methylene; The compound of formula (III) is reacted with tetraalkylammonium fluoride and the resulting compound of formula (IV) * ♦ ·· * ·· *. ...... * ··· * · !. «» The compound of formula I 'is oxidized, the resulting free carboxyl group is esterified and optionally deprotected; - preparing a compound of formula (I) wherein A is C2-C4 alkenylene, reacting a compound of formula (II) or (IV), as defined above, with a Wittig reagent that already contains a COOR 'group, and In this case, the protecting group is removed and the resulting compound is optionally reduced to form compounds of formula I wherein A is C2-C4 alkylene. A process for the preparation of a compound of formula I according to claim 1, wherein the group -A-COOR 'is located at the 6- or 7-position of the tetraling ring and A is the group -COOR' and a tetraling ring bond, or a C 2 or C 3 alkylene group or a C 2 alkenylene group, wherein the appropriately substituted starting compounds are used.