FI106027B - A process for the preparation of (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] -benzoic acid or its salt, and (S) -1- ( Preparation of N-acetyl-L-glutamine salt of 2-piperidinophenyl) -3-methyl-1-butylamine - Google Patents

Description

-10,602)

A process for the preparation of (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] -benzoic acid or a salt thereof, and (S) -1- ( N-acetyl-L-glutamine salt of 2-piperidinophenyl) -3-methyl-1-butylamine and its preparation - (For) (+) - 2-ethoxy-4- [N-5 [1- ( 2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid, as well as N-acetyl-L-glutamine amaltalt (s) (S) -1- (2-piperidinophenyl) -3-methyl-1- butylamin och dess framställning

EP-B-0,147,850 describes e.g. 2-Ethoxy-4- [N- [1- (2-piperidino-10-phenyl) -3-methyl-1-butyl] aminocarbonylmethyl] -benzoic acid racemate (code no .: AG-EE 388 ZW) of formula ch3 ch, \ /

CH

And the other two polymorphic forms of this compound. This compound and its physiologically acceptable salts have: valuable pharmacological properties, i.e., an effect on the metabolism of the intermediate, in particular, a blood glucose lowering effect.

25 Both enantiomers of this compound, i.e. (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid (code no .: AG-EE 623 ZW) and (R) (-) - 2-Ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid (code no .: AG -EE 624 30 ZW) blood glucose lowering effect was tested in female rats.

Surprisingly, it was discovered that the (S) -enantiomer (AG-EE 623 ZW) is a potent enantiomer and that it lasts for more than 6 hours in the rat.

106027 2 Based on these results in the rat, there is provision in humans for exclusive use of AG-EE 623 ZW, through which the dose can be reduced by 50% compared to the AG-EE 388 ZW. This and the relatively long duration of the effect could be demonstrated in man. However, in addition, it was discovered in human studies that AG-EE 623 ZW has surprising pharmacokinetic properties which, due to AG-EE 388 ZW data, were not predictable. AG-EE 623 ZW thus has surprising therapeutic advantages over the racemate AG-EE 388 ZW.

Surprising results in humans are: (a) AG-EE 623 ZW mirrors fall faster to zero than AG-EE 388 ZW mirrors, even at the same absolute dose, which was not expected due to the relatively long duration of the effect.

(B) In relation to the achieved blood glucose reduction, AG-EE 623 ZW exhibits substantially lower plasma mirrors than would have been expected with halving the AG-EE 388 ZW dose.

(c) The blood glucose lowering effect begins faster after ZW administration of AG-EE 623 than after ZW administration of AG-EE 388.

20

The clear difference between the two enantiomers is that, despite the relatively longer duration of action, the active enantiomer, AG-EE 623 ZW, is surprisingly eliminated substantially faster than the inactive enantiomer, AG-EE 624 ZW, as shown in Figures 1 and 2. Figure 1 then shows the plasma concentration of 25 AG-EE 623 ZW and AG-EE 624 ZW after intravenous administration of 1.0 mg AG-EE 388 ZW, and Figure 2 shows the AG-EE 623 ZW and AG -EE 624 ZW plasma concentration after administration of *, 1.0 mg AG-EE 388 ZW orally (solution) to 12 volunteer male subjects each. Thus, after administration of the racemate, the ineffective enantiomer, 30 AG-EE 624 ZW, was not only as an unnecessary ballast at plasma concentrations as high as the active enantiomer, AG-EE 623 ZW, but unexpectedly higher maxima and end mirrors. This is evident, for example, when administering a tablet containing 2 mg AG-EE 388 ZW or a tablet containing 3 mg CCC27 containing 1 mg AG-EE 623 ZW for 12 or 6 subjects, with maximum concentrations of 84 ± 25 or 28 ± 18 ng / ml, as well as concentrations at 19 ± 8 or 0.7 ± 1.0 ng / ml at 4 hours, 13 ± 6 or 0.3 ± 0.7 ng / ml at 5 hours, and 10 ± 6 or 0.3 ± 0.7 ng / ml.

This surprisingly faster onset of blood glucose lowering of AG-EE 623 ZW compared to AG-EE 388 ZW is particularly advantageous for diabetics because rapid onset results in optimal disease control.

Thus, compared to administration of AG-EE 388 ZW, the surprising advantage of administration of AG-EE 623 ZW is that it avoids unnecessarily high and long-lasting substance loads of the organism, which is of great importance in long-term treatment such as diabetes mellitus.

Human studies indicate that the novel (S) -enantiomer, i.e. (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] - As a carrier of the blood glucose lowering effect, surprisingly and due to its relatively long duration of action, benzoic acid exhibits superior properties over AG-EE 388 ZW, which far outweighs the "normal" advantage of the enantiomer over its racemate, i.e., the half-dose advantage.

The invention thus relates to a novel (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] -benzoic acid or (S) (+) - 2-ethoxy- 4-25 [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid, which is optically substantially pure, e.g. having an optical purity of at least ee = 95%, preferably 98-100 %, its physiologically acceptable salts with inorganic or organic acids or bases, medicaments containing this compound or its physiologically acceptable salts, and a process for their preparation.

The novel compound is obtained according to the invention by the following processes: 106027 4 a) (S) -amine of formula I

CH, CHS

= CH

ch2

5 I ^ H

c-nh2 oe0 * 10 is reacted with a carboxylic acid of general formula II - "" O "- oc2h5 wherein a 15 W is a carboxy group or a protected carboxy group, or any reactive derivatives thereof prepared in the reaction mixture, and subsequently deprotected if necessary.

Reactive derivatives of a compound of general formula II include, for example, its esters such as methyl, ethyl or benzyl ester, its thioesters such as methylthio or ethylthioester, its halides such as acid chloride, its anhydrides or imidazolidides.

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activator or dehydrating agent, e.g. phosphorus pentoxide, Ν, Ν'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or Ν, Ν'-thionyldiimidazole or triphenyl if osf ii or in the presence of an amino group activating agent, for example phosphorus trichloride, and in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, j a at 250 ° C, however, preferably at temperatures between -10 ° C and the boiling point of the solvent used. The reaction may also be carried out in the absence of a solvent, in addition, the water formed during the reaction may be separated by azeotropic distillation, for example by heating with toluene on a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieves.

When required, the subsequent cleavage of the protecting group is preferably carried out hydrolytically, conveniently in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in a base such as sodium hydroxide or calcium hydroxide, ethanol / water, water / isopropanol or water / dioxane at temperatures between -10 and 120 ° C, for example at room temperature and the boiling point of the reaction mixture.

The tert-butyl protecting group may also be cleaved in a therapeutically inert solvent such as methylene chloride, chloroform, benzene-20, toluene, tetrahydrofuran, dioxane or glacial acetic acid, and preferably in the presence of strong acids such as trifluoroacetic acid, hydrobromic acid, p-toluenesulfonic acid,

«

In addition, the benzyl group used as a protecting group may also be hydro-genolytically cleaved in the presence of a hydrogenation catalyst such as Pd / C in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

b) Cleavage of the (S) compound of general formula III 106027 6 ch3 ch3 </

?B

CH> H

^^^ CH-NH.CO-CH2 - / ^ \ - a (!!!)

Qq wherein A is a carboxylic acid derivative which is converted to a carboxy group by hydrolysis, thermolysis or hydrogenolysis.

Suitable hydrolysable groups include, for example, functional derivatives of a carboxy group, such as unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides, nitrile group, 15-tetrazolyl group, optionally substituted 1,3-oxazole, a -sol-2-yl group and as thermolytically cleavable groups, for example, esters with tertiary alcohols, for example tert-butyl ester, and as hydrogenolytically cleavable groups, for example, aralkyl groups, for example benzyl group.

The hydrolysis is conveniently carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or calcium hydroxide in a suitable solvent such as water, water / methanol, ethanol, -10 to 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture.

If A in the compound of general formula III has a nitrile or aminocarbonyl group, these groups can be converted to a carboxy group with 100% phosphoric acid at temperatures between 100 and 180 ° C, preferably at temperatures between 30 106027 7 120 and 160 ° C, or also with nitrite. , for example, sodium nitrite, in the presence of an acid such as sulfuric acid, when conveniently used as a solvent, at temperatures between 0 and 50 ° C.

For example, if A in the compound of general formula III has a tert-butyloxycarbonyl group, the tert-butyl group may also be cleaved thermally in an optionally inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid such as in the presence of hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid at temperatures between 0 and 100 ° C, preferably between 20 ° C and the boiling point of the solvent used.

For example, if A in the compound of general formula III has a benzyloxy-carbonyl group, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as Pd / C in a suitable solvent such as methanol, ethanol, methanol / water, ethanol / water, dioxane or dimethylformamide preferably at temperatures between 0 and 50 ° C, for example at room temperature and hydrogen pressure of 1 to 5 bar (100 to 500 kPa).

C) (S) Compound of general formula IV CH3 ch3 / /

CH

Wherein W is a carboxy group or an alkoxycarbonyl group having a total of 2-5 carbon atoms, wherein the alkyl portion of the alkoxy group may be substituted by a phenyl group, 1060278; with a compound of general formula x

Z - CH2 - CH3 V

wherein Z is a nucleophilically exchangeable group such as a halogen atom, a sulfonyloxy group, or also together with an adjacent hydrogen atom a diazo group, and subsequent hydrolysis or hydrogenolysis is required.

The reaction is conveniently carried out with the corresponding halide, sulfonic acid ester or sulfuric acid ester, for example ethyl bromide, ethyl iodide, diethyl sulfate, p-toluenesulfonic acid ethyl ester or methanesulfonic acid ethyl ester, or in the presence of triethylamine, preferably in a suitable solvent such as acetone, diethyl ether, tetrahydrofuran, dioxane, pyridine or dimethylformamide at temperatures between 0 and 100 ° C, preferably between 20 and 50 ° C.

If W in the compound of general formula IV has a carboxy group, this can be converted to the corresponding ester compound.

20

If required, the following hydrolysis is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or calcium hydroxide in a suitable solvent such as water, methanol, methanol, or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture, or subsequent hydrogenolysis is carried out in the presence of a hydrogenation catalyst such as Pd / C in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic dimethylformamide at a hydrogen pressure of 1 to 10 bar (0.1 to 1 MPa).

1CCC27 9 d) Enantioselectively reducing a compound of general formula VI αγ-CO-ch2-W-W = / (VI), -OC2O where W is a carboxy group or an alkoxycarbonyl group having a total of 2-5 carbon atoms, wherein the alkyl portion of the alkoxy group may be substituted by a phenyl group, and Y is a group of the formula 10 ^ CH3 Cu CH,? ^ CH3 CH3?

H \ / \ CH ^ - ° H \ / I

C ch3 ch3- ^ NC ch

Il II I

-C-NH-, -C-NH- or - C = NH - 15 and if necessary hydrolyze next.

The reduction is preferably carried out with hydrogen in the presence of a suitable chiral hydrogenation catalyst in a suitable solvent such as methanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran, methanol / tetrahydrofuran, methanol / methylene chloride / ethanol / methylene / however, preferably at temperatures between 20 and 50 ° C and hydrogen pressure between 1 and 1000 bar (0.1-100 MPa), preferably between 5 and 100 bar (0.5 and 10 MPa), and suitably adding 0.1 -5%, preferably 0.3-1%, of titanium (IV) tetraisopropylate, and preferably excluding air without oxygen. Preferably, the reduction is carried out with the (Z) form of the compound of general formula VI.

Suitable chiral hydrogenation catalysts are the corresponding metal ligand complexes such as Ru (OCO-CH 3) 2 [(S) -BINAP], Ru 2 Cl 4 [(S) -BINAP] 2 x N (C 2 H 5) 3, 30 Rh [(S) -BINAP-NBD ] ClO4 or Rh [(-) - NORPHOS-COD] BF4.

In catalytic hydrogenation, the benzyloxycarbonyl group can be simultaneously reduced and converted to a carboxy group.

106027 10

If required, the following hydrolysis is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or calcium hydroxide in a suitable solvent such as water, methanol, methanol, dioxane at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture.

e) Oxidation of the (S) compound of general formula VII with CH, CH,

CH

CH2 l ^ H / r \ ac - NH - CO - CH, —v VW "O * 11) \ = </ -v OCjHj

O

wherein W "is a group convertible by oxidation to a carboxy group.

Such an oxidizable group includes, for example, the formyl group and its acetals, the hydroxymethyl group and its ethers, the unsubstituted or substituted acyl group such as the acetyl, chloroacetyl, propionyl, malonic (1) -yl or malonic ester (1). yl group.

25

The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxane or glycol dimethyl ether at temperatures between 0 and 100 ° C, but conveniently at temperatures between 20 ° C and

and 50 ° C. However, the reaction is preferably carried out with silver oxide / sodium hydroxide, manganese dioxide / acetone or manganese dioxide / methylene chloride, hydrogen peroxide / sodium hydroxide, bromine or chlorine in sodium or potassium hydroxide, chromium trioxide / pyridine chloride.

106027 11 (f) Separating a mixture of an arbitrary amount of the (S) enantiomer of general formula Vili ch, ch3 \ /

CH

5 I

ch2 C ^ NH - CO - CH2 - V W (W)

fY

an arbitrary amount of the (R) -enantiomer of general formula IX CH, CH,

CH

CH, 15 L'H / 1 - C - NH - CO - CH2 - ('W (, x> 0C0 ^ 20) wherein W is a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl portion of the alkoxy group may be substituted with a phenyl group, preferably a 50/50 mixture, via diastereomeric addition products, complexes or salts thereof and, if necessary, by subsequent hydrolysis or hydrogenolysis.

The separation is preferably carried out by column or HPLC by forming diastereomeric addition products or complexes on a chiral phase.

When required, the following hydrolysis is carried out in the presence of either an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or calcium hydroxide in a suitable solvent such as water, methanol, water / dioxane at temperatures between -10 and 120 ° C, for example at room temperature and the boiling point of the reaction mixture, or subsequent hydrogenolysis is carried out in the presence of a hydrogenation catalyst such as Pd / C in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, or dimethylformamide at a hydrogen pressure of 1 to 10 bar (0.1 to 1 MPa).

The (S) enantiomer thus obtained according to the invention, which is suitably at least 90% optical purity, can be converted by fractional crystallization to the 10 (S) enantiomer having at least 95% optical purity, preferably 98-100%.

The same applies to the (S) compounds of the formulas III, IV and VII according to the invention, in particular their esters.

The (S) enantiomer thus obtained according to the invention can be converted into its salts, in particular for pharmaceutical use, into its salts with inorganic or organic acids or also with bases. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid, and sodium hydroxide, calcium hydroxy, lysine.

The compounds of formulas I to IX used as starting materials are partly known in the literature or are obtained by methods known per se.

* The (S) -amine of formula I can be obtained from the corresponding amine by cleavage of the racemate, for example by fractional crystallization of diastereomeric salts with suitable optically active acids, preferably N-acetyl-L-glutamic acid, and upon recrystallization as required 27, column chromatography or HPLC chromatography on chiral phases, optionally in the form of an acyl derivative, or formation of diastereomeric compounds which can be isolated and subsequently cleaved.

In addition, the (S) -amine of formula I can be obtained in high enantiomeric purity.

10 with enantioselective reduction with hydrogen in the presence of a suitable chiral hydrogenation catalyst, starting from the corresponding N-acyl ketimine or enamide, suitably adding 0.1 to 5% of titanium tetraisopropylate, and optionally followed by a chiral acyl group such as formyl or acetyl diastereoselective reduction of hydrazine in the presence of hydrogen in the presence of a suitable hydrogenation catalyst, suitably with addition of 0.1 to 5% of titanium tetraisopropylate, and optionally by subsequent cleavage of a chiral auxiliary, preferably by catalytic hydrogenolysis of a (S) -1-phenethyl group, - or by diastereoselective addition of the lithium compound to the corresponding nitrogen atom chirally substituted aldimine, optionally with addition of 0.1 to 10% of titanium tetraisopropylate, by hydrolysis and optionally separation of the resulting diastereomer and subsequent cleavage of a chiral auxiliary such as (R) -1-phenethyl by catalytic hydrogenolysis, and, if required, salt formation with suitable optically active acids, preferably N-acetyl L-glutamic acid alone and as well as the subsequent decomposition of the salt.

106027 14 Compounds of general formulas III, IV and VII used as starting materials are obtained by reaction of (S) -amine of formula I with the appropriate carboxylic acid or reactive derivatives thereof and possible subsequent cleavage of the protecting group employed.

The compound of general formula VI used as starting material is obtained by acylation of the corresponding imino compound or its organometallic complex with the corresponding carboxylic acid or its reactive derivatives, optionally further cleavage of the ester group.

10

The new (S) enantiomer is virtually non-toxic; for example, when administered to 5 male and 5 female rats at a time of 1000 mg / kg p.o. (suspension in 1% methylcellulose) no animal died during the 14 day observation period.

15

The (S) -enantiomer (AG-EE 623 ZW) and its physiologically acceptable salts prepared according to the invention are suitable for the treatment of diabetes mellitus due to their pharmacological and pharmacokinetic properties. To this end, AG-EE 623 ZW or its physiologically acceptable salts, optionally in combination with other active ingredients, may be formulated into conventional galenical formulations such as tablets, granules, capsules, powders, suppositories, suspensions or solutions for injection. The single dose for an adult is then "0.1 to 20 mg, preferably 0.25 to 5 mg, but especially 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 or 5.0 mg once, twice or thrice daily.

25

A further object of the invention is a novel (S) amine of formula I, which is a valuable intermediate in the preparation of a new (S) enantiomer, as well as its addition salts with inorganic or organic acids.

The following examples further illustrate the invention:

Example A

106027 15 (SV1- (2-Piperidino-phenyl) -3-methyl-1-butylamine) To a stirred solution of 122 g (0.495 mol) of racemic 1- (2-piperidinophenyl) -3-methyl-1-butylamine in 1000 ml: of acetone, add 93.7 g (0.495 mol) of N-acetyl-L-glutamic acid, reflux in a steam bath, and add methanol (about 80 mL total) in portions until a clear solution is obtained, after cooling and standing at room temperature overnight The crystals obtained are filtered off with suction, washed twice with 200 ml of cold acetone each time at -15 [deg.] C. and dried to give the product [98.9 g; melting point: 163-166 [deg.] C .; + 0.286 ° (c = 1 in methanol)] is crystallized from 1000 ml of acetone with 200 ml of methanol to give (S) -1- (2-piperidinophenyl) -3-methyl-1-butylamine L-15 as glutamic acid addition salt.

Yield: 65.1 g (60.4% of theory).

Melting point: 168-171 ° C Calculated: C 63.42 H 8.56 N 9.65 Found: 63.64 8.86 9.60 20 [α] D 20 = + 0.357 ° (c = 1 in methanol)

The free amine is obtained as an oil by, for example, liberating with sodium hydroxide or ammonia solution, extraction with, for example, toluene, ether, ethyl acetate or methylene chloride, as well as drying, filtration and concentration of the extract in vacuo.

The fSI configuration of the amine was demonstrated as follows: reaction of the amine with (S ') - 1-phenethyl isocyanate in ether to give the corresponding urea derivative [melting point: 183-184 ° C; [αβ0 = + 2.25 ° (c = 1 in methanol)], crystal growth in ethanol / water (8/1) and subsequent X-ray structure analysis resulting in the (S, S ') configuration for the urea derivative and thus the (S) configuration the amine used.

106027 16

The enantiomeric purity was determined as follows: 1. Acetylation of the amine sample with 1.3 equivalents of acetic anhydride in glacial acetic acid at 20 ° C overnight.

2. Investigation of the N-acetyl derivative (melting point: 128-132 ° C) by HPLC 5 on a Baker chiral phase HPLC column with (S) -N- (3,5-dinitrobenzoyl) -2-phenylglycine coupled covalently onto aminopropyl silica gel (particle size: 5 µm, spherical, 60 A particle size; column length: 250 mm at 4.6 mm internal diameter; eluent: n-hexane / isopropanol (100/5); elution rate: 2 ml / min; temperature: 20 ° C, UV detection at 254 nm.

Obtained: Peak 1 (R): Peak 2 (S) = 0.75%: 99.25%, ee (enantiomeric excess) = 98.5% (S).

(S) -amine can be converted to dihydrochloride hydrate with ethereal hydrogen chloride solution.

Melting point: 135-145 ° C (dec.)

Calcd. (X H 2 O): C, 56.99; H, 8.97; N, 8.31; Cl, 21.02. Found: 56.85; 8.93; 8.38; methanol)

Example B

N-acetyl-N-1- (2-piperidino-phenyl) -3-methyl-1-buten-1-yl-amine • c

To a solution of 20 g (81.8 mmol) of freshly prepared isobutyl (2-piperidin-25-dinophenyl) ketimine in 200 mL of acetonitrile are added 4.7 mL (81.8 mmol) of glacial acetic acid, 25, at room temperature. 7 g (98.2 mmol) triphenylphosphine, 34.2 mL (245 mmol) triethylamine and 7.9 mL (81.8 mmol) carbon tetrachloride are stirred for 18 hours at room temperature. Subsequently, it is evaporated in vacuo and partitioned between ethyl acetate and water. The organic extract is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / ethyl acetate = 10/1) to elute first the (E) form and then the (Z) form.

106027 17 (EV format:

Yield: 6.1 g (26% of theory),

Melting point: 135-137 ° C (ethyl acetate / petroleum ether)

Calculated: C 75.48 H 9.15 N 9.78 δ Found: 75.47 9.35 9.70 (Z) Form:

Yield: 3.1 g (13% of theory),

Melting point: 140-143 ° C (ethyl acetate) 10 Calculated: C 75.48 H 9.15 N 9.78

Found: 75.56 9.30 9.79

Example C

15 N-acetyl-N-1- (2-Diperidino-phenyl-3-methyl-1-buten-1-yl) -amine

To a stirred solution of 44 g (0.18 mol) of freshly prepared isobutyl- (2-piperidino-phenyl) -ketimine in 440 ml of toluene is added dropwise at 0 ° C 17 ml (0.18 mol) of acetic anhydride. Stir for 3 hours at 20 ° C and 15 hours at room temperature, then evaporate in vacuo, dissolve the evaporation residue in ethyl acetate, and shake several times with aqueous sodium hydrogencarbonate. The organic phase is dried, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / ethyl acetate = 5/1) to elute first the (E) -25 form and then the (Z) form.

(E1 form:. · Yield: 3.0 g (5.8% of theory), 30 (ZV form:

Yield: 17.8 g (34.5% of theory),

Melting point: 139-141 ° C (ethyl acetate) 106027 18

Calculated: C 75.48 H 9.15 N 9.78 Found: 75.68 8.99 9.86

Example D 5 N-Acetyl-Ni (SM- (2-piperidino-phenyl) -3-methyl-1-but-vinylamine) 0.57 g (1.99 mmol) of (Z) -N-acetyl-N- [1 - (2-Piperidino-phenyl) -3-methyl-1-buten-1-yl] -amine with a melting point of 139-141 ° C is dissolved in 10 ml of a degassed solvent mixture (methanol / methylene chloride = 5 / 1) in an argon atmosphere and added to a solution of 16.8 mg (1 mol%) of NOYORI catalyst Ru (O-acetyl) 2 [(S) -BINAP] (prepared from [Ru (COD) Cl of (S) -BINAP [= (S) -2,2'-bis (diphenylphosphino) -1,1'-naphthyl], triethylamine and sodium acetate), and 3.4 mg (0.5 mol. %) of titanium tetraisopropylate in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1) The reaction mixture is transferred to an autoclave, evacuated under vacuum of 10'2 mbar (1 Pa), flushed several times with hydrogen at 400 kPa and At 10 ° C and 10 MPa to stop hydrogen uptake (170 hours). The brown solution is then evaporated to dryness. in a blanket, boil the evaporation residue with 30 ml of n-hexane at reflux and filter while hot from the insoluble material. The filtrate was evaporated to give crystallization.

Yield: 0.31 g (54% of theory),

Melting point: 127-131 ° C

Enantiomeric purity. ee = 82% (S) [HPLC method: see Example A], 25% of the insoluble material obtained by boiling with 30 ml of n-hexane can be obtained by further boiling, filtering and crystallizing from a hexane solution 14% of the racemic N- acetylamine having a melting point of 154-156 ° C.

Example E

19 106027 (SV1- (2-piperidino-phenyl) -3-methyl-1-butylamine) 5 g (3.47 mmol) of N-acetyl-N - [(S) -1- (2-piperidino-phenyl) -3 -methyl-1-butyl] -amine (melting point: 128-133 ° C; ee = 99.4%) is refluxed in 10 ml of concentrated hydrochloric acid for 5.5 hours, cooled and poured into a mixture of concentrated ammonia and ice. , wash the organic phase with water, dry and filter, and evaporate in vacuo.

Yield: 0.84 g (98.8% of theory) of an oily amine.

Acetylate back with 0.42 mL (1.3 equivalents) of acetic anhydride in 8.4 mL of glacial acetic acid overnight at room temperature, evaporate in vacuo, partition the evaporation residue between ethyl acetate and saturated aqueous sodium bicarbonate and dry, filter, and evaporate the organic extract. yielding 0.83 g (84.7% of theory) of N-acetyl-N - [(S) -1- (2-piperidino-phenyl) -3-methyl-1-butyl] -amine (melting point: 130-132) ° C; ee = 99.4%).

20 Example F

2-Ethoxy-4- N - (1- (2-piperidino-phenyl) -3-methyl-1-buten-1-yl-aminocarbonylmethyl-benzoic acid ethyl ester Prepared from isobutyl (2-piperidino-phenyl) -ketimine and 3 ethoxy-4-ethoxycarbonylphenylacetic acid in accordance with Example B. Purification by column chromatography on silica gel (toluene / acetone = 10/1) elutes first the (E) form and then the (Z) form.

30 (E1 format:

Yield: 4% of theory,

Melting point: 101-103 ° C

106027 20

Calculated: C 72.77 H 8.00 N 5.85

Found: 72.74 7.78 5.86 (Z Form: 5 Yield: 28.1% of theory,

Melting point: 124-127 ° C (petroleum ether / toluene = 5/1)

Calculated: C 72.77 H 8.00 N 5.85

Received:. 72.90 7.86 5.83

10 Example G

Nf (5'-1-Phenethylphenyl-N '- (SH- (2-piperidinophenyl) -3-methyl-1-butvinylamine) 17 g (49 mmol) of N - [(S') - 1-Phenethyl] - isobutyl (2-piperidino-phenyl) -ketimine, boiling point 150-155 ° C / 0.3 torr (40 Pa) [prepared from isobutyl- (2-piperidinophenyl) -ketone and (S ') - 1-phenethyl amine (Fluka, ee = 99.6%) in toluene + triethylamine by dropwise addition of a solution of titanium tetrachloride in toluene] is dissolved in 170 ml of anhydrous ethanol, 1.7 g of titanium tetraisopropylate and 8 g of Raney are added. nickel and hydrogenated at 50 ° C and hydrogen-20 at 200 bar (20 MPa) After 20 hours, add another 8 g of Raney nickel and hydrogenate under the same conditions for another 52 hours, filter through a pad of celite over a G3 filter and evaporate the filtrate in vacuo. Yield: 13.1 g (76.6% of theory).

Boiling point: 152 ° C / 0.2 torr (27 Pa) 25 Calc'd: C 82.23 H 9.78 N 7.99

Found: 82.00 10.03 7.74 [α] D 20 = 55.3 ° (c = 1.1 in methanol)

Diastereomeric purity is determined by HPLC on a Lichrosorb RP18-HPLC column-30a from E. Merck (Germany); column length: 250 mm with an inside diameter of 4 mm; particle size; 7 pm. Eluent: methanol / dioxane / 0.1% aqueous sodium acetate, adjusted to pH 4.05 with acetic acid (135/60/5); Temperature: 23 ° C; UV detection at 254 nm.

106027 21

Obtained: Peak 1 (S, S '): Peak 2 (R, S') = 98.4%: 1.4%, but (diastereomeric excess) = 97.0% (S, S ').

Example H 5 fSII - (2-Piperidino-phenyl-3-methyl-1-butylamine) 12.5 g (36 mmol) of N - [(S ') -1-phenethyl] -N - [(S) -1 - (2-Piperidino-phenyl) -3-methyl-1-butyl] -amine with de = 97.0% (S, S ') is dissolved in 125 ml of water and 10 ml of concentrated water. Hydrochloric acid 1.3 g Pd / C (10%) is added and hydrogenated at 50 ° C and hydrogen pressure 5 bar (500 kPa) After uptake of hydrogen (10 hours), the catalyst is filtered off with a pad of celite. the organic extract is dried and filtered and evaporated in vacuo.

Yield: 6.4 g (72.1% of theory).

Boiling point: 115-117 ° C / 0.4 torr (53 Pa)

Enantiomeric purity: ee = 93.5% (S) [HPLC method (after acetylation above): see Example A], 20

Example I

: N - [[1 R - -1-Phenethyvinyl-Ni (S1-1- (2-piperidino-phenyl) -3-methyl-1-butyl] -amine) In a bath at 60 ° C, a stirred solution of 27.4 mmol ( 4 equivalents) of isobutylmagnesium bromide in 22 mL of anhydrous tetrahydrofuran, a solution of 2 g (6.84 mmol) of N - [(R ') -1-phenethyl] - (2-piperidinobenzaldimine) [prepared in equimolar] is added dropwise. of 2-piperidino-benzaldehyde and (R ') -1-phenethylamine by standing at room temperature overnight and then drying over sodium sulfate in ether] in 20 ml of anhydrous tetrahydrofuran After 18 hours the temperature of the bath is raised to 80 ° C 2 equivalents of isobutylmagnesium bromide in 11 ml of tetrahydrofuran At each time 12 hours at 80 [deg.] C., 2 equivalents of 2 equivalents of isobutylmagnesium bromide solution are added to each other.After about 90 hours at 80 [deg.] C., the excess is stirred. hydrochloric acid and evaporate to dryness under vacuum. The evaporation residue is dissolved in water and adjusted to pH 5 with concentrated ammonia. Extract with ether, dry the organic extract over sodium sulfate, filter, and evaporate in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / acetone = 95/5).

Yield: 0.20 g (8.3% of theory),

Melting point: <20 ° C

The diastereomeric purity is determined as in Example G by HPLC.

Obtained: Peak 1 (R, R '): Peak 2 (S, R') = 4.4%: 95.6%, but (diastereomeric excess) = 91.2% (S, R ').

A uniform mixture of 2.0 g of Schiff's base and a total of 6 equivalents of 15 equivalents of isobutylmagnesium bromide in toluene / tetrahydrofuran (4/1) and addition of 5% titanium (IV) tetraisopropylate and heating for 60 hours at 100 ° C in a glass bomb gave yield having de = 97.6% (S, R ') ·

Example K

1S-1-1-2-piperidinophenyl) -3-methyl-1-butylamine

A solution of 0.15 g (0.428 mmol) of N - [(R ') -1-phenethyl] -N - [(S) -1- (2-piperidinophenyl) -3-methyl-1- butyl i-amine (de = 91.2%), 0.47 mL (0.47 mmol) of 25 1 N hydrochloric acid and 1.5 mL of water are hydrogenated in the presence of 20 mg of Pd / C (10%). hours at 50 ° C and a hydrogen pressure of 3.4 bar (340 kPa). Filter through diatomaceous earth, adjust to concentrated alkaline pH with concentrated ammonia and extract <*. ethyl acetate. The extract is dried, filtered and evaporated in vacuo.

Yield: 0.066 g (62.8% of theory),

Melting point: <20 ° C

Enantiomeric purity: ee = 87.6% (S) [HPLC method (after previous acetylation): see Example A].

Example 1 23 106027 (S) -2-Ethoxy-4- N - (1- [2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid ethyl ester 5

To a solution of 0.47 g (1.91 mmol) of (S) -3-methyl-1- (2-piperidino-phenyl) -1-butylamine (ee = 98.5%) in 5 ml of anhydrous acetonitrile, 0.48 g (1.91 mmol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid, 0.60 g (2.29 mmol) of triphenylphosphine, 0.80 ml (5.73 mmol) of triethylamine and 10 0.18 ml of 1.91 mmol) of carbon tetrachloride and stirred for 20 hours at room temperature. Subsequently, it is evaporated in vacuo and partitioned between ethyl acetate and water. The organic extract is dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / ethyl acetate = 10/1).

Yield: 0.71 g (77.3% of theory),

Melting point: 110-112 ° C

Calculated: C, 72.47; H, 8.39; N, 5.83

Obtained: 72.29 8.42 5.80 The enantiomeric purity is determined by HPLC on a chiral phase HPLC column from Baker covalently coupled with (S) -N-3,5-dinitrobenzoyl leucine on aminopropyl / silica gel (particle size: 5 µm, spherical) , 60 A pore size; column length: 250 mm with internal diameter 4.6 mm; eluent: n-hexane / tetrahydrofuran / methylene chloride / ethanol (90/10/1/1); elution rate: 2 ml / min; : 20 ° C; UV detection at 242 nm).

Obtained: Peak 1 (R): Peak 2 (S) = 0.75%: 99.25%, ee = 98.5% (S).

106027

Example 2 24 (S) -2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

To a solution of 2.71 g (11 mmol) of anhydrous (S) -3-methyl-1- (2-piperidino-phenyl) -1-butylamine (ee = 98.5%) in 30 ml of absolute toluene is added at room temperature, 2.77 g (11 mmol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid and stir until a solution is obtained. Then 2.38 g of 10 (11.55 mmol) Ν, Ν'-dicyclohexylcarbodiimide are added and stirred at room temperature. After 24 hours, additional 0.54 g (2.14 mmol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid and 0.48 g (2.33 mmol) of Ν, Ν'-dicyclohexylcarbodiimide are added and stirred overnight. Next, cool to an internal temperature of + 5 ° C and filter off the precipitate formed on the suction flask, which is washed with 5 ml of toluene. The combined toluene filtrates are concentrated in vacuo to a volume of about 10 ml. The solution thus obtained is heated on a steam bath and stirred in portions of petroleum ether (55 ml total) to constant turbidity. Cool on ice to crystallize. Filter by suction and dried at 75 ° C / 4 torr (0.53 kPa). The product obtained (4.57 g; m.p. 20 - 1112 ° C; ee = 98.9%) is suspended in 50 ml of petroleum ether. Heat on a steam bath and add batches of toluene (8 mL total) until a solution is obtained. It is then cooled in ice and filtered through a suction flask, the crystalline product which is dried at 75 ° C / 4 torr (0.53 kPa).

Yield: 3.93 g (74.3% of theory),

Melting point: 117-118 ° C

Calculated: C, 72.47; H, 8.39; N, 5.83

Found: 72.44 8.43 5.93 [[α] D = + 9.4 ° (c = 1.01 in methanol)

Enantiomeric purity: ee = 99.9% [HPLC method: see Example 1] 30 25 106027

Example 3 (S) -2-Ethoxy-4- N - (1- (2-piperidinophenyl) -3-methyl-1-butylaminocarbonylmethyl] benzoic acid

A mixture of 3.79 g (7.88 mmol) of (S) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] - benzoic acid ethyl ester (ee = 99.9%) in 37 ml of ethanol, stirred at 60 ° C in a bath and 10 ml (10 mmol) of 1 N sodium hydroxide are added. After stirring for 4 hours at 60 ° C, 10 ml (10 mmol) of 1N hydrochloric acid are added in a warm atmosphere and allowed to cool to room temperature. After inoculating the seed crystal and standing overnight, leave to cool for an additional hour with ice stirring. The crystalline product is filtered off with a suction flask and washed twice with 5 ml of water each time. Next, it is dried at 75 ° C until it is next dried at 100 ° C / 4 torr (0.53 kPa) in vacuo-15 with phosphorus pentoxide.

Yield: 3.13 g (87.7% of theory),

Melting point: 130-131 ° C (high melting form)

Calculated: C 71.64 H 8.02 N 6.19

Found: 71.48 7.87 6.39 [.alpha.] D @ 20 = + 7.45 DEG (c = 1.06 in methanol)

Enantiomeric purity is determined by HPLC on a chiral phase HPLC column from ChromTech (Sweden) AGP (a1-acid glycoprotein) phase; Inner diameter: 4.0 mm; length: 100 mm; particle diameter: 5 pm. Temperature: 20 ° C; eluent: 0.1% aqueous KH 2 PO 4 solution (= A) + 20% acetonitrile (= B), gradient increase within 4 min to 40% (B); elution rate: 1 ml / min; UV detection at 240 nm. Retention Time (S) Enantiomer: 2.7 min; Retention time (R) enantiomer: 4.1 min. : · Found: (S) :( R) = 99.85%: 0.15%, ee = 99.7% (S).

30 Recrystallization does not change the melting point of a sample of ethanol / water (2/1). By heating the sample in petroleum ether / toluene (5/3), filtering the insoluble matter (melting point: 130-131 ° C) and cooling the filtrate.

• I

106027 26 it rapidly obtains a low melting form of the title compound having a melting point of 99-101 ° C.

Calculated: C 71.64 H 8.02 N 6.19

Found: 71.66 7.97 6.44 5

The low-melting form and the high-melting form differ in their IR-KBr spectra but not in their IR solution (methylene chloride).

If a sample of the low melting form is heated above its melting point, another melting point at 127-130 ° C is observed.

Recrystallization of the low melting form sample from ethanol / water (2/1) yields the high melting melt.

15

The high-melting form and the low-melting form were examined by the "Differential Scanning Calorimetry (DSC)" method [apparatus Mettler, TA-300 system; measuring cell: DSC 20; Fa. Mettler, CH-8306 Greifensee, Switzerland] to give the following result: 20 • (♦ «*« 106027 27

Compound Heating Rate Heating Rate Example_10 ° C / min_3 ° C / min_

High uniform melting peak uniform melting peak at a temperature of 133 ° C; mp 132 ° C; 5 melting enthalpies: 100 J / α melting enthalpies: 99.1 J / a

Low 1st peak at 57 ° C 1st peak at 54 ° C (very weak) (very weak; endothermic) 10 melting form 2nd peak at 78 ° C 2. endothermic peak (weak) at 104 ° C: melting point 102 ° C, melting enthalpy: 52 J / g 3. endothermic peak 3. exothermic baseline 15 107 ° C; crystallization enthalpy progression: 55 J / g melted at 104 ° C 4. endothermic 4. endothermic peak

peak at 132 ° C at 131 ° C, melting point: 130 ° C

20 Melting enthalpies: 25 J / g Melting enthalpies: 52 J / g •: Example 4 25 (S) -2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) ) -aminocarbonyl-methyl] -benzoic acid ethyl ester 0.79 g (1.65 mmol) of (Z) -2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butene) -1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester having a melting point of 124-127 ° C is dissolved in 10 ml of a degassed solvent mixture (methanol / methylene chloride = 5/1) under argon atmosphere and added to a solution of 17 mg NOYORI catalyst Ru (0-acetyl) 2 [(S) -BINAP]: ·; (prepared from [Ru (COD) Cl 2] n with (S) -BINAP [= (S) -2,2'-bis (diphenylphosphino) -1,1'-106027 28 binaphthyl], triethylamine and sodium acetate) and 3 mg of titanium tetrisopropylate in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1). The reaction mixture is transferred under vacuum at 10'2 mbar (1 Pa) to a degassed autoclave. Flush five times with hydrogen at 5 bar (500 kPa) and then hydrogenate at 30 ° C and 100 bar (10 MPa) to complete hydrogen uptake (154 hours). The brown solution is concentrated in vacuo, the evaporation residue is dissolved in 80 ml of ether, the insoluble brown flakes are filtered with activated carbon, and the clear pale yellow filtrate thus obtained is concentrated in vacuo. The evaporation residue (0.60 g) is refluxed in 60 ml of n-hexane under reflux and filtered from the insoluble material while hot. The filtrate is allowed to stand overnight at room temperature. The separated crystals are then filtered from it.

Yield: 0.45 g (56.7% of theory),

Melting point: 131-133 ° C (from 120 ° C after sintering) Enantiomeric purity: ee = 39% (S) [HPLC method: see Example 1].

Example 5 (S) -2-Ethoxy-4- N - (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonyl-20-methyl-benzoic acid ethyl ester

To a solution of 0.68 g (1.15 mmol) of (S) -2-hydroxy-4- [N- (1- (2-piperidino: phenyl) -3-methyl-1-butyl) aminocarbonylmethyl] - benzoic acid ethyl ester [melting point: 125-126 ° C; 25 [α] 20 D = + 12.87 ° (c = 1.01 in methanol)] in 5 ml of anhydrous dimethylformamide, add 0.05 g (1.15 mmol) of sodium hydride (55% in oil) and stir 0.5 hours at room temperature.

«• -.

A solution of 0.12 ml (1.15 mmol) of ethyl iodide in 2.5 ml of anhydrous dimethylformamide is then added dropwise and stirred for 5 hours at room temperature. Evaporate in vacuo, partition between dilute sodium hydroxide and chloroform, dry the organic extract, filter, and concentrate in vacuo. The evaporation residue is purified by column chromatography over silica gel (toluene / ethyl acetate = 10/1).

Yield: 0.48 g (67% of theory),

Melting point: 110-112 ° C 5 Calculated: C 72.47 H 8.39 N 5.83

Found: 72.61 8.54 5.97

Enantiomeric purity: ee = 98.5% (S) [HPLC method: see Example 1], Example 6 10 (S) -2-Ethoxy-4- [Nn-f2-diDeridino-phenyl-3-methyl-1-butyl] -aminocarbonyl-methyl Β-Benzoic acid-etwl esters

Prepared from (S) -2-hydroxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -15-aminocarbonylmethyl] -benzoic acid as in Example 5 using 2 equivalents of sodium hydride and 2 equivalents of ethyl iodide .

Yield: 42% of theory,

Melting point: 110-112 ° C Calculated: C 72.47 H 8.39 N 5.83 20 Found: 72.61 8.54 5.99

Enantiomeric purity: ee = 98.3% (S) [HPLC method: see Example 1], •:

Example 7 25 (SV + 1-2-Ethoxy-4-N-N- (2-piperidino-phenyl-3-methyl-1-butyl-aminocarbonylmethyl) -benzoic acid ethyl ester and (R1M-2-ethoxy-4) N- (1-1,2-piperidino-phenyl-3-methyl-1-butyl-aminocarbonylmethyl) -benzoic acid ethyl ester 30 920 mg (±) -2-ethoxy-4- [N- (1- (2-piperidino) -phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester is separated by 10 mg in single portions on a preparative chiral phase HPLC column from Baker to which: (S) -N-3,5 is covalently attached -dinitrobenzoylleucine for aminopropyl 106027 30 l / silica gel (particle size: 40 μιτι; column length: 250 mm with an inside diameter of 20 mm; eluent: n-hexane / tetrahydrofuran / ethanol / methylene chloride (180/20/3/2); elution rate: 21.25 ml / min; Temperature: 27 ° C; UV detection at 285 nm) eluting first with the (R) (-) - enantiomer (peak 1) and then with the 5 (S) (+) - enantiomer (peak 2).

Similarly, the cut and collected fractions are obtained after evaporation in vacuo:

Peak 1 fraction (R): 423 mg (crude),

Peak 2 fraction (S): 325 mg (crude).

10

In order to separate the impurities (including the 2,6-di-tert-butyl-4-methylphenol stabilizer in tetrahydrofuran), both fractions are each purified by column chromatography on silica gel (toluene / acetone = 10/1).

15 (RK-1 enantiomer:

Yield: 234.5 mg (51% of theory),

Melting point: 122-124 ° C (petroleum ether + acetone)

Calculated: C 72.47 H 8.39 N 5.83 Found: 72.40 8.18 5.71 [α] 20 = 8.3 ° (c = 1 in methanol).

; Yield: 131.2 mg (28.5% of theory),

Melting point: 122-124 ° C (petroleum ether / acetone = 8/1) 25 Calculated: C 72.47 H 8.39 N 5.83

Found: 72.28 8.44 5.70 [α] D 20 = + 8.3 ° (c = 1 in methanol) • - s

A Chiralcel OD column from 30 Daicel is also suitable for separating the enantiomers. On a 250 mm column by 4.6 mm internal diameter (eluent: absolute ethanol / (n-hexane + 0.2% diethylamine) = 5/95; temperature: 40 ° C; UV detection at 245 nm) () The R) enantiomer elutes after 6.8 min and the j · (S) enantiomer after 8.5 min.

31 106027

Example 8 (R 1M-2-ethoxy-4-N-n-f 2 -Dideridino-phenyl) -3-methyl-1-butyl-aminocarbonylmethyl-benzoic acid x 0.4 Η · 5

Prepared from 150 mg (0.312 mmol) of (R) (-) - 2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid of ethyl ester [m.p. 122-124 ° C; [α] D = 8.3 ° (c = 1 in methanol)] by saponification with 1N sodium hydroxide in ethanol as in Example 3.

Yield: 95.8 mg (66.7% of theory),

Melting point: 103-105 ° C (toluene / petroleum ether)

Calcd. (X 0.4 H 2 O): C 70.51 H 8.01 N 6.09

Found: 70.88 7.79 5.81

Molecular Peak M +: Calculated: 452 15 Found: 452 [α] D 20 = 6.5 ° (c = 1 in methanol)

Enantiomeric purity: ee = 99.7% (R) [HPLC method: see Example 3]. Example 9 (SV + V2-Ethoxy-4- N - (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonyl] -methyl-vinyl-benzoic acid x 0.4 H.0 25 Prepared 89 mg: (0.198 mmol) of (S) (+) - 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-2-butyl) aminocarbonylmethyl] benzoic acid ethyl ester [melting point: 122-124 ° C; [α] D + 8.3 ° (c = 1 in methanol)] by saponification with 1N sodium hydroxide in ethanol according to Example 3.

Yield: 44.5 mg (48.8% of theory), 30 Melting point: 102-103 ° C (toluene / petroleum ether)

Calculated: (x 0.4 H 2 O) C 70.51 H 8.01 Found: 70.80 8.06 [α] D 20 = + 6.7 ° (c = 1 in methanol) 106027

Enantiomeric purity: ee = 99.6% (S) [HPLC method: see Example 3]. Example 10 5 (S) -2-Ethoxy-4-N '- (1- (2-piperidino-phenvin-3-methyl-1-butyvinylaminocarbonyl) -methyl] -benzoic acid

0.26 g (0.47 mmol) of (S) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid benzyl ester are hydrogenated 10 (melting point: 91-92 ° C; [α] D 20 = + 9.5 °; c = 1.05 in methanol) in 10 ml of ethanol with 0.12 g of Pd / C (10%) At 50 ° C and a hydrogen pressure of 5 bar (500 kPa). After 5 hours, the catalyst is filtered on silica gel and evaporated in vacuo. The evaporation residue is crystallized from ethanol / water (2/1).

Yield: 0, 15 g (70% of theory),

Melting point: 130-131 ° C

Calculated: C 71.64 H 8.02 N 6.19

Found: 71.76 8.12 6.05

Enantiomeric purity: ee = 99.6% [HPLC method: see Example 3], Example 11 (S1-Ethoxy-N-N '- (2-piperidinophenyl) -3-methyl-1-butyl10-aminocarbonyl) • (: methyl ij-benzoic acid 25) 102 mg (0.20 mmol) of (S) -2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) are heated. aminocarbonylmethyl] -benzoic acid tert-butyl ester (melting point: 122-123 ° C; [α] D = + 8.7 °; c = 1 in methanol) in 5 ml of benzene together with a few crystals of p-toluenesulfonic acid hydrate for half a day under reflux. Melting point: 129-131 ° C Molar peak M +: Calculated: 452 • Found: 452 33

Example 12 106027 fS1-2-Ethoxy-4- N - (1- (2-piperidino-phenyl-3-methyl-1-butylamino-carbonyl) -methyl] -benzoic acid

200 mg (0.395 mmol) of (S) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid tert-butyl ester (m.p. : 122-123 ° C; [α] D 20 = + 8.7 °; c = 1 in methanol) in 2 ml of methylene chloride, together with 0.45 g (3.95 mmol) of trifluoroacetic acid overnight at room temperature. . Evaporate in vacuo and partition the evaporation residue between aqueous sodium bicarbonate and ethyl acetate. The organic extract is dried, filtered and concentrated in vacuo. The evaporation residue is crystallized from ethanol / water (2/1).

Yield: 115 mg (64.7% of theory),

Melting point: 126-128 ° C

Calculated: C 71.64 H 8.02 N 6.19

Found: 71.39 7.91 6.06 [α] D 20 = + 6.97 ° (c = 0.975 in methanol)

Enantiomeric purity: ee = 99.8% [HPLC method: see Example 3].

20

Example 13 • -: 0.25 µm AG-EE 623 ZW tablets The tablet contains: 0.250 mg of active ingredient 0.125 mg of N-methylglucamine 0.038 mg of polyvinylpyrrolidone 0.075 mg of polyoxyethylene polyoxypropylene polymer 0.150 mg of microcrystalline cellulose I «106027

Manufacturing:

The active ingredient and excipients are dissolved in water at 90 ° C or the microcrystalline cellulose is suspended and the dispersion is evaporated in vacuo. The dried mass 5 is screened with a 1 mm mesh size.

The active ingredient granulate is mixed with the following ingredients per tablet: 10 24,862 mg sodium carboxymethyl starch 24,000 mg microcrystalline cellulose 0.500 µm magnesium stearate 50,000 mg 15 This mixture is compressed into round, two-layer tablets weighing 5 mg and 5 mm in diameter.

Example 14 20 Tablets with 0.5 MA AG-EE 623 ZW The tablet contains: • * 0.500 mg of active ingredient 0.250 mg of N-methylglucamine 0.075 mg of polyvinylpyrrolidone 0.150 mg of polyoxyethylene polyoxypropylene polymer 0.300 mg of microcrystalline cellulose

Manufacturing:

The active ingredient and excipients are dissolved in water at 90 ° C or the microcrystalline cellulose is suspended and the dispersion is evaporated in vacuo. The dried pulp is screened with a 1 mm mesh size.

30 106027 35

The active ingredient granulate is mixed with the following ingredients per tablet: 24.225 mg of sodium carboxymethyl starch 5 24.000 mg of microcrystalline cellulose 0.500 mg of magnesium stearate 50,000 mg This mixture is compressed into round, two-layer tablets weighing 10 to 50 mg and 5 mm in diameter.

Example 15

Tablets containing 1.0 µm AG-EE 623 ZW 15

The tablet contains: 1.00 mg of active ingredient 0.50 mg of N-methylglucamine 0.15 mg of polyvinylpyrrolidone 20 0.03 mg of polyoxyethylene polyoxypropylene polymer 0.60 mg of microcrystalline cellulose «<: Preparation: 25 The active substance and the excipients are dissolved in water at 90 ° C. or the microcrystalline cellulose is suspended and the dispersion is evaporated in vacuo. The dried pulp is screened with a 1 mm mesh size.

• ·

The active ingredient granulate is mixed with the following ingredients per tablet: »106027 36 23.22 mg sodium carboxymethyl starch 24.00 mg microcrystalline cellulose 0.50 mg magnesium stearate 50.00 mg 5 This mixture is compressed into round, biconvex tablets weighing 5 mg and 5 mg.

Example 16 10

Tablets containing 1.5 ma AG-EE 623 ZW

The tablet contains: 1,500 mg of active ingredient 0.750 mg of N-methylglucamine 0.225 mg of polyvinylpyrrolidone 0.045 mg of polyoxyethylene polyoxypropylene polymer 0.900 mg of microcrystalline cellulose 20 Preparation:

The active ingredient and the excipients are dissolved in water at 90 ° C or microcrystalline

• I

: suspend the cellulose and evaporate in vacuo. The dried pulp is screened with a 1 mm mesh size.

25

The active ingredient granulate is mixed with the following ingredients per tablet: «« 23,080 mg of sodium carboxymethyl starch 30 23,000 mg of microcrystalline cellulose 0.500 µm magnesium stearate 50,000 mg I $ 106027 37 This mixture is compressed into round, two-layer tablets weighing 5 mm and halide.

Example 17 5

Tablets containing 2.0 ma AG-EE 623 ZW

The tablet contains: 2.00 mg of active ingredient 10 1.00 mg of L-lysine 1.00 mg of polyvinylpyrrolidone 1.00 mg of polyoxyethylene polyoxypropylene polymer 4.00 mg of microcrystalline cellulose 15

The ingredients are dissolved in water at 90 ° C or the microcrystalline cellulose is suspended and the dispersion is treated in a jet dryer. Next, the following ingredients are added per tablet: 20.35 mg microcrystalline cellulose 20.00 mg sodium carboxymethyl starch.

* 0.65 µm magnesium stearate 50.00 mg 25 This mixture is compressed into round, biconvex tablets weighing 50 mg and 5 mm in diameter and coated with hydroxypropyl methylcellulose to mask the taste.

• I

38 106027

Example 18

Tablets containing 2.5 mg AG-EE 623 ZW 5 The tablet contains: 2.50 mg active ingredient 1.25 mg L-lysine 1.25 mg polyvinylpyrrolidone 1.25 mg polyoxyethylene polyoxypropylene polymer 10 4.10 mg microcrystalline cellulose

Manufacturing:

The ingredients are dissolved in water at 90 ° C or suspended in microcrystalline cellulose and the dispersion is treated in a jet dryer. Next, the following ingredients are added per tablet: 19.50 mg of microcrystalline cellulose 19.50 mg of sodium carboxymethyl starch 20 0.65 µm of magnesium stearate 50.00 mg This mixture is compressed into round, biconvex tablets weighing 50 mg and 5 mm in diameter and coated with hydroxypropyl.

• ·

Example 19 39 106027

Tablets containing 3.0 MA AG-EE 623 ZW 5 The tablet contains: 3.0 mg of active ingredient 1.5 mg of L-lysine 1.5 mg of polyvinylpyrrolidone 1.5 mg of polyoxyethylene polyoxypropylene polymer 10

Manufacturing:

The ingredients are dissolved in water at 90 ° C and treated with a jet dryer. Next, the following ingredients are added per tablet: 21.5 mg microcrystalline cellulose 21.0 mg sodium carboxymethyl starch 50.0 mg 20 This mixture is compressed into round, biconvex tablets weighing 50 mg and 5 mm in diameter and coated with hydroxypropylmethylcellulose.

• «

Example 20 25

Tablets containing 5 mg AG-EE 623 ZW

The tablet contains: 5.0 mg of active ingredient 2.5 mg of L-lysine 2.5 mg of polyvinylpyrrolidone 2.5 mg of polyoxyethylene polyoxypropylene polymer. t.

106027 40

Manufacturing:

The ingredients are dissolved in water at 90 ° C and the solution is further treated with a jet dryer. Next, the following ingredients are added per tablet: 5 19.0 mg microcrystalline cellulose 18.5 mg sodium carboxymethyl starch 50.0 mg 10 This mixture is compressed into round, biconvex tablets weighing 50 mg and 5 mm in diameter and coated with hydroxypropylmethylcellulose.

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Claims (15)

A process for the preparation of physiologically active (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid and its salts with inorganic or organic acids or bases of the formula CH 2 CH, CH 2 NH - CO - CH 2 - V y - COOH (A). Characterized in that a) an (S) -amine of formula (I) c V CH aCH 2 H 2 NH 2 (O is reacted with a carboxylic acid of general formula (II) H00 C-CH 2 - w (H) iL oc2hs there W is a carboxy group or a carboxy group protected with a protecting group, or with its optionally prepared reactive derivatives and, if necessary, the protecting group used is then split, or b) an (S) compound of the general formula (III) is split off. CtL · CH, 3 \ / 3 CH CH2H, -v 5 NH - CO - CH2 - ^ \ —A (n |) ^ • ry οολ there A is a hydrolysis, thermolysis or hydrogenolysis of a carboxy group transferable carboxylic acid derivative, or c) an (S) compound of the general formula (IV) CH 15 CH CH2 μ. wherein NH is a carboxy group or alkoxycarbonyl group having together 2-5 carbon atoms, the alkyl portion of the alkoxy group being substituted with a phenyl group, is reacted with a compound of the general formula (V) Z-CH 2 -CH 3, (V) ✓ «where Z is a nucleophilic interchangeable group or also together with adjacent hydrogen atom is a diazo group, and if necessary, the resulting compound is hydrolyzed or hydrogenated, or d) a compound of the general formula (VI) is enantioselectively reduced \ —W (VI) Where W is a carboxy group or alkoxycarbonyl group having together 2 to 5 carbon atoms, the alkyl portion of the alkoxy group may be substituted by a phenyl group, and Y is a group of the formula nil CH 2 , 14 11 »| -C-NH-, -C-NH- - C = N - and, if necessary, the compound so obtained is then hydrolyzed or e) an (S) compound of the general formula (VII) ? H / Γ ~ '\ NH - CO - CH 2 - (f (V · 1) Wherein W 'is a group transferable by oxidation to a carboxy group, oxidized or f) a mixture consisting of any amount of an (S) enantiomer of the general formula (Vili) • *. CH 3 N 2 CH, CH CH 2 1 H 1 NH - CO - CH 2 - y - W '(VIII) f / OC2 H5 and any amount of an (R) -enantiomer of the general formula (IX) CH ,,. CH, 10 3 \ / 3 1U CH a? H H / -V NH - CO - CH 2 - PW '<IX) / - \ N> O = Λ 15 ^ carbon atoms, wherein the alkyl moiety of the alkoxy group may be substituted by a phenyl group and, if necessary, with subsequent hydrolysis or hydrogenolysis, and if necessary, the compound obtained is converted by recrystallization to a higher enantiomeric purity compound, ethanol / water (2). / 1) crystallization gives a higher melting form, the melting point of which is 130-131 ° C, and with petroleum ether / toluene (5/3) crystallization, a lower melting form having a melting point of 99-101 ° C is obtained, and the so obtained compound is converted to its salt, especially a physiologically acceptable salt with inorganic or organic acids or bases. Process according to claim 1, characterized in that a compound which is optically substantially pure is prepared. € • «· 106027 50 Method according to claim 2, characterized in that its optical purity is at least ee = 95%. Method according to claim 2, characterized in that its optical purity is at least ee = 98%. 5. N-acetyl-L-glutamine salt of (S) -1- (2-piperidino-phenyl) -3-methyl-1-butylamine of general formula (I) CH (I) 15 Process for the preparation of N-acetyl-L-glutamine salt of (S) -1- (2-piperidino-phenyl) -3-methyl-1-butylamine, characterized in that racemic 1- (2-piperidino-phenyl) ) -3-methyl-1-butylamine and N-acetyl-L-glutamic acid and the precipitated salt of (S) -1- (2-piperidino-phenyl) -3-methyl-1-butylamine are separated with N-acetyl-L -glutamic acid and, if necessary, crystallize. •. '