HU229278B1 - Process for the manufacturing of pharmaceutically active substances with ace - inhibitor effect and intermediates thereof and the novel intermediates - Google Patents

Description

The chemical of our invention is the storehouse of our invention

R ¹ is an aromatic hydrocarbon group containing one or more rings, optionally having one or more substituents selected from alkyl-alkoxy, hydroxy or amino, or a linear or branched C 1 -C 6 alkyl group.

R ² is a linear or branched alkyl group of 1 to 6 carbon atoms and

· X

R is a C 1-6 straight or branched alkyl group or a C 1-6 straight or branched alkyl group which is an aromatic hydrocarbon substituent with one or more rings, provided that when R is ethyl and R 1 'is ethyl, then R ^! : unlike this methyl.

A further object of the present invention is a process for the preparation of compounds of formula I wherein R ¹ , R ² and R ³ are as defined below, by reacting a compound of formula IV wherein R 1 'and R 2 are organic in a solvent in the presence of an acid binder in an amount of at least 2 molar equivalents of the compound of formula VI (wherein X is halogen or tertiary butoxycarbonyloxy and R * is as defined above).

The invention further relates to a process for preparing the compounds of formula (II) wherein ^R? and R ² is as defined above, by reacting a compound of formula (1) wherein R 1, R ⁴ and R ⁴ are as defined above, in an organic solvent.

Invention. another object of the invention is the process of formula II; for the preparation of compounds wherein R * and R ⁴ are as defined above, such that a compound of formula (V) wherein R 'and R' are present in an organic solvent in the presence of an acidic additive in an amount of at least 2 molar equivalents; with a compound of the formula wherein Rf and X are as defined above, and then reacting the compound of formula (I) so prepared in an organic solvent.

Another object of the present invention is a process for the preparation of formula (III). for the preparation of a compound wherein R * is phenyl, IC is ethyl, R ³ is ethyl, R ⁶ is hydrogen, and sub-formula (VII) of formula (III) (ramipril), as prepared above , a formula (II)! a compound wherein R ¹ and R ~ are as defined above, beosyl ester of (S, S, 5) ~ 2 ~ [3 J] -ocyano-caronic acid or a salt thereof, preferably a duo, followed by a. the benzyl group is removed by catalytic hydrogenation.

Ramlpril invention further relates a process for preparing such a way that one, prepared as described above 'compound is (II), wherein R * is a sub-group and R ^4' is ethyl (S _i S, S) -2-az.abiciklo [ 3.3.0joktáíi-3tipusű compounds were first prepared N- (ethoxycarbonyl) ~ gliein and wine chloride and heating the resultant aeüklorid intermediate with at 85 ^e C, by reaction of the corresponding cyclic anhydride burrow Gb »Rer, M 858, ). The reaction is illustrated in Scheme L

There are several processes known in the art for the preparation of compounds of formula (11). Usually the amino acids of formula (IV) are used as starting materials.

The oxydolidinediones of Formula IV are prepared by reacting the aminos and derivatives of Formula IV. In many cases, the product of the reaction is not isolated, nor even its formation is mentioned, but the above intermediates are subjected to an in situ peptide coupling reaction. For example, N- (1- (S) -ethoxycarbonyl-3-phenyl-propyl} -4- (S) -methyl-oxazolidm-2,5-diethyl compound wherein R is phenyl, R-ethyl) is first prepared by [1- (S) -ethoxycarboml-3-phenylpropyl] -L-alanine (a compound of formula (IV) in which R ^{1 is} phenyl, R ^{2 is} ethyl) and N, N '-carbomyl-dimethidazole are boiled under nitrogen for 15 minutes and the solution containing the reaction product was used directly in the next reaction step (Jem? 1F, &< RTI ID = 0.0 > H, < / RTI >

This treatment is shown in Scheme 2

The use of the oxazole carbonyl diimidazole of formula (')' Jan y Sekieiche ', Bichard Henry

5th

Λ.

other researches similarly, N, Opened, isolated and characterized (öúrienor, 91.02.1989; Mari © Mrs / uvfo Járná

Another method known in the art and frequently used is the preparation of oxazolidinediones of the general formula (IV) by reaction of the amylic acids of formula (IV) (Huang, Howard Jones, Clock J. Los, Bemard ioev EP 114667). 12.01 <1983; forymond 23. Fowssc / yeh, Jerry 1F, S'ri'cs, John T, onnk, Howard Jones, CJS 4,080,295 .03 Mar 1983,; rinton '7h.Wzariu _t Aenji ./support. «©, Pariuiwri Fanag / da, Jbkehria ATyorib -fPaíanabe EP 215335, 23.01

In another known process, an additional phosgene derivative, Rchloromethyl chlorononate, is used to prepare the oxazolidinediones of formula (II)

FöWíasM Aén / 7 Ifí & ve, Dec. 29, 1987).

3uáe /? An ö / ms / u, & 7j wh t ÍThm.n «.oe

Another is known

In the district, less toxic lake phosgene is used instead of phosgene.

Cá / RP 1279665 23.07.2002)

It is also known in the art to convert a compound of formula (IV) into a Naloxoxy (aralkoxyl) carbonyl derivative and this derivative to produce a mesyl compound.

European Patent No. 1,197,490 (Inventors; Ch & ng-Mmg Ckett, Fn-Líöng Lm, FoChíeh Ctó, Ü / ne, Whmag Ifa, filed May 15, 2004!). reacting the amino acids of formula IV (wherein R * is phen is ebi) with 1.2 molar equivalents of ebichloroformate in dichloroethane, followed by the reaction of the compound of formula V wherein R * R ² and R ³ are ethyl, with a carboxy activating reagent such as thionyl chloride, acetyl chloride. or with acetic anhydride to form the corresponding oxazolidinedione of formula II. The process is illustrated in the Scheme.

the 3.

compound of the general formula

In our research, we aimed at the general formula (11). using cyclic anhydrides (IV) as illustrated in Scheme 4.

By repeating the process of European Patent I 197 490 and following the reaction by chromatography, it has been found that, when the compound of formula (VI) is used in only a small molar excess, the starting material of formula (IV) is very slowly consumed. from the reaction mixture and the expected reaction product of formula (V) is similarly slow. Chromatographic analysis shows that a desired by-product is present in addition to the desired reaction product of formula (V) after consumption of the starting material.

The surprising discovery of the present invention is that when used in an amount of less than 2 molar equivalents of the compound of formula (VI) per molar amount of the compound of formula (IV), the reaction proceeds rapidly and homogeneously. Isolation and characterization of this product have shown that it is an armchair of the compounds of formula (I). wherein R 'is an aromatic hydrocarbon group containing one or more rings, optionally one or more. halogen, alkyl, alkoxy, hydroxy, or amino, or a linear or branched alkyl group of 1 to 6 carbon atoms, R ² is a linear or branched alkyl group of 1 to 6 carbon atoms and IV is a carbon atom of 1 to 6 carbon atoms. a linear or branched alkyl group or a linear or branched alkyl group of 1 to 6 carbon atoms containing one or more rings as an aromatic hydrocarbon group. Compounds of formula 0)

As a structure similar to the compounds of the formula amlnosic acid, they are known in the state of the mixed Lka. These compounds are generally prepared from N-alkoxy (aralkoxy) -carbonyl-amino acids (for general synthesis see Org Synth. Vet 63, 160-168, Ed Wltey 1985). The reaction is carried out in an organic solvent, usually Ν, Η-dimethylformamide or tetrahydrofuran, in the presence of H-methylmofoline, so that the starting compound can be reacted with 1 molar equivalents of alkyl or alkylaryl chloroformate at -20 ° C. According to the state of the art, the preparation of the mixed anhydrides below is intended to increase the reactivity of the carboxy group in the next synthesis step, which may be a peptide coupling reaction (D. Jukie et al., Eur. X Med. Chem. 1991, 921), chain extension (J, Cooperet ah, X Chem. Soc. Chim. Aeta, 786; B, Garrigues et al., Ladder, Letters 1986, 1685) or the karhoxy group reduction to hydroxy esopor. (V. Constantlnou-Kokoton, Org. Prep, Proeed.

bt 1999. 237; V. Capíar et ah. Croaöca Cfeim. Acta 2003.23.).

It is not known in the art to provide a process for converting derivatives of formula (I) into oxazo

The present invention is also based on the surprising realization that it. Reaction of compounds of formula (I) with thionyl chloride (II) oxazolldin-dione derivatives. This process provides an excellent opportunity for the preparation of compounds of formula II on an industrial scale. Namely, the new one. The intermediates of formula (.1) can be prepared by rapid reaction, pure and homogeneous, and isolated in particularly high purity. The general formula (I) can be easily and simply converted to the corresponding general formula (II).

Oxazolidinediones of formula (II) are important intermediates in the preparation of compounds of formula (ΙΠ).

general . is an aromatic hydrocarbon group containing one or more rings, optionally substituted with one or more substituents selected from the group consisting of halogen, alkylalkoxy, hydroxy or amino, or a linear or branched C 1-6 alkyl group;

· $ '

KI is a straight or branched alkyl group of 1 to 10 carbon atoms,

R ⁴ is a straight or branched alkyl group of 1 to 6 carbon atoms, optionally substituted,

R represents a hydrogen atom or a linear or branched alkyl group having from 1 to 10 carbon atoms or a sub-formula of formula VII which is part of the ring system C and represents a linear or branched linear or branched alkyl group of 7 carbon atoms aromatic hydrocarbon containing from 1 to 6 carbon atoms or 1 to 6 seconds of hydrogen atom ^. one or one substituent.

Compounds of formula (III) include important antihypertensive drugs such as ramipril and enalapril.

Interpretation of the present patent clauses is as follows.

is intended to mean a linear or branched saturated aliphatic hydrocarbon group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl.

1-pronik il, 1-boutique tertiary-hutil stl

The term "aryl" refers to an aromatic hydrocarbon group containing one or more rings which may carry one or more substituents selected from the same or different halogen, alkyl, alkoxy, hydroxy or amino groups.

"Aralkyl" refers to the above alkyl group containing one or more of the above aryl groups as substituents, e.g., benzyl, phenO-ethyl, β, β '' - d, and the like.

A preferred compound of formula (I) is that wherein R * is phenyl, R ^c and R 'are each ethyl. This compound is a valuable pharmaceutical intermediate that can be used to produce a narcotic pressure-reducing drug known internationally as ramipril.

The compounds of formula (I) of the present invention may be prepared by reacting a compound of formula (IV) in an organic solvent with at least 2 molar equivalents of a compound of formula (VI) in the presence of an acid scavenger. molar equivalent. preferably in an amount of 2.2 molar equivalents &lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; based on the amount of starting material (TV).

Preferably, the organic solvent is tetrahydrofuran. especially ethyl acetate, dichloromethane or acetone, preferably acetone

Organic amines (e.g., trlethylamine, pyridine, morpholine) or inorganic salts (e.g., sodium carbonate, potassium carbonate) may be used as the acid scavenger. Triethylamine is particularly preferably used as an acid acceptor.

In the starting compounds of formula (VI), X is preferably chlorine; in compounds of formula (VI), IV is preferably

The reaction proceeds readily at room temperature. The reaction time is short, about one hour.

It is a further object of the present invention to convert the compounds of formula (I) to the corresponding compounds of formula (I) by treating a compound of formula (I) with ionic chloride in an organic solvent.

Ttonyl chloride in an equimolar amount to a compound of formula (I) or in a molar excess of 1.5 to 2.5 times;

As starting material a compound of formula (I) is preferably used in which ^R? R ² and R ^{2 are} phenyl; ¹ is ethyl. In this case, the compound of formula (II) prepared is an intermediate used in the preparation of an antihypertensive drug called ramipril.

In the process, the solvent is preferably aprotic organic solvents, preferably

The reaction proceeds easily at low temperatures. The reaction was carried out for 5 ^hours. It can be carried out at temperatures between € and temperatures. The reaction time is a few hours.

The above process has the advantage that the intermediates of formula (1) can be prepared in a uniform, high purity form, and that the conversion of the compounds of formula (I) into the compounds of formula (II) can be carried out in a simple manner on an industrial scale.

The compounds of formula (III) can be converted into the compounds of formula (111) using methods known in the art.

m in the manufacture of chemicals.

which

R ^! is an aromatic hydrocarbon group containing one or more rings, optionally containing one or more halogen, alkylalkoxy, hydroxy or amino groups, or branched or unbranched alkyl substituents having from 1 to 6 carbon atoms;

waving 1-6 s <

straight, branched or branched

CSi · <“

R ' ^! is an optionally substituted C 1 -C 6 alkyl group;

R is a hydrogen atom or a straight or branched carbon chain of 1 carbon atom, or a partial formula (VII) of the formula (HI) is a part of the strain systems of the formula (C);

R ⁶ is hydrogen, C 1-6, straight or branched. an alkyl group or a linear or branched alkyl group of 1 to 6 carbon atoms containing an aromatic hydrocarbon group containing one or more rings in the presence of a sulfur substituent,

R ⁵ and R ⁶ 'to a fii) The general formula of the compound prepared as described above, (wherein R ^l and R are as defined above), formula (VIII), formula compound wherein R ⁴ of the above-defined, or a salt thereof is reacted. and, if desired, the ester of a compound of formula (III), esterified by a tertiary or hydrochloric acid reagent, may be linear, branched or branched.

i k

R ^t? 1-6 or 1-6 edges are straight or branched chain alkyl groups containing one or more ring aromatic hydrocarbyl substituents, converted to the corresponding carboxylic acid <IH) wherein R * is hydrogen, and if desired, the resulting (III) ) is converted to a salt thereof.

The compounds of formula (VIII) may be used in the form of their salts, such as hydrogen halide (e.g. hydrochloride) or aryl or alkyl sulfonate (e.g. tosylate).

The reaction of the compounds of formula (11) and (VIII) may be carried out in a manner known in the art

Conversion of esters (wherein R * is C 1 -C 6 straight or branched alkyl or C 1 -C 6 straight or branched alkyl containing one or more aromatic hydrocarbon substituents) to the corresponding carboxylic acid ( in which R ** is hydrogen) and salts of the carboxylic acid can be prepared using methods known in the art.

A further object of the present invention is to provide a process for the preparation of ramipril by reacting a compound of formula (at) wherein R ⁵ is fe with ethyl, tb, &lt; RTI ID = 0.0 &gt;&lt; / RTI &gt; benzyl-e

The reaction is carried out according to methods known in the art using an organic solvent and an acid scavenger. Organic solvents are preferably ethyl acetate

The reaction comprises acidic organic bases.

-amin or inorganic

I Sodium or Potassium ·

The reaction is carried out at a temperature of 5 to 10 ° C. The reaction time is usually one hour.

The benzH group is removed from the product by catalytic hydrogenation. Precious metals, preferably palladium and platinum, especially palladium, are used as catalysts.

The use of organic organic solvents, preferably ethanol, is further directed to a process for the preparation of ramipril by reacting a compound of formula (III) tn wherein R ¹ is phenyl, R ²

t. Reacts with (S, S, S) ~ 2-aza-bicyclo [3.3.3] octane-3-carboxylic acid

The coupling reaction is preferably carried out in a tetrahydrofuran solvent, refluxing the reaction mixture for several hours.

The process according to the invention has the advantage that the product of formula (I) can be obtained in the form of a homogeneous, high purity product, and that the conversion of the compound of formula (I) into the compound of formula (II) Further, the following examples will illustrate without limiting the invention to the examples.

Ethyl-2 (S) - {'N-etho-carbohydrate' N - (1 (S) - (ethoxycarbomyloxycarbonyl) 'ethyl] 2.79 g (0.01 mol) N' [1- (5) " The Toxicol ^: laryloyl-3-pyridyl] -X-base was suspended in 25 ml of acetone and 2.02 g (2.8 ml; 0.02 mol) of riethylamine were added. The reaction mixture is stirred until the starting material is dissolved, and 2.39 g (2.1 ml, 0.022 mol) of ethyl chlomfonnate are added dropwise so as to maintain the reaction temperature between 10 and 20 ° C. The reaction mixture was then stirred at room temperature for one hour. After stirring, the reaction mixture was cooled and stirred for 30 minutes at -2-2 ° C. The crystalline solid was filtered off and the filtrate was evaporated. The product is obtained in the form of a viscous oil. Yield 4.20 g (approximately 100%).

-1,

27.1742, 17j € DC%) d 7.25 (5H, m, ArH _M ); 4.55 (IK, t, FhCH ₂ CH ₂ CH), 4.34 (2H, q, > 7.0 Hz, OCBCH 3), 4.30-4.05 (5R m, Ala aH, 2 x OCBCH-Q; 2.85-2.75 (2H, ni FhCHA 2:35 to 2:20 (IH, m, FhCH _{2 CH2),} 2.20-1.95 (1H, m, PMMCHA 1:55 (3H, d,> 7.0 Hz, Ala-CIH); 1:35 (3H, t,> 7.0 Hz , OCIHCHA 1.27 (OH, t,> 7.3 Hz, 2 x

OCH2CH3).

Elemental analysis for CajH ^ NOg (423.47)

Found: C, 59.56; H, 6.90; N 3.31,

Found: C, 59.16; H, 6.81; N, 3.41.

N '- (1- (S) -Exoxycarbonyl-3-fentanyl-propyl) -4- (S) -methyl-oxazolidine-2,5-diol (4.23 g; 0.5 mmol) Dissolve i-tert-triethoxycarbonyl-N-methyl-1-acetoxycarbonyl-oxycarbamoyl-ethyl-4-phenylbutyrate in 10 mL of dichloromethane and add dropwise thereto L93 g (1.18 mL, 65 moles) of thionyl chloride in The reaction mixture is stirred at room temperature for 4.5 to 5 hours, and the solvent is then removed from the reaction mixture by evaporation. The brown viscous oil is kept at 3.5 ml msdl. dissolved in tert-butyl ether, stirred at &lt; 10 &gt; -5 &lt; 0 &gt; C and the precipitated crystals were collected by filtration to yield 1.95 g (64%) of crystals, m.p.

2.79 g (0.01 mole) of N- [1- (5) -ethoxy-carbonyl-3-methylpropyl] -1-alanine are suspended in 25 ml of acetone and 2.02 g (2.8 ml: 0.5 mole) of trieblamine are added to the suspension. . The reaction mixture was stirred until the solid dissolved, and 2.17 g (1.9 mL, 0.02 mol) of ethyl tetroformate was added dropwise, maintaining the reaction temperature between 10 and 20 ^° C. After stirring at room temperature for 1 hour, the reaction mixture was cooled and stirred at--2 to 2 ° C for an additional 30 minutes. The crystalline solid was filtered off and the filtrate was evaporated to dryness.

The residual oil was dissolved in dichloromethane (10 mL), bound to 5 ° C and treated with thiomium chloride (1.93 g, 1.18 mL, 0.0165 mole) while maintaining the reaction temperature at 5-10 ° C.

After addition of 1-chloride, the reaction mixture was stirred at room temperature for 4.5-5 hours. The solvent was distilled off and the residual brown viscous oil was dissolved in 3.5 mL of methyl tert-butyl. with ether. The solution was collected by filtration at -10 ° C to -5 ° C.

Yield 1.95 g (64%) of crystalline material.

° C

IR ^(cm-5): 2980,2930,1845,1770,1725, ^{H NMR (CDCri) <5 7.25 (5H, m, Ar H _{2 6th);} 4:40 (lH, q,> 7.0 Hz, the Ab>;. 456 (H, dd,> 5.0 Hz, PhCkRCTGCH) 4.23 <2H, <> 7.1 Hz, 0CMQ 2.80 m, PbCH _2); 2.50-2.40 (1H, m, PhCH> CHQ: 255-2.25 (HL m,

1.54 (3H, d,> 7.0 Hz, _Ala-CH3>, 1.28 (3H, t,> 7.1 Hz,

Elemental Analysis (30533)

Calculated: C, 62.94; H, 6.27; N, 4.59%.

Found: C, 62.90; H, 6.15; N, 4.67%.

(2S, 3aS, 6aS) ~ 1 ~ [(2S) -2 ~ [[(IS) -1 - (Ethoxy)

carboxylic acid <

pH] amino] ~ 1-oxopropopropyl] 0 g; (0.0887 mol) of benzyl ester hydrochloride (δ, S, 5) -2-azabicyclo (3.3.0] octane-3-carboxylic acid and 9.9 g (13.5 ml: 0.0975 mol) of ethyl acetate are added to 125 ml of ethyl acetate. 32.5 g (0.1065 mol) of N- (1- (5) -ethyloxycarbonyl-3-methylpropyl-4- (5) -ethyl'-oxazobin-2,5-dio®) were added dropwise with 125 ml of ethyl acetate. while maintaining the temperature of the reaction mixture at 5 to 10 ° C. The reaction mixture is then stirred at room temperature for four hours,

After stirring, the reaction mixture is cooled to 0-5 ° C and the salt.

we filter out the brew. Wash twice with 200 to 200 ml water with magnesium sulfate:

dried and evaporated. In this way, crude ramipril benzyl ester is obtained in 440 ml of ethanol. hydrogenation in the presence of palladium on activated carbon. The reaction mixture was evaporated and the residue was stirred with diisopropyl (260 mL) and stirred for one hour at 0-5 ° C to give 32.2 g (87%) of crude product, m.p.

The product was recrystallized from diethyl ether / diisopropyl ether to give 27.3 g (74%) of the purified product.

I07-WC,

The IR and tI-NMR spectra of the products are the same as those of the "Certified Retention Standard" issued by the United States Pharmacopoeia

Elemental Analysis C, _S H ₃₂ N ₂ O _S (416.53)

Calculated: C, 66.32; H, 7.74; N, 6.73%.

Found: C, 6637; H, 7.75; N, 6.64%.

Claims (15)

Donate your liver in the wake R is an aromatic hydrocarbon group containing one or more rings, optionally having one or more substituents selected from alkylalkoxy, hydroxy or amino, or a straight-chain alkylene group having 1 to 6 carbon atoms; ande is a linear or branched carbon monoalkyl group having 1 carbon atom; and is a linear or branched alkyl group of 1 to 6 carbon atoms or a linear or branched alkyl group of 1 to 6 carbon atoms containing an aromatic hydrocarbon group containing one or more rings as substituents: with the proviso that when R 'is ethyl and IV is ethyl, it is different from methyl. According to claim 1, k 'is an ethyl compound and R' is an ethyl group. meaning A process for the preparation of a compound of formula (I) according to claim 1, wherein R 'and R' · are as defined in claim 1, wherein t is a compound of the formula wherein R * and IV are as defined above in an organic solvent, in the presence of an acid scavenger, with at least 2 molar equivalents of the compound of formula VI, wherein X is halogen or tertiary butyloxycatonyloxy. and R ' ⁷ is as defined below. Process according to claim 3, characterized in that 1 molar equivalent of the compound of formula (IV) is preferably in the range of 2 to 3 molar equivalent of the compound of the formula (VI) 5. A .3. The process according to claim 1, wherein the organic solvent is tetrahydrofemn, ethyl acetate, dichloroethane or aetone, 6. The process of claim 5 wherein the organic solvent is aether. The process of claim 3 wherein the acid scavenger is an organic amine or an inorganic salt. 8. A process according to claim 7, wherein the organic amine is triethylamine, pyridine or mortoline, and the inorganic salt is sodium carbonate or potassium carbonate. The process according to claim 8, wherein the acid is amine The process according to claim 3, wherein X is chlorine and R is ethyl. Ϊ ·} 11. A process for the preparation of compounds of formula 11 wherein R? and R 2 is the same as defined in claim 1 wherein R ¹ , R ² and R 1 are as defined in the organic formula 32. The process according to claim 1, wherein the starting material in the compound of formula (I) used is R 1 ^. denotes phen The process according to claim 31 or 12, wherein the solvent is an aprotic solvent. because it is organic 14. A process according to claim 13, characterized in that it is an organic solvent 15. A method (Π) for preparing compounds of formula I wherein ^R! and IV are as defined in claim 1, characterized in that a formula (IV) afforded by R ^J and R ² are as defined above, in an organic solvent, at least 2 molar equivalents (VI) Ké acid acceptor, wherein X and R ³ represents the shoot claim jd compound is an organic compound of the same shoot, A15, process according to claim i, characterized in that the compound with the starting material (IV) R ^J is phenyl, ^R2 is of the formula thus obtained (I) and in the compound of formula (VI), V is ethyl and X is chlorine. 17, 15 or horse. Process according to claim 1, characterized in that 1 mol of the compound of the formula IV is present in an amount of 2 to 3 molar equivalents, preferably 2 molar equivalents of the chemical of the formula VI 18. The process according to any one of claims 15-17, wherein the acid acceptor is an organic amine or an inorganic salt. The process according to claim 18, wherein the organic amine is triethylamine, phidine or morphine. Process according to claim 19, characterized in that it is an acid acceptor 21. These compounds · To his drink, in which • í R ^! means an aromatic hydrocarbon group containing one or more rings, optionally having one or more alkyl substituents selected from the group consisting of alkyl, alkoxy, hydroxy or amino, or a linear or branched alkyl group of 1 to 6 carbon atoms; R ² is C 1 -C 6 straight or branched alkyl R ² is optionally substituted alkyl; R is hydrogen, alkyl or part of the formula (V6) of the formula (111); R &lt; 1 &gt; is hydrogen, C 1-6 straight or branched alkyl or C 1-6 straight chain or branched chain alkyl containing an aromatic hydrocarbon radical containing one or more rings in a sulfur substituent; ring system: ve. a compound of formula (II) prepared according to claim 11 or 15, wherein R ¹ and R ² are as defined above, R ⁴ , R ⁵ and R ^{6 of} formula (VIII) are as defined above or a salt thereof. and optionally the ester of formula (HI) so prepared wherein R * is a linear or branched C 1 -C 6 linear or branched alkyl group having from 1 to 6 carbon atoms which is substituted with one or more rings. aromatic hydrocarbon containing group may contain, converted to the corresponding (III) to the carboxylic acid of the formula wherein ^R6 is hydrogen, and optionally converting a compound needle in a salt. 22. Process for the (10) In the general formulas for the preparation of compounds wherein R ⁵ is phenyl, R ^": represents an ethyl group, Ro is hydrogen, and in formula (III), (VII), sub-formula corresponding to the group of formula (C) wherein , how is it. or a compound of formula (II) according to claim 15, wherein R * and R ² are as defined in the scope of the present claim, with (S, S, S) -2-azabicyclo [33.0] octane-3-carboxylic acid benzyl ester or a salt thereof; lűdroklorídjával preferably reacted, and then the benzyl group by catalytic hydrogenation r \ r ^2nd r 23..Eljárás (III) vegvület formula animal is as defined in claim 22 wherein, berries compound (11) prepared according to claim 11 or R ⁵ and Claim ⁶ wherein ^R! is phenyl, ^R2 is ethyl, (S, S, S) ~ 2 ~