WO2016079109A1

WO2016079109A1 - Process for the preparation of perhydroquinoxaline derivatives

Info

Publication number: WO2016079109A1
Application number: PCT/EP2015/076801
Authority: WO
Inventors: Michael Soeberdt
Original assignee: Dr. August Wolff Gmbh & Co. Kg Arzneimittel
Priority date: 2014-11-18
Filing date: 2015-11-17
Publication date: 2016-05-26

Abstract

The present invention relates to a process for the preparation of perhydroquinoxaline compounds according to the general formula (1) comprising the steps of a) reacting 5,6,7,8-tetrahydroquinoxalin-5-ol with a protection agent; b) catalytically hydrogenating the PG protected 5,6,7,8-tetrahydroquinoxalin-5-ol; c) chiral resolution of the racemic PG protected cis,cis-decahydroquinoxalin-5-ol; d) reacting the PG protected (4aS,5R,8a S)-decahydroquinoxalin-5-ol with a reagent X²-R¹; e) deprotecting the PG protected hydroxy group; f) reacting the α,β-aminoalcohol with sulfuryl chloride; g) reacting the 1,2,3-oxathiazolidine 2,2-dioxide with an amine HNR²R³; h) reacting the cis,trans-5-amino-decahydroquinoxaline with an activated carboxylic acid derivative ZCH₂COY to provide for the compound of formula (1); i) optionally converting the compound of formula (1) to pharmaceutically acceptable salts by reaction with the corresponding acid. Further, the invention relates to PG protected cis,cis- decahydroquinoxalin-5-ol, PG-protected (4a S,5R,8a S)-decahydroquinoxalin-5-ol and PG protected (4a R,5S,8a R)-decahydroquinoxalin-5-ol, and its preparation in enantiomeric pure forms.

Description

PROCESS FOR THE PREPARATION OF PERHYDROQUINOXALINE DERIVATIVES

The present invention relates to a process for the preparation of perhydroquinoxaline derivatives being useful as medicaments, particularly as analgesics, antipruritic and antiinflammatory agents, as well as to a process for the preparation of intermediates of these perhydroquinoxaline compounds, and to the intermediates themselves.

Treatment of pain is of great importance in medicine. Analgesic agents as a rule act by activating opioid receptors. Conventional opioids, such as morphine, are thus opioid analgesics which are often employed in clinical pain therapy because of their potent analgesic action. These activate the μ receptor. However, undesirable side effects of such pain therapy are sometimes considerable centrally mediated side effects, such as respiratory depression, vomiting and bradycardia. Possible psycho-dependencies are furthermore a disadvantage. In view of the large number of types of pain and inflammation and diseases associated with pain and inflammation, there is a great need for new active agents to treat these symptoms as well as economic and efficient processes for their preparation.

WO2009/080745 relates to perhydroquinoxaline derivatives useful as analgesic agents.

WO2014/184355 being published after the priority date of the present invention relates to a process for the preparation of perhydroquinoxaline derivatives. However, the process disclosed in WO2014/184355 lacks the additional step c) of the present invention, namely the step of chiral resulution.

The invention was based on the object to provide novel and improved processes for the preparation of perhydroquinoxaline compounds which can be used as pharmaceutical active compounds, in particular for combating pain, pruritus and inflammation. This object is achieved by the provision of a process for the preparation of perhydroquinoxaline compounds according to the general formula (I) as shown below or a pharmaceutically acceptable salt thereof:

wherein:

R¹ is chosen from the group comprising H; Q-Qo-alkyl; Q-Cio-cycloalkyl;

(COO(Ci-Cio-alkyl);

phenylalkyl with CrCe-alkyl, wherein the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising halogen, CrC₆- alkyloxy, NH₂, NH(Ci-C₅-alkyl), N(Ci-C₅-alkyl)₂, OH, S0₂(Ci-C₅-alkyl), SO(Ci-C₅-alkyl), CF₃, CN, N0₂, S0₂N(Ci-C₅-alkyl)₂, S0₂NH₂, S0₂NH(Ci-C₅-alkyl), S0₂NH(aryl), S0₂NH(phenyl) and/or S0₂NH(heteroaryl);

CrCio-acyl; heterocyclylacyl containing one, two, three or four hetero atoms chosen from the group comprising NH, O and/or S; phenylacyl, wherein the acyl radical is a Ci-C₆-acyl radical and the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising halogen, Ci-C₆-alkyloxy, COO(Ci-C₆- alkyl), NH₂, NH(Ci-C₅-alkyl), N(Ci-C₅-alkyl)₂, CONH₂, CONH(Ci-C₆-alkyl), CON(Ci-C₆- alkyl)₂, OH, S0₂(Ci-C₅-alkyl), SO(Ci-C₅-alkyl), CF₃, CN, N0₂, S0₂N(Ci-C₅-alkyl)₂, S0₂NH₂, S0₂NH(Ci-C₅-alkyl), S0₂NH(aryl), S0₂NH(phenyl) and/or S0₂NH(heteroaryl);

mono-, bi- or tricyclic heteroaryl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S;

mono-, bi- or tricyclic heteroarylalkyl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S, wherein the alkyl radical is a C -C alkyl radical;

mono-, bi- or tricyclic heteroarylacyl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S, wherein the acyl radical is a C -C - acyl radical and the heteroaryl radical can be substituted by one or more identical or different groups chosen from the group comprising halogen, Ci-C₆-alkyloxy, COOiC Ce-alkyl), NH₂, NH(Ci-C₅-alkyl), N(Ci-C₅-alkyl)₂, CONH₂, CONH(Ci-C₆-alkyl), CON(Ci-C¼-alkyl)₂, OH, CF₃, CN, N0₂, and/or S0₂NH₂; mono-, bi- or tricyclic (heteroaryl)alkenylacyl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S, wherein the acyl radical is a Ci-C₆-acyl radical and the alkenyl radical is a C₂-C₆-alkenyl radical;

C(0)NH(Ci-Cio-alkyl); C(O)N(C₁-C₁₀-alkyl)₂, wherein the two alkyl radicals may form a saturated substituted or unsubstituted ring with the N atom; C(0)NH(aryl); C(0)NH(benzyl); C(O)(C₃-C₁₀-cycloalkyl); COO(aryl); COO(benzyl); COO(C₃-C₁₀- cycloalkyl);

(CH₂)_g-COOH, wherein g is 1, 2, 3 or 4; (CH₂)_h-COO(Ci-C₆-alkyl), wherein h is 1, 2, 3 or 4; (CH₂)i-CONH₂, wherein i is 1, 2, 3 or 4;

C(0)NH-(CH₂)_j-COOH, wherein j is 0, 1, 2, 3 or 4; C(0)NH-(CH₂)_k-COO(Ci-

Ce-alkyl), wherein k is 0, 1, 2, 3 or 4; C(0)NH-(CH₂)i-CONH₂, wherein 1 is 0, 1, 2, 3 or 4;

COO-(CH₂)_m-COOH, wherein m is 0, 1, 2, 3 or 4; COO-(CH₂)_n-COO(Ci-Ci₀- alkyl), wherein n is 0, 1, 2, 3 or 4; COO-(CH₂)_p-C(0)NH₂, wherein p is 0, 1, 2, 3 or 4; C(O)-

(CH₂)_q-COOH, wherein q is 0, 1, 2, 3 or 4; C(O)-(CH₂)_r-COO(C₁-C₁₀-alkyl), wherein r is 0, 1, 2, 3 or 4; C(0)-(CH₂)_s-C(0)NH₂, wherein s is 0, 1, 2, 3 or 4; C(0)-(CH₂)_t-C(0)NH(d-C₆- alkyl), wherein t is 0, 1, 2, 3 or 4; C(0)-(CH₂)_u-C(0)N(C₁-C₆-alkyl)₂, wherein u is 0, 1, 2, 3 or

4;

C(0)-(CH₂)_v-NH₂, wherein v is 0, 1, 2, 3 or 4; C(0)-(CH₂)_w-OR', wherein w is 0, 1, 2, 3 or 4 and R' is H or CrCe-acyl; C(0)-(CH₂)_x-C(0)NH-(CH₂)_yC(0)NH₂, wherein x is 0, 1, 2 or 3 and wherein y is 0, 1, 2 or 3;

S0₂(Ci-C₆-alkyl); S0₂-(CH₂)_z-heteroaryl, wherein z is 0, 1, 2 or 3; S0₂(CH₂)_a- heterocyclyl, wherein a is 0, 1, 2 or 3 and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising halogen, OH, CN, oxo and/or CrCe-alkoxy; S0₂N(C₁-C₆-alkyl)₂ or SC^NHCCrCe-alkyl), wherein the alkyl radical can be substituted by halogen, C₁-C₄-alkoxy and/or OH; S0₂NH(C₃-C₆- cycloalkyl); S0₂NH-C(0)0(C₁-C₆-alkyl);

R 2 , R 3 are in each case identical or independent of each other and are chosen from the group comprising H; C Cio-alkyl; Q-Cio-cycloalkyl,

or

R 2 and R 3 form, together with the nitrogen to which they are bonded, a saturated or unsaturated 3- to 8-membered N-heterocycle, wherein this can be substituted by one or more identical or different groups chosen from the group comprising halogen, OH, C - C₄-alkyloxy, COOH, COO(Ci-Ci₀-alkyl), CONH₂, CONH(Ci-Ci₀-alkyl), CON(Ci-C₁₀- alkyl)₂, CN, and/or 0-C(0)(Ci-C₆ alkyl);

Z is chosen from the group comprising phenyl, which can be substituted by one or more identical or different groups chosen from the group comprising halogen, CrCs-alkyl, CrCs-alkoxy, NH₂, NH(Ci-C₅-alkyl), N(Ci-C₅-alkyl)₂, OH, S0₂(Ci-C₅-alkyl), SO(Ci-C₅- alkyl), CF₃, CN, N0₂, S0₂N(Ci-C₅-alkyl)₂, S0₂NH₂, S0₂NH(Ci-C₅-alkyl), S0₂NH(aryl), S0₂NH(phenyl) and/or S0₂NH(heteroaryl), wherein the substituents may form a ring;

a mono- or bicyclic aryl or heteroaryl containing one or two hetero atoms chosen from the group comprising N, O and/or S, wherein the aryl or heteroaryl group can be substituted by one or more identical or different groups chosen from the group comprising halogen, Ci-C₄-alkoxy, NH₂, NH(d-C₅-alkyl), N(Ci-C₅-alkyl)₂, OH, S0₂(Ci-C₅-alkyl), SO(Ci-Cs-alkyl), CF₃, CN, N0₂, S0₂N(Ci-C₅-alkyl)₂, S0₂NH₂,

S0₂NH(aryl), S0₂NH(phenyl) and/or S0₂NH(heteroaryl), wherein the process comprises the following steps:

a) reacting 5,6,7, 8-tetrahydroquinoxalin-5-ol with a protection agent X^PG in the presence of a base to introduce a protecting group PG at the alcohol function, wherein X¹ is a suitable leaving group; b) catalytically hydrogenating the PG protected 5,6,7,8-tetrahydroquinoxalin-5-ol obtained in step a) under stereoselective reduction of the pyrazine ring to obtain PG protected cis,cis-decahydroquinoxalin-5-ol; c) chiral resolution of the racemic PG protected cis,cis-decahydroquinoxalin-5-ol obtained in step b) into its enantiomeric forms, namely PG protected (4aS,5R,8aS)- decahydroquinoxalin-5-ol and PG protected (4aR,5S,8aR)-decahydroquinoxalin-5-ol; d) reacting the PG protected (4aS,5R,8aS)-decahydroquinoxalin-5-ol obtained in step c) with a reagent X 2 -R 1 to regio selectively introduce the substituent R 1 at the 1-N atom of the (4aS,5R,8aS)-decahydroquinoxalin-5-ol, wherein X is a suitable leaving group; e) deprotecting the PG protected hydroxy group in the product obtained in step d) to provide for the corresponding ,β-aminoalcohol; f) reacting the ,β-aminoalcohol obtained in step e) with sulfuryl chloride in the presence of a base to provide for the corresponding 1,2,3-oxathiazolidine 2,2-dioxide; g) reacting the 1,2,3-oxathiazolidine 2,2-dioxide obtained in step f) with an amine

HNR 2 R 3 , followed by treatment with an acid to introduce the residue -NR 2 R 3 under inversion of the stereogenic center to provide for (4aR,5S,8aS)-5-amino-decahydroquinoxaline; h) reacting the (4aR,5S,8aS)-5-amino-decahydroquinoxaline obtained in step g) with an activated carboxylic acid derivative ZCH₂COY, wherein Y is a suitable leaving group, preferably with an acid chloride Z-CH₂COCl, under acylation in 4-position to provide for the compound of formula (1); i) optionally converting the compound of formula (1) obtained in step h) to pharmaceutically acceptable salts by reaction with the corresponding acid.

The definitions of R 1 to R 3 and Z as used in the reaction steps are the same as in the definition of formula (I).

Generally speaking, the present invention basically relates to a process for the preparation of perhydroquinoxaline compounds according to the general formula (1) as defined above comprising the steps of a) reacting 5,6,7, 8-tetrahydroquinoxalin-5-ol with a protection agent; b) catalytically hydrogenating the PG protected 5,6,7,8-tetrahydroquinoxalin-5-ol; c) chiral resolution of the racemic PG protected cis,cis-decahydroquinoxalin-5-ol; d) reacting the PG protected (4aS,5R,8aS)-decahydroquinoxalin-5-ol with a reagent X 2 -R 1 ; e) deprotecting the PG protected hydroxy group; f) reacting the ,β-aminoalcohol with sulfuryl chloride; g) reacting the 1,2,3-oxathiazolidine 2,2-dioxide with an amine HNR 2 R 3 ; h) reacting the cis,trans-5-amino-decahydroquinoxaline with an activated carboxylic acid derivative ZCH₂COY to provide for the compound of formula (1); i) optionally converting the compound of formula (1) to pharmaceutically acceptable salts by reaction with the corresponding acid. Further, the invention relates to PG protected cis,cis- decahydroquinoxalin-5-ol, PG-protected (4aS,5R,8aS)-decahydroquinoxalin-5-ol and PG protected (4aR,5S,8aR)-decahydroquinoxalin-5-ol, and its preparation in enantiomeric pure forms. It has been found, surprisingly, that the novel process according to the invention allows the preparation of perhydroquinoxaline compounds of formula (1) in a highly efficient and economic way. In particular, the process of the invention allows obtaining not only the perhydroquinoxaline compounds of formula (1) in high yields and selectivity but also intermediate compounds being valuable starting materials for further chemical syntheses. According to the process of the invention the compounds of formula (I) can be prepared in large scale. The compounds of formula (I) and certain intermediates can be isolated and purified by crystallization avoiding time-consuming and cost intensive column chromatographic separation steps. This leads to a distinct saving of costs and minimizes the waste of chemicals. Accordingly the process of the invention also significantly contributes to the protection of the environment.

The process of the invention is shown in the following reaction schemes. As explained by the accompanying description, the specific reaction conditions indicated in the respective reaction steps are for illustrative purposes only and in no way limiting the invention:

Reaction Scheme 1:

Synthesis of enantiopure perhydroquinoxalines with cis,trans stereochemistry

Optionally substituted perhydroquinoxalines with cis,trans stereochemistry can be obtained in enantiomerically pure form as shown in Reaction Scheme 1. Racemic 5,6,7,8- tetrahydroquinoxalin-5-ol can be protected with a bulky protecting group PG by reaction with a reagent X^PG such as tert-butyldimethylsilyl trifluoromethanesulfonate or tert- butyldimethylsilyl chloride in the presence of a base like 2,6-lutidine or imidazole in a solvent such as DCM. A stereoselective reduction of the pyrazine ring can be achieved by hydrogenating the protected 5,6,7, 8-tetrahydroquinoxalin-5-ol with 1-10 bar hydrogen in the presence of a catalyst like platinum dioxide in a solvent such as a mixture of acetic acid and methanol or ethanol. The product with cis,cis configuration, O-protected (4aSR,5RS,8aSR)- decahydroquinoxalin-5-ol, is obtained exclusively. Separation of the two enantiomers can be achieved for example by addition of a suitable enantiomerically pure chiral acid like 1,4-di-p- toloyl-D-tartaric acid or 1,4-di-p-anisoyl-D-tartaric acid in a suitable solvent like ethanol or methanol resulting in crystallization of the diastereomeric salt of protected (4aS,5R,8aS)- decahydroquinoxalin-5-ol. The diastereomeric salt can be purified by recrystallization from a solvent such as a mixture of DCM and methanol. Following recrystallization the free base of protected (4aS,5R,8aS)-decahydroquinoxalin-5-ol is liberated by basic extraction of solution of the salt in a solvent like DCM with a base such as aqueous sodium hydroxide solution. Various substituents R¹ can be introduced regioselectively by reacting O-protected

(4aS,5R,8aS)-decahydroquinoxalin-5-ol with reagents X 2 -R 1 in an inert solvent like DCM or THF with or without a base such as triethylamine. Subsequently the hydroxy group is deprotected. A tert-butyldimethylsilyl protecting group, for example, can be removed by reaction with a reagent such as ammonium fluoride in a solvent like methanol under reflux conditions. Alternatively, methanesulfonic acid or HC1 can be used to cleave a TBDMS protecting group. The ,β-aminoalcohol thus obtained is reacted with sulfuryl chloride in the presence of a base like triethylamine in an inert solvent such as DCM at reduced temperature to yield the corresponding 1,2,3-oxathiazolidine 2,2-dioxide. The residue -NR 2 R 3 can be introduced by reacting optionally substituted 1,2,3-oxathiazolidine 2,2-dioxide with an amine HNR 2 R 3 in a solvent like acetonitrile at elevated temperature followed by treatment with an acid such as aqueous hydrochloric acid. The reaction takes place under inversion of the stereogenic center. Therefore, a compound with cis,trans substitution, optionally substituted (4aS,5S,8aS)-decahydroquinoxalin-5-amine, is obtained exclusively. Acylation in 4-position can be performed by reacting optionally substituted (4aS,5S,8aS)-decahydroquinoxalin-5- amine with an acid chloride Z-CH₂COCl in a solvent like DCM with or without the presence of a base such as DIEA or TEA. Alternatively, other methods known for coupling amides to amines can also applied. Acids Z-CH₂COOH can be activated e.g. by formation of anhydrides or mixed anhydrides or by using activating groups like carbodiimides and triazolols. The target compounds can be used as such or being converted to pharmaceutically acceptable salts such as a fumarate, tosylate or L-tartrate by reacting the free base with the corresponding acid, e.g. fumaric acid, p-toluenesulfonic acid or L-tartaric acid in a suitable solvent like acetone or THF. The salt of the final product can be purified by recrystallization. In a specific embodiment of the invention, R can be a protecting group, e.g. a Boc, Cbz, benzyl, allyl, Alloc group, which is orthogonal to PG and can be cleaved once the residues -

NR 2 R 3 and -COCH₂Z have been introduced. Subsequent reaction with reagents X-R 1 as described above yields the target compounds.

Reaction Scheme 2:

Isolation of enantiomerically pure protected (4aR,5S,8aR)-decahydroquinoxalin-5-ol

Reaction Scheme 2 shows the isolation of protected (4aR,5S,8aR)-decahydroquinoxalin-5-ol from the racemic mixture by addition of a suitable enantiomerically pure chiral acid like 1,4- di-p-toloyl-L-tartaric acid or 1,4-di-p-anisoyl-L- tartaric acid in a suitable solvent like ethanol or methanol resulting in crystallization of the diastereomeric salt. The diastereomeric salt can be purified by recrystallization from a solvent such as a mixture of DCM and methanol. Following recrystallization the free base of protected (4aR,5S,8aR)-decahydroquinoxalin-5-ol is liberated by basic extraction of solution of the salt in a solvent like DCM with a base such as aqueous sodium hydroxide solution.

In general, the term "obtained in step" as used in the description of the reaction steps according to the invention is intended to include intermediate reaction steps, that means it is not necessary (but possible) to directly react the reaction product of one step in the subsequent step as claimed. In fact, the respective products obtained in any of the reaction steps a) to i) may be isolated and/or purified in a conventional manner (such as re-crystallization or distillation or other purification methods known to the skilled person) before being used in the subsequent reaction step. This also includes further reactions between the steps a) to i) used e.g. for purification purposes such as derivatization to intermediate products that can be purified more easily and/or efficiently etc. These reactions include conventional steps known to the skilled person. Alternatively parts of the process of the invention (namely two or more of the process steps a) to i)) may be carried out as "one pot synthesis" without isolation and/or purification of the intermediate reaction products. According to an embodiment of the invention the process consists of the process steps a) to i).

Preferably according to the present invention the respective process steps a) to i) are carried out as follows:

In step a) of the process of the invention the starting product 5,6,7,8-tetrahydroquinoxalin-5- ol is commercially available (such as from 2Daybiochem Co. Ltd., Zhuankou, Wuhan, China, Accel Pharmtech LLC, East Brunswick, NJ, USA, Ellanova Laboratories, New Haven, CT, USA and FCH Group, Chernigov, Ukraine). Alternatively it can be obtained according to a synthesis published in Houminer et al., J. Hetercyclic Chem. 17, 647 (1980). It can also be prepared starting with 5,6,7,8-tetrahydroquinoxaline via the acetate intermediate as published in Jiang et al., Chem. Commun. (2010), 46, 7259 and subsequent hydrolysis of the acetate. It can also be prepared according to the following reaction scheme:

Reaction Scheme 3:

Synthesis of racemic 5,6,7,8-tetrahydroquinoxalin-5-ol

5,6,7, 8-Tetrahydroquinoxaline can be oxidized with a peracid such as meta-chloroperbenzoic acid or monoperoxyphthalate hexahydrate in a solvent like DCM or water to yield the corresponding N-oxide (Leclerc and Fagnou, Angewandte Chemie, Int. Ed. (2006), 45, 7781). Acylation with a reagent such as trifluoroacetic anhydride or acetic anhydride in a solvent like DCM or toluene followed by treatment with a base like lithium hydroxide in a mixture of water and DCM yields racemic 5,6,7,8-tetrahydroquinoxalin-5-ol.

Moreover, the protection agent X^PG used in step a) of the process of the present invention may be any agent that contains a (bulky) protection group PG being suitable to protect a hydroxyl/alcohol function and a leaving group X¹ being cleaved by the reaction of step a). These agents are generally known to the skilled person. Preferably the protection agent is selected from the group of trialkylsilyl halogenides, such as TMS-C1, TIPS-Cl, and TBDMS- Cl, triarylsilyl halogenides, mixed alkylarylsilyl halogenides, such as TBDPS-C1, and trialkylsilyl triflates, such as TMS-OTf and TBDMS-OTf. Suitable reaction conditions such a temperature, solvents, appropriate base etc. are properly selected by the skilled person based on his general knowledge in organic protection group chemistry.

In step b) of the process of the invention the catalytic hydrogenation of the PG protected 5,6,7, 8-tetrahydroquinoxalin-5-ol is preferably carried out using hydrogen gas and a transition metal catalyst such as Pd or Pt. More preferably the catalyst comprises Pt or Pt0₂. Suitable reaction conditions such a temperature, pressure, solvents, appropriate hydrogenation catalyst etc. are properly selected by the skilled person based on his general knowledge in catalytic hydrogenation chemistry. By the reaction of step b) the pyrazine ring is stereoselectively reduced to obtain PG protected cis,cis-decahydroquinoxalin-5-ol.

In step c) of the process of the invention the chiral resolution preferably is done by cl) crystallization, c2) reaction with chiral resolving agents, or c3) chiral chromatography. The chiral resolving agents used in the reaction c2) are preferably selected from tartaric acid derivatives such as 1,4-di-p-toloyl-D-tartaric acid, 1,4-di-p-anisoyl-D-tartaric acid, and 2- chlocyphos. Other agents known by the skilled person can be used as well. More preferably, the reaction c2) comprises reacting the racemic PG protected cis,cis-decahydroquinoxalin-5- ol with the chiral resolving agent, separating the diastereomers obtained, and separating the chiral resolving agent from the desired diastereomer to obtain pure enantiomeric PG protected (4aS,5R,8aS)-decahydroquinoxalin-5-ol. Suitable conditions used in these steps may be those of conventional chiral resolution steps known to the skilled person. The chiral chromatography c3) preferably includes chiral high performance liquid chromatography (HPLC) or column chromatography or flash chromatography (FC). These methods are generally known to the skilled person and can be carried out in a conventional manner also in the process of the present invention.

In step d) of the process of the invention the substituent R¹ is regioselectively introduced at the 1-N atom of the (4aS,5R,8aS)-decahydroquinoxalin-5-ol obtained in step c) by reaction with a reagent X 2 -R 1 at suitable reaction conditions. While R 1 is as defined as in formula (I) herein, X is a suitable leaving group preferably selected from halogenides, such as chlorides and bromides, triflates, tosylates, mesylates, carboxylates, and tert.butyl carbonate. In some instances R¹ can be introduced by addition of reagents such as isocyanates and cyclic acid anhydrides.

In step e) of the process of the invention the PG protected hydroxy group in the product obtained in step d) is deprotected to provide for the corresponding ,β-aminoalcohol. Reaction conditions are not critical according to the invention and can be suitably determined by the skilled person.

Similarly, in step f) of the process of the invention involving the reaction of the ,β- aminoalcohol with sulfuryl chloride in the presence of a base the reaction conditions are not critical and can be selected following the common general knowledge. By the reaction the 1,2,3-oxathiazolidine 2,2-dioxide is obtained.

In step g) of the process of the invention the 1,2,3-oxathiazolidine 2,2-dioxide is reacted with an amine HNR 2 R 3 , wherein R 2 and R 3 are defined as in formula (1) herein, followed by treatment with a suitable acid. Reaction conditions can be properly selected by the skilled person. By this reaction the residue -NR 2 R 3 is introduced under inversion of the stereogenic center, and optionally substituted (4aR,5S,8aS)-5-amino-decahydroquinoxaline is obtained.

In step h) of the process of the invention an activated carboxylic acid derivative ZCH₂COY is used, wherein Z is as defined as in formula (1) herein and Y is a suitable leaving group preferably selected from halogenides, such as chlorides and bromides, and ZCH₂C0₂. Herein Z may be different from the Z introduced into the (4aR,5S,8aS)-5-amino- decahydroquinoxaline according to step h), namely when mixed anhydrides are used as the activated carboxylic acid derivative. Accordingly, preferred carboxylic acid derivatives used in step h) are carboxylic acid halogenides and carboxylic acid anhydrides (also mixed anhydrides). Most preferred are acid chlorides Z-CH₂COCl. Suitable reaction conditions are properly selected by the skilled person. As a result the compound of formula (1) is obtained under acylation in 4-position of the optionally substituted (4aR,5S,8aS)-5-amino- decahydroquinoxaline. Finally according to step i), if present, the compounds of formula (1) obtained may be converted to pharmaceutically acceptable salts by reaction with the corresponding acid in a common way. Moreover, the present invention also relates to intermediates obtained in the course of the process of the invention. In particular, the present invention relates to the cis,cis- decahydroquinoxalin-5-ol as obtained in step b) in racemic form, wherein the 5-hydroxy group is protected by a protection group PG as defined above, preferably selected from TBDMS, TMS, TBDPS, and TIPS. The present invention also relates to the PG protected cis,cis-decahydroquinoxalin-5-ol in the form of its pure (4aS,5R,8aS) and/or (4aR,5S,8aR) enantiomers as obtained in step c).

In order to obtain both enantiomers suitable chiral resolving agents used in reaction step c2) may be selected from tartaric acid derivatives such as 1,4-di-p-toloyl-D-tartaric acid, 1,4-di-p- toloyl-L-tartaric acid, 1,4-di-p-D-anisoyl-tartaric acid, 1,4-di-p-L-anisoyl-tartaric acid, (S)-(-)- 2-chlocyphos, and (R)-(+)-2-chlocyphos. The process for obtaining both enantiomers comprises reacting the racemic PG protected cis,cis-decahydroquinoxalin-5-ol with the chiral resolving agent, separating the diastereomers obtained, and separating the chiral resolving agent from the desired diastereomer to obtain pure enantiomeric PG protected (4aS,5R,8aS)- decahydroquinoxalin-5-ol and PG protected (4aR,5S,8aR)- hydroxydecahydroquinoxalin-5- ol. Regarding the conditions the same applies as mentioned above with respect to step c2).

The intermediate compounds (PG protected cis,cis-decahydroquinoxaline-5-ol) both in racemic form as well as the separated enantiomers are valuable starting products for several chemical synthesis routes of other pharmaceutical compounds such as for the preparation of potential κ opioid receptor agonists and μ opioid receptor antagonists, δ opioid receptor modulators, <¾ adrenoceptor antagonists, antimuscarinic compounds, P2X₇ antagonists, norepinephrine uptake inhibitors, serotonin uptake inhibitors, dopamine uptake inhibitors, and Ι ΐβ-hydroxy steroid dehydrogenase inhibitors.

The perhydroquinoxaline compounds of formula (1) prepared according to the invention are named following the IUPAC nomenclature. In addition, the stereochemistry of the compounds of formula (1) follow the CIP nomenclature (Cahn-Ingold-Prelog) and may be specified as (4aR,5S,8aS) as long as the radical R¹ has the highest priority. Alternatively, if the priority under IUPAC of the C(0)CH₂Z moiety is higher than the one of R¹ the stereochemistry is defined as (4aS,8S,8aR). In the following general description, in the absence of any definition to the contrary, whenever the stereochemistry of the compounds of formula (1) in general is referred to, it is assumed that the radical R¹ has the highest priority and, thus, the (4aR,5S,8aS) definition applies. Consequently, the enantiomer of the compounds of formula (1) is referred to as the (4aS,5R,8aR) form.

The compounds of formula (I) prepared according to the invention have an improved analgesic, antipruritic and antiinflammatory action. A particular advantage of the compounds prepared according to the invention is the fact that the compounds have an analgesic action predominantly in the peripheral system.

Without wishing to be bound by a particular theory, it is assumed that not only the perhydroquinoxaline ring structure of the compounds prepared according to the invention has a considerable influence on the advantageous properties of the compounds, but in particular the specific stereochemistry in the perhydroquinoxaline ring structure as shown in formula (1). In particular, the compounds prepared according to the invention have been shown to act as K opioid receptor agonists. This action is assumed to be responsible for the pharmaceutical efficacy.

One advantage of the compounds prepared according to the invention is that they have a high affinity for the κ opioid receptor that is significantly higher than the affinity observed according to WO2009/080745. An advantage of a high selectivity of binding to the κ opioid receptor can be provided in that no or only mildly centrally mediated side effects occur. A particular advantage of a high selectivity of binding to the κ opioid receptor can be provided in that it is possible to reduce the risk of a psycho-dependency.

In the context of the present invention, unless stated otherwise, the term "heteroaryl" is to be understood as meaning mono-, bi- or tricyclic heteroaryl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S. Preferred heteroaryl radicals are chosen from the group comprising pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, pyridazinyl, 1,3,5-triazinyl, quinolyl, isoquinolyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, thiazolyl, oxazolyl, isoxazolyl, oxazolidinyl, pyrrolyl, carbazolyl, indolyl, isoindolyl, furyl, benzofuryl, benzofuranyl, 1,3-benzodioxolyl, thienyl and/or benzothienyl.

The term "CrCio-alkyl" according to the invention includes, unless stated otherwise, straight- chain, branched or cyclic alkyl groups, preferably chosen from the group comprising methyl, ethyl, n-/i-propyl, n-/i-/tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl and/or decyl.

The term "heterocyclyl" according to the invention includes saturated, mono- or diunsaturated cyclic alkyl radicals having 3 to 10 carbon atoms that contain one, two, three or four hetero atoms chosen from the group comprising NH, O and/or S. Q-Ce-alkoxy groups according to the invention are preferably chosen from the group comprising methoxy, ethoxy, linear or branched propoxy and/or butoxy.

The term "halogen" according to the invention includes fluorine, chlorine, bromine and iodine, fluorine or chlorine being preferred, in particular chlorine.

The term "aryl" according to the invention includes aromatic radicals having 6 to 20 carbon atoms, preferably phenyl, naphthyl, indenyl, and biphenyl. The term "aryl" also includes carbocycles. In the context of the present invention, if not indicated otherwise, the term "acyl" means "Q- Cio-acyl", namely including the groups HC(O)- (formyl) and (C₁-C9)-C(0)-, wherein (C Cg) means linear, branched or cyclic alkyl or alkenyl groups. HC(O)- (formyl) and CH₃-C(0)- (acetyl) are preferred. In preferred embodiments of the process for preparation of the compounds of formula (1) the residues R 1 , R2 , R 3 and Z are as defined in the dependent claims 2 to 5. Preferably in the compound according general formula (1) R¹ is chosen from the group comprising H; C Cs-alkyl; COO(C₁-C₄-alkyl);

benzyl;

Ci-C₄-acyl; C(0)C₄-C6-cycloalkyl; heterocyclylacyl containing NH or O in the ring; phenylacyl, wherein the acyl radical is a Q-acyl radical and the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising COO(Ci-C₃-alkyl) and CONH₂;

mono-cyclic heteroaryl containing one hetero atom chosen from the group of

N, O and S;

mono-cyclic heteroarylalkyl containing one or two hetero atom chosen from the group of N, O and S, wherein the alkyl radical is a CrC₃ alkyl radical;

mono-cyclic heteroarylacyl containing one or two hetero atoms chosen from the group of N, O and S, wherein the acyl radical is a Q-acyl radical and the heteroaryl radical can be substituted by one or more identical or different groups chosen from the group comprising COO(Ci-C₃-alkyl) and CONH₂;

mono-cyclic (heteroaryl)alkenylacyl containing one hetero atom chosen from the group of N, O and S, wherein the acyl radical is a Q-acyl radical and the alkenyl radical is a C₂-C₄-alkenyl radical;

C(0)NH(Ci-C₃-alkyl); C(0)N(Ci-C₃-alk l)₂, wherein the two alkyl radicals may form a saturated halogen substituted or unsubstituted ring with the N atom; C(0)NH(phenyl); C(0)NH(benzyl); C(0)(C₃-C₆-cycloalkyl); COO(benzyl);

C(0)NH-(CH₂)_j-COOH, wherein j is 0 or 1; C(0)NH-(CH₂)_k-COO(Ci-C₃- alkyl), wherein k is 0 or 1; C(0)NH-(CH₂)i-CONH₂, wherein 1 is 0 or 1;

COO-(CH₂)_m-COOH, wherein m is 0 or 1; COO-(CH₂)_n-COO(Ci-C₃-alkyl), wherein n is 0 or 1; COO-(CH₂)_p-C(0)NH₂, wherein p is 0 or 1; C(0)-(CH₂)_q-COOH, wherein q is 0 or 1; C(0)-(CH₂)_r-COO(C₁-C₃-alkyl), wherein r is 0 or 1; C(0)-(CH₂)_s- C(0)NH₂, wherein s is 0 or 1; C(0)-(CH₂)_t-C(0)NH(C₁-C₃-alkyl), wherein t is 0 or 1; C(O)- (CH₂)_u-C(0)N(Ci-C₃-alkyl)₂, wherein u is 0 or 1;

C(0)-(CH₂)_v-NH₂, wherein v is 0 or 1; C(0)-(CH₂)_w-OR\ wherein w is 0 or 1 and R' is H or acetyl; C(0)-(CH₂)_x-C(0)NH-(CH₂)_yC(0)NH₂, wherein x is 0 or 1 and wherein y is 0 or 1 ; SC^Ci-Ce-alkyl); S0₂-(CH₂)_z-heteroaryl, wherein z is 0 or 1; S0₂(CH₂)_a- heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or CrQ-alkoxy; 80₂Ν(^-¾- alkyl)₂ or SO^HiC Cs-alkyl), wherein the alkyl radical can be substituted by F, CI, Ci-C₃- alkoxy and/or OH; S0₂NH(C₃-C₆-cycloalkyl); S0₂NH-C(0)0(C₁-C₃-alkyl);

R 2 , R 3 are identical or different and are chosen from the group comprising H, methyl, ethyl, n-propyl, and i-propyl,

or

R 2 and R 3 form, together with the nitrogen to which they are bonded, a saturated or mono-unsaturated 4- to 6-membered N-heterocycle, wherein this can be substituted by one or more identical or different groups chosen from the group comprising F, CI, OH, CONH₂, CN, and/or 0-C(0)(Ci-C₃ alkyl);

Z is chosen from the group comprising

phenyl, which can be substituted by one or more identical or different groups chosen from the group comprising F, CI, CrC₃-alkyl, Ci-C₃-alkoxy, OH, CF₃, and N0₂, wherein two OH substituents may be connected by an ether bridge to form a ring or wherein two Ci-C₃-alkyl groups may be connected to form a saturated ring; and

a mono- or bicyclic aryl or heteroaryl containing one hetero atom chosen from the group of N and S, wherein the aryl or heteroaryl group can be substituted by one or more identical or different groups chosen from the group comprising F, CI, Ci-C₃-alkyl, Q-C3- alkoxy, OH, CF₃, and N0₂.

More preferably in the compound according to general formula (1):

R¹ is chosen from the group consisting of

heterocyclylacyl containing NH or O in the ring; phenylacyl, wherein the acyl radical is a Q-acyl radical and the phenyl radical is substituted by one or more of COO(Ci- C₃-alkyl) and CONH₂;

mono-cyclic heteroarylacyl containing one or two hetero atoms chosen from the group of N, O and S, wherein the acyl radical is a Q-acyl radical and the heteroaryl radical is substituted by one or more of COO^-C^alky!) and CONH₂; mono-cyclic (heteroaryl)alkenylacyl containing one hetero atom chosen from the group of N, O and S, wherein the acyl radical is a Q-acyl radical and the alkenyl radical is a C2-C₄-alkenyl radical;

C(0)NH(Ci-C₃-alkyl); C(0)N(C₁-C₃-alkyl)₂, wherein the two alkyl radicals form a saturated halogen substituted or unsubstituted ring with the N atom; C(0)NH (phenyl); C(0)NH(benzyl); COO(benzyl);

(CH₂)_g-COOH, wherein g is 1, 2, 3 or 4; (CH₂)_h-COO(Ci-C₆-alkyl), wherein h is 1, 2, 3 or 4; (CH₂)_rCONH₂, wherein i is 1, 2, 3 or 4;

C(0)NH-(CH₂)_j-COOH, wherein j is 0 or 1; C(0)NH-(CH₂)_k-COO(Ci-C₃- alkyl), wherein k is 0 or 1 ; C(0)NH-(CH₂)i-CONH₂, wherein 1 is 0 or 1 ;

COO-(CH₂)_m-COOH, wherein m is 0 or 1; COO-(CH₂)_n-COO(Ci-C₃-alkyl), wherein n is 0 or 1; COO-(CH₂)_p-C(0)NH₂, wherein p is 0 or 1; C(0)-(CH₂)_s-C(0)NH₂, wherein s is 0 or 1; C(0)-(CH₂)_t-C(0)NH(C₁-C₃-alkyl), wherein t is 0 or 1; C(0)-(CH₂)_u- C(0)N(Ci-C₃-alkyl)₂, wherein u is 0 or 1;

C(0)-(CH₂)_v-NH₂, wherein v is 1; C(0)-(CH₂)_w-OR', wherein w is 1 and R' is

H or acetyl;

S0₂(Ci-C₆-alkyl); S0₂-(CH₂)_z-heteroaryl, wherein z is 0 or 1; S0₂(CH₂)_a- heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or Ci-C₃-alkoxy; SC^N^C Cr alkyl)₂ or SC^NHiC Cs-alkyl), wherein the alkyl radical can be substituted by F, CI, CrC₃- alkoxy and/or OH; S0₂NH(C₃-C₆-cycloalkyl); S0₂NH-C(0)0(C₁-C₃-alkyl);

or

Z is chosen from the group comprising phenyl, which can be substituted by one or more identical or different groups chosen from the group comprising F, CI, C Cs-alkyl, Ci- -alkoxy, OH, CF₃, and N0₂, wherein two OH substituents may be connected by an ether bridge to form a ring or wherein two Cr -alkyl groups may be connected to form a saturated ring; and

a mono- or bicyclic aryl or heteroaryl containing one hetero atom chosen from the group of N and S, wherein the aryl or heteroaryl group can be substituted by one or more identical or different groups chosen from the group comprising F, CI, Ci-C₃-alkyl, Q-C3- alkoxy, OH, CF₃, and N0₂. Particularly preferably in the compound according to general formula (1):

R¹ is chosen from the group comprising H; Ci-C₃-alkyl; COO(C₁-C₄-alkyl);

benzyl;

CrC₄-acyl; C(0)C₄-C6-cycloalkyl; heterocyclylacyl containing NH or O in the ring; phenylacyl, wherein the acyl radical is a Q-acyl radical and the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising COO(Ci-C₃-alkyl) and CONH₂;

mono-cyclic heteroaryl containing one hetero atom chosen from the group of

N, O and S;

mono-cyclic heteroarylalkyl containing one or two hetero atom chosen from the group of N, O and S, wherein the alkyl radical is a C C₃ alkyl radical;

mono-cyclic heteroarylacyl containing one or two hetero atoms chosen from the group of N, O and S, wherein the acyl radical is a Q-acyl radical and the heteroaryl radical can be substituted by one or more identical or different groups chosen from the group comprising COOCCrQ-alkyl) and CONH₂;

C(0)NH(C₁-C₃-alkyl); C(0)N(C₁-C₃-alkyl)₂, wherein the two alkyl radicals may form a saturated halogen substituted or unsubstituted ring with the N atom; C(0)NH(phenyl); C(0)NH(benzyl); C(0)(C₃-C₆-cycloalkyl); COO(benzyl);

(CH₂)_g-COOH, wherein g is 1, 2, 3 or 4; (CH^_h-COOCCrCe-alkyl), wherein h is 1, 2, 3 or 4; (CH₂)_rCONH₂, wherein i is 1, 2, 3 or 4; C(0)NH-(CH₂)_j-COOH, wherein j is 0 or 1; C(0)NH-(CH₂)_k-COO(Ci-C₃- alkyl), wherein k is 0 or 1; C(0)NH-(CH₂)i-CONH₂, wherein 1 is 0 or 1;

C(0)-(CH₂)_v-NH₂, wherein v is 0 or 1; C(0)-(CH₂)_w-OR', wherein w is 0 or 1 and R' is H or acetyl; C(0)-(CH₂)_x-C(0)NH-(CH₂)_yC(0)NH₂, wherein x is 0 or 1 and wherein y is 0 or 1 ;

S0₂(C₁-C₆-alkyl); S0₂-(CH₂)_z-heteroaryl, wherein z is 0 or 1; S0₂(CH₂)_a- heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or Ci-C₃-alkoxy; S0₂N(Ci-C₃- alkyl)₂ or S0₂NH(Ci-C₃-alkyl), wherein the alkyl radical can be substituted by F, CI, C C₃- alkoxy and/or OH; S0₂NH(C₃-C₆-cycloalkyl); S0₂NH-C(0)0(Ci-C₃-alkyl);

R 2 and R 3 form, together with the nitrogen to which they are bonded, a mono- unsaturated 6-membered N-heterocycle, that may be substituted by one or more of F, CI, OH, CONH₂, CN, and/or 0-C(0)(Ci-C₃ alkyl);

Z is chosen from the group comprising

phenyl, which can be substituted by one or more identical or different groups chosen from the group comprising F, CI, Ci-C₃-alkyl, Ci-C₃-alkoxy, OH, CF , and N0₂, wherein two OH substituents may be connected by an ether bridge to form a ring or wherein two CrC₃-alkyl groups may be connected to form a saturated ring; and

Particularly preferably in the compound according to general formula (1):

R¹ is chosen from the group comprising H; Ci-C₃-alkyl; COO(C₁-C₄-alkyl); benzyl;

mono-cyclic heteroaryl containing one hetero atom chosen from the group of

N, O and S;

C(0)-(CH₂)_v-NH₂, wherein v is 0 or 1; C(0)-(CH₂)_w-OR\ wherein w is 0 or 1 and R' is H or acetyl; C(0)-(CH₂)_x-C(0)NH-(CH₂)_yC(0)NH₂, wherein x is 0 or 1 and wherein y is 0 or 1 ;

S0₂(C₁-C₆-alkyl); S0₂-(CH₂)_z-heteroaryl, wherein z is 0 or 1; S0₂(CH₂)_a- heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or Ci- -alkoxy; S0₂N(Ci-C₃- alkyl)₂ or

wherein the alkyl radical can be substituted by F, CI, Q-C3- alkoxy and/or OH; S0₂NH(C₃-C₆-cycloalkyl); S0₂NH-C(0)0(Ci-C₃-alkyl);

or

Z is either a tetrahydronaphthyl or a 2,3-dihydrobenzo-l,4-dioxinyl residue, optionally substituted by one or more of F, CI, Ci-C₃-alkyl, Ci-C₃-alkoxy, OH, CF , and N0₂.

Particularly preferred radicals R¹ according to the invention are as follows:



Particularly preferred radicals NR 2 R 3 according to the invention are as follows:

Particularly preferred radicals Z according to the invention are as follows:

Without being bound by a particular theory, it is assumed that the action of the compounds prepared according to the invention is not only based on the steric action of the perhydroquinoxaline group, in particular in combination with the structural element R¹, but even more on the specific cis-trans stereochemistry and the (4aR,5S,8aS) form of the compounds as indicated in formula (1).

The compounds prepared according to the invention can furthermore be used in the form of their acids or their bases or in the form of their salts, in particular the physiologically acceptable salts, or in the form of their solvates, in particular their hydrates.

The pharmaceutically acceptable salts can be base addition salts. These include salts of the compounds according to the invention with inorganic bases, such as alkali metal hydroxides, alkaline earth metal hydroxides, or with organic bases, such as mono-, di- or triethanolamine. Acid addition salts, in particular with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, or with amino acids, can further advantageously be used. Pharmaceutically acceptable salts of the compounds according to the invention are chosen, for example, from the group comprising chlorides, bromides, iodides, hydrochlorides, hydrobromides, sulfonates, methanesulfonates, sulfates, hydrogen sulfates, sulfites, hydrogen sulfites, phosphates, nitrates, methanoates, acetates, proprionates, lactates, citrates, glutarates, maleates, malonates, malates, succinates, tartrates, oxalates, fumarates, benzoates, p- toluenesulfonates and/or salts of amino acids, preferably the proteinogenic amino acids.

The compounds prepared according to the invention are suitable for use as medicaments. They are capable of having an analgesic, antipyretic, antipruritic, antiinflammatory and/or spasmolytic action.

In preferred embodiments, one advantage of the compounds is that these compounds pass the blood-brain barrier to only a small extent. This makes it possible for the compounds prepared according to the invention to be usable in particular as peripherally acting analgesics and antiinflammatory agents.

In advantageous embodiments the compounds prepared according to the invention can be used in particular for therapeutic and/or prophylactic treatment, diagnosis and/or therapy of diseases chosen from the group comprising pain- or pruritus-related diseases and/or inflammatory diseases.

Diseases that may be treated with the compounds prepared according to the present invention are, for example, described in US 2011/0212882 Al being incorporated herein by reference.

In the following the preparation of the compounds of formula (1) according to the present invention and of related reference compounds is described in more detail.

In the schemes, preparations and examples below, various reagent symbols and abbreviations have the following meanings: Alloc allyloxycarbonyl

Boc tert-butoxycarbonyl

Cbz benzyloxycarbonyl

DCM dichloromethane

DIEA ethyl-diisopropylamine

DMF N,N-dimethylformamide

e.e. enantiomeric excess

h hour(s)

HOAc acetic acid

IPC in-process control

mCPBA 3-chloroperbenzoic acid

MeCN acetonitrile

MeOH methanol

mp melting point

OTf trifluoromethanesulfonate

PG protecting group

TBDMS tert-butyldimethylsilyl

TBDPS tert-butyldiphenlylsilyl

TEA triethylamine

TFAA trifluoroacetic acid anhydride

THF tetrahydrofuran

TIPS triisopropylsilyl

TMS trimethylsilyl

wt.% weight percent

EXAMPLES

Synthesis of methyl (4aR,5S,8aS)-4-r(3,4-dichlorophenyl)acetyl1-5-(pyrrolidin-l-yl)octa- hydroquinoxaline-l(2H)-carboxylate as fumarate salt:

Step a): (RS)-5-{[tert-butyl(dimethyl)silyl]oxy}-5,6, 7,8-tetrahydroquinoxaline

The reactor was charged with imidazole (4.05 kg) and a solution of (RS)-5, 6,7,8- tetrahydroquinoxalin-5-ol (7.14 kg) in DCM (102 kg). At a temperature of ~5°C a solution of TBDMSC1 (7.86 kg) in dichloromethane (14.8 kg) was dosed. After completion of the reaction, water (32.2 kg) and acetic acid (1.48 kg) were added. After phase separation and washing of the organic layer with aq. sodium bicarbonate (0.94 kg in 35.6 kg water) and water (36.5 kg), a solvent switch from dichloromethane to n-heptane (38.4 kg) was performed. The solution in n-heptane was filtered over a screening filter to remove technical impurities. The n-heptane phase was treated with water (7.46 kg) and acetonitrile (22.2 kg). The water/acetonitrile layer was extracted with n-heptane (24.8 kg). The combined n-heptane layers was concentrated and a solvent switch to methanol (57.7 kg) was performed. The resulting solution was telescoped to the next stage: 98% yield. Purity: 84%area.

Step b): (4aRS,5SR,8aRS)-5-{[tert-butyl(dimethyl)silyl]oxy}decahydroquinoxaline

The reactor was charged with platinum oxide (0.53 kg), acetic acid (2.92 kg) and the solution of (RS)-5-{ [tert-butyl(dimethyl)silyl]oxy}-5,6,7,8-tetrahydroquinoxaline (74.9 kg, 17.8 wt.%). The hydrogenation was performed at 3.5 bar and ~45°C. The conversion was complete after overnight stirring. The catalyst was removed over filter aid. The resulting filtrate was telescoped as such to the next stage of the process: -90% yield. Purity 76%area

Step c): (4aS,5R,8aS)-5-{[tert-butyl(dimethyl)silyl]oxy}decahydroquinoxalinium di-p- toluoyl-D-tartrate

(+)-Di-p-toluoyl (D)-tartaric acid (24.4 kg) and methanol (45.7 kg) were charged to the reactor. The batch was heated to 45-50°C. Subsequently, the solution of (4aRS,5SR,8aRS)-5- { [tert-butyl(dimethyl)silyl]oxy}decahydroquinoxaline (96 kg, obtained from the previous reaction step) was dosed to this mixture at the given temperature. After dosing the batch was cooled. Crystallization occurred at 27 °C. An additional amount of methanol (20.1 kg) was charged. Aging of the batch was performed overnight followed by filtration. The product was washed with methanol (18.1 kg). The material was dried on the filter at 40°C.

The crude product was dissolved on the filter dryer using dichloromethane (115 kg) and methanol (98.2 kg). After dissolution was complete, the solution was transferred to the reactor and heated to reflux to remove the dichloromethane. A solvent strip was performed with fresh methanol (49.5 kg) to remove all residual dichloromethane. Extra methanol (30.0 kg) was charged and the salt was allowed to crystallize. The product was filtered off, washed with methanol (39.4 kg) and dried on the filter. Yield: 11.58 kg (13.6 mol), purity 99.2 area, e.e. 99.9%.

Step d): Methyl (4aS,5R,8aS)-5-{[tert-butyl(dimethyl)silyl]oxy}octahydroquinoxaline- l(2H)-carboxylate hydrochloride

The salt was neutralized with aqueous sodium hydroxide solution (9.25 kg in 52.0 kg water) and was extracted towards methyl tert.butyl ether (86.2 kg). The organic phase was washed with water (57.0 kg) After a solvent switch towards dichloromethane (76.8 kg) a solution of methyl chloroformate ((1.29 kg) in DCM (7.72 kg)) was added to the solution of (4aS,5R,8aS)-5-{ [tert-butyl(dimethyl)silyl]oxy}decahydroquinoxaline while keeping the temperature at -10°C. The mixture was allowed to warm up to room temperature and stirred until completion of the reaction (>2 h). The excess of methyl chloroformate was decomposed by the addition of methanol (4.85 kg). The batch was stirred at ambient temperature for at least 1 h. The resulting solution was telescoped to the next stage as such. Purity was 97.6%area.

Step e): Methyl (4aS,5R,8aS)-5-hydroxyoctahydroquinoxaline-l(2H)-carboxylate

The solution of methyl (4aS,5R,8aS)-5-{ [tert-butyl(dimethyl)silyl]oxy}octahydro- quinoxaline-l(2H)-carboxylate hydrochloride from the previous step was concentrated applying atmospheric distillation and a solvent switch toward methanol (21.8 kg) was accomplished. Aqueous hydrochloric acid (1.65 kg 30 wt.% HC1 in 12.2 kg water) was added. The reaction mixture was reacted at 50°C. After complete conversion, the batch was cooled and an aqueous potassium carbonate solution (5.36 kg in 29.0 kg water) was added. The batch was heated to 40°C and methyl tert.butyl ether was removed by vacuum distillation. Dichloromethane (30.3 kg) was added and the product was extracted towards the organic layer. The aqueous phase was extracted twice with dichloromethane (30 kg each). The combined organic layer was azeotropically dried by stripping with dichloromethane (32.9 kg). The resulting solution was telescoped to the next stage. Purity was 97.0%area. Step f): Methyl (6aS,9aR,9bS)octahydro-6H-[l,2,3]oxathiazolo[3,4,5-de]quinoxaline-6- carboxylate 2,2-dioxide

To the solution of the previous stage was added triethylamine (4.22 kg). The resulting solution was cooled to -15°C and a solution of sulfuryl chloride (2.22 kg) in dichloromethane (8.08 kg) was slowly added. After stirring the batch for 1 h at -15°C and overnight at ambient temperature the excess sulfuryl chloride was hydrolyzed by slow addition of water (15.5 kg). Phases were separated and the organic layer was washed with 5 wt.% aqueous sodium bicarbonate solution (15 kg) and water (15.4 kg). The resulting organic layer was azeotropically dried and concentrated. 2-Propanol (23 kg) was added. Under vacuum -40 L solvent were removed. The residual mixture was cooled to -8°C, causing the cyclic sulfamate to crystallize. The crude product was filtered and washed on the filter with cold 2-propanol (8 kg) and methyl tert.-butylether (2.2 kg). The material on the filter was dried overnight on the filter. Purity was 98.8%area.

Step g): Methyl (4aR,5S,8aS)-5-(pyrrolidin-l-yl)octahydroquinoxaline-l(2H)-carboxylate

Methyl (6aS,9aR,9bS)octahydro-6H-[l,2,3]oxathiazolo[3,4,5-de]quinoxaline-6-carboxylate 2,2-dioxide was dissolved on the filter using acetonitrile (9.61 kg) and pyrrolidine (2.15 kg). The solution was stirred at 70°C to full conversion. The excess pyrrolidine was removed from the solution by vacuum distillation, i.e. applying a strip with toluene (1 x 12 kg, 4 x 6 kg toluene). To the resulting mixture was added 3 wt.% aqueous hydrochloric acid (14.65 kg). The upper organic layer was removed as waste. The aqueous layer was extracted with methyl tert.butyl ether (2 x 5 kg). The upper organic layer was removed as waste. The aqueous layer was made alkaline to pH 11 by the addition of aqueous potassium carbonate (2.72 kg in 13.6 kg water), and was subsequently extracted with dichloromethane (3 x 18 kg). The combined organic layer was azeotropically dried and concentrated. The resulting solution was telescoped to the next stage. Purity was 99.4%area.

Step h): Methyl (4aR,5S,8aS)-4-[(3,4-dichlorophenyl)acetyl]-5-(pyrrolidin-l-yl)octahydro- quinoxaline-l(2H)-carboxylate

The reaction was performed under nitrogen atmosphere. To 3,4-dichlorophenylacetic acid (1.53 kg) was added N,N-dimethylformamide (62.2 g) and dichloromethane (22.9 kg). While keeping the batch temperature below 15°C, a solution of oxalyl chloride (0.945 kg) in dichloromethane (2.22 kg) was added slowly. The reaction mixture was stirred for 2 h. The prepared solution of the acid chloride was dosed at 8°C to a prepared solution of methyl (4aR,5S,8aS)-5-(pyrrolidin- l-yl)octahydroquinoxaline- 1 (2H)-carboxylate (ex-previous step) and triethylamine (0.462 kg). After the reaction was regarded as complete, a 5 wt.% aqueous sodium carbonate solution (17.4 kg) was dosed. The organic layer was washed twice with demineralized water (17 kg and 20 kg). The organic layer was solvent switched to acetone (2 x 13 kg), the concentrated solution was screened through a 1 μηι filter. The resulting mixture was telescoped to the next stage. Purity was 83.6 area. Step i): l-[(4aR,5S,8aS)-4-[(3,4-Dichlorophenyl)acetyl]-l-(methoxycarbonyl)decahydro- quinoxalin-5-ylJpyrrolidinium fumarate

Furamic acid USP/NF grade (0.725 kg) and screened acetone (66.9 kg) were charged to a reactor and heated to 44°C. To this mixture was dosed the solution of methyl (4aR,5S,8aS)-4- [(3,4-dichlorophenyl)acetyl]-5-(pyrrolidin-l-yl)octahydro-quinoxaline-l(2H)-carboxylate in acetone (10.97 kg, contains 6.14 mol, ex-previous step). A slurry was obtained. Under vacuum acetone (71 L) was removed by distillation, and the batch was cooled to 17°C. The resulting mixture was filtered. The cake was washed with acetone (2 x 2.2 kg). The wet cake (3.32 kg) was discharged from the filter and transferred to a vacuum oven. The fumarate salt was dried at 68°C for 34 h. After discharge 2.44 kg product were obtained: Purity >99 area, e.e. >99.8 .

Synthesis of (4aR,5S,8aR)-5-{rtert-butyl(dimethyl)silyl1oxy}decahvdroquinoxalinium di- p-toluoyl-L-tartrate (step c))

(-)-Di-p-toluoyl (L)-tartaric acid (62.6 g) was stirred in ethanol (5 volumes) at 45°C until a solution was formed. Subsequently, (4aRS,5SR,8aRS)-5-{ [tert-butyl(dimethyl)silyl]oxy}- decahydroquinoxaline (29.1 g) in ethanol (6 volumes) was dosed to this mixture at the given temperature. The solution turned into a suspension and was cooled to ambient temperature. The suspension was filtered and the solids washed twice with ethanol (2 volumes each). The crude product was dried at 40°C under vacuum.

The crude product was stirred in methanol (10 volumes) at 35°C. DCM was added until a clear solution was obtained (8 volumes). DCM was distilled of at atmospheric pressure. Methanol (4 volumes) was added during the distillation. A total of 10 volumes of solvents were distilled off. The remaining solution was cooled to ambient temperature at which crystallization started. Additional methanol (2 volumes) was added to improve stirrability. The suspension was filtered and the solids were washed twice with methanol (2 volumes). Yield: 48.6 g (81% with regard on the desired diastereomer), purity 98.3%area, e.e. >98%. Purity (in area) of intermediates and final products was determined with HPLC.

Claims

1. A process for the preparation of a perhydroquinoxaline compound according to the general formula (1) as shown below or a pharmaceutically acceptable salt thereof:

R¹ is chosen from the group comprising H; CrCio-alkyl; d-Cio-cycloalkyl;

(COO(Ci-Cio-alkyl);

phenylalkyl with Q-Ce-alkyl, wherein the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising halogen, C -C - alkyloxy, NH₂, NH(Ci-C₅-alkyl), N(Ci-C₅-alkyl)₂, OH, S0₂(Ci-C₅-alkyl), SO(Ci-C₅-alkyl),

CF₃, CN, N0₂, S02N(Ci-C₅-alkyl)₂, S0₂NH₂,

S0₂NH(aryl),

S0₂NH(phenyl) and/or S0₂NH(heteroaryl);

C Cio-acyl; heterocyclylacyl containing one, two, three or four hetero atoms chosen from the group comprising NH, O and/or S; phenylacyl, wherein the acyl radical is a C C₆-acyl radical and the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising halogen, Q-Ce-alkyloxy, CCK Q-Ce- alkyl), NH₂, NH(d-C₅-alkyl), N(Ci-C₅-alkyl)₂, CONH₂, CONH(d-C₆-alkyl), CON(d-C₆- alkyl)₂, OH, S0₂(Ci-C₅-alkyl), SO(Ci-C₅-alkyl), CF₃, CN, N0₂, S0₂N(Ci-C₅-alkyl)₂,

S0₂NH₂, SOzNHCCi-Cs-alkyl), S0₂NH(aryl), S0₂NH(phenyl) and/or S0₂NH(heteroaryl);

mono-, bi- or tricyclic heteroarylalkyl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S, wherein the alkyl radical is a CrC₆ alkyl radical; mono-, bi- or tricyclic heteroarylacyl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S, wherein the acyl radical is a CrC₆- acyl radical and the heteroaryl radical can be substituted by one or more identical or different groups chosen from the group comprising halogen, CrCe-alkyloxy, COC Ci-Ce-alkyl), NH₂, NH(Ci-C₅-alk l), N(Ci-C₅-alkyl)₂, CONH₂, CONH(Ci-C₆-alkyl), CON(Ci-C¼-alkyl)₂, OH, CF₃, CN, N0₂, and/or S0₂NH₂;

mono-, bi- or tricyclic (heteroaryl)alkenylacyl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S, wherein the acyl radical is a C C₆-acyl radical and the alkenyl radical is a C₂-C₆-alkenyl radical;

C(0)NH(Ci-Cio-alkyl); C(O)N(C₁-C₁₀-alkyl)₂, wherein the two alkyl radicals may form a saturated substituted or unsubstituted ring with the N atom; C(0)NH(aryl); C(0)NH(benzyl); C(O)(C₃-Ci₀-cycloalkyl); COO(aryl); COO(benzyl); COO(C₃-Ci₀- cycloalkyl);

C(0)NH-(CH₂)_j-COOH, wherein j is 0, 1, 2, 3 or 4; C(0)NH-(CH₂)_k-COO(Ci- Ce-alkyl), wherein k is 0, 1, 2, 3 or 4; C(0)NH-(CH₂)i-CONH₂, wherein 1 is 0, 1, 2, 3 or 4;

COO-(CH₂)_m-COOH, wherein m is 0, 1, 2, 3 or 4; COO-(CH₂)_n-COO(C₁-C₁₀- alkyl), wherein n is 0, 1, 2, 3 or 4; COO-(CH₂)_p-C(0)NH₂, wherein p is 0, 1, 2, 3 or 4; C(O)- (CH₂)_q-COOH, wherein q is 0, 1, 2, 3 or 4; C(O)-(CH₂)_r-COO(Ci-Ci₀-alkyl), wherein r is 0, 1, 2, 3 or 4; C(0)-(CH₂)_s-C(0)NH₂, wherein s is 0, 1, 2, 3 or 4; C(0)-(CH₂)_t-C(0)NH(C₁-C₆- alkyl), wherein t is 0, 1, 2, 3 or 4; C(0)-(CH₂)_u-C(0)N(C₁-C₆-alkyl)₂, wherein u is 0, 1, 2, 3 or 4;

C(0)-(CH₂)_v-NH₂, wherein v is 0, 1, 2, 3 or 4; C(0)-(CH₂)_w-OR', wherein w is 0, 1, 2, 3 or 4 and R' is H or Ci-C₆-acyl; C(0)-(CH₂)_x-C(0)NH-(CH₂)_yC(0)NH₂, wherein x is 0, 1, 2 or 3 and wherein y is 0, 1, 2 or 3;

S0₂(Ci-C₆-alkyl); S0₂-(CH₂)_z-heteroaryl, wherein z is 0, 1, 2 or 3; S0₂(CH₂)_a- heterocyclyl, wherein a is 0, 1, 2 or 3 and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising halogen, OH, CN, oxo and/or Ci-C₆-alkoxy; S0₂N(C₁-C₆-alkyl)₂ or S0₂NH(Ci-C₆-alkyl), wherein the alkyl radical can be substituted by halogen, Ci-C4-alkoxy and/or OH; S0₂NH(C₃-C₆- cycloalkyl); S0₂NH-C(0)0(Ci-C₆-alkyl); R 2 , R 3 are in each case identical or independent of each other and are chosen from the group comprising H; CrCio-alkyl; d-Cio-cycloalkyl,

or

R 2 and R 3 form, together with the nitrogen to which they are bonded, a saturated or unsaturated 3- to 8-membered N-heterocycle, wherein this can be substituted by one or more identical or different groups chosen from the group comprising halogen, OH, Cr C₄-alkyloxy, COOH, COO(Ci-Cio-alkyl), CONH₂, CONH(Ci-Cio-alkyl), CON(Ci-Ci₀- alkyl)₂, CN, and/or 0-C(0)(d-C₆ alkyl); Z is chosen from the group comprising phenyl, which can be substituted by one or more identical or different groups chosen from the group comprising halogen, CrCs-alkyl, Ci-Cs-alkoxy, NH₂, NH(d-C₅-alkyl), N(Ci-C₅-alkyl)₂, OH, S0₂(Ci-C₅-alkyl), SO(d-C₅- alkyl), CF₃, CN, N0₂, S0₂N(Ci-C₅-alkyl)₂, S0₂NH₂, SOzNHCC Cs-alkyl), S0₂NH(aryl), S0₂NH(phenyl) and/or S0₂NH(heteroaryl), wherein the substituents may form a ring;

a mono- or bicyclic aryl or heteroaryl containing one or two hetero atoms chosen from the group comprising N, O and/or S, wherein the aryl or heteroaryl group can be substituted by one or more identical or different groups chosen from the group comprising halogen, Ci-C₄-alkoxy, NH₂, NHCCrCs-alkyl), N(Ci-C₅-alkyl)₂, OH, S0₂(Ci-C₅-alkyl), SO(Ci-Cs-alkyl), CF₃, CN, N0₂, S0₂N(Ci-C₅-alkyl)₂, S0₂NH₂, S0₂NH(Ci-C₅-alkyl), S0₂NH(aryl), S0₂NH(phenyl) and/or S0₂NH(heteroaryl) characterized in that the process comprises the following steps: a) reacting 5,6,7, 8-tetrahydroquinoxalin-5-ol with a protection agent X^PG in the presence of a base to introduce a protecting group PG at the alcohol function, wherein X¹ is a suitable leaving group; b) catalytically hydrogenating the PG protected 5,6,7,8-tetrahydroquinoxalin-5-ol obtained in step a) under stereoselective reduction of the pyrazine ring to obtain PG protected cis,cis-decahydroquinoxalin-5-ol; c) chiral resolution of the racemic PG protected cis,cis-decahydroquinoxalin-5-ol obtained in step b) into its enantiomeric forms, namely PG protected (4aS,5R,8aS)- decahydroquinoxalin-5-ol and PG protected (4aR,5S,8aR)-decahydroquinoxalin-5-ol; d) reacting the PG protected (4aS,5R,8aS)-decahydroquinoxalin-5-ol obtained in step c) with a reagent X 2 -R 1 to regio selectively introduce the substituent R 1 at the 1-N atom of the (4aS,5R,8aS)-decahydroquinoxalin-5-ol, wherein X is a suitable leaving group; e) deprotecting the PG protected hydroxy group in the product obtained in step d) to provide for the corresponding ,β-aminoalcohol; f) reacting the ,β-aminoalcohol obtained in step e) with sulfuryl chloride in the presence of a base to provide for the corresponding 1,2,3-oxathiazolidine 2,2-dioxide; g) reacting the 1,2,3-oxathiazolidine 2,2-dioxide obtained in step f) with an amine

2. The process according to claim 1, wherein in general formula (1):

R¹ is chosen from the group comprising H; C Cs-alkyl; COO(C₁-C₄-alkyl);

benzyl;

mono-cyclic heteroaryl containing one hetero atom chosen from the group of

N, O and S;

COO-(CH₂)_m-COOH, wherein m is 0 or 1; COO-(CH₂)_n-COO(C₁-C₃-alkyl), wherein n is 0 or 1; COO-(CH₂)_p-C(0)NH₂, wherein p is 0 or 1; C(0)-(CH₂)_q-COOH, wherein q is 0 or 1; C(0)-(CH₂)_r-COO(Ci-C₃-alkyl), wherein r is 0 or 1; C(0)-(CH₂)_s- C(0)NH₂, wherein s is 0 or 1; C(0)-(CH₂)_t-C(0)NH(C₁-C₃-alkyl), wherein t is 0 or 1; C(O)- (CH₂)_u-C(0)N(Ci-C₃-alkyl)₂, wherein u is 0 or 1 ;

C(0)-(CH₂)v-NH₂, wherein v is 0 or 1; C(0)-(CH₂)_w-OR\ wherein w is 0 or 1 and R' is H or acetyl; C(0)-(CH₂)_x-C(0)NH-(CH₂)_yC(0)NH₂, wherein x is 0 or 1 and wherein y is 0 or 1 ;

S0₂(C₁-C₆-alkyl); S0₂-(CH₂)_z-heteroaryl, wherein z is 0 or 1; S0₂(CH₂)_a- heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or Ci-C₃-alkoxy; SC^N^C Cr alkyl)₂ or SC^NHiC Cs-alkyl), wherein the alkyl radical can be substituted by F, CI, Ci-C₃- alkoxy and/or OH; S0₂NH(C₃-C₆-cycloalkyl); S0₂NH-C(0)0(C₁-C₃-alkyl);

or

Z is chosen from the group comprising

3. The process according to claim 1 and/or claim 2, wherein in general formula

(1): R¹ is chosen from the group consisting of

heterocyclylacyl containing NH or O in the ring; phenylacyl, wherein the acyl radical is a Q-acyl radical and the phenyl radical is substituted by one or more of COO(Cr C₃-alkyl) and CONH₂;

mono-cyclic heteroarylacyl containing one or two hetero atoms chosen from the group of N, O and S, wherein the acyl radical is a Q-acyl radical and the heteroaryl radical is substituted by one or more of COOiC Cs-alkyl) and CONH₂; mono-cyclic (heteroaryl)alkenylacyl containing one hetero atom chosen from the group of N, O and S, wherein the acyl radical is a Q-acyl radical and the alkenyl radical is a C2-C₄-alkenyl radical;

H or acetyl;

or

4. The process according to claim 1 and/or claim 2, wherein in general formula

(1):

R¹ is chosen from the group comprising H; CrC₃-alkyl; COO(C₁-C₄-alkyl);

benzyl;

mono-cyclic heteroaryl containing one hetero atom chosen from the group of N, O and S;

C(0)NH(Ci-C₃-alkyl); C(0)N(Ci-C₃-alkyl)₂, wherein the two alkyl radicals may form a saturated halogen substituted or unsubstituted ring with the N atom; C(0)NH(phenyl); C(0)NH(benzyl); C(0)(C₃-C₆-cycloalkyl); COO(benzyl); (CH₂)_g-COOH, wherein g is 1, 2, 3 or 4; (CH₂)_h-COO(Ci-C₆-alkyl), wherein h is 1, 2, 3 or 4; (CH₂)i-CONH₂, wherein i is 1, 2, 3 or 4;

C(0)NH-(CH₂)_j-COOH, wherein j is 0 or 1; C(0)NH-(CH₂)_k-COO(d-C₃- alkyl), wherein k is 0 or 1; C(0)NH-(CH₂)i-CONH₂, wherein 1 is 0 or 1;

COO-(CH₂)_m-COOH, wherein m is 0 or 1; COO-(CH₂)_n-COO(C₁-C₃-alkyl), wherein n is 0 or 1; COO-(CH₂)_p-C(0)NH₂, wherein p is 0 or 1; C(0)-(CH₂)_q-COOH, wherein q is 0 or 1; C(0)-(CH₂)_r-COO(Ci-C₃-alkyl), wherein r is 0 or 1; C(0)-(CH₂)_s- C(0)NH₂, wherein s is 0 or 1; C(0)-(CH₂)_t-C(0)NH(C₁-C₃-alkyl), wherein t is 0 or 1; C(O)- (CH₂)_u-C(0)N(C₁-C₃-alkyl)₂, wherein u is 0 or 1;

S0₂(Ci-C₆-alkyl); S0₂-(CH₂)_z-heteroaryl, wherein z is 0 or 1; S0₂(CH₂)_a- heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or Ci-C₃-alkoxy; 80₂Ν(^-¾- alkyl)₂ or SO^HiC Cs-alkyl), wherein the alkyl radical can be substituted by F, CI, CrC₃- alkoxy and/or OH; S0₂NH(C₃-C₆-cycloalkyl); S0₂NH-C(0)0(C₁-C₃-alkyl); R 2 and R 3 form, together with the nitrogen to which they are bonded, a mono- unsaturated 6-membered N-heterocycle, that may be substituted by one or more of F, CI, OH, CONH₂, CN, and/or 0-C(0)(Ci-C₃ alkyl);

Z is chosen from the group comprising

a mono- or bicyclic aryl or heteroaryl containing one hetero atom chosen from the group of N and S, wherein the aryl or heteroaryl group can be substituted by one or more identical or different groups chosen from the group comprising F, CI, CrC₃-alkyl, CrC₃- alkoxy, OH, CF₃, and N0₂.

5. The process according to claim 1 and/or claim 2, wherein in general formula

(1):

R¹ is chosen from the group comprising H; Ci-Q-alkyl; COO(C₁-C₄-alkyl);

benzyl;

mono-cyclic heteroaryl containing one hetero atom chosen from the group of

N, O and S;

COO-(CH₂)_m-COOH, wherein m is 0 or 1; COO-(CH₂)_n-COO(Ci-C₃-alkyl), wherein n is 0 or 1; COO-(CH₂)_p-C(0)NH₂, wherein p is 0 or 1; C(0)-(CH₂)_q-COOH, wherein q is 0 or 1; C(0)-(CH₂)_r-COO(C₁-C₃-alkyl), wherein r is 0 or 1; C(0)-(CH₂)_s- C(0)NH₂, wherein s is 0 or 1; C(0)-(CH₂)_t-C(0)NH(C₁-C₃-alkyl), wherein t is 0 or 1; C(O)- (CH₂)_u-C(0)N(Ci-C₃-alkyl)₂, wherein u is 0 or 1; C(0)-(CH₂)v-NH₂, wherein v is 0 or 1; C(0)-(CH₂)_w-OR', wherein w is 0 or 1 and R' is H or acetyl; C(0)-(CH₂)_x-C(0)NH-(CH₂)_yC(0)NH₂, wherein x is 0 or 1 and wherein y is 0 or 1 ;

S0₂(C₁-C₆-alkyl); S0₂-(CH₂)_z-heteroaryl, wherein z is 0 or 1; S0₂(CH₂)_a- heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or CrQ-alkoxy; SC^N^C Cr alkyl)₂ or

wherein the alkyl radical can be substituted by F, CI, Q-C3- alkoxy and/or OH; S0₂NH(C₃-C₆-cycloalkyl); S0₂NH-C(0)0(C₁-C₃-alkyl);

or

6. The process as claimed in one of claims 1 to 5, wherein the chiral resolution in step c) is done by cl) crystallization, c2) reaction with chiral resolving agents, or c3) chiral chromatography.

7. The process as claimed in claim 6, wherein the chiral resolving agents are selected from tartaric acid derivatives such as 1,4-di-p-toloyl-D-tartaric acid, 1,4-di-p-anisoyl- D-tartaric acid, and 2-chlocyphos.

8. The process as claimed in claim 6 and/or claim 7, wherein the reaction c2) comprises reacting the racemic PG protected cis,cis-decahydroquinoxalin-5-ol with the chiral resolving agent, separating the diastereomers obtained, and separating the chiral resolving agent from the desired diastereomer to obtain pure enantiomeric PG protected (4aS,5R,8aS)- decahydroquinoxalin-5-ol.

9. The process as claimed in one of claims 1 to 8, wherein X -PG is selected from the group of tnalkylsilyl halogenides, such as TMS-Cl, TIPS-Cl, and TBDMS-Cl, triarylsilyl halogenides, mixed alkylarylsilyl halogenides, such as TBDPS-Cl, and trialkylsilyl triflates, such as TMS-OTf and TBDMS-OTf.

10. The process as claimed in one of claims 1 to 9, wherein X is selected from halogenides, such as chlorides and bomides, triflates, tosylates, mesylates, carboxylates, and tert.butyl carbonate.

11. The process as claimed in one of claims 1 to 10, wherein Y is selected from halogenides, such as chlorides and bromides, and ZCH₂CO₂ .

12. A cis,cis-decahydroquinoxalin-5-ol, wherein the 5-hydroxy group is protected by a protection group PG preferably selected from TBDMS, TMS, TBDPS, and TIPS.

13. The cis,cis-decahydroquinoxalin-5-ol as claimed in claim 12 in the form of its (4aS,5R,8aS) and/or (4aR,5S,8aR) enantiomer.

14. A process for the preparation of the cis,cis-decahydroquinoxalin-5-ol as claimed in claim 12 and/or claim 13, comprising the steps of: a) reacting 5,6,7, 8-tetrahydroquinoxalin-5-ol with a protection agent X^X-PG in the presence of a base to introduce a protecting group PG at the alcohol function, wherein X¹ is a suitable leaving group; b) catalytically hydrogenating the PG protected 5,6,7,8-tetrahydroquinoxalin-5-ol obtained in step a) under stereoselective reduction of the pyrazine ring to obtain PG protected cis,cis-decahydroquinoxalin-5-ol; c) chiral resolution of the racemic PG protected cis,cis-decahydroquinoxalin-5-ol obtained in step b) into its enantiomeric forms, namely PG protected (4aS,5R,8aS)- decahydroquinoxalin-5-ol and PG protected (4aR,5S,8aR)-decahydroquinoxalin-5-ol.

15. The process as claimed in claim 14, wherein the chiral resolution in step c) is done by cl) crystallization, c2) reaction with chiral resolving agents, or c3) chiral chromatography, and wherein the chiral resolving agents c2) are preferably selected from tartaric acid derivatives such as 1,4-di-p-toloyl-D-tartaric acid, 1,4-di-p-toloyl-L-tartaric acid, 1,4-di-p-D-anisoyl-tartaric acid, 1,4-di-p-L-anisoyl-tartaric acid, (S)-(-)-2-chlocyphos, and (R)-(+)-2-chlocyphos.

16. The process as claimed in claim 14 and/or claim 15, wherein the reaction c2) comprises reacting the racemic PG protected cis,cis-decahydroquinoxalin-5-ol with the chiral resolving agent, separating the diastereomers obtained, and hydrolyzing the desired diastereomer to obtain pure enantiomeric PG protected (4aS,5R,8aS)-decahydroquinoxalin-5- ol and/or PG protected (4aR,5S,8aR)-decahydroquinoxalin-5-ol.