WO2016020403A1

WO2016020403A1 - Preparation of a benzoic acid derivative and its use for the preparation of suvorexant

Info

Publication number: WO2016020403A1
Application number: PCT/EP2015/067993
Authority: WO
Inventors: Kathrin HÖFERL-PRANTZ; Roland Barth; Frank Richter; Borut ZUPANCIC
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 2014-08-04
Filing date: 2015-08-04
Publication date: 2016-02-11
Anticipated expiration: 2017-02-04

Abstract

The present invention relates to a process for the preparation of a compound of formula (1) wherein the process is based on the use of an organolithium reagent and wherein R^a, R^b, R^c and R^d are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, -NR⁶R⁷, -SR and -NO₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group. The present invention further relates as to a compound obtained or obtainable by said method and to a compound of formula (1) as such. Further, the present invention relates to use of the compound of formula (1) for the preparation of Suvorexant.

Description

Preparation of a Benzoic Acid Derivative and its Use for the Preparation of Suvorexant The present invention relates to a process for the preparation of a compound of formula 1),

consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, -NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group. The present invention relates further to a compound obtained or obtainable by said method and to a compound of formula (1) as such. Further, the present invention relates to use of the compound of formula (1) for the preparation of Suvorexant employing the compound of formula (1).

BACKGROUND OF THE INVENTION

Orexin is a neurotransmitter that regulates wakefulness and appetite. Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behavior disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive feeding behaviors; binge/purge feeding behaviors; cardiovascular diseases; diabetes; appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; Froehlich's syndrome; adenohypophysis disease; hypophysis disease; adenohypophysis hypofunction; adenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome

(anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischemic or hemorrhagic stroke; subarachnoid hemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, and angina; migraine; urinary bladder incontinence, e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lag syndrome; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism- amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders and other diseases related to general orexin system dysfunction.

Some orexin receptor antagonists are capable of influencing at least some of the above described pathological conditions. In particular, orexin receptor antagonists capable of promoting sleep in animals and humans are described in the art. One example for such an orexin receptor antagonist is [(7R)-4-(5-chloro-l,3-benzoxazol-2-yl)-7-methyl-l,4- diazepan-l-yl][5-methyl-2-(2H-l ,2,3-triazole-2-yl)phenyl]methanone which has the structure according to Formula XI)

and which is, e.g., described in US 2008/0132490, WO 2008/069997 and Cox et al, Journal of Medicinal Chemistry 2010, 53(14): 5320-5332. Alternative names for this compound are 5-chloro-2- {(5R)-5-methyl-4-[5-methyl-2-(2H- 1 ,2,3-thiazol-2-yl)benzoyl]- l,4-diazepan-l-yl}-l,3-benzobenzoxazol and [(R)-4-(5-chloro-benzooxazol-2-yl)-7- methyl-[l,4]diazepan-l-yl]-(5-methyl-2-[l,2,3]triazole-2-yl-phenyl)-methanone.

The synthesis of Suvorexant is based on the synthesis of the three main building blocks, i.e. the diazapane ring, the benzoxazole ring as well as the triazole building block. These building blocks are coupled to each other to give the desired product. The triazole building block is usually coupled in the form of an acid or an acid chloride to the diazepane ring. Such a synthesis is e.g. described in WO2008069997 and in Cox et al, J. Med. Chem. 2010, 53: 5320. In this synthesis, 2-iodo.5.methylbenzoic acid is converted in the presence of a copper catalyst and triazole to give 5-methyl-2-(2H-l,2,3-triazole- 2yl)benzoic acid. After having synthesized the triazole building block, this building block is coupled as acid or acid chloride to the diazapene ring and the resulting compound is then, after a deprotection step, coupled to the oxazole ring. However, the 2-iodo.5.methylbenzoic acid is a comparatively costly starting material which renders the process disadvantageous. Further, in this synthesis, regioisomer may be formed since the triazole may be coupled via any one of the present NH groups. These regioisomer need to be separated via column chromatography, which is difficult, and thus renders the process disadvantageous for industrial scale.

A similar synthesis is described in WO2012148553 or Baxter et al, Org. Process Res. Dev. 2011, 15: 367. In this synthesis, 2-iodo.5.methylbenzoic acid is converted in the presence of a copper catalyst and triazole to give 5-methyl-2-(2H-l,2,3-triazole- 2yl)benzoic acid. The resulting triazole building block is then coupled to a benzoxazole substituted diazepane.

A further synthesis is described in CN 103012293 A. In this synthesis, a 2-hydrazinobenzoic acid is converted upon synthesis with glyoxal and hydroxyl amine in a copper catalyzed reaction to give the carboxy substituted triazole building block.

Thus, there is still the need for an improved synthesis of triazole building blocks which provides the building block in high yield with low costs and which in particular avoids the formation of regioisomeric impurities which are hard or even impossible to purify away. Further, there is the need for an improved synthesis of Suvorexant which provides Suvorexant in high yields and which overcomes the disadvantages of the processes described above, such as the use of costly starting materials.

Surprisingly, it was found that this object can be solved by a process for the preparation of a com ound of formula (1)

consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, -NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group, and wherein the process comprises

(a) providing a compound of formula II)

(b) reacting the compound of formula (II) with an organolithium reagent in an aprotic solvent to give an intermediate compound of formula (III)

(c) reacting the intermediate compound of formula (III) with an electrophile E* to give the compound of formula (1).

The term halogen in the context of E is denote to mean a halogen residue, i.e. in particular -CI, -Br or -I.

Further, the present invention relates to a process for the preparation of a compound of formula A) or a pharmaceutically acceptable salt or solvate thereof

and wherein R¹ is selected from the group consisting of H, PG¹ and R^A, with R^A being

preferably

wherein PG¹ is a suitable protecting group and wherein n is 0 or 1, the process comprising

(i) providing a compound of formula la)

wherein E is halogen, -CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated ester group -C(=0) -X,

wherein the compound (la) is provided by a method as described above, reacting the com ound of formula (la) with a compound of formula (Al)

preferably (Al *)

wherein R^la is selected from the group consisting of H, PG¹, and R^A, with R^A being

wherein PG¹ is a suitable protecting group and wherein R^la may be the same or may differ from R¹, and wherein in case n is 0, R^la is preferably not H, (iii) optionally converting the R^la into R¹ if R¹ and R^la differ from each other, to give the compound of formula (A), preferably (Al *).

Furthermore, the present invention relates to a compound obtained or obtainable by any of the above described method, and to a com ound of formula (1)

wherein R^a, R^b, R^c and R^d are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, -NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group, with the proviso that E is not COOH.

Further, the present invention also relates to a process for the preparation of a compound of formula A) or a pharmaceutically acceptable salt or solvate thereof

(ia) providing a compound of formula la)

wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X , and wherein X is not CI and R⁵ is not OH, or

wherein the compound comprises less than 1000 ppm, more preferably less than 100 ppm, preferably less than 10 ppm, more preferably 0 ppm, of the regioisomeric side product havin the structure:

preferably wherein the compound (la) is obtained or obtainable by a method described above,

reacting the compound of formula la) with a compound of formula (Al)

preferably (Al *)

wherein R^la is selected from the group consisting of H, PG¹ and R^A, with R^A being

wherein PG¹ is a suitable protecting group and wherein R^la may be the same or may differ from R¹ and, wherein in case n is 0, R^la is preferably not H,

(iii) optionally converting the R^la into R¹ if R¹ and R^la differ from each other, to give the compound of formula (A), preferably (Al *).

DETAILED DESCRIPTION

As described above, the present invention relates to a process for the preparation of a compound of formula (1) as well as to a compound obtained or obtainable by said method and to a com ound of formula (1) as such

consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, -NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group,

The compound of formula ( 1 )

As described above compound (1) has the structure

consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, -NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group.

Within the meaning of the present invention, the term "alkyl" relates to non-branched alkyl residues and branched alkyl residues. The term also encompasses alkyl groups which are further substituted by one or more suitable substituents. The term "substituted alkyl" as used in this context of the present invention preferably refers to alkyl groups being substituted in any position by one or more substituents, preferably by 1, 2, 3, 4, 5 or 6 substituents, more preferably by 1, 2, or 3 substituents. If two or more substituents are present, each substituent may be the same or may be different from the at least one other substituent. There are in general no limitations as to the substituent. The substituents may be, for example, selected from the group consisting of aryl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino, acylamino, including alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, nitro, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, trifluoromethyl, cyano and azido. Preferred substituents of such organic residues are, for example, halogens, such as fluorine, chlorine, bromine or iodine, amino groups, hydroxyl groups, carbonyl groups, thiol groups and carboxyl groups.

The term "heteroalkyl" refers to alkyl residues comprising one or more heteroatoms or functional groups, such as, by way of example, -0-, -S-, -NH-, -NH-C(=0)-, - C(=0)-NH- and the like.

The term "cycloalkyl" refers to alkyl groups which form a ring, such as a 5-membered, 6-membered or 7-membered ring, e.g. cyclopentyl or cyclohexyl.

The term "heterocycloalkyl" refers to cycloalkyl groups comprising one or more heteroatoms or functional groups, such as, by way of example, -0-, -S-, -NH-, -NH- C(=0)-, -C(=0)-NH-, and the like, such as, e.g., morpholino, piperazinyl or piperidinyl, alkylaryl, arylalkyl and heteroaryl.

Within the meaning of the present invention, the term "aryl" refers to, but is not limited to, optionally suitably substituted 5- and 6-membered single-ring aromatic groups as well as optionally suitably substituted multicyclic groups, for example bicyclic or tricyclic aryl groups. The term "aryl" thus includes, for example, optionally substituted phenyl groups or optionally suitably substituted naphthyl groups. Aryl groups can also be fused or bridged with alicyclic or heterocycloalkyl rings which are not aromatic so as to form a polycycle, e.g. benzodioxolyl or tetraline.

The term "heteroaryl" as used within the meaning of the present invention includes optionally suitably substituted 5- and 6-membered single-ring aromatic groups as well as substituted or unsubstituted multicyclic aryl groups, for example tricyclic or bicyclic aryl groups, comprising one or more, preferably from 1 to 4, such as 1, 2, 3 or 4, heteroatoms, wherein in case the aryl residue comprises more than 1 heteroatom, the heteroatoms may be the same or different. Such heteroaryl groups including from 1 to 4 heteroatoms are, for example, benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenylyl, napthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, or indolizinyl.

The term "optionally substituted aryl" and the term "optionally substituted heteroaryl" as used in the context of the present invention describes moieties having substituents replacing a hydrogen on one or more atoms, e.g. C or N, of an aryl or heteroaryl moiety. Again, there are in general no limitations as to the substituent. The substituents may be, for example, selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino, acylamino, including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido, amidino, nitro, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonate, sulfamoyl, sulfonamido, trifluoromethyl, cyano, azido, cycloalkyl, such as, e.g., cyclopentyl or cyclohexyl, heterocycloalkyl, such as, e.g., morpholino, piperazinyl or piperidinyl, alkylaryl, arylalkyl and heteroaryl. Preferred substituents of such organic residues are, for example, halogens, such as fluorine, chlorine, bromine or iodine, amino groups, hydroxyl groups, carbonyl groups, thiol groups and carboxyl groups.

Preferably compound (1) comprises less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm, more preferably 0 ppm, of a regioisomeric side product having the structure:

based on the total weight of compound (1) (thus the weight including the weight of the regiosomeric side product).

Residues R^a, R^b, and R^d

Residues R^a, R^b, and R^d are preferably, independently of each other, H or alkyl.

More preferably residues R^a, R^b, and R^d are H.

Thus, the present invention also relates to the preparation of a compound of formula (1), as described above, and a compound obtainable or obtained by said process as well as to the compound as such the compound having the structure

Further, the present invention relates to the processes for the preparation of a compound of formula (A) and a compound of formula (A) obtained or obtainable by said processes, as described above, wherein in step (i), a com ound having the structure

is provided.

Residue R^c

Residue R^c is preferably H or alkyl, more preferably selected from the group consisting of H, methyl, ethyl, propyl and butyl, more preferably H or methyl, most preferably methyl.

Thus, the present invention also relates to the preparation of a compound of formula (1), as described above, and a compound obtainable or obtained by said process as well as to the compound as such the compound havin the structure

is provided. Preferably, residues R^a, R^b, and R^d are H and residue R^c is -CH₃, the compound of formula (1) thus having the structure (la)

Residue E

As mentioned above, E is an electrophilic group. The term "electrophilic group" as used herein means any functional group attached to the phenyl ring that can accept a pair of electrons.

Preferably, E is selected from the group consisting of halogen, -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X. In an embodiment of the invention R⁵ is not OH. Hence, preferably, E is selected from the group consisting of halogen, -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -0-alkyl,-H and X with X being the leaving group of the activated group -C(=0)-X. The term "leaving group" as used in this context of the present invention is denoted to mean a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage upon reaction with a nucleophile, such as with an amine group of the diazepane building block. Examples of leaving groups are, inter alia, halogens, sulfonic esters (such as, inter alia, the mesyl and tosyl grou or any one of the following groups

Preferably, residue E is -CN or -C(=0)R⁵.

Thus, the present invention also relates to the preparation of a compound of formula (1), as described above, wherein residue E is -CN or -C(=0)R⁵, the compound having the structure

preferably to a compound of formula (la), wherein residue E is -CN or -C(=0)R⁵, the compound having the structure

preferably

wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated ester group -C(=0)-X.

Further, the present invention relates to a compound obtained or obtainable by the above described method the compound havin the structure (1)

wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X, preferably R⁵ is selected from the group consisting of 0-alkyl,-H and X, wherein the compound preferably comprises less than 1000 ppm, more preferably less than 100 ppm, preferably less than 10 ppm, more preferably 0 ppm, of a regioisomeric side product having the structure:

Further, the present invention relates to a compound obtained or obtainable by the above described method the compound havin the structure (la)

wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X, preferably R⁵ is selected from the group consisting of 0-alkyl,-H and X, with X being the leaving group of the activated group -C(=0)-X, wherein the compound preferably comprises less than 1000 ppm, more preferably less than 100 ppm, 100 ppm, preferably less than 10 ppm, more preferably 0 ppm, of the regioisomeric side product having the structure:

based on the total weight of compound (la) (thus the weight including the weight of the regiosomeric side product)

Further, the present invention relates to a compound obtained or obtainable by the above described method, wherein the com ound has the structure

wherein R⁵ is selected from the group consisting of -O-Alkyl, OH, -H and X with X being the leaving group of the activated group -C(=0)-X , wherein X is not CI.

Preferably E is -CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O- ethyl, -H and X, wherein X is in articular selected from the group the group consisting of

The compound of formula (II)

The compound of formula (II) has the structure

As described above, residues R^a, R^b, and R^d are preferably, independently of each other, H or alkyl. Residue R^c is preferably alkyl, more preferably methyl.

Thus, the compound of formula (II) preferabl has the structure (Ila)

Step (b)

In step (b), the compound of formula (II), preferably of formula (Ila), is reacted with an organolithium reagent in an aprotic solvent to give an intermediate compound of formula (III)

preferably (Ilia)

The reaction may be carried out in any suitable aprotic solvent known to those skilled in the art. Preferably, the reaction is carried out in an organic aprotic solvent selected from the group consisting of diethylether, Tetrahydrofuran, 2-methyltetrahydrofuran, hexane, pentane, cyclopentane, cyclohexane, heptane, toluene and mixtures of two or more thereof. Most preferably, diethylether is used as solvent.

The organolithium reagent is preferably selected from the group consisting of n-butyllithium, sec-butyllithium, tert-butyllithium, isopropyllithium, more preferably the reagent is n-butyllithium.

Preferably, the reaction is carried out at a temperature in the range of from -85 °C to - 20 °C, more preferably in the range of from -85 °C to -50°C more preferably in the range of from -80 °C to -60°C. During the reaction, the temperature may be varied or held essentially constant.

The mol equivalents of the organolithium compound to compound of formula (II) is preferably in the range of from 0.8 to 4, more preferably in the range of from 0.9 to 2.5, more preferably 0.95 to 1.1.

Preferably, when providing the reaction mixture to be reacted in (b), the compound of formula (II) is first admixed with at least a portion of a suitable solvent and is preferably cooled to the temperature range mentioned above. The organolithium reagent is then added which, for example, can be employed as mixture with at least a portion of the solvent or as such.

Compound (II) is preferably allowed to react with the organolithium reagent for a time in the range of from 10 min to 3 h, more preferably in the range of from 10 min to 2 h, more preferably in the range of from 10 min to 1 h. Compound (II) is then preferably reacted, without any intermediate purification step, in step (c).

Step (c) Step (c) of the invention comprises the reacting of the intermediate compound of formula (III) with an electrophile E* thereby forming, optionally after at least one further step, the compound of formula (1) comprising the electrophilic group E.

An electrophile is a reagent attracted to electrons. Electrophiles are positively charged or neutral species having vacant orbitals that are attracted to an electron rich centre. An electrophile participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.

The electrophile E* is preferably a halogen, a hydantoin, a N-halosuccinimide, CO, CH₂0, C0₂ or a group Z-C(=0)-Y, wherein Z is a leaving group which departs upon reaction with compound (III) and wherein Y is -OH, H or -R⁵, wherein R⁵ is, as defined above, i.e. selected from the group consisting of -O-alkyl, -OH, -H and X being a leaving group as defined above. Preferably X is X being a halogen (residue), a sulfonic ester (such as, inter alia, the mes l and tosyl group) or any one of the following groups

Z is preferably-N(CH₃)₂, or -R⁵ with R5 being preferably -O-alkyl, i.e. Z is preferably - N(CH₃)₂ or -O-AlkyL .

Preferably E* is selected from the group consisting of C0₂, carbonates, formiates, formamides, halogens, preferably E* is an alkylformiate or an alkylcarbonate or C0₂, more preferably E* is selected from the group consisting of C0₂, ethylcarbonate, methylcarbonate, ethylformiate and methylformiate.

Preferably, the reaction is carried out in the same aprotic solvent used in step (c). Thus, the solvent is preferably selected from the group consisting of diethylether, Tetrahydrofuran, 2-methyltetrahydrofuran, hexane, pentane, cyclopentane, cyclohexane, heptane, toluene and mixtures of two or more thereof. Most preferably, diethylether is used as solvent. Preferably step (c) and step (b) are carried out in one pot.

Preferably, the reaction is carried out at a temperature in the range of from -85 °C to -20 C, more preferably in the range of from -85 °C to -50 °C , more preferably in the range of from -80 °C to -60 . During the reaction, the temperature may be varied or held essentially constant. The term halogen in the context of E* is denoted to mean a halogen molecule, i.e. in particular Cl₂, Br₂ or I₂.

In case, E is a halogen residue, E* is preferably a halogen. Thus, in this case, the compound of formula (III) is preferably reacted with Cl₂, I₂ or Br₂, more preferably with Cl₂ or I₂ to give the compound of formula (1) with E being a halogen residue, in particular -CI or -I.

In case, E is -C(=0)R⁵ with R⁵ being -OH, E* is preferably C0₂. Thus, in this case, the compound of formula (III) is preferably reacted with C0₂ to give the compound of formula (1) with E being -COOH.

In case E is -C(=0)R⁵, with R⁵ being -O-alkyl or X, E* is preferably Z-C(=0)-Y or C0₂, with Y being _R⁵ with R⁵ being -O-alkyl or X. Thus, compound (III) is reacted with Z- C(=0)-Y with Y being _R⁵, such as in particular with a carbonate having the structure C(=0)( 0-alkyl)₂, to directly give the compound (1). In this case, E* is thus preferably an alkylcarbonate, more preferably methylcarbonate or ethylcarbonate.

Alternatively, compound (III) is reacted with C0₂ to give an intermediate compound comprising a carboxylic acid and the carboxylic acid is then transformed in at least one further step, such as by esterification, to the compound (1) with E being -C(=0)R⁵, with R⁵ being -O-alkyl or X. This reaction is preferred in case E is -C(=0)R⁵, with R⁵ being X and with X being a halogen (residue), a sulfonic ester (such as, inter alia, the mesyl and tosyl group) or an one of the following groups

In case E is -C(=0)R⁵ with R⁵ being H, E* is preferably Z-C(=0)-Y, with Y being H, and with Z being a leaving group, as described above, preferably with Z being -N(CH₃)₂. This compound may further be transformed to E being -COOH via oxidation if desired.

In case, E is CN, E* is preferably C0₂. Thus, in this case, the compound of formula (III) is preferably reacted with C0₂ give an intermediate compound comprising a carboxylic acid and the carboxylic acid is then transformed in at least one further step to give the compound of formula (1). Preferably, the -COOH group is transformed to a group - C(=0)-NH₂ and then dehydrated to give the group -CN. These steps are carried out by ways known to those skilled in the art. The group -CO(NH₂) may be obtained e.g. by activation of the -COOH group and subsequent reaction with ammonia. The dehydration may e.g. be carried out by reaction with cyanuric chloride.

It is to be understood that in this case, compound (1) may be isolated or may be directly further processed to give the compound of formula (A). If such isolation is carried out, this may be carried out by any method known to those skilled in the art. Such isolation may comprise one or more stages wherein preferably at least one stage comprises a purification, such as an extraction and/or a precipitation and/or filtration.

Step (a)

Compound (II), preferably compound (Ila), may be provided by any suitable method known to those skilled in the art.

Preferably, the provision of compound (II), in step (a) comprises

(al) providing a compound of formula IV) or a salt thereof

(a2) reacting the compound of formula (IV) or the salt thereof with glyoxal

to give the compound of formula (II).

Thus, the present invention also relates to a the preparation of a compound of formula (1), as described above, and a compound obtainable or obtained by said process as well as to the compound as such, wherein step (a) comprises

(a) providing a compound of formula (II) by a method comprising

(al) providing a compound of formula (IV) or a salt thereof

(IV),

(a2) reacting the compound of formula (IV) or the salt with glyoxal to give the compound of formula II)

(II). Preferably, compound (II) has the structure Ila)

case, in step (a) compound (Ila) is provided, wherein this provision comprises providing a compound of formula (IVa) or a salt thereof

(a2) reacting the compound of formula (IVa) or the salt thereof with glyoxal

to give the compound of formula (Ila).

Thus, the present invention also relates to a the preparation of a compound of formula (la), as described above, and a compound obtainable or obtained by said process as well as to the compound as such, wherein step (a) comprises

(a) providing a compound of formula (Ila) by a method comprising

(al) providing a compound of formula (IVa) or a salt thereof

(a2) reacting the compound of formula (IVa) or the salt thereof with glyoxal to give the compound of formula (Ila).

Further, the present invention also relates to the preparation of a compound of formula (A), as described above, and a compound obtainable or obtained by said process as well as to the compound as such, wherein the provision of compound (la) in step (i) comprises

(a) providing a compound of formula (Ila) by a method comprising

(al) providing a compound of formula (IVa) or a salt thereof

(IVa), (a2) reacting the compound of formula (IVa) or the salt thereof with glyoxal to give the compound of formula (Ila), and transforming compound (Ila) to compound (la).

The transformation of compound (Ila) to (al) is preferably carried out by a method comprising the steps (b) and (c), as described above, preferably comprising the steps

(b) reacting the compound of formula (Ila) with an organolithium reagent in an aprotic solvent to give an intermediate com ound of formula (Ilia)

(c) reacting the intermediate compound of formula (Ilia) with an electrophile E* to give the compound of formula (la).

Compound of formula (IV)

The compound of formula (IV) has the structure

wherein preferably, the compound (IV) in (al) is provided in the form of a salt, preferably the HC1 salt.

Preferably, the compound (IV) has the structure

and is more preferably provided as salt, most preferably as HC1 salt.

Step (al)

In step (a2), the compound of formula (IV), preferably (Iva) is reacted with glyoxal.

Thereby, preferably as intermediate product, preferably a product having the structure (V)

preferably of (Va)

is obtained which is then, either after isolation or in situ, transformed to compound (II), preferably (Ha).

Preferably, the reaction in step (a2) is carried out in the presence of a copper salt, preferably Cu(OTf)₂. More preferably, first compound (V), preferably compound (Va), is prepared which is optionally isolated and thereafter, compound (V), preferably (Va), is transformed, in the presence of Cu(OTf)₂, to compound (II).

Thus, step (a2) preferably comprises

(a2.1) reacting the compound of formula (IV), preferably (IVa) with glyoxal to give a compound of formula (V), preferably (Va),

(a.2.2) optionally isolating the compound of formula (V), preferably (Va),

(a.2.3) transforming the compound of formula (V), preferably (Va), in the presence of a copper salt, preferably Cu(OTf)₂ to give the compound of formula (II), preferably (II a).

Thus, the present invention also relates to the preparation of a compound of formula (1), as described above, preferably of a compound (la), and a compound obtainable or obtained by said process as well as to the compound as such, wherein step (a2) of step (a) comprises

(a.2.2) optionally isolating the compound of formula (V), preferably (Va),

(a.2.3) transforming the compound of formula (V), preferably (Va), in the presence of a copper salt, preferably Cu(OTf)₂ to give the compound of formula (II), preferably (II a). Further, the present invention also relates to the preparation of a compound of formula (A), as described above, and a compound obtainable or obtained by said process as well as to the compound as such, wherein the provision of compound (la) in step (i) comprises

(a) providing a compound of formula (Ila) by a method comprising

(a 1) providing a compound of formula (IVa) or a salt thereof

(a2) reacting the compound of formula (IVa) or the salt thereof with glyoxal to give the compound of formula (Ila), wherein the reacting is carried out by a process comprising

(a.2.1) reacting the compound of formula (IVa) with glyoxal to give a compound of formula (Va)

(a.2.2) optionally isolating the compound of formula (Va),

(a.2.3) transforming the compound of formula (Va), in the presence of a

copper salt, preferably Cu(OTf)₂ to give the compound of formula (Ila).

Further, the present invention also relates to a compound of formula (V), preferably (Va), as such as well as to a compound of formula (V), preferably (Va), obtained by a method comprising the steps (a2.1) and (a.2.2).

The reaction in step (a2) may be carried out in any suitable solvent known to those skilled in the art.

Preferably, the reaction in (a2.1) is carried out in an acidic solvent, preferably in acidic acid. Preferably, the reaction in (a2.1) is carried out at a temperature in the range of from 25°C to 80°C, more preferably in the range of from 40°C to 60°C. During the reaction, the temperature may be varied or held essentially constant.

Generally, when providing the reaction mixture to be reacted in (a.2.1), the sequence of mixing the components of the reaction mixture is not subject to specific restrictions. Preferably, the compound of formula (IV), preferably (IVa), is first admixed with at least a portion of the solvent and, to the resulting mixture, glyoxal is added which, for example, can be employed as mixture with at least a portion of the solvent or as such.

The isolation in step (a2.2) may be carried out by any method known to those skilled in the art. Such isolation may comprise one or more stages wherein preferably at least one stage comprises purification, such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like. Preferably compound (V) is precipitated and filtered off.

The mol equivalents of the copper salt, preferably Cu(OTf)₂, to compound of formula (V) is preferably in the range of from 0 to 0.1, more preferably in the range of from 0.01 to 0.03.

Step (al)

The compound (A)

As mentioned above the compound of formula (A) has the structure

wherein PG is a suitable protecting group and wherein n is 0 or.

Thus the compound (A) has, e.g., the structure (Aa) or (Ab)

Thus, the present invention also relates to a method, as described above, and to a compound obtained or obtainable by said method, wherein the compound (A) has the

Residue R :

As descried above, R¹ is selected from the group consisting of H, PG¹ and R^A, with being

wherein PG¹ is a suitable protecting group.

Thus, compound (A) is preferably selected from the group consisting of

The term "suitable protecting group" as used herein is denoted to encompass any amino protecting group. The term "protecting group" as such refers to a chemical moiety that can be selectively attached to and removed from a particular chemically reactive functional group in a molecule to prevent it from participating in undesired chemical reactions. The protecting group will vary depending on reaction conditions to be employed and the presence of additional reactive or protecting groups in the molecule. It is understood that the term "amino protecting group" is a chemical moiety being attached to a former amino group. After removal of the protecting group, the free amine is regained. Representative protecting groups for amino groups are well known to those skilled in the art and are described, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis 1999, Third Edition, Wiley, N.Y., and references cited therein. An "amino-protecting group" preferably includes both acyclic as well as cyclic protecting groups. A "cyclic protecting group" is a group which, together with the N to which it is bound, forms a cyclic group.

Preferred protecting groups for PG¹ include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl and the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t-butyldi- methylsilyl and triisopropylsilyl. Particularly preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl and the like. More preferably, PG¹ is selected from the group consisting of Benzyl, t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and Phthalimide, more preferably PG¹ is a Boc group or a Cbz group, more preferably Boc.

Thus, compound (A) is preferably selected from the group consisting of

A bond shown as " in any one of the compounds shown herein is denoted to represent a single bond, wherein the resulting structure including the bond encompasses the isolated S isomer, the isolated R isomer, as well as mixtures of the S and R isomer. Thus, the present invention also relates to methods for the preparation of a compound (A), as described above, and a compound obtained or obtainable by any of these processes, wherein the compound has a structure selected from

Preferably, compound (A) is (A*) and is selected from the group consisting of

Preferably in R¹ is selected from the roup consisting of H,

more preferably, wherein

la

Residue R

As described above, R^la is selected from the group consisting of H, PG¹ and R^A, with R^A being

wherein PG¹ is a suitable protecting group. It is to be understood that R^la may be different from R¹ or may be the same

Preferably in R^la is selected from the group consisting of H,

^" orTfr OH

CI . more preferably, wherein R ^a is H or — 0 _s

most preferably R^la is H.

Step (i) The compound of formula (la) may be provided by any method known to those skilled in the art.

In an embodiment, the compound (la) is thus provided by a method comprising the steps (a) to (c) as mentioned above.

Preferably, the provision in step (i) comprises

(a) providing a compound of formula (Ila) by a method comprising

(al) providing a compound of formula (IVa) or a salt thereof

(a2) reacting the compound of formula (IVa) or the salt with glyoxal to give the compound of formula (Ila

The compound (la) obtained or obtainable by the above described method, preferably comprises less than 1000 ppm, more preferably less than 100 ppm, preferably less than 10 ppm, more preferably 0 ppm, of the regioisomeric side product

based on the total weight of compound (la) (thus the weight including the weight of the regiosomeric side product (lb)

Most preferably, in compound (la), E is not COOH and not CI, preferably not COOH and not a halogen.

In a further embodiment, in step (i), compound (la) is provided wherein X is not CI and E is not COOH.

In a further embodiment, in step (i), compound (la) is provided wherein compound (la) comprises less than 1000 ppm, more preferably less than 100 ppm, preferably less than 10 ppm, more preferably 0 ppm, of the re ioisomeric side product

Step (ii)

In step (ii), the compound of formula (la) is reacted, i.e. coupled with the compound of formula (Al)

preferably with the compound of Al *)

wherein R^la is PG¹, and wherein n is preferably 0, wherein R^la is selected from the group consisting of H, PG¹, and R^A, with R^A being

and wherein R^la may be the same or may differ from R¹, and wherein in case n is 0, R^la is preferably not H.

As mentioned above, E is preferably selected from the group consisting of -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X.

The coupling is preferably carried out in the presence of a suitable base, preferably an organic base, most preferably an amino group comprising base, most preferably a base selected from the group consisting of diisopropylamine (DIEA), triethylamine (TEA), N-methylmorpholine, N-methylimidazole, l,4-diazabicyclo[2.2.2]octane (DABCO), N- methylpiperidine, N-methylpyrrolidine, 2,6-lutidine, collidine, pyridine, 4- dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). As regards the reaction conditions used in this coupling step, preferably the reaction is carried out in an organic solvent, such as N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, acetone, dimethyl acetamide (DMA), dimethyl formamide (DMF), formamide, tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, tert.-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, tetrachloromethane and mixtures of two or more thereof. More preferably, the reaction is carried out in dichloromethane.

The temperature of the coupling reaction is preferably in the range of from 0 to 100 °C, more preferably in the range of from 5 to 50 °C, and especially preferably in the range of from 15 to 30 °C. During the course of the reaction, the temperature may be varied, preferably in the above given ranges, or held essentially constant.

In case E is C(=0)R⁵ with R⁵ being -O-alkyl or X, compound (la) preferably readily reacts with the NH group of compound (Al), optionally in the presence of a suitable base as mentioned above without the need to add a catalyst or a coupling reagent. However, in case of R⁵ being alkyl, activating agents such as EtMgBr or A1C1₃ may be added.

If R⁵ is OH, a coupling reagent is required in order to react compound (la) and (Al) with each other. Such coupling reagents include, but are not limited to, oxalyl chloride, HATU (0-(7-azabenzotriazole-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); HO At (l-hydroxy-7-azabenzotriazole), HBTU (0-benzotriazole-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate); TBTU (2-(lH-benzotriazole-l-yl)-l,l,3,3- tetramethyluronium hexafluorophosphate); TFFH (N,N',N",N"-tetramethyluronium-2- fluoro-hexafluorophosphate); BOP (benzotriazole-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate); PyBOP (benzotriazole- 1 -yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate; EEDQ (2-ethoxy-l-ethoxycarbonyl-l,2-dihydro-quinoline); DCC (dicyclohexylcarbodiimide); DIPCDI (diisopropylcarbodiimide); HOBt (1-hydroxybenzotriazole); NHS (N-hydroxysuccinimide); MSNT (l-(mesitylene-2- sulfonyl)-3-nitro-lH-l,2,4-triazole); aryl sulfonyl halides, e.g. triisopropylbenzenesulfonyl chloride, EDC (l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, CDC (1- cyclohexyl-3-(2-morpholinoethyl)carbodiimide), Pyclop, T3P, CDI, Mukayama's reagent, HODhbt, HAPyU, TAPipU, TPTU, TSTU, TNTU, TOTU, BroP, PyBroP, BOI, TOO, NEPIS, BBC, BDMP, BOMI, AOP, BDP, PyAOP, TDBTU, BOP-Cl, CIP, DEPBT, Dpp- Cl, EEDQ, FDPP, HOTT, TOTT, PyCloP.

In case E is C(=0)H, the reaction with (Al) is preferably carried out in the presence of an oxidizing agent, in particular in the presence of tBuOOH .

In case E is -CN, the reaction with (Al) is preferably carried out in the in the presence of a basic organometallic reagent, preferably an alkylaluminum or a Grignard reagent, more preferably a Grignard reagent, in particular in the presence of EtMgBr

Step (iii)

In the optional step (iii), R^la is converted into R¹ if R¹ and R^la differ from each other. Thus, it is to be understood that R^la may be different from R¹ or may be the same. In case R¹ differs from R^la, step (iii) is carried out. In case R¹ is equal to R^la, step (iii) is omitted.

It is thus to be understood that the compound obtained in step (ii) corresponds to the compound (A), in case R^la is equal to R¹.

In case R^la is different from R¹, the compound obtained in step (ii) is transformed in step (iii) to give the compound of formula (A) wherein this transformation may be carried out in one or in multiple steps.

By way of example, the following preferred embodiments are mentioned:

Preferably, (A) is (Ax)

providing a compound of formula la)

as described above according to the process of the invention,

wherein E is -CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-Alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X,

reacting the compound of formula la) with a compound (Al)

preferably with the com ound of (Al *)

wherein R^la is H, PG¹ or R^A, with R^A bein

pre era y

and optionally reducing the compound of step (ii) in case n in compound Al is 1 and n in compound Ax is 0,

converting R^la into R¹ if R¹ and R^la differ from each other, by

(iiia) removing the protecting group PG¹ in case R^la is PG¹ and reacting the compound of step (ii) with

wherein X* is a leaving group, preferably CI, or by (iiib) reacting the compound of step (ii) with

wherein X* is a leaving group, preferably CI, in case R^la is H,

It is to be understood that in case (A) is (Ax) and R^la is

step (iii) is omitted.

Further preferably, (A)

more preferably

case, the process preferably comprises:

providing a compound of formula la)

as described above according to the process of the invention, wherein E is -CN -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, and X with X being the leaving group of the activated group -C(=0)-X,

(ϋ) reacting the compound of formula (la) with a compound (Al)

preferably with the com ound of (Al *)

wherein R^la is PG¹ and wherein the compound of step (ii) is reduced in case n in Ay is 0 and n in compound Al is 1.

Further preferably, (A) is (Az)

more preferably

case, the process preferably comprises:

providing a compound of formula la)

as described above according to the process of the invention, wherein E is -CN C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, and X with X being the leaving group of the activated group -C(=0)-X, reacting the compound of formula la) with a compound (Al)

preferably with the com ound of (Al *)

wherein R^la is H, PG¹

and wherein in case n in compound Al is 1, and n in compound Az is 0, the compound of step (ii) is reduced,

(iii) converting R^la into R¹ if R¹ and R^la differs from each other, by

(iiia) removing the protecting group PG¹ in case R^la is H.

It is to be understood that in case (A) is (Ay) and R^la is H, step (iii) is omitted.

Preferably, (A) has the structure

case, the process preferably comprises

providing a compound of formula la)

as described above according to the process of the invention, wherein E is -CN C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, and X with X being the leaving group of the activated group -C(=0)-X,

(ϋ) reacting the compound of formula (la) with a compound (Al)

preferably with the com ound of (Al *)

wherein R^la is R^A, with R^A bein

preferably

and wherein the compound is reduced in case n in compound (Al) is 1 to give the compound of formula (IX).

Or, the process preferably comprises

(i) providing a compound of formula la)

as described above according to the process of the invention, wherein E is -CN C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, and X with X being the leaving group of the activated group -C(=0)-X, reacting the compound of formula (la) with a compound (Al)

preferably with the compound of (Al *)

wherein R^la is PG¹ or H, and optionally reducing the compound of step (ii) in case n in compound Al is 1,

converting R^la into R¹ by

(iiia) removing the protecting group PG¹ in case R¹ is PG¹ and reacting the compound of step (ii) with

wherein X* is a leaving group, preferably CI, or by

(iiib) reacting the compound of step (ii) with

wherein X* is a leaving group, preferably CI, in case R¹ is H,

to give the compound of formula (IX).

In step (ii), the compound is reduced in case in compound (A) n is 0 and in compound (Al) n is 1. Alternatively, such reduction may also be carried out in step (iii). In this reduction, a reduction of the carbonyl group is carried out.

Preferably, the reduction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE (methyl-tert-butyl ether), DIPET (diisopropylether), toluene, acetonitrile, CH₂CI₂ and mixtures of two or more thereof.

Preferably, the reduction is carried out at a temperature in the range of from -20 °C to 110 °C.

Preferably, the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH₄, NaCNBH₃, NaBH(OAc)₃, LiAlH₄, LiBH₄ and H₂ in the presence of transition metals, wherein the transition metal is preferably selected from the group consisting of IR, Pt, Fe, Rh, Pd, Re, Ru, Ni and Co. More preferably, the reducing agent is selected from the group consisting of NaBH₄, NaCNBH₃, NaBH(OAc)₃, LiAlH₄ and LiBH₄, more preferably the reducing agent is NaBH₄, NaCNBH₃ or NaBH(OAc)_3, more preferably NaBH₄.

Reaction with compound (XII) As mentioned above, the compound obtained in (ii) may be reacted with a compound of formula (XII)

wherein X* is a leaving group.

The term leaving group in the context of compound (XII) is denoted to encompass any group that departs upon reaction of compound (XII) with an amine. Preferred leaving groups are -CI, -S, -SMe, -SEt or -Br, in particular -CI or -Br.

Preferably, the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of dichloromethane, DMF, DMSO, NMP (N-methyl pyrrolidone), methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile, tetrametyhlharnstoff (tetramethylurea), dimethylacetamid, EtOAc, iPrOAc, hexan, cyclohexan, heptan and mixtures of two or more thereof.

Preferably, the reaction is carried out at a temperature in the range of from 0 to 110 ° C, more preferably in the range of from 20 to 80 °C, more preferably in the range of from 40 to 80 °C, more preferably at room temperature. During the reaction, the temperature may be varied or held essentially constant.

The compounds are preferably allowed to react for a time in the range of from 10 min to 72 h, more preferably in the range of from 30 min to 24 h, more preferably in the range of from 1 h to 12 h.

It is to be understood that after any one of the above-mentioned steps, it is conceivable that the reaction mixture obtained is subjected to a suitable work-up, such as an isolation of the respective compound. Such working up may comprise one or more stages wherein preferably at least one stage comprises purification, such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like. Alternatively, some reactions may be carried out with the crude intermediate products or even in situ.

Preparation of the compound of formula (Al)

The compound of formula (Al) may be provided by any method known to those skilled in the art. Preferably, compound (Al) is provided by a process comprising

(aa) providing a compound of formula (XX)

wherein R^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R^E is alkyl, more preferably wherein R^E is methyl, ethyl or propyl, more preferably wherein R^E is methyl, and wherein R^la is selected from the group consisting of H, PG¹, and R^A, with R^A being

and wherein R ^a is a protecting group PG ^a,

(bb) reacting the compound of formula (XX) with a base

(cc) removing the protecting group PG^2a,

to give the compound of formula (Al), preferably (Al *), wherein in (bb) or (cc), the compound is reduced in case n in Al is 0.

Preferably in R^la is selected from the roup consisting of H, and

more preferably R^la is H or

most preferably R^la is H.

PG^2a is a suitable protecting group. Preferred protecting groups for PG^2a include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl and the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t-butyldimethylsilyl and triisopropylsilyl. Particularly preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl and the like. Most preferably, PG^2a is a Boc group or a Cbz group, more preferably Cbz. R^E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably R^E is alkyl, more preferably R^E is methyl, ethyl or propyl, more preferably R^E methyl.

Step (bb)

In step (bb) of the process of the invention, the compound of formula (XX) is reacted with a base and optionally subsequently reduced to give after step (cc) the compound (A). Upon reaction with the base, the 7-membered ring is formed ("cyclization reaction").

The reaction may be carried out in any suitable solvent known to those skilled in the art. Preferably, the cyclization reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of R^E-OH, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof, with R^E being as described above and below, preferably wherein R^E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl. Preferably the solvent has the structure R^E-OH, with R^E being as described above and below, preferably wherein R^E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R^E is alkyl, more preferably wherein R^E is methyl, ethyl or propyl, more preferably wherein R^E is methyl. Preferably, the cyclization is carried out at a temperature in the range of from -20 to 80 °C, more preferably in the range of from 0 to 50°C, more preferably in the range of from 20 to 30 °C. During the reaction, the temperature may be varied or held essentially constant.

Preferably, as base, a base selected from the group consisting of NaOR^E, sodium- tert.butoxide, potassium-tert.butoxide, NaNH2, DBU (l,8-Diazabicycloundec-7-ene), Tetramethylguanidine, Na-CH₂S(0)CH₃ and mixtures of two or more thereof is employed, with R^E being selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R^E is alkyl, more preferably wherein R^E is methyl, ethyl or propyl, more preferably wherein R^E is methyl. Most preferably, the base is thus sodium methanolate.

The weight ratio of base to compound of formula (XX) is preferably in the range of from 0 to 8, more preferably in the range of from 1 to 5.

Generally, when providing the reaction mixture to be reacted in (bb), the sequence of mixing the components of the reaction mixture is not subject to specific restrictions. Preferably, the compound of formula (XX) is first admixed with at least a portion of a suitable solvent and, to the resulting mixture, the base is added which, for example, can be employed as mixture with at least a portion of the solvent or as such. Compound (XX) is preferably allowed to react with the base for a time in the range of from 0 to 24, more preferably in the range of from 0 to 5, more preferably in the range of from 0 to 3.

In case in compound (Al) n is 1, in step (bb) the compound of formula (XX) is reacted with a base to give, optionally after further steps, the compound (Al). In this case, no additional reduction step is necessary. Directly upon reaction with the base, the 7-membered ring of compound (Al) is formed ("cyclization reaction").

In case in compound (Al) n is 0, in step (bb) the compound of formula (XX) is reacted with a base which is thereafter or in step (cc) reduced to give, after step (cc) and optionally after further steps, the compound (Al). In this case, a reduction of the carbonyl group is thus carried out.

It is to be understood that in this case compound may be isolated or may be directly reduced in situ to give the compound of formula (XX). If such isolation is carried out, this may be carried out by any method known to those skilled in the art. Such isolation may comprise one or more stages wherein preferably at least one stage comprises purification, such as an extraction and/or a precipitation and/or filtration.

Step (cc)

As mentioned above, the protecting group PG^2a may be removed. The way of removing the protecting group PG^2a depends on the protecting group used. Suitable methods are known to those skilled in the art. Preferably, in case the protecting group R² is a Cbz protecting group, the removal of PG^2a is carried out under reductive conditions. More preferably, the removal is carried out with hydrogen and a metal catalyst, preferably a palladium catalyst, more preferably, the protecting group is removed with Pd/C. The removal of group PG^2a may be carried out in any suitable solvent known to those skilled in the art.

Preferably, the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, iPrOH, nPrOH, EtOAc, iPrOAc and mixtures of two or more thereof. Preferably, the removal of group PG^2a is carried out at a temperature in the range of from 0 °C to 100 °C, more preferably in the range of from 10 °C to 70 °C, more preferably at room temperature 20 °C to 50 °C, more preferably at room temperature. In case hydrogen is used, the reaction is preferably carried out at a pressure in the range of from 1 to 4 bar, more preferably, 1.0 to 2.5 bar.

The compound is preferably allowed to react for a time in the range of from 10 min to 180 min, more preferably in the range of from 20 to 120 min, more preferably in the range of from 30 to 60 min.

Optional reduction of the compound obtained in (bb) or (cc) As mentioned above, in case in compound (Al) n is 0, the compound obtained in (cc) or (bb) is reduced. In this case, a reduction of the carbonyl group is thus carried out.

Preferably, the reduction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE, DIPET, toluene, acetonitrile, CH₂CI₂ and mixtures of two or more thereof.

Preferably, step (cl) is carried out at a temperature in the range of from -20 °C to 110 °C.

Racemic mixture/isolated Stereoisomer

Compound (XX) preferably has either the structure

or consists of a mixture of

(XX*) and R^ECT ^O (XX**)

In case compound (Al) has the structure (Al *), preferably in step (aa), compound (XX) is provided in the correct stereochemistr , i.e. as compound (XX*)

This compound is then employed in step (bb) instead of the racemic mixture consisting of (XX*) and (XX**) shown above.

According to an alternative preferred embodiment, in case compound (XX) consists of a racemic mixture, in step (bb), in the cyclization reaction of compound (XX), a compound (Al) consisting of a racemic mixture is obtained. Preferably, in this case, a chiral resolution of (Al) is carried out.

The racemic mixture in this case consists of the com ounds (Al *) and (Al **)

wherein the compound (Al) contains from 20 to 75 % % by weight of the compound of formula (Al *) based on the total weight of the sum of (Al *) and (Al **). In case the preparation of the isolated (Al *) or (A*) is desired, preferably, the mixture comprising (Al *) and (Al **) is resolved by chiral resolution.

Preferably, this is carried out by

(I) adding a single stereoisomer of a chiral acid, preferably of tartaric acid, and precipitating, preferably crystallizing, a chiral acid salt (T) of compound (Al), thereby obtaining a mixture comprising the precipitated, preferably crystallized, chiral acid salt, preferably tartaric acid salt, (T) and the solvent,

(II) preferably separating the precipitated, preferably crystallized, chiral acid salt (T) of the compound of formula (Al) from the mixture obtained in (I), wherein the chiral acid salt (T) contains at least than 80 % by weight of the chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al),

(III) converting the chiral acid salt (T) to the free base.

The term "single stereoisomer of a chiral acid" in this context is denoted to mean that the chiral acid comprises less than 1 % by weight, preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no impurities of respective other stereoisomers of the chiral acid, based on the total weight of the chiral acid.

Preferably, in step (I), upon addition of the chiral acid in a suitable solvent, a chiral acid salt (T*) of at least part of the compound of formula (XX) is formed, and at least part of this chiral acid salt (T*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (T) and the solvent.

The chiral acid is preferably of a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, preferably Dibenzoyl tartaric acid.

Preferably, the process thus comprises

(I) forming a chiral acid salt, preferably a tartaric acid salt, (T*) of at least part of the compound of formula (Al) by treating the compound of formula (Al) with a single stereoisomer of a chiral acid, preferably of a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, in a suitable solvent, and precipitating, preferably crystallizing, at least part of the salt (T*) formed, thereby obtaining a mixture comprising the precipitated, preferably crystallized, salt (T) and the solvent;

(II) preferably separating the precipitated, preferably crystallized, chiral acid salt (T) of the compound of formula (Al) from the mixture obtained in (I), wherein the chiral acid salt (T) of the compound of formula (Al) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al),

(III) converting the chiral acid salt (T) of (Al) to the free base (Al *).

Thus, the present invention also relates to a process, as described above, and a compound obtained or obtainable by the above described method the method comprising

(aa) providing a compound of formula (XX),

(bb) reacting the compound of formula (XX) with a base and optionally reducing the compound in case n in Al is 0 and/or purifying the compound, to give a compound (Al) which consists of an enantiomeric mixture of the compounds (Al *) and (Al **

forming a chiral acid salt, preferably a tartaric acid salt, (T*) of at least part of the compound of formula (Al) by treating the compound of formula (Al) with a single stereoisomer of a chiral acid, preferably of a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, in a suitable solvent, and precipitating, preferably crystallizing, at least part of the salt (T*) formed, thereby obtaining a mixture comprising the precipitated, preferably crystallized, salt (T) and the solvent,

(II) preferably separating the precipitated, preferably crystallized, chiral acid salt (T) of the compound of formula (Al) from the mixture obtained in (I), wherein the chiral acid salt (T) of the compound of formula (Al) contains at least

80 % by weight of the chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al),

(III) converting the chiral acid salt (T) of (Al) to the free base (Al *), wherein (A) is (Al *).

Step (I)

Preferably, the compound of formula (Al) employed in (I) contains of from 40 to 60 % by weight of the compound of formula (Al *) based on the total weight of the sum of (Al *) and (Al **).

In step (b), at least part of the compound of formula (Al) obtained in the cyclization reaction is transformed into the corresponding chiral acid salt, preferably tartaric acid salt, (T*). The chiral acid salt (T*) contains the chiral acid salt of the compound of formula (Al *), e.g. in an amount in the range of from 1 to 80 % by weight, such as in the range of from 10 to 70 % by weight, or in the range of from 30 to 60 % by weight, or in the range of from 45 to 55 % by weight, based on the total amount of the chiral acid salt (T*).

Subsequently, at least part of (T*) is precipitated, preferably crystallized. This is preferably achieved by contacting (treating) the compound of formula (Al) in a suitable solvent with the chiral acid. Thereby, a mixture comprising the crystallized chiral acid salt (T) of the compound of formula (Al *) and the solvent is formed. As mentioned above, the precipitated, preferably crystallized, tartaric acid salt (T) of the compound of formula (Al) contains at least 80 % by weight of chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al).

It is to be noted that the mixture obtained in step (I) may comprise further compounds, in particular non crystalline forms of the compound of formula (Al) and salts thereof. Preferably, the mixture obtained in step (I) comprises non-crystalline forms of the compound of formula (Al **) and chiral acids salts thereof.

The chiral acid salt (T*) of the compound of formula (Al) is denoted to encompass all chiral acid salts of compound (Al) formed in step (I) including the chiral acid salt (T) which precipitates as well as all chiral acid salts formed which remain dissolved. Thus, the chiral acid salt (T*) may comprise a mixture of chiral acid salts of compounds of formula (Al *) and (Al **). Preferably, in step (I) and (II), thus a chiral resolution of the stereoisomers (Al *) and (Al **) is carried out.

As to the solvent used in step (I), any suitable organic solvent in which the compound of formula (Al) is sufficiently soluble may be used. In particular, the solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH₂CI₂, ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketone, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof. More preferably, the suitable solvent comprises acetone or methanol, more preferably the suitable solvent is acetone or methanol.

It is to be understood that in step (I) a further solvent may be added in order to precipitate, preferably crystallize, the chiral acid salt (T). In this case, the mixture obtained in step (I) preferably additionally comprises said further solvent.

This further solvent may be added prior to, together with or after the addition of the chiral acid to the compound of formula (Al). According to a preferred embodiment, the compound of formula (Al) is dissolved in the suitable solvent mentioned above and a mixture, preferably a solution of the chiral acid, in a further solvent is added to the solution, wherein the further solvent and the suitable solvent may be the same or may be different.

In particular, the further solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH₂CI₂, ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketone, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof. More preferably, the suitable solvent comprises acetone or methanol, more preferably the further solvent is acetone or methanol.

Thus, the present invention also relates to a process for the preparation of a chiral acid salt (T) of a compound of formula (Al), as described above, and a chiral acid salt (T) of the compound of formula (Al), obtained or obtainable by said process, wherein step (I) comprises dissolving the compound of formula (Al) in the suitable solvent and adding a solution of the chiral acid dissolved in a further solvent to the solution, wherein the further solvent and the suitable solvent are preferably the same, more preferably acetone or methanol.

Preferably, the compound of formula (Al) is dissolved in the suitable solvent and the mixture is heated to a temperature in the range of from 20 to 80 °C, more preferably to a temperature in the range of from 30 to 60 °C more preferably to a temperature in the range of from 30 to 50 °C, more preferably to a temperature in the range of from 30 to 40 °C, prior to the addition of the tartaric acid. During the heating step, the temperature may be varied, constantly or stepwise, or held essentially constant. Preferably, the mixture is heated until a clear solution of the compound of formula (Al) in the suitable solvent is obtained. Optionally, the mixture is afterwards cooled to room temperature.

The precipitation, preferably the crystallizing, in step (I) is preferably carried out at a temperature in the range of from 0 to 60 °C, wherein the temperature is preferably continuously or stepwise decreased. The chiral acid may thus e.g. be added to a solution of the compound of formula (Al) in the suitable solvent which has been previously heated or which has been previously heated and afterwards cooled to a specific temperature, or which has not been previously heated.

After the addition of the chiral acid derivative, and optionally the further solvent, the mixture may again be heated or alternatively be cooled, or the temperature may be held constant. Preferably, the mixture is cooled to a temperature in the range of from 0 to 50 °C, more preferably to a temperature in the range of from 0 to 40 °C, more preferably to a temperature in the range of from 10 to 30 °C.

Preferably, the mixture obtained in step (I) consists of the chiral acid salt (T), optionally the unreacted chiral acid derivative, optionally the unreacted compound of formula (Al), optionally the further chiral acid salts (salt (T*) minus the amount of precipitated chiral acid salt (T)), the suitable solvent and optionally the further suitable solvent.

Step (II)

In the optional step (II) of the process of the invention, the chiral acid salt (T) is separated from the mixture obtained in step (I).

The separation may be carried out by any suitable method known to those skilled in the art. Preferably, the separating in step (II) is carried out by centrifugation or filtration, preferably filtration.

It is to be understood that the separated salt may be subjected to a further treatment such as an after-treatment such as a purification step and/or lyophilization.

Preferably, the obtained chiral acid salt (T) of the compound of formula (Al) contains at least 85 % by weight, more preferably at least 95 % by weight, more preferably at least 96 % by weight, more preferably at least 97 % by weight, more preferably at least 98 % by weight, more preferably at least 99 % by weight, more preferably at least 99,5 % by weight, more preferably at least 99,9 % by weight, of the tartaric salt of the compound of formula (Al *), based on the total weight of chiral acid salt of the compound of formula (Al), i.e. based on the sum of (Al **) and (Al *). More preferably, the chiral acid salt (T) of the compound of formula (Al) consists of the chiral acid salt of the compound of formula (Al *).

According to a preferred embodiment, compound (Al) is

and consists of a mixture of

and O

In this case, the chiral acid is preferably or a di-toluoyl tartaric acid, more preferably L-di- toluoyl tartaric acid (LTTA). Most preferably R¹ = H and the chiral acid is L-di-toluoyl tartaric acid. In this case, the suitable solvent is preferably methanol.

According to a further preferred embodiment, Al consist of a mixture of

W^'" and

wherein R² = H.

In this case, the chiral acid is preferably a di-benzoyl tartaric acid, more preferably D-di- benzoyl tartaric acid (DBTA). Most preferably R¹ = Cbz and the chiral acid is D-di- benzoyl tartaric acid. In this case, the suitable solvent is preferably acetone.

Step (aa)

The compound of formula (XX) may be provided by any suitable method known to those skilled in the art.

Preferably, compound (XX) provided in step (a) according to the invention comprises

(aal) reacting a compound of formula (Ilia) H ^{1 a}^_{NH R2a (nia)} with a compound of formula (IVa)

O O

X ^OR^E (IVa)

to give a compound of formula V)

wherein R^laa is H, PG¹, R^A or PG^laa and wherein R^2a is PG^2a, and wherein PG^laa and PG^: are, independently of each other, suitable protecting groups,

(aa2) optionally purifying the compound of formula (Va),

(aa3) reducing the compound of formula (Va),

(aa4) optionally replacing R^laa with R^la in case R^la and R^laa differ from each other, to give the compound of formula (XX).

Compound (1) and (la)

The resent invention is further directed to a compound of formula (1)

consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, — NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group, with the proviso that E is not COOH.

Regarding R⁶ or R⁷ being heteroaryl, it is preferred that the heteroaryl is an unsubstituted heteroaryl or alternatively, regarding R⁶ or R⁷ being heteroaryl, it is preferred that the heteroaryl, is selected from the group consisting of benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenylyl, napthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, or indolizinyl

Regarding R^a, R^b, R^c and R^d, it is preferred that they are independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, carbonyl, alkoxy, hydroxyl, -NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl and heterocycloalkyl.

Regarding E, it is preferred that E is selected from the group consisting of halogen, -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O- Alkyl, -H and X with X being the leaving group of the activated group -C(=0)-X. Regardin X, it is referred that X is selected from the group consisting of

Regarding R^c, it is preferred that it is alkyl, more preferably methyl.

Regarding R^a, R^b and R^d, it is preferred that they are H.

Hence, a preferred compound according to the present invention is he compound of structure (la)

wherein E is selected from the group consisting of -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-Alkyl, -H and X with X being the leaving group of the activated roup -C(=0)-X. Preferably, X is selected from the group consisting of

Hence, preferably, the present invention relates to a com ound having the structure

wherein R⁵ is selected from the group consisting of -0-Alkyl,-H and X with X being the leaving group of the activated group -C(=0)-X, wherein X is not CI. Preferably E is -CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O- ethyl, -H and X, wherein X is in articular selected from the group the group consisting of

Preferably the compound of formula (1) or of formula (la) contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities.

Compound (XX) and Compound (XX*)

As mentioned above, the compound of formula (XX) provided in step (aa) has either the structure (XX*) or consists of a mixture of (XX*) and (XX**).

According to one preferred embodiment, in step (aa), the compound of formula (XX*) is provided, thus the "isolated isomer" with R configuration. The term "isolated isomer" in this context is denoted to mean that the compound of formula (XX*) comprises less than 1 % by weight of compound (XX**), preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no compound of formula (XX**) based on the total weight of (XX*) and (XX**).

In case the compound of formula (XX*) is provided in step (a), the provision preferably either comprises a chiral resolution step or an enantioselective reaction step, such as enantioselective reduction of the double bond present in compound (Va).

The chiral resolution may be carried out by any suitable method known to those skilled in the art, such as resolution by crystallization or by chiral chromatography, such as chiral HPLC. Preferably, the chiral resolution during step (aa) is carried out by crystallization employing an optical pure resolving agent, preferably an optical pure chiral acid. Preferanly the chiral acid is tartaric acid or a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, more preferably, the chiral acid is tartaric.

As solvent in such crystallization, preferably a solvent selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH₂CI₂, ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketone, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof, is employed. More preferably, the solvent comprises methylisobutylketone, preferably is methylisobutylketone .

The reduction in step (aa3) may be carried out in a stereoselective or in a non- stereoselective manner.

The reduction may be carried out by any suitable manner known to those skilled in the art. Preferably, a metal catalyst and hydrogen is used. The metal catalyst is preferably selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh and mixtures of two or more thereof. In case of a stereoselective reduction, the metal catalyst is preferably selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh, and mixtures of two or more thereof. Preferably, the catalyst comprises Fe and/or Rh.

The reaction is preferably carried out at a hydrogen pressure in the range of from 1 to 25 bar, more preferably, 2.5 to 10 bar. During the reaction, the pressure may be varied or held essentially constant.

Preferably, the reaction is carried out at a temperature in the range of from 10 to 100 °C, more preferably in the range of from 20 to 60 °C, more preferably at 25 to 40 C. During the reaction, the temperature may be varied or held essentially constant.

The reaction may be carried out in any suitable solvent known to those skilled in the art. Preferably, the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof. Preferably, the solvent is methanol or TFE.

According to one preferred embodiment, the catalyst is a palladium catalyst, more preferably Pd/C. In case of Pd/C, the reaction is preferably carried out in a non- stereoselective manner. The term "non-stereoselective manner" is denoted to mean that a racemic mixture of compounds (XX*) and (XX**) is obtained. Thus, the present invention also relates to a process, as described above, wherein step (aa) comprises the steps (aal) to (aa4), as described above, and wherein in step (aa3), the compound is reduced with Pd/C.

In case R^laa differs from R^la, step (aa4) is carried out. Depending on the respective groups to be replaced, step (aa4) comprises one or multiple steps, such a deprotection step and/or a protection step and/or a coupling step with a compound of formula (XII) as described above

to give the compound of formula (XX).

Methods for attaching and removing of a protecting group are known to those skilled in the art and depend on the respective protecting group employed.

Representative protecting groups for amino groups are well known to those skilled in the art and methods for attaching them to amino groups as well as removing them are described, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis 1999, Third Edition, Wiley, N.Y., and references cited therein.

In case, the protecting group is a Boc group, the removal is preferably carried out under acidic conditions. More preferably, the removal is carried out with HC1 or TFA.

The removal of such protecting groups may be carried out in any suitable solvent known to those skilled in the art. Preferably, the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof. Preferably, the removal is carried out at a temperature in the range of from 0 to 40 °C, more preferably in the range of from 10 to 30 °C, more preferably at room temperature. During the reaction, the temperature may be varied or held essentially constant.

In case, the protecting group is a Cbz group, the removal is preferably carried out under reductive conditions. More preferably, the removal is carried out with hydrogen and a metal catalyst, preferably a palladium catalyst, more preferably the protecting group is removed with Pd/C. The removal of such a protecting group may be carried out in any suitable solvent known to those skilled in the art. Preferably, the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluol, acetonitrile, EtOAc, iPrOAc, hexane, cyclohexane, heptane, dimethylacetamid and mixtures of two or more thereof. Preferably, the removal is carried out at a temperature in the range of from 0 to 60 °C, more preferably in the range of from 10 to 50 °C, more preferably at room temperature. During the reaction, the temperature may be varied or held essentially constant. In case hydrogen is used, the reaction is preferably carried out at a pressure in the range of from 1 to 3 bar, more preferably, 1.5 to 2.5 bar. Use as antagonists oforexin receptor activity

The compound of formula (IX) obtained or obtainable by the above-described process or a pharmaceutical composition comprising this compound is useful in a method of antagonizing orexin receptor activity. Thus, the present invention also describes the compound of formula (IX) obtained or obtainable by the above-described process or a pharmaceutical composition comprising this compound for use as antagonists of orexin receptor activity, in particular for use in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with orexin receptors, in particular for enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep; increasing stage 2 sleep; decreasing fragmentation of sleep patterns; treating insomnia; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian patient in need thereof.

In particular, the compound of formula (IX) obtained or obtainable by the above described process or a pharmaceutical composition comprising this compound is used for treating or preventing a sleep disorder, in particular for enhancing the quality of sleep or for treating insomnia in a mammalian patient, in particular for treating or controlling obesity in a mammalian patient.

As used herein, the terms "treatment" and "treating" refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such a disease or disorder.

By way of example, the following particularly preferred embodiments of the invention are mentioned:

1. A rocess for the preparation of a compound of formula (1)

wherein the process comprises

(a) providing a compound of formula II)

The process of embodiment 1, wherein the electrophilic group is obtained upon addition of the compound of formula (III) to the electrophile E*.

The process of embodiment 1 or 2, wherein E* is selected from the group consisting of a halogen, a hydantoin, N-halosuccinimide, CO, CH₂0, C0₂ and a group Z-C(=0)-Y, wherein Z is a leaving group which departs upon reaction with compound (III) and wherein Y is -OH, H or -R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H with X being a leaving group, preferably with X being a halogen (residue), a sulfonic ester or any one of the following groups

The process of any of embodiments 1 to 3, wherein E is selected from the group consisting of halogen, -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-Alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X.

The process of embodiment 4, wherein E is -CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-ethyl, -H and X.

The process of embodiment 4 or 5, wherein X is selected from the group consisting of

The process of any of embodiments 1 to 6, wherein R^c is alkyl, preferably methyl.

The process of any of embodiments 1 to 7, wherein R^a, R^b and R^d are H.

The process of any of embodiments 1 to 8, wherein the compound of formula (1) has the structure (la)

The process of any of embodiments 1 to 9, wherein step (a) comprises

(al) providing a compound of formula (IV) or a salt thereof,

(a2) reacting the compound with glyoxal

to give the compound of formula (II).

The process of embodiment 10, wherein the reaction in step (a2) is carried out in the presence of a copper salt, preferably Cu(OTf)₂.

The process of embodiment 10 or 11, wherein the compound of formula (IV) has the structure (IV a)

The process of any of embodiments 10 to 12, wherein the compound (II) has the structure (Ila)

The process of any of embodiments 1 to 13, wherein the compound of formula (1) contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities.

A process for the preparation of a compound of formula (A) or a pharmaceutically acceptable salt or solvate thereof

wherein (A) is preferably (A*)

(i) providing a compound of formula la)

wherein E is CN or -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X,

preferably

wherein the compound (la) is provided by a method according to any one of embodiments 1 to 14, and/or

wherein X is not CI and R⁵ is not OH, and/or

wherein the compound comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product

(ii) reacting the compound of formula (la) with a compound of formula (Al)

referably (Al *)

and wherein R^la may be the same or may differ from R¹, and wherein in case n is 0, R^la is preferably not H,

(iii) optionally converting the R^la into R¹ if R¹ and R^la differ from each other, to give the compound of formula (A), preferably (A*).

A process for the preparation of a compound of formula (A) or a pharmaceutically acce table salt or solvate thereof

being

preferably

wherein PG is a suitable protecting group and wherein n is 0 or 1, the process comprising

(i) providing a compound of formula la)

according to the method as disclosed in any one of embodiments 1 to 14, wherein E is CN or -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X,

preferably

wherein X is not CI and R⁵ is not OH, and/or

reacting the compound of formula la) with a compound of formula (Al)

preferably (Al *)

(i) providing a compound of formula la)

reacting the compound of formula la) with a compound of formula (Al)

preferably (Al *)

The process of any embodiments 15 to 17, wherein the compound (la) is provided by a method according to any one of embodiments 1 to 14 and X is not CI and R⁵ is not OH. The process of any of embodiments 15 to 17, wherein the compound (la) is provided by a method according to any one of embodiments 1 to 14 and wherein compound (la) comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product.

The process of any of embodiments 15 to 19, wherein X is selected from the group consistin of

The process of any of embodiments 15 to 20, wherein the compound (la) is provided by a method according to any one of embodiments 1 to 14.

The process of any of embodiments 15 to 21, wherein the provision of compound (la) in step (i) comprises

(a) providing a compound of formula (II) by a method comprising

(al) providing a com ound of formula (IVa) or a salt thereof

(a2) reacting the compound of formula (IVa) or the salt with glyoxal to give the compound of formula Ila)

reacting the compound of formula (II) with an organolithium reagent aprotic solvent to give an intermediate compound of formula (Ilia)

(Ilia),

(c) reacting the intermediate compound of formula (Ilia) with an electrophile E* to give the compound of formula (la)

The process of embodiment 22, wherein compound (la) comprises less than 1000 pm of the regioisomeric side product (lb)

The process of any of embodiments 15 to 23, wherein (A) has the structure (Aa),

preferably (Aa*)

and wherein (Al) has the structure (Ala)

preferably

The process of any of embodiments 15 to 24, wherein (A) has the structure (Ab)

preferably (Alb*)

and wherein (Al) has the structure Alb)

preferably

The rocess of any of embodiments 15 to 25, wherein (A) has the structure

according to the method as disclosed in any one of embodiments 1 to 14, wherein E is -CN or -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of -O-Alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X, wherein X is preferably selected from the roup consisting of

reacting the compound of formula la) with a compound (Al)

referably (Al *)

preferably (A2*)

and optionally reducing the compound in case n is 1 , (iii) removing the protecting group PG¹

(iv) reacting the com ound of step (iii) with

wherein X* is a leaving group, preferably CI,

to give the compound of formula (IX).

The process of an of embodiments 15 to 26, wherein (A) has the structure

the process comprising

(i) providing a compound of formula la)

according to the method as disclosed in any one of embodiments 1 to 14, wherein E is -CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-Alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X,

wherein X is referabl selected from the group consisting of

(ii) reacting the compound of formula (la) with a compound (Al), wherein the compound of formula (Al) is (AO)

preferably (AO*)

wherein R^{1 A}, with R^A being

preferably — ' Ό ,

and optionally reducing the compound of step (ii) in case n is 1 ,

to give the compound of formula (IX).

The process of any of embodiments 15 to 27, wherein step (a) of step (i) comprises (al) providing a compound of formula (IVa) or a salt thereof,

(a2) reacting the compound with glyoxal

to give the compound of formula Ila)

A compound of formula (1) obtained or obtainable by a process according to any one of embodiments 1 to 14, preferably wherein the compound contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities. A compound of formula (1)

wherein R^a, R^b, R^c and R^d are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl,— NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group, with the proviso that E is not COOH,

wherein the heteroaryl is preferably a unsubstituted heteroaryl or

wherein the heteroaryl is preferably selected from the group consisting of benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenylyl, napthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, or indolizinyl.

The compound of formula (1) of embodiment 30, wherein R^a, R^b, R^c and R^d are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, carbonyl, alkoxy, hydroxyl, - NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl and heterocycloalkyl.

The compound of formula (1) of embodiment 30 or 31, wherein E is selected from the group consisting of halogen, -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-Alkyl, -H and X with X being the leaving group of the activated group -C(=0)-X.

The compound of embodiment 32, wherein X is selected from the group consisting of

The compound of any of embodiments 30 to 33, wherein R^c is alkyl, preferably methyl.

The compound of any of embodiments 30 to 34, wherein R^a, R^b and R^d are H.

The compound of structure (la

wherein E is selected from the group consisting of -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-Alkyl, -H and X with X being the leaving group of the activated group -C(=0)-X.

The compound of embodiment 36, wherein X is selected from the group consisting of

The compound of any of embodiments 30 to 37, wherein the compound contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities.

A compound of formula (IX)

obtained or obtainable by a process according to any one of embodiment 15 to 28. Use of a compound of formula la)

wherein E is -C(=0)R⁵, wherein R⁵ is sseelleeccted from the group consisting ethyl, -H and X for the reparation of a compound of formula (IX)

or a pharmaceutically acceptable salt or solvate thereof,

with X being the leaving group of the activated group -C(=0)-X, preferably with X being selected from the roup consisting of

Use of embodiment 40, wherein compound (la) is prepared according to any of embodiments 1 to 14.

wherein (A) is preferabl (A*)

and wherein R¹ is selected from the group consisting of H, PG¹ and R^A, with R^ being

preferably

(i) providing a compound of formula (la)

wherein E is CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl,— H and X with X being the leaving group of the activated group -C(=0)-X, wherein X is not CI

reacting the compound of formula (la) with a compound of formula Al)

(iii) optionally converting the R^la into R¹ if R¹ and R^la differ from each other,

to give the compound of formula (A), preferably (A*).

43. The process of embodiment 42, wherein the compound of formula (I) is prepared according to any of embodiments 1 to 14.

44. The process of 42 or 43, wherein (A) has the structure

providing a compound o (la)

(la),

wherein E is CN or -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of -O-alkyl,— H and X with X being the leaving group of the activated group -C(=0)-X, wherein X is not CI, wherein X is preferably selected from the roup consisting of

reacting the compound of formula (la) with a compound (Al)

preferably (Al *)

wherein R^la is PG¹

to give a compound of formula A2)

preferably (A2*)

and optionally reducing the compound in case n is 1 ,

(iii) removing the protecting group PG¹

(iv) reacting the compound of ste (iii) with

wherein X* is a leaving group, preferably CI,

to give the compound of formula (IX).

The process of any of embodiments 42 to 44, wherein n is 1.

The process of an of embodiments 42 to 45, wherein (A) has the structure

the process comprising

(i) providing a compound o (la)

(la),

wherein E is CN or -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of -O-alkyl,— H and X with X being the leaving group of the activated group -C(=0)-X, wherein X is not CI, wherein X is preferably selected from the group consisting of

reacting the compound of formula (la) with a compound (Al), wherein the compound of formula Al) is (AO)

preferably (AO*)

wherein R¹ is R^A, with R^A bein

preferably \^^{^}o

and optionally reducing the compound of step (ii) in case n is 1 , to give the compound of formula (IX).

The process of embodiment 46, wherein n is 1.

(A), wherein (A) is preferabl (A*)

(i) providing a compound of formula la)

wherein E is CN or -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X, and wherein the compound of formula (la) comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product

reacting the compound of formula (la) with a compound of formula (Al)

preferably (Al *)

The process of embodiment 48, wherein the compound of formula (I) is prepared according to any of embodiments 1 to 14.

The process of an of embodiments 47 to 49, wherein (A) has the structure

the process comprising

(i) providing a compound of formula (la)

(la),

wherein E is CN or -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of -O-alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X, and wherein the compound of formula (la) comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product, wherein X is preferably selected from the group consisting of

reacting the com ound of formula (la) with a compound (Al)

preferably (Al *)

wherein R^la is PG¹

to give a compound of formula A2)

preferably (A2*)

(A2*), and optionally reducing the compound in case n is 1 ,

(iii) removing the protecting group PG

(iv) reacting the compound of step (iii) with

wherein X* is a leaving group, preferably CI,

to give the compound of formula (IX).

The process of any of embodiments 48 to 50, wherein n is 1.

The process of an of embodiments 48 to 51, wherein (A) has the structure

the process comprising

(i) providing a compound of formula (la)

wherein E is -CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-Alkyl, -OH, -H and X with X being the leaving group of the activated group -C(=0)-X, and wherein the compound of formula (la) comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product

wherein X is preferabl selected from the group consisting of

preferably (AO*)

wherein R¹ is R^A, with R^A being

The process of embodiment 52, wherein n is 1.

wherein (A) is preferabl (A*)

(A*), and wherein R¹ is selected from the group consisting of H, PG¹ and R^A, with R^A being

preferably τ—χ ' Ό>*- ,

(i) providing a compound o (la)

(la)

wherein E is -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of - O-alkyl,— H and X with X being the leaving group of the activated group - C(=0)-X, wherein X is not CI and wherein the compound of formula (la) comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product

reacting the compound of formula la) with a compound of formula (Al)

preferably (Al *)

The process of embodiment 54, wherein the compound of formula (I) is prepared according to any of embodiments 1 to 14.

The process of embodiment 54 or 55, wherein A) has the structure

the process comprising

(i) providing a compound of formula la)

wherein E is -CN or -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of -O-Alkyl, -H and X with X being the leaving group of the activated group -C(=0)-X, wherein X is not CI and wherein the compound of formula (la) comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product

selected from the group consisting of

reacting the compound of formula la) with a compound (Al)

referably (Al *)

and optionally reducing the compound in case n is 1 ,

(iii) removing the protecting group PG¹ reacting the compound of step (iii) with

wherein X* is a leaving group, preferably CI,

to give the compound of formula (IX).

The process of any of embodiments 54 to 56, wherein n is 1.

The process of an of embodiments 54 to 57, wherein (A) has the structure

the process comprising

(i) providing a compound o (la)

(la),

wherein E is -CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-Alkyl, -H and X with X being the leaving group of the activated group -C(=0)-X,

wherein X is referabl selected from the group consisting of

reacting the compound of formula (la) with a compound (Al), wherein the compound of formula (Al) is (AO)

preferably (AO*)

wherein R¹ is R^A, with R^A bein

preferably

59. The process of embodiment 58, wherein n is 1.

EXAMPLES

Example 1:

p-tolylhydrazine hydrochloride (80 g, 504.22 mmol) was dissolved in acetic acid (700 mL, 60 %) at slightly elevated temperatures (50 °C). In a second vessel, glyoxal (27 g, 40 % in water, 186.37 mmol) was diluted with acetic acid (200 mL, 60 %). Then, the warm p-tolylhydrazine hydrochloride was added slowly and the solution turned dark red. After 3 h, a suspension formed which was cooled to 10 °C and filtered. The residue was washed with ethyl acetate and dried under vacuum at 50 °C to give 47.03 g (70 %>). Further purification is possible by suspending the residue in ethanol (650 mL) and heating the suspension to reflux for 45 min. After cooling the suspension to 8 °C, the orange precipitate was filtered, washed with ethanol and dried under vacuum at room temperature to give 45.5 g (68 %) product.

1H NMR (500 MHz, d⁶-dmso) δ = 10.21 (s, 2H), 7.60 (s, 2H), 7.01 (d, J = 8.20 Hz, 4H), 6.88 (d, J = 8.20 Hz, 4H), 2.20 (s, 6H)

1³C NMR (125 MHz, d⁶-dmso) δ = 142.5, 136.3, 129.5, 127.3, 111.9, 20.2

Example 2:

(2-chloro-4-methylphenyl)hydrazine hydrochloride (10 g, 51.78 mmol) was dissolved in acetic acid (70 mL, 60 %) at slightly elevated temperatures (50 °C). In a second vessel, glyoxal (2.55 g, 40 % in water, 17.61 mmol) was diluted with acetic acid (30 mL, 60 %). Then, the warm hydrazine was added slowly and a suspension formed. The suspension was filtered and the residue was washed with isopropyl alcohol and dried under vacuo .

1H NMR (500M Hz, d⁶-dmso) δ = 9.90 (s, 2H), 8.01 (s, 2H), 7.29 (d, J = 8.20 Hz, 2H), 7.16 (d, J = 0.85 Hz, 2H), 7.05 (dd, J = 0.95, 7.88 Hz, 2H), 2.22 (s, 6H)

1³C NMR (125 MHz, d⁶-dmso) δ = 139.7, 138.5, 129.5, 129.1, 128.6, 116.1, 113.9, 19.7

Example 3:

The glyoxal imine (60 g, 225.3 mmol) and Cu(OTf)₂ (1.2 g, 3.64 mmol) were heated under reflux in toluene (500 mL) for 4h. Toluene was removed and the residue was dissolved in ethyl acetate (300 mL) and washed with a saturated K₂CO₃ solution (2x75 mL). The organic solution was dried with Na₂S0₄ and MsOH (14.6 mL, 225.3 mmol) was added and cooled to 0 °C to remove p-toluidine. After filtration, the organic solvent was evaporated and the residue (54 g) was purified by vacuum distillation (92 °C bp, 7 mbar) to get 30.1 g (82 %) of white crystalline product.

1H NMR (500 MHz, d⁶-dmso) δ = 8.08 (s, 2H), 7.90 (d, J = 9.14 Hz, 2H), 7.36 (d, J = 8.19 Hz, 2H), 2.36 (s, 3H)

¹³C NMR (125 MHz, d⁶-dmso) δ = 137.2, 137.1, 136.1, 130.0, 118.4, 20.5 Example 4:

The glyoxal imine (5.2 g, 15.5 mmol) and Cu(OTf)₂ (120 mg, 0.36 mmol) were heated under reflux in toluene (100 mL) for 24h. Additional Cu(OTf)₂ (900 mg, 2.7 mmol) was added and stirred for additional 24 h under reflux. Toluene and water were added, layers were separated and the aqueous layer extracted with ethyl acetate. The organic solution was dried with Na₂S0₄ and the residue was purified by column chromatography (cyclohexane + ethyl acetate = 50 + 1) to give 2.40 g of the triazole.

1H NMR (500 MHz, CDC1₃) δ = 7.57 (s, 2H), 7.46 (d, J = 8.19 Hz, 1H), 7.38 (d, J 1.26 Hz, 1H), 7.19 (dd, J = 1.26, 8.19 Hz, 1H), 2.42 (s, 3H)

¹³C NMR (125 MHz, CDC1₃) δ = 140.9, 135.7, 135.4, 131.2, 129.2, 128.1, 127.4, 21.0

Example 5:

To p-tolyl triazole (5 g, 31.41 mmol) in diethyl ether (160 mL) at -70 °C, tBuLi (22.2 mL, 1.7 M in pentane, 37.69 mmol) was added. After 1 h, a solution of DMF (8 mL, 105 mmol) in diethyl ether (17 mL) was added over 1.5 h. The reaction mixture was allowed to reach - 35 °C over 30 min and was quenched by the addition of brine and warmed to room temperature. Layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over Na₂S0₄ and the solvent was removed under reduced pressure. Purification by column chromatography (cyclohexane + ethyl acetate = 12 + 1) gave 2.05 g (35 %) of the aldehyde.

1H NMR (500 MHz, CDC1₃) δ = 10.27 (s, 1H), 7.90 (s, 2H), 7.82 (s, 1H), 7.79 (d, J = 8.19 Hz, 1H), 7.51 (dd, J = 1.57, 8.19Hz, 1H), 2.47 (s, 3H)

¹³C NMR (125 MHz, CDC1₃) δ = 190.3, 138.9, 136.4, 134.8, 128.9, 123.8, 21.0

Example 6:

Method 1: Pinnick oxidation of the aldehyde:

The aldehyde (50 mg, 0.267 mmol) was added to a solution of NaH₂P0₄ (96 mg, 0.8 mmol) of tBuOH (0.5 mL) and water (0.5 mL). 2-methyl-2-butene (0.45 mL, 5.34 mmol) was added followed by NaC10₂ (72.5 mg, 0.8 mmol). After 18 h, ethyl acetate and a saturated NH₄C1 solution were added. Layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over Na₂S0₄ and the solvent was removed under reduced pressure.

Method 2: C0₂ quench of lithiation:

To p-tolyl triazole (300 mg, 1.88 mmol) in diethyl ether (10 mL), tBuLi (1.33 mL, 1.7 M in pentane, 2.26 mmol) was added at -80 °C. After 1 h, C0₂ was slowly bubbled through the solution for 2 h. The reaction mixture was allowed to reach -50 °C and was quenched by the addition of water and warmed to room temperature. Layers were separated and the aqueous layer was extracted with ethyl acetate. The aqueous layer containing the acid was lyophilized and the acid purified by column chromatography.

1H NMR (500 MHz, d⁶-dmso) δ = 12.95 (bs, 1H), 8.04 (s, 2H), 7.62 (d, J = 8.19 Hz, 2H), 7.50 (d, J = 8.19 Hz, 2H), 2.42 (s, 3H)

¹³C NMR (125 MHz, d⁶-dmso) δ = 167.5, 138.7, 135.9, 132.0, 129.8, 128.2, 124.3, 20.4 Example 8:

Method 1: By I₂ quench of lithiation:

To p-tolyl triazole (300 mg, 1.88 mmol) in diethyl ether (10 mL), tBuLi (1.33 mL, 1.7 M in pentane, 2.26 mmol) was added at -80 °C. After 1 h, a solution of iodine (2.39 g, 9.42 mmol) in diethyl ether (10 mL) was added slowly. The reaction mixture was allowed to reach -50 °C over 2h and was quenched by the addition of water and warmed to room temperature. Layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over Na₂S0₄ and the solvent was removed under reduced pressure. Purification by column chromatography (cyclohexane + ethyl acetate = 50 + 1) gave the pure product as white crystals. Method 2: By Hundsdiecker reaction:

A solution of the acid (30 mg, 0.15 mmol), (iBu₃P)AuCl (64 mg, 0.15 mmol) and Ag₂0 (34 mg, 0.15 mmol) in DMF (0.5 mL) was stirred for 18 h at 100 °C. Diiodo-5,5- dimethylhydantoin (52 mg, 0.15 mmol) was added and stirring was continued at 60 °C for 2 h. The reaction was quenched by the addition of a 10 % Na₂S₂0₃ solution and DCM was added. The layers were separated and the aqueous layer extracted with DCM. The combined organic layer was washed with water, dried and the solvent removed.

Method 3: Photo-induced decarboxylation:

A solution of the acid (200 mg, 0.98 mmol) and diiodo-5,5-dimethylhydantoin (866 mg, 2.46 mmol) in CC1₄ (10 mL) was heated under reflux and irradiated with an UV-lamp (254 nm). After 18 h water was added. Layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over Na₂S0₄ and the solvent was removed under reduced pressure.

1H NMR (500 MHz, CDC1₃) δ = 7.86 (s, 2H), 7.82 (d, J = 1.0 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.27 (dd, J = 0.9, 8.0 Hz, 1H), 2.39 (s, 3H)

¹³C NMR (125 MHz, CDC1₃) δ = 141.4, 140.9, 140.7, 135.4, 129.6, 127.3, 92.6, 20.7

Example 9:

A 3 -necked round bottom flask equipped with a nitrogen inlet and a magnetic stirrer was charged with 2-(p-tolyl)-2H-l,2,3-triazole (2.0 g, 12.56 mmol, 1.0 equiv) and dry Et₂0 (70 mL). The resulting clear solution was cooled to -75° C and i-BuLi (1.7 M in pentane, 8.8 mL, 1.2 equiv) was added via syringe under nitrogen. The mixture was stirred for 30 min under an atmosphere of nitrogen. An addition funnel was attached and charged with Br₂ (1.3 mL, 2.0 equiv) and Et₂0 (10 mL). At -75° C, the bromine solution was carefully added to the organometallics solution, followed by stirring at -65° C for 1.5 h. Now, the reaction was quenched using a 5 % sodium thiosulfate solution (150 mL) and the mixture was allowed to warm to ambient temperature. The organic layer was washed with sodium thiosulfate solution (5 wt.-%) and brine and dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude material was purified using column chromatography (Si0_2, cyclohexane : ethyl acetate 50 : 1) yielding 2-(2-bromo-4- methylphenyl)-2H-l,2,3-triazole as an orange oil.

1H NMR (500 MHz, d⁶-DMSO) δ = 8.11 (s, 2H), 7.71 (d, J = 0.9 Hz, 1H), 7.50 (d, J = 8.05 Hz, 1H), 7.39 dd, J = 1.05, 8.05 Hz, 1H), 2.41 (s, 3H) ¹³C NMR (125 MHz, d⁶-DMSO) δ = 141.8, 136.9, 135.9, 133.8, 129.2, 128.0, 118.1, 20.4 Example 10:

Method 1: Aryl-lithium addition to diethyl carbonate

To p-tolyl triazole (300 mg, 1.88 mmol) in diethyl ether (10 mL), tBuLi (1.33 mL, 1.7 M in pentane, 2.26 mmol) was added at -80 °C. After 1 h, a solution of diethyl carbonate (1.1 lg, 9.42 mmol) in diethyl ether (10 mL) was added slowly. The reaction mixture was allowed to reach -50 °C over 2 h and was quenched by the addition of water and warmed to room temperature. Layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over Na₂S0₄ and the solvent was removed under reduced pressure.

Method 2: From the carboxylic acid by acid-catalyzed esterification

A 100 mL round-bottom flask equipped with a magnetic stirrer bar was charged with 5- methyl-2-(2H-l,2,3-triazole-2-yl)benzoic acid (5.0 g, 24.6 mmol, 1.0 equiv) and ethanol (25 mL). After addition of concentrated sulphuric acid (100 L) and powdered 4 A molecular sieves (lg), the mixture was heated to 80° C (reflux condenser) overnight. The crude reaction mixture was filtered over a pad of Celite and evaporated, yielding ethyl 5- methyl-2-(2H-l,2,3-triazole-2-yl)benzoate (2.4 g, 42%) as a brownish oil.

1H NMR (500 MHz, CDC1₃) δ = 7.80 (s, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 1.4, 8.0 Hz, 1H), 4.20 (q, J = 7.15Hz, 2H), 2.45 (s, 3H), 1.14 (t, J = 7.09 Hz, 3H)

¹³C NMR (125 MHz, CDC1₃) δ = 166.9, 138.9, 136.2, 135.3, 132.3, 130.5, 127.3, 124.6, 61.4, 21.0, 14.0

Example 11:

KMn0₄ (96 mg, 0.607 mmol) was dissolved in a 2 : 1 CH₃CN : water mixture (2.5 mL), then tetrabutylammonium bromide (10 mg) was added and heated to 55 °C. A solution of the imine (100 mg, 0.303 mmol) in CH₃CN (1.5 mL) was added over 2 h and stirring was continued for 18 h. The reaction was cooled to room temperature, the solids were filtered off and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and saturated NaHC0₃ solution. Layers were separated and the organic layer was extracted repeatedly with saturated NaHC0₃ solution. The organic layer was dried over Na₂S0₄ and the solvent was removed under reduced pressure.

1H NMR (500 MHz, CDC1₃) δ = 7.84 (s, 2H), 7.68 (d, J = 8.20 Hz, 1H), 7.40 (s, 1H),7.35 (dd, J = 1.10, 7.72 Hz, 1H), 6.18 (bs, 1H (NH)), 5.13 (bs, 1H (NH)), 3.46 (m, 2H), 3.31 (m, 2H), 2.42 (s, 3H), 1.44 (s, 9H)

¹³C NMR (125 MHz, CDC1₃) δ = 168.3, 138.9, 135.7, 135.5, 131.3, 130.7, 129.2, 124.1, 53.4, 40.4, 38.7, 21.0

Example 12:

The aldehyde (lg, 5.34mmol) and Boc-ethylenediamine (873 mg, 5.34 mmol) were dissolved in toluene (60 mL) and MS 4 A was added. Toluene (50 mL) was removed by distillation and a second toluene portion (50 mL) added and azeotropically distilled again. The mixture was filtered over Celite and the solvent removed in vacuum. The product crystallized upon standing and was used without further purification.

1H NMR (500 MHz, C₆D₆) δ = 8.39, (s, 1H), 8.00 (s, 1H), 7.61 (d, J = 8.83 Hz, 1H), 7.43 (s, 2H), 6.80 (dd, J = 1.58, 8.20 Hz, 1H), 4.81 (bs, 1H (NH)), 3.43-3.35 (m, 4H), 1.95 (s, 3H), 1.44 (s, 9H)

¹³C NMR (125 MHz, C₆D₆) δ = 159.2, 155.8, 138.5, 138.0, 135.7, 131.5, 129.8, 129.2, 124.5, 78.49, 61.3, 41.7, 28.5, 20.7

Example 14:

To a solution of the acid (10.4 g, 51.2 mmol) in THF (250 mL), CDI (8.7 g, 53.7 mmol) was added. After 3.5 h, aqueous NH₃ solution (174.1 g, 25% in water, 2.56 mol) was added. The biphasic mixture was stirred at room temperature for 75 min. The pH was adjusted to pH 7 with 6 N HC1 and DCM were added. The layers were separated and the organic layer was washed with water, dried over Na₂S0₄ and the solvent was removed under reduced pressure. The residue was stirred with diethyl ether for 30 min, filtered and washed with diethyl ether to give 7.9 g (76 %) of the primary amide.

1H NMR (300 MHz, d⁶-dmso) δ = 8.01 (s, 2H, H_triazoi_yi), 7.79 (br s, 1H, NH), 7.61 (d, J = 8.1 Hz, 1H, H_arom), 7.40 (d, J = 8.4 Hz, 1H, H_arom), 7.38 (s, 1H, H_arom), 7.32 (br s, 1H, NH), 2.40 (s, 3H, CH₃).

13C NMR (75 MHz, d⁶-dmso) δ = 168.6, 138.0, 135.8, 134.6, 132.0, 130.5, 129.0, 123.8, 20.0.

Example 15:

Method 1: Dehydration of the primary amide

A solution of the primary amide (7.3 g, 36.1 mmol) in DMF (150 mL) was cooled to 0 °C and cyanuric chloride (13.3 g, 72.2 mmol) was added. After 1 h, water (200 mL) was added over 30 min and the suspension was stirred for 1 h at room temperature. The precipitate was filtered and washed with water. To remove the cyanuric acid, DCM/water was added to the residue and the pH was adjusted to pH 10.5 with 10 N NaOH. The solid product was filtered off and additional amounts were isolated from the organic layer. The organic layer was dried over Na₂S0₄ and the solvent was removed under reduced pressure to give 4.4 g of the nitril in total.

Method 2: Starting from the iodo-derivative

A screw-cap vial equipped with magnetic stirrer bar was charged with 2-(2-iodo-4- methylphenyl)-2H-l,2,3-triazole (100 mg, 0.35 mmol, 1 equiv), Cu(OAc)₂ (12 mg, 0.07 mmol, 0.2 equiv), triphenyl phosphine oxide (39 mg, 0.14 mmol, 0.4 equiv), Ag₂0 (81 mg, 0.35 mmol, 1.0 equiv) and acetonitrile (1.2 mL). The vial was capped and the resulting mixture was stirred at 120 °C overnight. The conversion to 5-methyl-2-(2H- 1,2,3- triazole-2-yl)benzonitrile was 20 % as determined by RP-HPLC.

1H NMR (300 MHz, d⁶-dmso) δ = 8.24 (s, 2H, Htriazoiyi), 7.93 (d, J = 8.4 Hz, 1H, Harom), 7.86 (s, 1H, H^), 7.69 (d, J = 8.3 Hz, 1H, H^), 2.40 (s, 3H CH₃).

13C NMR (75 MHz, d⁶-dmso) δ = 139.0, 137.7, 137.3, 135.2, 122.9, 116.6, 103.8, 20.0.

Example 16: Method A: EtMgBr

Method B: Me₃AI

Ci₀H₈N C₁₆H₂₀N₄O

MW: 184,20 MW: 284,36

Method 1:

A solution of azepane (248 μί, 2.2 mmol) in THF (1.0 mL) was added to a solution of EtMgBr (0.67 mL of a 3.0 M solution in Et₂0, 2.0 mmol) in THF (6.0 mL) over a period of 30 minutes at room temperature. The reaction mixture was stirred for one hour at room temperature. A solution of the benzonitrile (110 mg, 0.6 mmol) in THF (2.0 mL) was added over a period of 30 minutes at room temperature. The reaction mixture was stirred at room temperature and the formation of the amide was monitored by HPLC. Work-up and isolation see method 2.

Method 2:

A solution of Me₃Al (2.0 M in toluene, 3.75 mL, 7.5 mmol) was added to a solution of azepane (562 μΐ, 5.0 mmol) in toluene (6.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for one hour. The benzonitrile (368 mg, 2.0 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 1 hour and at 100 °C overnight. HPLC indicated complete conversion of the starting material. The reaction mixture was poured on a mixture of ethyl acetate (30 mL) and HC1 (2.0 M, 25 mL) and stirred for 15 minutes. Ethyl acetate was added to the aqueous phase (containing the amide product) and the pH was adjusted to pH = 10 by the addition of NaOH (10.0 M). The organic layer (containing the amide product) was dried over MgSC^, filtered and concentrated to give the amide (400 mg) as a partly solid material. An analytical sample was purified by crystallization from Et₂0 to give the amide as yellow crystalline material.

1H NMR (300 MHz, d⁶-dmso, 60 °C) δ = 9.31 (v. br. s, 1H, NH), 8.15 (s, 2H, CH_triazoi) 8.00 (d, / = 8.3 Hz, 1H, H_arom), 7.63 (d, / = 8.3 Hz, 1H, H_arom), 7.50 (s, 1H, H^), 3.74 (br. d ~ s, / = n.a., 2H, CH₂), 3.21 (v. br. d, J = n.a., 2H, CH₂), 2.50 and 2.45 (s, 1.36 + 1.64 = 3H, CH₃), 1.84 (v. br. s, 2H, CH₂), 1.51 - 1.59 (v. br. d ~ s, / = n.a., 6H, 3xCH₂).

13C NMR (75 MHz, d⁶-dmso) δ = 162.7, 138.5, 137.0, 133.7, 132.9, 129.7, 122.0, 121.9, 51.4, 48.5, 27.1, 27.0, 25.5, 25.1, 20.3.

Syntheses of activated carboxylates (AC1 - AC7):

Example 17:

Perfluorophenyl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate (AO)

A round-bottom flask equipped with a magnetic stirrer bar was charged with CH₂CI₂ (70 mL) and 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoic acid (2.0g, 9.4 mmol, 1 equiv). To the clear solution, pentafluoro phenol (1.72 g, 9.4 mmol, 1 equiv) and EDC hydrochloride (1.79 g, 9.4 mmol, 1 equiv) were successively added. After addition of DMAP (0.23 g, 1.9 mmol, 0.2 equiv), the clear solution was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness under reduced pressure and purified by column chromatography (Si0₂, cyclohexane/ethyl acetate 9 : 1), yielding perfluorophenyl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate (2.5 g, 72 %) as a colorless powder.

1H NMR (500 MHz, CDC1₃) δ = 7.83 (s, 2H), 7.78 (d, J = 8.20 Hz, 1H), 7.76 (d, J = 1.40, 1H), 7.54 (dd, J = 1.40, 8.25 Hz, 1H), 2.51 (s, 3H)

¹³C NMR (125 MHz, CDC1₃) δ = 162.8, 139.2, 136.6, 136.1, 134.0, 131.1, 124.6, 123.6, 21.1 (C^ omitted due to low intensity)

¹⁹F NMR (470 MHz, CDC1₃) δ = -151.2 (m), -157.8 (t, J = 21.7 Hz), -162.3 (m)

Example 18:

(lH-imidazol-l-yl)(5-methyl-2-(2H-l,2,3-triazole-2-yl)phenyl)methanone (AC2)

A round-bottom flask equipped with a magnetic stirrer bar was charged with 5-methyl-2- (2H-l,2,3-triazole-2-yl)benzoic acid (7.0 g, 34.5 mmol, 1.0 equiv) and THF (70 mL). The resulting clear, brown solution was cooled to -0° C using an ice-bath, followed by portion wise addition of di(lH-imidazol-l-yl)methanone (6.33 g, 37.9 mmol, 1.0 equiv). The reaction mixture was stirred under nitrogen atmosphere at ambient temperature for 3 h.

Afterwards, the solution was concentrated under reduced pressure and re-dissolved in ethyl acetate. After addition of H₂0, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (Si0₂, PhMe/ethyl acetate 1 : 1) yielded (lH-imidazol-l-yl)(5-methyl-2-

(2H-l,2,3-triazole-2-yl)phenyl)methanone (7.29 g, 83 %) as a colorless powder. 1H NMR (500 MHz, CDC1₃) δ = 7.98 (d, J= 8.35 Hz, 1H), 7.78 (br s, 1H), 7.62 (s, 2H), 7.50 (dd, J = 1.35, 8.40 Hz, 1H), 7.40 (d, J = 1.25 Hz, 1H), 7.26 (br s overlapping with solvent signal, 1H), 6.96 (br s, 1H), 2.45 (s, 3H)

¹³C NMR (125 MHz, CDC1₃) δ = 165.0, 138.6, 137.3, 136.2, 134.8, 133.2, 130.9, 129.8, 125.3, 122.0, 116.8, 21.0

Example 19:

(Isobutyl carbonic) 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoic anhydride (AC3)

A round-bottom flask equipped with a magnetic stirrer bar was charged with 5-methyl-2- (2H-l,2,3-triazole-2-yl)benzoic acid (5.0 g, 24.6 mmol, 1.0 equiv) and THF (250 mL). The resulting solution was cooled to -0° C, followed by successive addition of triethyl amine (3.58 mL, 25.8 mmol, 1.05 equiv) and isobutyl chloroformate (3.35 mL, 25.8 mmol, 1.05 equiv). The reaction mixture was stirred at ambient temperature for 1 h. Subsequently, the precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with saturated NaHC0₃ solution. The organic layer was washed with H₂0, dried over anhydrous sodium sulfate and concentrated under reduced pressure, yielding (isobutyl carbonic) 5-methyl-2-(2H- 1,2,3- triazole-2-yl)benzoic anhydride (6.6 g, 88%) as an orange-brown oil.

1H NMR (500 MHz, CDC1₃) δ = 7.80 (s, 2H), 7.70 (d, J = 8.20 Hz, 1H), 7.64 (d, J = 1.45 Hz, 1H), 7.45 (dd, J = 1.45, 8.20 Hz, 1H), 3.98 (d, J = 6.60 Hz, 2H), 2.42 (s, 3H), 1.96 (sept, J = 6.71 Hz, 1H), 0.91 (d, J = 6.75 Hz, 6H)

¹³C NMR (125 MHz, CDC1₃) δ = 161.0, 148.6, 139.0, 136.4, 135.9, 133.8, 131.2, 124.3, 124.1, 75.4, 27.6, 20.9, 18.7

Example 20:

S-benzo[d]thiazol-2-yl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzothioate (AC4)

A round bottom flask equipped with a magnetic stirrer bar was charged with 2,2'- Dithiobis(benzothiazole) (12.3 g, 37.1 mmol, 1.51 equiv), DMF (150 mL), PPh₃ (10.2 g, 37.1 mmol, 1.51 equiv) and 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoic acid (5.0 g, 24.6 mmol, 1 equiv). The reaction mixture was stirred overnight at ambient temperature, followed by addition of H₂0 and ethyl acetate. The aqueous layer was extracted with ethyl acetate after which the combined organic layers were washed twice with aqueous LiCl- solution (5 wt.-%) and once with brine. Drying over anhydrous sodium sulfate, filtration and evaporation yielded the crude product which was further purified by column chromatography (heptane/ethyl acetate/NEt₃ 90 :9 : 1). S-benzo[d]thiazol-2-yl 5-methyl-2- (2H-l,2,3-triazole-2-yl)benzothioate (2.67 g, 31%) was obtained as a yellow-orange oil which solidifies upon storage at 2 °C to 4 C.

Mixture of 2 rotamers, major rotamer (maj. rot.) / minor rotamer (min. rot.) = 2: 1

1H NMR (500 MHz, C₆D₆) δ = 8.16 (d, J = 8.35 Hz, 1H, min. rot.), 7.99 (d, J = 8.15 Hz, 2H, maj. rot.), 7.65 - 7.62 (m, 3H, maj. rot.+min. rot.), 7.49 (d, J = 1.25 Hz, 1H, min. rot.), 7.37 (d, J = 7.85 Hz, 2H, maj. rot.), 7.28 (s, 4H, maj. rot.), 7.10 - 7.06 (m, 2H, maj. rot.), 7.03, (d, J = 1.20 Hz, 2H, maj. rot.), 6.98 - 6.93 (m, 3H, maj. rot.+min. rot.), 6.87 (s, 2H, min. rot.), 6.79 (d, J = 8.23, 1.33 Hz, 1H, min. rot.), 6.74 (dt, J = 0.92, 7.66 Hz, 1H, min. rot.), 6.69 - 6.65 (m, 2H, maj. rot.), 6.44 (dd, J = 7.90, 0.95 Hz, 1H, min. rot.), 1.86 (s, 3H, min. rot.), 1.74 (s, 6H, maj. rot.)

Example 21:

l,3-dioxoisoindolin-2-yl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate (AC5)

A round bottom flask equipped with a magnetic stirrer bar was successively charged with 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoic acid (3.0 g, 14.8 mmol, 1 equiv), N-hydroxy phtalimide (2.60 g, 15.54 mmol, 1.05 equiv), EDC hydrochloride (3.04 g, 15.54 mmol, 1.05 equiv), and dichloromethane (74 mL). The reaction mixture was stirred overnight at ambient temperature, followed by addition of H₂0 (74 mL). The aqueous layer was separated and extracted twice with dichloromethane (74 mL). The combined organic layers were washed brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, yielding l,3-dioxoisoindolin-2-yl 5-methyl-2-(2H-l,2,3-triazole-2- yl)benzoate as a brownish solid.

1H NMR (500 MHz, C₆D₆) δ = 7.70 - 7.63 (m, 2H), 7.52 (s, 2H), 7.29 - 7.24 (m, 2H), 6.77 - 6.73 (m, 2H), 6.72 - 6.68 (m, 1H), 1.71 (s, 3H) Example 22:

2,5-dioxopyrrolidin-l-yl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate (AC6)

A round bottom flask equipped with a magnetic stirrer bar was successively charged with 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoic acid (3.0 g, 14.8 mmol, 1 equiv), N-hydroxysuccinimide (1.84 g, 15.54 mmol, 1.05 equiv), EDC hydrochloride (3.04 g, 15.54 mmol, 1.05 equiv), and dichloromethane (74 mL). The reaction mixture was stirred at ambient temperature for 1.5 h, followed by addition of H₂0 (74 mL). The aqueous layer was separated and extracted twice with dichloromethane (74 mL). The combined organic layers were washed in brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, yielding 2,5-dioxopyrrolidin-l-yl 5-methyl-2-(2H- l,2,3-triazole-2-yl)benzoate (4.4 g, 99 %) as a brownish solid.

1H NMR (500 MHz, CDC1₃) δ = 7.84 (s, 2H), 7.79 (d, J = 8.25 Hz, 1H), 7.77 (d, J = 1.35 Hz, 1H), 7.52 (dd, J = 1.40, 8.25 Hz, 1H), 2.85 (br s, 4H), 2.48 (s, 3H)

1³C NMR (125 MHz, CDC1₃) δ = 168.9, 162.3, 139.0, 136.7, 136.2, 134.3, 131.2, 124.1, 121.4, 25.8, 21.1

Example 23:

l,l,l,3,3,3-hexafluoropropan-2-yl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate (AC7)

A round bottom flask equipped with magnetic stirrer bar was charged with 5-methyl-2- (2H-l,2,3-triazole-2-yl)benzoic acid (2.0 g, 9.4 mmol, 1 equiv), CH₂C1₂ (94 mL) and hexafluoro /sopropanol (1.57 g, 9.4 mmol, 1.0 equiv). After addition of EDC hydrochloride (1.79 g, 9.4 mmol, 1.0 equiv) and DMAP (0.23 g, 1.87 mmol, 0.2 equiv), the reaction mixture was stirred at ambient temperature for 1 h. The solvent was evaporated under reduced pressure followed by purification of the crude product by column chromatography (Si0_2, cyclohexane /ethyl acetate 50: 1). l,l,l,3,3,3-hexafluoropropan-2-yl 5-methyl-2-(2H- l,2,3-triazole-2-yl)benzoate (2.5 g, 75%) was obtained as a yellowish oil, which solidifies at 2 °C to 4 °C.

1H NMR (500 MHz, d⁶-DMSO) δ = 8.08 (s, 2H), 7.81 (d, J = 8.25 Hz, 1H), 7.70 - 7.65 (m, 1H), 7.64 - 7.61 (m, 1H), 6.99 (sept, J = 6.28 Hz, 1H), 2.46 (s, 3H)

1³C NMR (125 MHz, CDC1₃) δ = 163.8, 139.8, 137.2, 135.8, 134.8, 130.5, 134.6, 123.3, 120.9 (q, J = 238.3 Hz, (CF₃)₂), 67.1 (sept, J = 33.5 Hz, OCH(CF₃)₂), 20.8

Amidation reactions of carbonyl and carboxyl-derivatives: General experimental procedures

General procedure 1: Amidation of ethyl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate using A1C1₃

A screw-cap vial equipped with a magnetic stirrer was charged with toluene (0.2 mL), ethyl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate (50 mg, 0.22 mmol, 1.0 equiv) and the respective amine (0.32 mmol, 1.5 equiv). To this mixture was added powdered 4 A MS (15 mg) and A1C1₃ (43 mg, 0.32 mmol, 1.5 equiv). The vial was capped, placed in a sand bath and heated to 120°C. After stirring for 7 h at 120 °C, the conversion to the corresponding amide was determined by RP-HPLC using previously isolated material as reference.

General procedure 2: Amidation of ethyl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate using EtMgBr

Under nitrogen atmosphere, a flame-dried two-necked flask equipped with a magnetic stirrer and bubble counter was charged with dry THF (2 mL) and the amine (0.86 mmol, 2.0 equiv). At ambient temperature, EtMgBr solution (1M in THF, 0.87 mL, 2.0 equiv) was added via syringe. The solution was stirred at ambient temperature until the gas evolution ceased. Afterwards, a solution of ethyl 5-methyl-2-(2H-l,2,3-triazole-2- yl)benzoate (100 mg, 0.43 mmol, 1.0 equiv) in dry THF (0.5 mL) was added dropwise via syringe and the mixture was stirred at ambient temperature for 48 h. The conversion to the desired amide was determined by RP-HPLC using previously isolated material as reference.

General procedure 3: Amidation of activated carboxylates (AO, AC3 - AC7) standard conditions

A round bottom flask equipped with a magnetic stirrer bar was charged with the respective activated carboxylate (0.27 mmol, 1.0 equiv) and CH₂C1₂ (2.7 mL) and cooled to 0°C to 5 °C with an ice bath. After addition of DIPEA (138 mL, 0.81 mmol, 3 equiv) and the corresponding amine (0.32 mmol, 1.2 equiv), the reaction mixture was stirred at ambient temperature or 40°C, respectively. The conversion to the desired amide was determined by RP-HPLC using previously isolated material as reference. General procedure 4: Oxidative amidation of 5-methyl-2-(2H-l,2,3-triazole-2- yl)benzaldehyde using tert-butyl hydroperoxide

A screw-cap vial equipped with a magnetic stirrer bar was charged with dry acetonitrile (2.6 mL) and 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzaldehyde (150 mg, 0.8 mmol, 1.0 equiv). To the clear, orange solution was added the respective amine (1.04 mmol, 1.3 equiv) and a iert-butyl hydroperoxide solution (70 wt-% in H₂0, 1.04 mmol, 1.3 equiv). The reaction mixture was heated to 100 °C and the progress of the reaction was monitored by RP-HPLC using previously isolated material as reference.

General procedure 5: Amidation of (lH-imidazol-l-yl)(5-methyl-2-(2H-l,2,3-triazole- 2-yl)phenyl)methanone (AC2) using pyridine hydrochloride as activator

A screw-cap vial equipped with a magnetic stirrer bar was charged with (lH-imidazol-1- yl)(5-methyl-2-(2H-l,2,3-triazole-2-yl)phenyl)methanone (100 mg, 0.39 mmol, 1.0 equiv) and dichloromethane (3.9 mL). To the stirred solution were added DIPEA (201 mL, 1.2 mmol, 3.0 equiv), the corresponding secondary amine (0.47 mmol, 1.2 equiv) and pyridine hydrochloride (93 mg, 0.79 mmol, 2.0 equiv). After capping the vial, the reaction mixture was heated to 90 °C and the progress of the reaction was monitored by RP-HPLC using previously isolated material as reference.

(5-Methyl-2-(2H-l,2,3-triazole-2-yl)phenyl)(pyrrolidin-l-yl)methanone

According to general procedure 1, 2, 3 (using AC1 or AC3 - AC7 as activated carboxylate), 4 or 5

1H NMR (500 MHz, CDC1₃) δ = 7.84 (d, J = 8.20 Hz, 1H), 7.77 (s, 2H), 7.30 (dd, J = 1.26, 8.19 Hz, 1H), 7.24 (d, J = 1.58 Hz, 1H), 3.60 (t, J = 7.09 Hz, 2H), 2.96 (m, 2H), 2.41 (s, 3H), 1.87 (m, 2H), 1.75 (m, 2H)

1³C NMR (125 MHz, CDC1₃) δ = 167.9, 138.5, 135.6, 133.6, 130.5, 130.4, 128.5, 122.1, 47.9, 45.6, 25.6, 24.5, 21.0

Tert-butyl 4-(5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoyl)-l,4-diazepane-l-carboxylate

According to general procedure 3 (using ACl or AC3 - AC6 as activated carboxylate) or 4

1H NMR (500 MHz, CDC1₃) δ = 7.89 - 7.82 (m, 1H), 7.77 (s, 2H), 7.31 (br d, J = 8.30 Hz, 1H), 7.16 (br s, 1H), 4.00 - 2.98 (series of overlapping multiplets, 8H), 2.41 (s, 3H), 2.07 - 1.31 (series of overlapping multiplets, 11H)

Benzyl 5-methyl-4-(5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoyl)-l,4-diazepane-l- carboxylate

According to general procedure 3 (using ACl, AC3 or AC4 as activated carboxylate)

1H NMR data is in accordance with reference spectrum for the corresponding (R)-enantiomer (Cox et al, J. Med. Chem 2010, 53: 5320).

(R)-(4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-l,4-diazepan-l-yl)(5-methyl-2-(2H- l,2,3-triazole-2-yl)phenyl)methanone (Suvorexant)

According to general procedure 3 (using ACl, AC3 or AC4 as activated carboxylate) and 5

1H NMR data is in accordance with reference spectrum from literature (Cox et al., J. Med. Chem 2010, 53: 5320).

Claims

1. A process for the preparation of a compound of formula (1)

wherein R^a, R^b, R^c and R^d are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, -NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group,

wherein the process comprises

(a) providing a compound of formula II)

(b) reacting the compound of formula (II) with an organolithium reagent in an aprotic solvent to give an intermediate com ound of formula (III)

The process of claim 1 , wherein the electrophilic group is obtained upon addition of the compound of formula (III) to an electrophile E*.

The process of claim 1 or 2, wherein E is selected from the group consisting of halogen, -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of - O-Alkyl, -OH, -H and X with X being the leaving group of the activated group - C(=0)-X.

4. The process of claim 3, wherein E is -CN or -C(=0)R⁵, wherein R⁵ is selected from the group consisting of-O-ethyl, -H and X.

5. The process of claim 3 or 4, wherein X is selected from the rou consisting of

6. The process of any of claims 1 to 5, wherein the compound of formula (1) has the structure (la)

The process of any of claims 1 to 6, wherein the compound of formula (1) contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities.

A process for the preparation of a com ound of formula (A)

or a pharmaceutically acceptable salt or solvate thereof, wherein (A) is preferably (A*)

pre era y

(i) providing a compound of formula la)

wherein E is -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of

-O-alkyl, -OH, -H and X with X being the leaving group of the activated group C(=0)-X,

wherein the compound of formula (la) is provided by a method according to any one of claims 1 to 7, and/or

wherein X is not CI and R⁵ is not OH, and/or

reacting the compound of formula la) with a compound of formula (Al)

preferably (Al *)

wherein R^la is selected from the roup consisting of H, PG¹ and R^A, with R^A being

and wherein R^la may be the same as or may differ from R¹, and wherein in case n is 0, R^la is preferably not H,

(iii) optionally converting R^la into R¹ if R¹ and R^la differ from each other, to give the compound of formula (A), preferably (A*).

9. A process for the preparation of a com ound of formula (A)

pre era y

wherein PG¹ is a suitable protecting group and wherein n is 0 or 1, the process comprising (i) providing a compound of formula (la)

wherein E is -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of

-O-alkyl, -OH, -H and X with X being the leaving group of the activated group - C(=0)-X,

wherein the compound of formula (la) is provided by a method according to any one of claims 1 to 7,

(ii) reacting the compound of formula la) with a compound of formula (Al)

preferably (Al *)

and wherein R^la may be the same as or may differ from R¹, and wherein

0, R^la is preferably not H,

10. A process for the preparation of a compound of formula (A)

pre era y

(i) providing a compound of formula la)

wherein E is -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of

-O-alkyl, -OH, -H and X with X being the leaving group of the activated group - C(=0)-X, wherein X is not CI and R⁵ is not OH,

(ii) reacting the compound of formula (la) with a compound of formula (Al)

preferably (Al *)

11. A process for the preparation of a com ound of formula (A)

preferably _s

(i) providing a compound of formula la)

wherein E is -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of

-O-alkyl, -OH, -H and X with X being the leaving group of the activated group C(=0)-X, and wherein the compound comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product

reacting the compound of formula la) with a compound of formula (Al)

preferably (Al *)

and wherein R^la may be the same as or may differ from R¹, and wherein in case n is

0, R^la is preferably not H,

The process of any of claims 8 to 11, wherein X is not CI and R⁵ is not OH.

The process of any of claims 8 to 12, wherein the compound of formula (la) comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product.

The process of an of claims 8 to 13, wherein (A) has the structure

and wherein the process comprises

providing a compound of formula la)

according to the method as claimed in any one of claims 1 to 7, wherein E is -CN or -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of

-O-alkyl, -OH, -H and X with X being the leaving group of the activated group -C =0)-X, wherein X is preferably selected from the group consisting of

reacting the compound of formula la) with a compound of formula (Al)

preferably (Al *)

wherein R^la is PG¹,

to give a compound of formula A2)

preferably (A2*)

and optionally reducing the compound in case n is 1 ,

(iii) removing the protecting group PG¹ _,

(iv) reacting the compound of step (iii) with

wherein X* is a leaving group, preferably CI,

to give the compound of formula (IX).

15. The process of any of claims 8 to 13, wherein (A) has the structure

according to the method as claimed in any of claims 1 to 7, wherein E is -CN or - C(=0)R⁵, wherein R⁵ is selected from the group consisting of

-O-alkyl, -OH, -H and X with X being the leaving group of the activated group - C(=0 -X, wherein X is preferably selected from the group consisting of

reacting the compound of formula (la) with a compound of formula (Al), wherein the compound of formula (Al is (AO)

preferably (AO*)

(AO*), wherein R¹ is R^A, with R^A bein

preferably

and optionally reducing the compound of step (ii) in case n is 1 ,

to give the compound of formula (IX).

16. A compound of formula (1), obtained or obtainable by a process according to any one of claims 1 to 7, preferably wherein the compound contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities.

17. A com ound of formula ( 1 )

consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, -NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group, with the proviso that E is not COOH, and wherein the compound preferably has the structure la)

18. The compound of formula (1) of claim 17, wherein R^a, R^b, R^c and R^d are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, carbonyl, alkoxy, hydroxyl, - NR⁶R⁷, -SR and -N0₂, wherein R⁶ and R⁷ are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl heterocycloalkyl.

The compound of formula (1) of any of claims 16 to 18, wherein E is selected from the group consisting of halogen, -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -H and X with X being the leaving group of the activated group -C(=0)-X, and wherein X is preferably selected from the group consistin of

The compound of formula (la) of any of claims 16 to 19, wherein E is selected from the group consisting of -CN and -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-alkyl, -H and X with X being the leaving group of the activated group -C(=0)-X, wherein X is preferably selected from the group consistin of

The compound of any of claims 16 to 20, wherein the compound contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities.

A compound of formula (IX)

obtained or obtainable by a process according to any of claims 8 to 15.

23. Use of a compound of formula la)

wherein E is -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-ethyl, -H and X, for the reparation of a compound of formula (IX)

or a pharmaceutically acceptable salt or solvate thereof,

The use of claim 23, wherein E is -C(=0)R⁵, wherein R⁵ is selected from the group consisting of -O-ethyl, -H and X.

Use of claim 23 or 24, wherein compound of formula (la) is prepared according to claims 1 to 7. A process for the preparation of a com ound of formula (A)

preferably

providing a compound of formula la)

wherein the compound of formula (la) is provided by a method according to any one of claims 1 to 7

wherein E is -C(=0)R⁵ , wherein R⁵ is selected from the group consisting of

-O-alkyl, -OH, -H and X with X being the leaving group of the activated group - C(=0)-X, wherein the compound of formula (la) is provided by a method according to any one of claims 1 to 7 and/or

wherein X is not CI and R⁵ is not OH, and/or

reacting the compound of formula (la) with a compound of formula (Al)

preferably (Al *)

(v) optionally converting R^la into R¹ if R¹ and R^la differ from each other, to give the compound of formula (A), preferably (A*).