WO2016020404A1

WO2016020404A1 - Process for the resolution of (r,s)-diazepane and diazepanone derivatives

Info

Publication number: WO2016020404A1
Application number: PCT/EP2015/067994
Authority: WO
Inventors: Roland Barth; Marius KAUFMANN
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 an acid salt (T) of a compound of formula (A) (A) as well as to the acid salt (T) and the compound (A) as such,wherein R¹ is selected from the group consisting of H, PG¹ and R^A, with R^A being or and wherein PG¹ is a suitable protecting group, and wherein n is 0 or 1, wherein the acid salt (T) is the salt of one stereoisomer of a chiral acid, preferably wherein the chiral acid salt is a tartaric acid derivative salt, preferably wherein the tartaric acid derivative salt is selected from the group consisting of 2,3-ditoluoyl tartaric acid salt, 2,3-dibenzoyl tartaric acid salt, 2,3-dianisoyl tartaric acid salt, 2,3-dibenzoyl tartaric acid mono(dimethylamide) salt and a mixture of two or more thereof. Further the present invention relates to use of (T) and/or (A) for the preparation of suvorexant.

Description

Process for the resolution of (R,S)-diazepane and diazepanone derivatives

The present invention relates to a process for the preparation of an acid salt (T) of a comound of formula (A) as well as to the acid salt (T) and the compound (A) as such

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

and wherein PG¹ is a suitable protecting group, and wherein n is 0 or 1, wherein the acid salt (T) is the salt of one stereoisomer of a chiral acid, preferably wherein the chiral acid salt is a tartaric acid derivative salt, preferably wherein the tartaric acid derivative salt is selected from the group consisting of Ditoluoyl tartaric acid salt (2,3-Ditoluoyl tartaric acid salt), Dibenzoyl tartaric acid salt (2,3-Dibenzoyl tartaric acid salt), Dianisoyl tartaric acid salt (2,3-Dianisoyl tartaric acid salt), 2,3-Dibenzoyl tartaric acid mono(dimethylamide salt or a mixture of two or more thereof. Further the present invention relates to use of (T) and/or (A) for the preparation of suvorexant, an orexin receptor antagonist.

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; behaviour 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; hypeiprolac- tinemia; hypophysis tumour/adenoma; hypothalamic diseases; inflammatory bowel dis- ease; gastric dyskinesia; gastric ulcers; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; adrenohypophysis hypo function; adrenohypophysis 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; myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; 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; emesis, nausea, vomiting; conditions associated with visceral pain such as irritable bowel syndrome, and angi- na; migraine; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasom- nia; 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 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 they are 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- 1 ,3-benzoxazol-2-yl)-7-methyl- 1 ,4-diazepan- 1 -yl] [5-methyl-2- (2H-l,2,3-triazol-2-yl)phenyl]methanone which has the structure according to Formula I

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

The synthesis of [(7R)-4-(5-chloro-l,3-benzoxazol-2-yl)-7-methyl-l,4-diazepan-l-yl][5- methyl-2-(2H-l,2,3-triazol-2-yl)phenyl]methanone (hereinunder also referred to as "Su- vorexant" or "orexin receptor antagonist") is described in WO 2008/069997. In particular, a synthesis that is based on a chiral resolution of the racemic 1,4 diazepane derivative by chiral HPLC is described.

Patent application WO2008/008518 discloses the synthesis of the racemic 1,4 diazepane derivative. This synthetic route is similar to the process disclosed in WO2008/069997. However, according to the process of WO2008/008518 protection of the free amino group is not necessary. WO2008/008518 discloses the resolution of the racemic 1,4 diazepane derivative via chiral HPLC.

The chiral resolution of enantiomers of the 1,4 diazepane derivative via chiral HPLC has some disadvantages in the context of the suvorexant synthesis that render this method not adapt to an industrial process: it has a low to moderate throughput, it uses a large amount of solvent, it has high cost and it generates a large amount of waste.

Hence there is the need to provide an efficient and simple method for the resolution of racemic intermediate compounds prepared during the synthesis of suvorexant. .

Summary of the invention

Hence, the present invention, relates to a process for the preparation of an acid salt (T) of a compound of formula (A)

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

and wherein PG¹ is a suitable protecting group, and wherein n is 0 or 1, wherein the acid salt (T) is the salt of one stereoisomer of a chiral acid, preferably wherein the chiral acid salt is a tartaric acid derivative salt, preferably wherein the tartaric acid derivative salt is selected from the group consisting of 2,3-Ditoluoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid salt, 2,3-Dianisoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) salt or a mixture of two or more thereof, the process comprising

(a) providing a compound of formula A)

(A) consisting of an enantiomeric mixture of the compounds (la) and (lb)

wherein the compound (A) contains of from 20 to 75 % by weight % of the com- pound of formula (la) based on the total weight of the sum of (la) and (lb) in a suitable solvent,

(b) adding a single stereoisomer of a chiral acid, preferably wherein the chiral acid is a tartaric acid derivative, wherein preferably the tartaric acid derivative is selected from the group consisting of 2,3-Ditoluoyl tartaric acid, 2,3-Dibenzoyl tartaric ac- id, 2,3-Dianisoyl tartaric acid, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, thereby obtaining a mixture comprising a precipitated preferably crystallized acid salt (T) and the solvent,

(c) preferably separating the precipitated, preferably crystallized, acid salt (T) from the mixture obtained in (b),

wherein the acid salt (T) contains at least 80 % by weight of the chiral acid salt of the compound of formula (la) based on the total weight of the acid salt of the compound of formula (A).

Preferably in the process of the invention, when n=0 and

is Y—x " ^"O - , then the tartaric acid derivative is not D-di-benzoyl tartaric acid (DBTA).

Preferably, in the process of the invention, when n=0, R is not T—x " ^"O

Preferably, in the process of the invention, when n=0, R¹ is H or PG¹.

Preferably in the process of the invention, n is 1.

Further, the present invention is directed to a process for the preparation of a compound of formula (A)

wherein n is = 0, R¹ is selected from the group consisting of PG¹ and R^A, with R^A being

and wherein PG¹ is a suitable protecting group, the compound consisting of a mixture of the compounds la) and (lb)

the process comprising

(aa) providing a compound of formula (II*)

wherein R² is a protecting group PG³, preferably a protecting group PG³ selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloroacetate, phthalimide, preferably Boc,

(ab) converting compound (II)* to compound (III*)

O

_K ,_/\ ^ H-R²

N

R¹ (IIP);

removing R a give a compound of formula (IV*)

(iv*);

(ad) subjecting the compound (IV*) to cyclization conditions,

to give the compound of formula (A) with n = 0.

PG3 is a protecting group as defined above in connection with the term "suitable protecting group", PG³ is preferably a protecting group selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloroacetate, phthalimide, preferably Boc,

Further, the present invention relates to a process for the preparation of suvorexant

comprising

(i) preparing an acid salt (T) of a compound of formula (A)

as described above,

(ii) transforming the acid salt to suvorexant.

Further, the present invention is directed to a process for the preparation of a compound of formula (IV*)

(IV*);

wherein R² is protecting group PG³, preferably a protecting group PG³ selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloroacetate, phthalimide, preferably Boc, and wherein R¹ is selected from the group consisting of PG¹ and R^A, with R^A being

the process comprising

(aa) providing a compound of formula (II*)

converting compound (II)* to compound (III*)

O

_K , /\ ^ H-R²

N

R¹ (III*);

(ac) removing R 2 to give the compound of formula (IV*)

(IV*).

Additionally, the present invention is directed to an acid salt (T) as well as a compound of formula (A) obtained or obtainable by any one of the above mentioned processes.

Further, the present invention is directed to acid salt T) of a compound of formula (A)

and wherein PG¹ is a suitable protecting group, and wherein n is 0 or 1, wherein the acid salt is a single stereoisomer of a chiral acid, a single stereoisomer of a tartaric acid, more preferably of a 2,3-Ditoluoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid salt, 2,3- Dianisoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) salt or a mixture of two or more thereof, wherein compound (A) consists of a mixture of the com- pounds (la) and lb)

wherein the acid salt (T) of the compound of formula (A) contains at least 80 % by weight of the acid salt of the compound of formula (la) based on the total weight of the acid salt of the compound of formula (A).

Further, the present invention is directed to a com ound of formula (A)

wherein n is = 0, R¹ is selected from the group consisting of H, PG¹ and R^A, with R^A being

and wherein PG is a suitable protecting group, and wherein n is 0 or l ,the compound consisting of an enantiomeric mixture of the com ounds (la) and (lb)

Further, the present invention is directed to the use of an acid salt (T), as described for the preparation of suvorexant S)

Further, the present invention is directed to the use of a compound (A), as described above, for the preparation of suvorexant.

Detailed Description of the Invention

SYNTHESIS OF ACID SALT (T) AND ITS RESOLUTION AND HYDROLYSIS

The present inventors have studied resolving agents, solvents and their combinations to resolve a synthetically obtained racemic derivative of formula (A). The present inventors indeed have found that by preparing the salt of the compound of formula (A) with a stereoisomer of a chiral acid an effective resolution of the two enantiomers of formula (la) and (lb) is obtained.

As mentioned above, the present invention relates to a the preparation of an acid salt (T) of a compound of formula (A), as well as to an acid salt (T) obtained or obtainable by said rocess, wherein the compound (A) has the structure

(a) providing a compound of formula A)

consisting of an enantiomeric mixture of the compounds (la) and (lb)

wherein the compound (A) contains of from 20 to 75 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb) in a suitable solvent,

(b) adding a single stereoisomer of a chiral acid, preferably wherein the chiral acid is a tartaric acid derivative, wherein preferably the tartaric acid derivative is selected from the group consisting of 2,3-Ditoluoyl tartaric acid, 2,3-Dibenzoyl tartaric acid, 2,3-Dianisoyl tartaric acid, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, thereby obtaining a mixture comprising a precipitated preferably crystallized acid salt (T) and the solvent,

Preferably in the process of the invention, when n=0 and R is

, then the tartaric acid derivative is not D-di-benzoyl tartaric acid (DBTA). Preferably in the process of the invention, when n^: 0, R¹ is not

Preferably in the process of the invention, when n^: 0, R is H or PG¹.

Preferably in the process of the invention,

Compound (A)

As described above, the compound of formula A) has the structure

and consists of an enantiomeric mixture of the com ounds la) and (lb)

Thereby, the compound of formula (A) preferably contains of from 20 to 75 %, more pref- erably of from 40 to 60 % by weight % of the compound of formula (la), more preferably of from 45 to 55 % by weight, based on the total weight of the sum of (la) and (lb), More preferably the compound of formula (A) is a racemic mixture of the compound of formula (la) and (lb).

In these structures, n is 0 or 1 as described above.

Thus the compound A) has, e.g., the structure (Al) or (AO)

It is to be understood that in case compound (A) has the structure (Al), the compound sists of an enantiomeric mixture of the compounds (Al-Ia) and (Al-Ib)

Thereby, the compound of formula (Al) preferably contains of from 40 to 60 % by weight %, more preferably of from 45 to 55 % by weight, of the compound of formula (Al-Ia), based on the total weight of the sum of (Al-a) and (Al-Ib), More preferably the compound of formula (Al) is a racemic mixture of the compound of formula (Al-Ia) and (Al-Ib). Further, it is to be understood that in case compound (A) has the structure (AO), the compound consists of an enantiomeric mixture of the com ounds (AO-la) and (AO-lb)

Thereby, the compound of formula (AO) preferably contains of from 40 to 60 % by weight %, more preferably of from 45 to 55 % by weight %, of the compound of formula (AO-la), based on the total weight of the sum of (AO-a) and (AO-lb), More preferably the compound of formula (AO) is a racemic mixture of the compound of formula (AO-la) and (AO-lb).

Residue R¹ :

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

wherein PG¹ is a suitable protecting group.

Thus, the compound of formula (A) has, a structure selected from the group consisting of i.e. a structure selected from the group consisting of

and ^^OH A bond shown as " in any one of the compounds shown above and below is denoted to represent a single bond, wherein the resulting structure including the bond encompasses the single (isolated) S isomer or the single (isolated) R isomer as well as mixtures of the S and R isomer.

The protecting group PG¹

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, Third Edition, Wiley, N.Y., 1999, 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 (fluo- renylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl, PNZ, trifluoroacetate, phtalimideand 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 triiso- propylsilyl. Particularly preferred amino -protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl, Cbz, PNZ, Alloc, Trifluoroacetate, Phthalimide and the like. Most 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.

Preferably, R¹ is R^A or PG1 , more preferably PG , more preferably Cbz or Boc, more preferably Cbz.

Thus, compound (A) has preferably the structure

more preferably n is 0 and (A) has the structure

According to a further preferred embodiment, R is H. Thus, compound (A) has preferably the structure

more preferably n is 1 and (A) has the structure

Acid salt (T)

As mentioned above, according to the present invention, the acid salt (T) is the salt of the compound of formula (A) with a single stereoisomer of a chiral acid , preferably wherein the chiral acid is a single stereoisomer of a tartaric acid derivative, more preferably wherein preferably the tartaric acid derivative is selected from the group consisting of 2,3- Ditoluoyl tartaric acid, 2,3-Dibenzoyl tartaric acid, 2,3-Dianisoyl tartaric acid, 2,3- Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof. More preferably the tartaric acid is a dibenzoyl- tartaric acid or a ditoluoyl tartaric acid

According to the present invention, the acid salt (T), when n=0 and R is

is not D-di-benzoyl tartaric acid (DBTA).

According to the present invention, in the acid salt (T), when n=0, preferably R is not

According to the present invention, in the acid salt (T) when n=0 preferably R¹ is H or PG^1'

According to the present invention, the acid salt (T) is preferably wherein n=l .

It is to be understood that, if the chiral acid is a tartaric acid or tartaric acid derivative, a salt between two molecules of (A) and one molecule of the a chiral acid may be formed. Such salts are thus encompassed by the term "the acid salt (T)".

The acid salt (T) according to the present invention contains at least 80 % by weight of the chiral acid salt of the compound of formula (la), preferably at least 85 % by weight, more preferably at least 95% by weight, even more preferably at least 99% by weight salt of the compound of formula (la) based on the total weight of the acid salt of the compound of formula (A).

According to the present invention, preferably the acid salt (T) of the compound of formula (A) consists of the acid salt, preferably the tartaric acid salt, of the compound of formula (la).

Preferably according to the present invention the acid salt (T) of the compound of formula (A), preferably wherein in formula (A) R¹ is Cbz or Boc, contains at least 80 % by weight, more preferably at least 86 % by weight, more preferably at least 97 % by weight, more preferably at least 98 % by weight, more preferably at least 99 % by weight, more prefera- bly at least 99,5 % by weight, more preferably at least 99,9 % by weight, of the acid salt of the compound of formula (la) preferably wherein in formula (la) R¹ is Cbz or Boc, based on the total weight of the acid salt of the compound of formula (A).

More preferably according to the present invention the acid salt (T) of the compound for- mula (A), preferably wherein in formula (A) R¹ is Cbz, contains at least 80 % by weight, more preferably at least 85 % 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 acid salt of the compound of formula (la), preferably wherein in formula (la) R¹ is Cbz, based on the total weight of the acid salt of the compound of formula (A). Preferably, the chiral acid salt is a dibenzoyl tartaric acid salt or a ditoluoyl tartaric acid. i.e. a single stereoisomer of dibenzoyl tartaric acid salt or ditoluoyl tartaric acid. Preferably, in case in compound (A) n is 1, the tartaric acid derivative is a di-toluoyl tartaric acid, more preferably L- di-toluoyl tartaric acid (LTTA). In particular, in this case (A) has the structure

Preferably, in case in compound (A) n is 0, the tartaric acid derivative is a di-benzoyl tartaric acid, more preferably D-di-benzoyl tartaric acid (DBTA), preferably in this case when

R is — " ^"O , then the tartaric acid derivative is not D-di-benzoyl tartaric acid (DBTA). In particular, in case n=0 (A) has the structure

Cbz-N

Step b):

As mentioned above, in step b) a single stereoisomer of a chiral acid, is added, thereby a mixture comprising a precipitated preferably crystallized acid salt (T) and the solvent is obtained.

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. In case the chiral acid is a tartaric acid derivative being a mixture of two or more of 2,3-Ditoluoyl tartaric acid, 2,3-Dibenzoyl tartaric acid, 2,3-Dianisoyl tartaric acid and 2,3-Dibenzoyl tartaric acid mono(dimethylamide), respectively, this means that of each of the chiral acid derivatives within the mixture only a single stereoisomer is present.

The principle of the resolution is based on the selective precipitation of one of two diaster- eoisomer salts having different solubility in a selected solvent. The present inventors have found that by preparing an acid salt (T) of the compound of formula (A) with a stereoisomer of a chiral acid two stereoisomers of the compound of formula (A) with a different solubility in a selected solvent are provided, wherein one diastereoisomer precipitates, while the other remains in solution. The skilled person understands that both diastereoiso- mers and hence both enantiomers are rendered available with this method. Once the precipitated diastereoisomer has been filtered off, the diastereoisomer in solution may be further isolated (e.g. by evaporating the solvent, and/or precipitating it from another solvent etc.). According to the present invention, the enantiomer (la) preferably predominantly precipitates.

The chiral acid according to the present invention is any chiral acid suitable to prepare two diastereoisomers of compound (A) having different solubility. More preferably the chiral acid is selected from a tartaric acid, as mentioned above.

According to the present invention, preferably the tartaric acid derivative is selected from the group consisting of 2,3-Ditoluoyl tartaric acid, 2,3-Dibenzoyl tartaric acid ("Benzoyl tartaric acid), 2,3-Dianisoyl tartaric acid, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof.

According to the present invention the mole ratio of the compound of formula (A) relative to the stereoisomer of the chiral acid is in the range of from 1 : 0.5 to 1 : 1.

According to the present invention the resolution of the two enantiomers of the compound of formula (A) occurs via precipitation of the salt (T) of one of the two enantiomers. Preferably, the precipitation is a crystallisation.

The selective precipitation, preferably crystallization, may be achieved in the solvent during the formation of the acid salts (T) or e.g. because the temperature after the formation of the acid salts (T) is lowered or for both reasons.

As to the solvent used in step (I), any suitable organic solvent in which the compound of formula (A) 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, methylisobu- tyl ketone, 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. According to the present invention, preferably if in formula (A) n is 1, the suitable solvent is methanol

According to the present invention, preferably if n is 0, the the suitable solvent is acetone.

Preferably, in case in compound (A) n is 1, the tartaric acid derivative is a di-toluoyl tartar- ic acid, more preferably L-di-toluoyl tartaric acid (LTTA) and methanol is employed as solvent. In particular, in this case (A) has the structure

Preferably, in case in compound (A) n is 0, the tartaric acid derivative is a di-benzoyl tartaric acid, more preferably D-di-benzoyl tartaric acid (DBTA) and acetone is employed as solvent. In particular, in this case and (A) has the structure

It is to be understood that in step (b) 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 (b) 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 (A). According to a preferred embodiment, the compound of formula (A) 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 further solvent com- prises acetone or methanol, more preferably the further solvent is acetone or methanol.

According to the present invention, preferably when in formula (A) n is 1 , the further suitable solvent is methanol, and

According to the present invention, preferably when n is 0, the further suitable solvent is acetone.

Thus, the present invention also relates to a process for the preparation of a chiral acid salt (T) of a compound of formula (A), as described above, and a chiral acid salt (T) of the compound of formula (A), obtained or obtainable by said process, wherein step (I) com- prises dissolving the compound of formula (A) 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 methanol or acetone.

Preferably, the compound of formula (A) is dissolved in the suitable solvent and the mix- ture 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 (A) in the suitable solvent is obtained. Optionally, the mixture is afterwards cooled to room temperature.

The precipitation, preferably the crystallizing, in step (b) 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 com- pound of formula (A) 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.

If the precipitation is crystallization, optionally, seed crystals, preferably crystal salt of the compound to be precipitated can be added.

In a preferred embodiment of the first aspect, step b) comprises forming an acid salt (T*) of at least part of the compound of formula (A) by treating the compound of formula (A) with the chiral acid, and precipitating, preferably crystallizing, at least part of the an acid salt (T*) formed, thereby obtaining a mixture comprising the precipitated, preferably crystallized acid salt (T) and the solvent.

Preferably, the process thus comprises

(a) providin a compound of formula (A)

(b) forming a chiral acid salt, preferably a tartaric acid salt, (T*) of at least part of the compound of formula (A) by treating the compound of formula (A) 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;

Preferably in the process, when n=0 and R¹ is

rivative is not D-di-benzoyl tartaric acid (DBTA)

Preferably in the process, when n=0, R¹ is not

Preferably in the process when n=0, R¹ is H or PG¹.

Preferably in the process, n is 1.

According to this preferred embodiment, in step (b), at least part of the compound of formula (A) 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 (la), 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. Thereby, a mixture comprising the crystallized chiral acid salt (T) of at least part of the compound of for- mula (A) and the solvent is formed. As mentioned above, the precipitated, preferably crystallized, tartaric acid salt (T) of the compound of formula (A) contains at least 80 % by weight of chiral acid salt of the compound of formula (la) based on the total weight of the chiral acid salt of the compound of formula (A). It is to be noted that the mixture obtained in step (b) may comprise further compounds, in particular non crystallized forms of the compound of formula (la) and salts thereof. Preferably, the mixture obtained in step (I) comprises non-crystalline forms of the compound of formula (lb) and chiral acids salts thereof.

The chiral acid salt (T*) of the compound of formula (A) is denoted to encompass all chiral acid salts of compound (A) formed in step (b) 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 (lb) and (la). (T*) in the present context thus indicates the salt of both enantiomers and hence it is a mixture of two diastereoisomers.

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 70 °C to 0 °C °C, more preferably to a temperature in the range of from 50 °C to 0 °C, more preferably to a temperature in the range of 25 °C to 20 °C.

Preferably, the mixture obtained in step (b) consists of the chiral acid salt (T), optionally the unreacted chiral acid derivative, optionally the unreacted compound of formula (A), 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 (c)

As mentioned above in step (c) preferably the precipitated, preferably crystallized, acid salt (T) is separated, from the mixture obtained in (b). Any suitable method of separation can be used according to the present invention. Preferably, the separating in step (c) 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 (A) 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 (la), based on the total weight of chiral acid salt of the compound of formula (A), i.e. based on the sum of (la) and (lb). More preferably, the chiral acid salt (T) of the compound of formula (A) consists of the chiral acid salt of the compound of formula (lb). Preferably step (c) comprises filtering off the acid salt (T) from the mixture obtained in (b) and optionally purifying the acid salt (T), wherein preferably the purification is a further crystallization or the purification is a chromatographic purification. The salt (T) is recovered with a good enantiomer ratio. Preferably the enantiomer ratio (e.r.) is of at least 80₍τ₎:20, preferably is of at least 90₍τ₎: 10, more preferably in of at least 95(T₎:5, even more preferably is of at least 95(τ₎: 1 , wherein the higher value in the ratios refers to the precipitated salt (T), preferably measured with chiral HPLC.

Optional steps d) and/or e)

The process according to the present invention may further comprising

(d) recrystallizing the acid salt (T) obtained in (c); and

(e) separating the acid salt (T) from the mixture obtained in (d) and optionally purifying the acid salt (T).

According to the present invention to further improve the purity and the enantiomer ratio of the compound of formula (A) the precipitated salt (T) of step c) can be crystallized or re-crystallized (if the precipitate is already crystalline).

The precipitated or the crystalline salt (T) is collected and dissolved in a suitable solvent. Typically the solvent is chosen such that the acid salt (T) is soluble in this solvent above a certain temperature and crystalizes below a certain temperature. Preferably, the solvent for the purpose of the recrystallization step (d) is selected from the group consisting of EtOH (ethanol), i-PrOH (iso-propanol), nPrOH (n-propanol), acetone, toluene, MTBE (Methyl- tert-butylether), 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 methanol or acetone, preferably the solvent is methanol or acetone.

In particular,

- if in formula (A) n is 1 , the suitable solvent is methanol, and

- if n is 0, the suitable solvent is acetone.

The crystallization of the acid salt (T) may occur at any suitable temperature. The skilled person understands that for the very same acid salts (T) formed the temperature conditions to achieve the selective precipitation may vary in accordance to the quantity and the kind of solvent or mixture of one or more solvents used. Preferably, the crystallization occurs at a temperature in the range of 0 to 50°C, preferably at a temperature in the range of from 0 to 20 °C, more preferably in the range of form 0 to 10°C. Optionally, seed crystals, preferably seed crystal of the compound to be precipitated can be added to favor the crystallization.

Step a) According to step a) the compound of formula A)

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

and wherein PG is a suitable protecting group, and wherein n is 0 or 1.

As mentioned above, compound (A) consists of an enantiomeric mixture of the compounds la) and (lb)

Compound (A) preferably contains of from 20 to 75 % by weight of the compounds of formula (la) and (lb). According to a preferred embodiment of the invention, compound (A) contains of from 40 to 60 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb). More preferably, compound (A) contains 45 to 55 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb). Even more preferably, compound (A) is a racemic mixture of compound (la) and (lb).

In a preferred embodiment of the invention compound (A) wherein R¹ is Cbz, contains of from 20 to 75 % by weight of the compounds of formula (la) and (lb) wherein R¹ is Cbz. Preferably, compound (A) wherein R¹ is Cbz, contains of from 40 to 60 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb), wherein R¹ is Cbz. More preferably compound (A) wherein R¹ is Cbz, contains 45 to 55 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb), wherein R¹ is Cbz. Even more preferably compound (A) wherein R¹ is Cbz, is a ra- cemic mixture of compound (la) and (lb), wherein R¹ is Cbz. According to this embodiment, n is preferably 0.

In a further preferred embodiment of the invention compound (A) wherein R¹ is H, contains of from 20 to 75 % by weight of the compounds of formula (la) and (lb) wherein R¹ is H. Preferably, compound (A) wherein R¹ is H, contains of from 40 to 60 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb), wherein R¹ is H. More preferably compound (A) wherein R¹ is H, contains 45 to 55 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb), wherein R¹ is H. Even more preferably compound (A) wherein R¹ is H, is a racemic mixture of compound (la) and (lb), wherein R¹ is H According to this embodiment, n is preferably 1.

Step (a)

As far as the preparation of the compound of formula (A) no particular restrictions exists. As mentioned above patent applications WO2008/008518 and WO2008/069997 disclose the synthesis of the racemic 1,4 diazepane derivative. In preferred embodiments the invention provides two synthesis for the preparation of compound (A) that can be then resolved into the desired enantiomer of formula (la) or (lb) according to the present invention.

According to a preferred embodiment, step (a) comprises

(a') providing a compound of formula (II)

wherein R^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, het- eroaryl, 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, wherein R^2a is a suitable protecting group,

(a") reacting the compound of formula (II) with a base, removing R^2a, and optionally reducing the compound,

to give the compound of formula (A).

As described above, R^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably 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 is methyl.

R^2a, is a suitable protecting group, preferably selected from the group consisting of carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylme- thyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl, PNZ, trifluoroacetate, phtalimide 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 R^2a is selected from the group consisting of Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl, Cbz, PNZ, Alloc, Trifluoroacetate, Phthalimide and the like. Most preferably, R^2a is selected from the group consisting of Benzyl, t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and Phthalimide, more preferably R^2a is Boc.

Step (a")

In step (a") of the process of the invention, the compound of formula (II)

is reacted with a base, R ^a is removed, and the resulting compound is optionally subse- quently to the removal or prior to the removal reduced, to give, optionally after further steps, the compound (A). Upon reaction with the base, the 7-membered ring of compound (A) 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, ace- tonitrile 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, het- eroaryl 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 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, more preferably in the range of from 0 to 50, more prefera- bly 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, Na-tert.butoxid, K-tert.butoxid, NaNH2, DBU, Tetramethylguanidin, Na-CH₂S(0)CH₃ and mixtures of two or more thereof is employed, with R^E being selected from the group consisting of al- kyl, 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 methyl. Most preferably, the base is thus sodium methanolate.

The weight ratio of base to compound of formula (II) 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 (b), the sequence of mixing the components of the reaction mixture is not subject to specific restrictions. Preferably, the compound of formula (II) 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 (II) 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 n in compound (A) is 1 (compound Al), in step (a") the compound of formula (II) is reacted with a base to give, optionally after further steps, the compound (A). In this case, no additionally reduction step is necessary. Directly upon reaction with the base, the 7-membered ring of compound (A) is formed ("cyclization reaction").

In case compound (A) n in compound (A) is 0 (compound AO), in step (a") the compound of formula (II) is reacted with a base to give, as intermediate product (compound Al), which is thereafter reduced to give, optionally after further steps, the compound (A). In this case, a reduction of the carbonyl group is thus carried out. Thus, the present invention also relates to a process, as described above, as well as to a compound obtained or obtainable by said process, wherein step (a") further comprises reducing the compound of formula (la).

The way of removing R^2a depends on the respective protecting group employed. Such methods are known to those skilled in the art. In case R^2a is Boc, the removal is preferably carried out under acidic conditions.

Preferably, step (a") comprises

(a" 1) reacting the compound of formula (II) with a base and removing R^2a to give a composition comprising a compound of formula Al)

(a"2) optionally purifying the composition obtained in (a' Ί),

(a' '3) optionally reducing the compound of formula (Al) to give a compound of formula (AO)

As mentioned above with respect to step (a"), the reaction with the base in step (a" 1) is preferably carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopro- pylether, toluene, acetonitrile and mixtures of two or more thereof. Preferably the solvent has the structure R^E-OH is employed, 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 reaction with the base in step (a" l) is carried out at a temperature in the range of from -20 to 80, more preferably in the range of from 0 to 50, more preferably in the range of from 20 to 30 °C. During the reaction, the temperature may be varied or held essentially constant.

As to step (a"3), step (a"3) 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 there- of.

Preferably, step (a" 3) is carried out at a temperature in the range of from -20 °C to 1 10

°C.

Preferably, in step (a" 3), the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH₄, NaCNBH₃, NaBH(OAc)₃, LiAlH₄, LiBH₄ and ¾ 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.

Step (α ')

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

Preferably, compound (II) provided in step (a) according to the invention comprises (a' l) reacting a compound of formula (III)

with a compound of formula (IV)

to give a compound of formula (V)

wherein R^la is H, PG¹, R^A or PG^la and wherein PG^la is a suitable protecting group, (a'2) optionally purifying the compound of formula (V),

(a'3) reducing the compound of formula (V),

(a'4) optionally replacing R^la with R¹,

to give the compound of formula (II).

Thus, the present invention also relates to a process as described above, and a compound obtained or obtainable by said process, wherein step (a') comprises steps (a' l) to (a'4), as described above.

Further, the present invention also relates to a process for the preparation of a compound of formula (II) and a compound obtained or obtainable by said method, the method comprising

(a' 1) reacting a compound of formula (III)

R^{1 a}HNL

^* NHR^2a (HI)

with a compound of formula (IV)

O o

AA

to give a compound of formula (V)

wherein R^la is H, R¹, PG¹, R^A or PG^la and wherein PG^la is a suitable protecting group,

(a'2) optionally purifying the compound of formula (V),

(a'3) reducing the compound of formula (V),

(a'4) optionally replacing R^la with R¹ ,

to give the compound of formula (II).

Further, the present invention also relates to a compound of formula (V)

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

Step (a '3)

In step (a'3), the compound of formula (V) is reduced to give a compound having the structure

Thus, the present invention also relates to a process for the preparation of a compound of formula (Ila), and a compound obtainable or obtained by said process, the process com- prising

(a' l) reacting a compound of formula III)

with a compound of formula (IV)

to give a compound of formula (V)

wherein R^la is H, R¹, PG¹, R^A or PG^la and wherein R^2a and PG^2a are, independently of each other, suitable protecting groups,

(a'2) optionally purifying the compound of formula (V),

(a'3) reducing the compound of formula (V),

to give the compound of formula (Ila).

Further, the present invention also relates to the compound of formula (Ila) as such. It is to be understood that compound (Ila) preferably consists of a mixture of (Ila*) and (Ila**) as shown below

(Ila*) (Ila**)

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 or a mixture of two or more thereof. Preferably, the catalyst comprises Pd and/or Fe and/or Rh, wherein the Fe, if present, is preferably present as part of a catalyst ligand.

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 cyclization 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 (N-methylpyrrolidone), methanol, ethanol, propa- nol, 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 prefera- bly Pd/C.

R^la and R¹

As mentioned above, R^la is H, PG¹, R^A or PG^la, and wherein PG^la and PG^2a are, independently of each other, suitable protecting groups. Preferred protecting groups for PG^la include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carbox- ybenzyl), 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^la is a Boc group or a Cbz group, more preferably Boc.

Preferred protecting groups for PG^2a include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Al- loc (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 (CBZ), Fmoc, benzyl, acetyl, benzoyl, trityl and the like. Most prefera- bly, PG^2a is a Boc group or a Cbz group, more preferably Cbz.

Step (a 'l)

In step (a' l), a compound of formula (III) is reacted with a compound of formula (IV) to give the compound of formula (V).

Preferably, step (a' l) is carried out at a temperature in the range of from 0 to 80 °C, more preferably in the range of from 10 to 50 °C, more preferably in the range of from 20 to 35 °C. During the reaction, the temperature may be varied or held essentially constant.

Preferably, an organic solvent is used in step (a' l), more preferably 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. Most preferably, the reaction is carried out in dichloromethane.

Preferably, (a' l) is carried out in the presence of a catalysing agent, such as a dehydrating reagent or an acidic catalyst. The term "dehydrating agent" is denoted to mean an agent which removes water from the reagents such as by absorption. Such dehydrating agents are known to those skilled in the art. Preferably, the catalysing agent is Si0₂ or a molecular sieve or a mixture thereof. More preferably, the catalysing agent is Si0₂.

Step (a '2)

Preferably, the reaction mixture obtained in step (a' l) is subjected to a suitable work-up in step (a'2), such as an isolation of the respective compound of formula (V). Such working up may comprise one or more stages wherein preferably at least one stage comprises a purification step, such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like. Preferably, the reaction mixture is filtered to remove the the catalysing agent, such as Si0₂, and the solvent is removed, such as under reduced pressure.

More preferably, compound (V) is further purified, e.g. by distillation. According to a further preferred embodiment, wherein n is = 0 and wherein R¹ is PG¹ or R^A, with R^A being

preferably R¹ is PG¹, step (a) comprises,

(aa) providing a compound of formula (II*)

wherein R² is protecting group PG³, preferably a protecting group PG³ selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloroacetate, phthalimide, preferably Boc,

converting compound (II)* to compound (III*)

O

.NH-R²

N

R¹ (III^s5

removing R² a give a compound of formula (IV*)

(iv*);

(ad) subjecting the compound (IV*) to cyclization conditions,

to give the compound of formula (A) with n=0.

Thus, the present invention also relates to a process for the preparation of (T) as described above as well as to a process for the preparation of (A), as described above, and to (T) and (A), obtained or obtainable by said process, respectively,

wherein n is = 0 and wherein R¹ is PG¹ or R^A, with R^A bein

preferably R¹ is PG¹, step (a) comprises,

(aa) providing a compound of formula (II*)

converting compound (II)* to compound (III*)

O

_K , /\ ^ H-R²

N

R¹ (IIP);

removing R² a give a compound of formula (IV*)

R¹ (IV*);

(ad) subjecting the compound (IV*) to cyclization conditions,

to give the compound of formula (A) with n=0.

Further, the present invention is directed to a process for the preparation of a compound of formula (IV*), and to a compound obtained or obtainable by said process,

O

R¹ (IV*);

the process comprising

(aa) providing a compound of formula (II*)

(ab) converting compound (II)* to compound (III*)

(ac) removing R²

to give the compound of formula (IV*)

R¹ (IV*).

Further, the present invention also relates to compounds (II*) and (III*) as such. Preferably, R¹ is Cbz.

Step (ab)

In step (ab) according to the invention, compound (II)*

O O

^J ..^ . NH-R

I is converted, i.e. reduced, to compound (III*)

O

, NH-R²

N

R¹ (III*).

Preferably, step (ab) comprises

(aba) reducing compound (II*) to give a compound of formula (Ila*)

OH

, NH-R^

ΊΜ '

H (Ila*);

(abb) converting compound (Ila*) to compound (Ilia*),

OH

. /\ /\ . NH-R²

R¹ (Ilia*);

(abc) subjecting the compound of formula (Ilia*) to oxidizing conditions, obtaining a compound of formula (III*)

(III*).

Step (aba) The reduction may be carried out by any suitable method known to those skilled in the art.

As to the solvent used no particular restrictions exist provided that the compound of formula (VI*) is obtained. Preferably, the solvent is selected from the group consisting of Di- ethylether, diisopropylether, methyltertbutlyether, tetrahydroiuran, methyltetrahydrofuran, pentane, hexane, cyclopentane, cyclohexane, heptane, toluene, acetonitrile, dichlor- methane, methanol, ethanol, propanol, butanol, isopropanol, isobutanol, t-butanol and mixtures of two or more thereof.

As to the temperature at which the reaction of step (aba) is carried out, no particular restrictions exist provided that the reduction of the compound of formula (VI*) is obtained. Preferably, the reaction is carried out at a temperature in the range of from 30 °C to 110 °C, more preferably in the range of from 0 °C to 70 °C, more preferably in the range of from 10 °C to 40 °C.

As to the reducing conditions no particular restrictions exist provided that the compound of formula (II*) is formed. Preferably, the reducing conditions comprise or are provided by a reagent selected from the group consisting of NaBH₄, NaCNBH₃, NaBH(OAc)₃, LiAlH₄, LiBH₄ and ¾ 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, NaCNBH_3, LiAlH₄ or NaBH(OAc)_3, more preferably NaBH₄ or LiAlH₄.

More preferably, step (aba) comprises

(abal) subjecting compound (Ha*) to reducing conditions, obtaining the compound of formula (Ilaa*)

(aba2) optionally isolating compound (Ilaa*),

(aba3) subjecting the compound of formula (Ilaa*) to further reducing conditions, to give the compound of formula (Ila*).

As mentioned above, in step (abal) the compound (Iia*) is subjected to reducing conditions, and the compound of formula (Ilaa*) is obtained.

As to the solvent used no particular restrictions exist provided that the compound of formula (VI*) is obtained. Preferably, the solvent is selected from the group consisting of diethy- lether, diisopropylether, methyltertbutlyether, tetrahydroiuran, methyltetrahydrofuran, pentane, hexane, cyclopentane, cyclohexane, heptane, toluene, acetonitrile, dichloromethane, methanol, ethanol, propanol, butanol, isopropanol, isobutanol, t-butanol and mixtures of two or more thereof.

As to the temperature at which the reaction of step (abal) is carried out, no particular restrictions exist provided that the reduction of the compound of formula (Ilaa*) is obtained. Preferably, the reaction is carried out at a temperature in the range of from - 30 °C to 110 °C, more preferably in the range of from 0 °C to 70 °C, more preferably in the range of from 10 °C to 40 °C.

As mentioned above, in optional step (aba2) compound (Ilaa*) is optionally isolated.

Means for isolating compound (Ilaa*) are known to the skilled person in the art, they may include precipitation, preferably crystallization, evaporation of the solvent etc.

In step (aba3) the compound of formula (Ilaa*) is preferably subjected to further reducing conditions, to give the compound of formula (Ila*).

As to the solvent used no particular restrictions exist provided that the compound of formula (VI*) is obtained. Preferably, the solvent in step (aba3) and the solvent used in (abal) differ from each other, Preferably, the solvent is selected from the group consisting of TFA, diethylether, diisopropylether, methyltertbutlyether, tetrahydrofuran, methyltetrahy- drofuran, pentane, hexane, cyclopentane, cyclohexane, heptane, toluene, acetonitrile, di- chlormethane, methanol, ethanol, propanol, butanol, isopropanol, isobutanol, t-butanol and mixtures of two or more thereof.

As to the temperature at which the reaction of step (aba3) is carried out, no particular restrictions exist provided that the reduction of the compound is obtained. Preferably, the reaction is carried out at a temperature in the range of from - 30 °C to l l0 °C , more preferably in the range of from 0 °C to 70 °C, more preferably in the range of from 10 °C to 40 °C.

As to the reducing conditions in step (abal) no particular restrictions exist provided that the compound of formula (Ila*) is formed. Preferably, the reducing conditions comprise or are provided by a reagent selected from the group consisting of NaBH₄, NaCNBH₃, NaBH(OAc)₃, LiAlH₄, LiBH₄ and ¾ 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, NaCNBH_3, or NaBH(OAc)_3, more preferably NaBH₄.

As to the reducing conditions in step (aba3) no particular restrictions exist provided that the compound of formula (Ila*) is formed. Preferably, the reducing conditions comprise or are provided by a reagent selected from the group consisting of NaBH₄, NaCNBH₃, NaBH(OAc)₃, LiAlH₄, LiBH₄ and ¾ 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, NaCNBH_3, LiAlH₄ or NaBH(OAc)_3, more preferably NaBH₄ or LiAlH₄.

Step (abb)

In step (abb), the compound (Ila*)

is converted to the compound (Ilia*),

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

and wherein PG¹ is a suitable protecting group.

In this step, the amine group is either protected with a protecting group PG1 or attached to the group R^A. No particularly restriction exists with respect to the protection group PG^Lprovided that is an amino protecting group. PG¹ is aimed to protect the amino group from subsequent electrophilic reaction. Hence preferably the PG¹ is selected from protecting group PG¹ that protect amines from electrophiles. Additionally, it is preferred that the deprotection conditions of group R¹ are different from the deprotection conditions of group R².

Preferred suitable protecting group PG¹ are selected from the group consisting of carbox- ybenzyl (Cbz), Bn (benzyl), Alloc (Allyloxycarbonyl) , Fmoc (Fluorenylmethyloxycar- bonyl), PNZ (p-Nitrobenzylcarbamoyl), more preferably Cbz. .

According to a preferred embodiment of the invention R¹ is Cbz. Methods for attaching such protecting groups to amines are known to those skilled in the art. This may e.g. be accomplished by reacting the compound with a compound PG'-X, wherein X is a leaving group

In case, R¹ is R^A with R^A bein

the compound (Ila*) is preferably reacted with a compound R -X, wherein X is a leaving group.

The term leaving group 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.

As to the solvent in which the reaction of step (abb) is carried out, no particular restrictions exist provided that the compound of formula (III*) is obtained. 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, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutyl- ether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.

Preferably, the reaction of step (abb) is carried out at a temperature in the range of from 0 to 80 ° C, more preferably in the range of from 10 to 50 °C, more preferably in the range of from 20 to 35 °C, more preferably at room temperature. During the reaction, the temperature may be varied or held essentially constant.

Step (abc)

In step (abc), the compound of formula (Ilia*) is subjected to oxidizing conditions, thereby obtaining a compound of formula (III*)

As to the oxidizing reagent with which the oxidation reaction of step (abc) is carried out, no particular restrictions exist provided that the compound of formula (III*) is obtained. Preferably the oxidizing reagent is selected from the group consisting of from (2,2,6,6- tetramethylpiperidin-l-yl)oxidanyl, TEMPO, reagents based on activated DMSO, Dess- Martin periodinane, IBX, transition metal based reagents such as Cr(VI), Mn(VII), Pb(IV) and mixtures of two or more thereof.

The process uses the oxidizing agent in a molar ratio relative to compound (III*) which is in the range of from 1 :0.1 to 1.1.

As to the solvent in which the reaction of step (abc) is carried out, no particular restrictions exist provided that the compound of formula (III*) is obtained. Preferred solvents are selected from the group consisting of Dichloromethane, chloroform, diethylether, diisopropylether, methyltertbutylether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylacetate, iso- propylacetate, tert.butanol, pentane, hexane, heptane, cyclopentane, cyclohexane, toluene and mixtures of two or more thereof. As to the temperature in which the reaction of step (abc) is carried out, no particular restrictions exist provided that the compound of formula (III*) is obtained. Preferably the temperature is in the range of from -30 °C to 110 °C, more preferably the temperature is in the range of from 0 °C to 70 °C, more preferably the temperature is in the range of from 20 °C to 40 °C

According to an alternative preferred embodiment, step (ab) comprises

(abx) converting compound (Ila*) to compound (IIIx*),

(aby) reducing the compound (IIIx*)

to give compound (III*).

Step (abx)

In this step, the amine group is either protected with a protecting group PG¹ or attached to the group R^A. No particularly restriction exists with respect to the protection group PG^Lprovided that is an amino protecting group. PG¹ is aimed to protect the amino group from subsequent electrophilic reaction. Hence preferably the PG¹ is selected from protecting group PG¹ that protect amines from electrophiles. Additionally, it is preferred that the deprotection conditions of group R¹ are different from the deprotection conditions of group R².

Preferred suitable protecting group PG¹ are selected from the group consisting of carbox- ybenzyl (Cbz), Bn (benzyl), Alloc (Allyloxycarbonyl), Fmoc (Fluorenylmethyloxycarbon- yl), PNZ (p-Nitrobenzylcarbamoyl), more preferably Cbz. According to a preferred embodiment of the invention R¹ is Cbz. Methods for attaching such protecting groups to amines are known to those skilled in the art. This may e.g. be accomplished by reacting the compound with a compound PG'-X, wherein X is a leaving group

In case, R¹ is R^A with RA bein

the compound (Ila*) is preferably reacted with a compound R'-X, wherein X is a leaving group. Preferred leaving groups are -CI, -S, -SMe, -SEt or -Br, in particular -CI or -Br.

As to the solvent in which the reaction of step (abx) is carried out, no particular restrictions exist provided that the compound of formula (IIIx*) is obtained. Preferred solvents are selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH₂CI₂, ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, iso- propyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketone, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof.

As to the temperature in which the reaction of step (abx) is carried out, no particular restrictions exist provided that the compound of formula (IIIx*) is obtained. Preferably, the reaction is carried out at a temperature in the range of from 0 to 80 °C, more preferably in the range of from 10 to 50 °C, more preferably in the range of from 20 to 35 °C, more preferably at room temperature. During the reaction, the temperature may be varied or held essentially constant.

Step (aby)

As to the reduction in step (aby), the reduction may be accomplished directly or via intermediate

which is then subjected to oxidizing conditions.

The reduction may be carried out by any suitable method known to those skilled in the art.

As to the solvent used no particular restrictions exist provided that the compound of formula (VI*) is obtained. Preferably, the solvent is selected from the group consisting of TFA, diethylether, diisopropylether, methyltertbutlyether, tetrahydrofuran, methyltetrahy- drofuran, pentane, hexane, cyclopentane, cyclohexane, heptane, toluene, acetonitrile, di- chlormethan, methanol, ethanol, propanol, butanol, isopropanol, isobutanol, t-butanol and mixtures of two or more thereof.

As to the temperature at which the reaction of step (aby) is carried out, no particular re- strictions exist provided that the reduction of the compound of formula (III*) is obtained. Preferably, the reaction is carried out at a temperature in the range of from - 30 °C to 110 °C, more preferably in the range of from 0 °C to 70 °C, more preferably in the range of from 10 °C to 40 °C.

As to the reducing conditions no particular restrictions exist provided that the compound of formula (III*) is formed. Preferably, the reducing conditions comprise or are provided by a reagent selected from the group consisting of NaBH₄, NaCNBH₃, NaBH(OAc)₃, LiAlH₄, LiBH₄ and ¾ 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, NaCNBH_3, L1AIH₄ or NaBH(OAc)_3, more preferably NaBH₄ or LiAlH₄, in particular NaBH₄.

In case an oxidation is carried out, as mentioned above, no particular restrictions exist provided that the compound of formula (III*) is obtained. Preferably the oxidizing reagent is selected from the group consisting of from (2,2,6,6-tetramethylpiperidin-l-yl)oxidanyl, TEMPO, reagents based on activated DMSO, Dess-Martin periodinane, IBX, transition metal based reagents such as Cr(VI), Mn(VII), Pb(IV) and mixtures of two or more there- of.

The process uses the oxidizing agent in a molar ratio relative to compound to be oxidized which is in the range of from 1 :0.1 to 1 : 1, preferably in the range of from 1 : 0.5 .to 1 :1.

Step (ac)

In step (ac), the protecting group R² is removed to a give a compound of formula (IV*)

Methods for removal of protecting groups are known to those skilled in the art.

Preferably R² is is BOC and R² in (ac) is preferably removed under acidic conditions, preferably with TFA.

Step (ad)

In step (ad) the compound (IV*) is subjected to cyclization conditions.

As to the cyclization conditions of step (ad) no particular restrictions exist provided that the compound of formula (A) is obtained. Preferably the cyclization condition is a reductive amination.

As to the reductive amination reagent of step (ad) no particular restrictions exist provided that the compound of formula (A) is obtained. Preferably the reductive amination reagent is selected from the group consisting of NaBH₄, NaCNBH₃, NaBH(OAc)₃, LiAlH₄, LiBH₄ and ¾ 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.

As to the solvent in which the reaction of step (ad), preferably the reductive amination is carried out, no particular restrictions exist provided that the compound of formula (A) is obtained. Preferred solvents are selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE, DIPET (diisopropylether), toluene, acetonitrile, CH₂CI₂ and mixtures of two or more thereof. As to the temperature in which the reaction of step (ad) preferably reductive amination is carried out, no particular restrictions exist provided that the compound of formula (A) is obtained. Preferably the temperature is selected from the range of from -20 °C to 110 °C.

Step (aa)

No particular restriction exist with respect to the provision of the compound of formula (II*). Preferably step (aa) comprises

(aal) providing a mixture comprising a compound of formula (VII*) or of formu- la (VIII*)

and a compound of formula IX*)

in a solvent; preferably a solvent selected from the group consisting of toluene, xylene, xylene, mesitylene and decaline, preferably xylene

(aa2) subjecting the mixture of step (aal) to suitable reaction conditions, preferably heating the mixture

to give the compound of formula (II*).

As mentioned above, in step (aa.1.1) a mixture comprising a compound of formula (VII*) or of formula (VIII*) and a compound of formula (IX*) is provided in a solvent.

As to the solvent, no particular restrictions exist provided that the compound of formula (V*) is obtained. Preferred solvents are selected from the group consisting of of toluene, xylene, xylene, mesitylene and decaline, more preferably of the solvent is xylene.

Step (aa2)

As mentioned above, in step (aa2) the mixture of step (aal) is subjected to suitable reaction conditions, preferably wherein preferably the reaction condition comprises heating the mixture to give the compound of formula (II*).

Preferably, the reaction is carried out at a temperature in the range of from 80°C to 160 C.

As to the solvent in which the reaction of step (aa2) is carried out, no particular restrictions exist provided that the compound of formula (II*) is obtained. Preferred solvents are selected from the group consisting of toluene, xylene, xylene, mesitylene and decaline, more preferably of the solvent is xylene. As to the reaction condition of step (aa2), no particular restrictions exist provided that the compound of formula (V*) is obtained. Preferably, however, the reaction mixture is y heated at a temperature of at least 80 °C, preferably of at least 150 °C.

Product (II*) may be optionally isolated and optionally crystallized, before further use.

PROCESS FOR THE PREPARATION OF SUVOREXANT

In a third aspect the present invention relates to a process for the preparation of suvorexant of formula (S), as well as to suvorexant of formula (S), obtained or obtainable by said process

the process comprising

(i) preparing an acid salt (T) of a compound of formula (A)

as prepared according to the first aspect of the invention;

transforming the acid salt to suvorexant.

According to the present invention, the salt (T) of the compound of formula (A), preferably of formula (AO) is converted to the free base, preferably under basic conditions, to provide the enantiomer (la) of the compound of formula (A), preferably (AO-la). Compound (la), such as compound (Al-Ia) or compound (AO-la). This compound, in which preferably Rl is PG¹ or R^A, more preferably PG¹ or

is then preferably used for the syn- thesis of suvorexant.

As far as the preparation of suvorexant from this compound is concerned, no particular restrictions exists. Patent applications WO2008/008518 and WO2008/069997 disclose the synthesis of suvorexant that can be used also according to the present invention starting from the enantiomer (la) of the compound of formula (A ).

Preferably, step (ii) comprises

(ii-a) optionally converting the salt (T) of the compound of formula (A), preferably of the compound of formula (AO)

to the free base, preferably under basic conditions, to provide the enantiomer (la)

of the compound of formula (A), preferably (AO-la),

/ . H

N ^'

R-, -Ν

(AO-la)

wherein R¹ is preferably P ¹ or

(ii-b) reacting the salt (T) or the com ound of (ii-a) with a compound of formula

wherein E is -COOH or a reactive carboxy group,

(ii-c) optionally removing PG¹ and attaching

to the compound of step (ii-b) in case ft¹ is PG¹.

Step (ii-b)

If in step (ii-b), the respective compound is reacted, i.e. coupled, with a compound of formula (XI), wherein E is -COOH or a reactive carboxy group.

The term "reactive carboxy group" as used in this context of the present invention is intended to mean an activated carboxylic acid derivative that reacts readily with electrophilic groups, such as an NH group, optionally in the presence of a suitable base, in contrast to those groups that require a further catalyst, such as a coupling reagent, in order to react. The term "activated carboxylic acid derivative" as used herein preferably refers to acid halides, such as acid chlorides, and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides, such as isobutyloxycarbonylchloride and the like, isothiocyanates or isocyanates, anhydrides derived from reaction of the carboxylic acid with Ν,Ν'- carbonyldiimidazole and the like, and esters derived from activation of the corresponding carboxylic acid with a coupling reagent. Such coupling reagents include, but are not limited to, HATU (0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophos- phate); HOAt, HBTU (0-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro- phosphate); TBTU (2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophos- phate); TFFH (N,N',N",N"-tetramethyluronium-2-fluoro-hexafluorophosphate); BOP (ben- zotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate); PyBOP (ben- zotriazol-l-yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate; EEDQ (2-ethoxy-l- ethoxycarbonyl-l,2-dihydro-quinoline); DCC (dicyclohexylcarbodiimide); DIPCDI (diiso- propylcarbodiimide); 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) car- bodiimide hydrochloride, CDC (l-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-C1 , CIP, DEPBT, Dpp-Cl, EEDQ, FDPP, HOTT, TOTT, PyCloP.

In case E is -COOH, the reaction is preferably carried out in the presence of a catalyst, such as a coupling reagent, or a reagent that forms in situ an acid chlorid with E, such as oxalyl chloride, and preferably further in the presence of a base. Preferably, in this case, the coupling reagent is selected from the group consisting of HATU (0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); HOAt, HBTU (0-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); TBTU (2-(lH- benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate); TFFH (N,N',N",N"- tetramethyluronium-2-fluoro-hexafluorophosphate); BOP (benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate); PyBOP (benzotriazol-l-yl- oxy-trispyrrolidino-phosphonium hexafluorophosphate; EEDQ (2-ethoxy-l- ethoxycarbonyl-l,2-dihydro-quinoline); DCC (dicyclohexylcarbodiimide); DIPCDI (diiso- propylcarbodiimide); 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) car- bodiimide hydrochloride, CDC (l-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-C1 , CIP, DEPBT, Dpp-Cl, EEDQ, FDPP, HOTT, TOTT, PyCloP.

More preferably, E is a reactive carboxy group, in particular-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, preferably wherein X is selected from the group consistin of

Step (ii-c)

In case R¹ is

the process further comprises the removal of the protecting group and the attachment of the residue

Methods for removing protecting groups are known to those skilled in the art. Preferably, PG¹ is Cbz and the group sis removes under reductive conditions.

The attachment of the residue

is preferably carried out by reacting the compound with a compound of formula (XII)

wherein X* is a leaving group. The term leaving group 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, this reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of dichloromethane, dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydro- furan, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile, tetramethylurea, dimethylacetamide, EtOAc, iPrOAc, hexane, cyclohex- ane, heptane 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.

In case R¹ is already

step (ii-c) is omitted.

In case n is 1 , the process further comprises a reducing step.

The term "alkyl" as used herein refers to a linear or branched a I ky I group. Preferably "ai- kyi" is a Ci-C<, alkyl containing from 1 to 6 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyi or hexyl.

The term "aryl" as used herein herein means an aromatic carbocycl ic moiety such as phenyl, bi henyl or naphty .

The term "arylalkyl" as used herein refers to a compound or subst itucnt containing both aliphatic and aromatic structures as disclosed herein under the terms "alkyl" and "aryl" The term "heteroaryl" as used herein means an aromatic hetcrocyclc ring of 5 to 1 0 members and hav ing at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono-and bicyclic ring systems. Representative heteroaryls include (but are not limited to ) fury I, benzofuranyl, thiophenyl. ben- zothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl. isoquinoliny l, oxazoiyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, ben- zothiazoiyl, isothiazolyl, pyridazinyl, pyrimidinyl. pyrazinyl, triazinyl, cinnol inyl, phthala- zinyl, triazolyl, tetrazolyl, quinazolinyl, and benzodioxolyl.

The term "cycloalkyl" as used herein means saturated carbocyclic radicals and, unless otherwise specified, a cycloalkyl radical typically has from 3 to 7 carbon atoms, preferably from. 3 to 6 carbon atoms, more preferably from 3 to 5 carbon atoms and most preferably from 3 to 4 carbon atoms. Representativ e cycloai kyis include (but are not limited to) cy- clopropyl, cyclobutyl, eyciopentyl. cyclohexyl .

The term "heterocycloalkyl" as used herein means a monocyclic heterocyclic ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms in- dependently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optional ly quaternized. Preferably is a 5-6 membered heterocycie. Heterocycies include heteroaryls as defined above. The hetcrocyclc may be attached v ia any heteroatom or carbon atom. Thus, the term includes ( but is not limited to ) morpholinyl. pyridinyl, pyrazinyl, pyrazolyl, th ia- zolyl, triazolyl. imidazolyl. oxadiazolyl, oxazoiyl, isoxazolyl, pyrrolidinonyl, pyrrolidinyl. pipcridinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydro- pyranyl, tetrahydropyridinyl, t e t ra h yd ro p yr imidinyi, tetrahydrothiophenyl, tetrahydrothi- opyranyl, and the like.

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

1. A process for the preparation of an acid salt T) of a compound of formula (A)

and wherein PG is a suitable protecting group, and wherein n is 0 or 1, wherein the acid salt (T) is the salt a single stereoisomer of a chiral acid, preferably wherein the chiral acid salt is a tartaric acid derivative salt, preferably wherein the tartaric acid derivative salt is selected from the group consisting of 2,3- Ditoluoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid salt, 2,3-Dianisoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) salt or a mixture of two or more thereof

the process comprising

(a) providing a compound of formula A)

consistin of an enantiomeric mixture of the com ounds (la) and (lb)

wherein the compound (A) contains of from 20 to 75 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb) in a suitable solvent, (b) adding a single stereoisomer of a chiral acid, preferably wherein the chiral acid is a tartaric acid derivative, wherein preferably the tartaric acid derivative is selected from the group consisting of 2,3-Ditoluoyl tartaric acid, 2,3- Dibenzoyl tartaric acid, 2,3-Dianisoyl tartaric acid, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, thereby obtaining a mixture comprising a precipitated preferably crystallized acid salt (T) and the solvent,

The process of embodiment 1, wherein when n=0 and

Y—x " ^"O - , then the tartaric acid derivative is not D-di-benzoyl tartaric acid (DBTA).

The process of embodiment 1, wherein when n=0 and R is not — " ^"O

The process of embodiment 1, wherein n=0 and R¹ is H or PG¹

The process of embodiment 1, wherein n=l .

A process of any of embodiments 1 to 5, wherein step b) comprises forming an acid salt (T*) of at least part of the compound of formula (A) by treating the compound of formula (A) with the chiral acid, and precipitating, preferably crystallizing, at least part of the an acid salt (T*) formed, thereby obtaining a mixture comprising the precipitated, preferably crystallized acid salt (T) and the solvent.

The process of any of embodiments 1 to 6, wherein the acid salt (T) of the compound formula (A) contains at least 85% by weight, more preferably at least 90 % by weight, more preferably at least 95 % 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 chiral acid salt of the compound of formula (la), based on the total weight of the acid salt (T) of the compound of formula (A).

The process of any of embodiments 1 to 7, wherein the compound of formula (A) contains of from 40 to 60 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb), more preferably wherein the compound of formula (A) is a racemic mixture of the compound of formula (la) and (lb). The process of any of embodiments 1 to 8, wherein n is 1 and the tartaric acid derivative is a di-toluoyl tartaric acid, more preferably L-di-toluoyl tartaric acid (LTTA).

The process of any of embodiments 1, 3 to 9, wherein n is 0 and the tartaric acid derivative is a di-benzoyl tartaric acid, more preferably D-di-benzoyl tartaric acid (DBTA).

The process of any of embodiments 1 to 9, wherein the acid salt (T) of the compound of formula (A) consists of the tartaric salt of the compound of formula (la).

The process of any of embodiments 1 to 11, wherein the suitable solvent in (a) 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, tetrahydro- furan, dichloromethane, methylisobutylketone, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof.

The process of any of embodiments 1 to 12, wherein n is 0.

The process of any of embodiments 1 to 13, wherein n is 0 and R¹ is PG¹ or R^A, preferably PG or

, more preferably PG , more preferably Cbz.

The process of any of embodiments 1 to 14, wherein n is 0 and R is PGi, preferably Cbz.

The process of any of embodiments 1 to 12 , wherein n is 1.

17. The process of any of embodiments 1 to 12, wherein n is 1 and R¹ is preferably H,

PG¹ or R^A, preferably H, PG¹ or , more preferably H or PG¹, more preferably H.

18. The process of any of embodiments 1 to 12, 16 to 17, wherein n is 1 and the suitable solvent is methanol.

19. The process of any of embodiments 1 to 8 and lOto 15, wherein n is 0 and the suitable solvent is acetone.

0. The process of any of embodiments 1 to 19, wherein (c) comprises filtering off the acid salt (T) from the mixture obtained in (b) and optionally purifying the acid salt

(T).

1. The process of any of embodiments 1 to 20, wherein step (a) comprises (a') providing a compound of formula (II)

wherein R^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, het- eroaryl, 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^2a is a suitable protecting group

(a") reacting the compound of formula (II) with a base and optionally reducing the compound

to give the compound of formula (A).

The process of embodiment 21, wherein step (a') comprises

(a' l) reacting a compound of formula (III)

with a compound of formula (IV)

to give a compound of formula V)

wherein R^la is H, PG¹, R^A or PG^la and wherein R^2a is PG² and wherein PG^la and PG^2a are, independently of each other, suitable protecting groups,

(a'2) optionally purifying the compound of formula (V),

(a'3) reducing the compound of formula (V),

(a'4) optionally replacing R^la with R¹ if R^la and R¹ differ from each other, to give the compound of formula (II).

The process of any of embodiments 1 to 20, wherein n is = 0 and wherein R¹ is PG¹ or R^A, with R^A being

preferably R¹ is PG¹, and wherein step (a) comprises

(aa) providing a compound of formula (II*)

wherein R² is protecting group PG³, preferably a protecting group PG³ selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloro- acetate, phthalimide, preferably Boc,

(ab) converting compound (II)* to compound (III*)

O

_K ,_/\ ^ H-R²

N

R¹ (III*);

(ac) removing R² to a give a compound of formula (IV*)

R¹ (IV*);

(ad) subjecting the compound (IV*) to cyclization conditions,

to give the compound of formula (A) with n = 0.

The process of any of embodiments 1 to 23, wherein n is = 0 and wherein R is

PG¹.

The process of embodiment 23 or 24, wherein R is Cbz.

The process of any of embodiments 23 to 25, wherein the cyclization conditions in (ad) comprise reductive amination conditions.

The process of embodiment 26, wherein the reductive amination conditions comprise a reagent selected from the group consisting of NaBH₄, NaCNBH₃,

NaBH(OAc)₃, LiAlH₄, LiBH₄ and ¾ 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.

The process of any of embodiments 23 to 26, wherein R² is preferably Boc and wherein R² in (ac) is preferably removed under acidic conditions, preferably with TFA. The process of any of embodiments 23 to 28, wherein step (ab) comprises

(aba) reducing compound (II*) to give a compound of formula (Ila*)

(abb) converting compound (Ila*) to compound (Ilia*),

OH

. /\ /\ . NH-R²

R¹ (Ilia*);

The process of embodiment 29, wherein the oxidizing conditions in (abc) comprise a oxidizing reagent selected from (2,2,6,6-tetramethylpiperidin-l-yl)oxidanyl, TEMPO, reagents based on activated DMSO, Dess-Martin periodinane, IBX, transition metal based reagents such as Cr(VI), Mn(VII), Pb(IV) and mixtures of two or more thereof.

The process of embodiment 29 or 30 wherein step (aba) comprises

(abal) subjecting compound (Ila*) to reducing conditions, obtaining the compound of formula (Ilaa*)

(aa2.2) optionally isolating compound (Ilaa*),

(aa2.3) subjecting the compound of formula (Ilaa*) to further reducing conditions, to give the compound of formula (Ila*).

The process of any of embodiments 23 to 28, wherein step (ab) comprises

(abx) converting compound (Ila*) to compound (IIIx*),

(IIIx*);

(aby) reducing the compound (IIIx*) to give compound (III*).

The process of any embodiments 23 to 32, wherein (aa) comprises

(aal) providing a mixture comprising a compound of formula (VII*) or of formula (VIII*)

and a compound of formula IX*)

to give the compound of formula (II*).

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

and wherein PG is a suitable protecting group,

the com ound consisting of a mixture of the compounds (la) and (lb)

the process comprising

(aa) providing a compound of formula (II*)

wherein R² is protecting group PG³, preferably a protecting group PG³ se lected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloro acetate, phthalimide, preferably Boc,

converting compound (II)* to compound (III*)

O

_K , /\ ^ H-R²

N

R¹ (IIP);

removing R² a give a compound of formula (IV*)

R¹ (IV*);

(ad) subjecting the compound (IV*) to cyclization conditions,

to give the compound of formula (A) with n = 0.

The process of embodiment 34, wherein R¹ is Cbz.

The process of embodiment 34 or 35 wherein the cyclization conditions in (ad) comprise reductive amination conditions.

The process of embodiment 36, wherein the reductive amination conditions com- prise a reagent selected from the group consisting of NaBH₄, NaCNBH₃,

The process of any of embodiments 34 to 37, wherein R² is preferably BOC and wherein R² in (ac) is preferably removed under acidic conditions, preferably with

TFA.

The process of any of embodiments 34 to 38, wherein step (ab) comprises

(aba) reducing compound (II*) to give a compound of formula (Ila*)

(abb) converting compound (Ila*) to compound (Ilia*),

(Ilia*);

O

, NH-R²

N

R¹ (III*)

The process of embodiment 39, wherein the oxidizing conditions in (abc) comprise a oxidizing reagent selected from (2,2,6,6-tetramethylpiperidin-l-yl)oxidanyl, TEMPO, reagents based on activated DMSO, Dess-Martin periodinane, IBX, transition metal based reagents such as Cr(VI), Mn(VII), Pb(IV) and mixtures of two or more thereof.

The process of embodiment 39 or 40, wherein step (aba) comprises

(aa2.2) optionally isolating compound (Ilaa*),

The process of any of embodiments 34 to 38, wherein step (ab) comprises

(abx) converting compound (Ila*) to compound (IIIx*),

(IIIx*);

(^aby) reducing the compound (IIIx*)

to give compound (III*).

The process of any of embodiments 34 to 42, wherein (aa) comprises

and a compound of formula (IX*)

,NHR²

Η,Ν^' (XI*)

to give the compound of formula (II*).

A process for the pre aration of suvorexant

comprising

(i) preparing a acid salt (T) of a compound of formula (A)

(ii) according to the method of any of embodiments 1 to 32, transforming the acid salt to suvorexant,

wherein preferably when n=0 and R is — " ^"O then the tartaric acid derivative is not DBTA or wherein preferably when n=0 and R¹ is not

or wherein preferably when n=0, R¹ is H or PG¹.

The process of embodiment 44, wherein step (ii) comprises

(ii-a) optionally converting the salt (T) of the compound of formula (A),

preferably of the compound of formula (AO)

to the free base, preferably under basic conditions, to provide the enantio- mer (la)

of the compound of formula (A), preferably (AO-la),

. H

/ N ^'

R-, -Ν

(AO-la)

wherein R¹ is preferably PG¹ or

(ii-b) reacting the tartaric acid salt or the compound of (ii-a) with a compound formula

wherein E is -COOH or a reactive carboxy group,

optionally removing PG¹ and attaching

to the compound of step (ii-b) in case R¹ is PG¹.

A process for the preparation of a compound of formula (IV*)

the process comprising

(aa) providing a compound of formula (II*)

wherein R² is protecting group PG³, preferably a protecting group PG³ selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloroacetate, phthalimide, preferably Boc, and

(ab) converting compound (II)* to compound (III*)

(ac) removing R²

to give the compound of formula (IV*)

O

R¹ (IV*).

The process of embodiment 46, wherein step (aa) comprises

(aal) providing a mixture comprising a compound of formula (VII*) or of formula VIII*)

O O^CH₃ (yip) ^ (VIII*)

and a compound of formula (IX*)

u_M^ NHR²

^H2^N ^ (XI*)

to give the compound of formula (II*). The process of embodiment 46 or 47, wherein step (ab) comprises

(aba) reducing compound (II*) to give a compound of formula (Ila*)

(abb) converting compound (Ila*) to compound (Ilia*),

OH

. /\ /\ .NH-R²

R¹ (Ilia*);

A process for the preparation of a compound of formula (II*)

wherein R² is protecting group, preferably a protecting group selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloroacetate and phthalimide, preferably Boc,

the process comprising

O O^CH₃ (yip) ^ (VIII*)

and a compound of formula (IX*)

u_M^ NHR²

^H2^N ^ (XI*)

(aa2) subjecting the mixture of step (aal) to suitable reaction conditions, preferably heating the mixture to give the compound of formula (II*).

An acid salt (T) obtained or obtainable by a process of any of embodiments 1 to 33.

The acid salt of embodiment 50, wherein when n=0 and R¹ is

then the tartaric acid derivative is not D-di-benzoyl tartaric acid (DBTA).

The acid salt of embodiment 50, wherein when n=0 and R is not

The acid salt of embodiment 50, wherein n=0 and R¹ is H or PG¹

The acid salt of embodiment 50, wherein n=l .

A compound of formula (A) obtained or obtainable by a process according to any of embodiments 34 to 43.

Suvorexant obtained or obtainable by a process according to embodiment 44 or 45. A compound of formula (IV*) obtainable by a process according to any of embodiments 46 to 48.

An acid salt (T) of a compound of formula (A)

wherein R is selected from the group consisting of H, PG and R , with R being

and wherein PG¹ is a suitable protecting group, and wherein n is 0 or 1, wherein the acid salt (T) is the salt of a single stereoisomer of a chiral acid, preferably wherein the chiral acid salt is a tartaric acid derivative salt, preferably wherein the tartaric acid derivative salt is selected from the group consisting of 2,3-Ditoluoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid salt, 2,3-Dianisoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) salt or a mixture of two or more thereof , wherein the acid salt (T) contains at least 80 % by weight of the chiral acid salt of the compound of formula (la)

based on the total weight of the acid salt of the compound of formula (A).

The acid salt of embodiment 58, wherein when n=0 and R is

then the tartaric acid derivative is not D-di-benzoyl tartaric acid (DBTA)

The acid salt of embodiment 58, wherein when n=0 and R is not

The acid salt of embodiment 58, wherein n=0 and R¹ is H or PG^1'

The acid salt of embodiment 50, wherein n=l .

The acid salt (T) of any of embodiments 58 to 62, wherein the acid salt (T) of the compound formula (A) contains at least 85% by weight, more preferably at least 90 % by weight, more preferably at least 95 % 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 chiral acid salt of the compound of formula (la), based on the total weight of the acid salt (T) of the compound of formula (A).

The acid salt (T) of any of embodiments 58 to 63 , wherein the compound of formula (A) contains of from 40 to 60 % by weight % of the compound of formula (la) based on the total weight of the sum of (la) and (lb),

more preferably wherein the compound of formula (A) is a racemic mixture of the compound of formula (la) and (lb).

The acid salt (T) of any of embodiments 58 to 64, wherein n is 1 and the tartaric acid derivative is a di-toluoyl tartaric acid, more preferably L-di-toluoyl tartaric acid (LTTA)

The acid salt (T) of any of embodiments 53 to 66, wherein n is 0 and the tartaric acid derivative is a di-benzoyl tartaric acid, more preferably D-di-benzoyl tartaric acid (DBTA). The acid salt (T) of any of embodiments 58 to 66, wherein the acid salt (T) of the compound of formula (A) consists of the tartaric salt of the compound of formula (la).

A compound of formula (A)

wherein R is selected from the group consisting of H, PG and R , with R being

and wherein PG¹ is a suitable protecting group, and wherein n is 0 or 1, the com ound consisting of a mixture of the com ounds (la) and (lb)

The compound of embodiment 68, wherein n is 0 and R¹ is Cbz.

The compound of embodiment 68, wherein n is 1 and R¹ is selected from the consisting of H, PG¹ and R^A, with R^A being

and wherein PG¹ is a suitable protecting group, preferably Cbz.

A compound of formula (IV*)

O

- NH,

R¹ (IV*);

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

A compound of formula (II*)

wherein R² is protecting group PG³, preferably a protecting group PG³ selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloroacetate, phthalimide, preferably Boc.

A compound of formula (III*)

O

_K , /\ ^ H-R²

N

R¹ (IIP);

and wherein R² is protecting group PG³, preferably a protecting group PG³ selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloroacetate, phthalimide, preferably Boc

A compound of formula (Ila*)

Use of an acid salt (T) of embodiment 50 or any of embodiments 58 to 67 for the preparation of suvorexant.

76. Use of a compound (A) of embodiment 55 or 68 to 70 for the preparation of suvorexant.

77. Use of a compound (IV*) of embodiment 71 for the preparation of suvorexant.

78. Use of a compound (II*) of embodiment 72 for the preparation of suvorexant.

79. Use of a compound (III*) of embodiment 73 for the preparation of suvorexant. Use of a compound (Ila*) of embodiment 74 for the preparation of suvorexant. A process for the preparation of an acid salt (T) of a compound of formula (A)

the process comprising

(a) providing a compound of formula A)

consisting of an enantiomeric mixture of the com ounds (la) and (lb)

wherein the acid salt (T) contains at least 80 % by weight of the chiral acid salt of the compound of formula (la) based on the total weight of the acid salt of the compound of formula (A), and wherein step (a) comprises

(a') providing a compound of formula (II)

to give the compound of formula (A).

A process for the preparation of an acid salt (T) of a compound of formula (A)

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

wherein the acid salt (T) is the salt a single stereoisomer of a chiral acid, preferably wherein the chiral acid salt is a tartaric acid derivative salt, preferably wherein the tartaric acid derivative salt is selected from the group consisting of 2,3-Ditoluoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid salt, 2,3-Dianisoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) salt or a mixture of two or more thereof, the process comprising

(a)providin a compound of formula (A)

(b) adding a single stereoisomer of a chiral acid, preferably wherein the chiral acid is a tartaric acid derivative, wherein preferably the tartaric acid derivative is selected from the group consisting of 2,3-Ditoluoyl tartaric acid, 2,3- Dibenzoyl tartaric acid, 2,3-Dianisoyl tartaric acid, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, thereby obtaining a mixture comprising a precipitated preferably crystallized acid salt (T) and the solvent,

wherein the acid salt (T) contains at least 80 % by weight of the chiral acid salt of the compound of formula (la) based on the total weight of the acid salt of the compound of formula (A), and

wherein n is = 0, R¹ is PG¹ or R^A, with R^A bein

preferably R¹ is PG¹, and wherein step (a) comprises

(aa) providing a compound of formula (II*)

wherein R² is protecting group PG³, preferably a protecting group PG³ se lected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloro- acetate, phthalimide, preferably Boc,

converting compound (II)* to compound (III*)

O

_K , /\ ^ H-R²

N

R¹ (IIP);

removing R² to a give a compound of formula (IV*)

(IV*);

(ad) subjecting the compound (IV*) to cyclization conditions,

to give the compound of formula (A) with n=0.

The present invention is further illustrated by the following examples.

Examples

Preparation of tert.-Butyl (2-(3-oxobutanamido)ethyl)carbamate via condensation of Boc-ethylenediamine and 2,2,6-trimethyl-4H-l,3-dioxin-4-one:

C7H 16N2O2 C7H 10O3 C11 H20N2O4

MW: 160,21 MW: 142,15 MW: 244,29

A mixture of Boc-ethylenediamine (112.7 g, calcd as 95%, 668 mmol) and 2,2,6-trimethyl- 4H-l,3-dioxin-4-one (100.0 g, calcd. as 95%, 668 mmol) in xylene (150 mL) was refluxed for 100 minutes. It is important that the oil bath is preheated to 150 °C prior to the addition of the reaction vessel. The volatiles were removed by distillation under reduced pressure (9 mbar, 80 °C) and the crude product (brown oil) was taken up in Et₂0 (600 mL) for crystallization. The solution was stirred at room temperature over night and at 0 °C for 2 hours. The solid was filtered, washed with Et₂0 (200 mL) and dried (50 mbar, room temperature) to give 77.7 g tert.-Butyl (2-(3-oxobutanamido)ethyl)carbamate. Additional material (8.4 g) was obtained from the mother liquor after a second crystallization, tert. -Butyl (2-(3- oxobutanamido)ethyl)carbamate (86.1 g, 51% yield), white crystalline solid.

1H NMR (CDCls, 300 MHz): δ = 7.24 (br. s, 1H), 4.95 (br. s, 1H), 3.40 (s, 2H), 3.38 (m, 2H), 3.26 (m, 2H), 2.26 (s, 3H), 1.43 (s, 9H). ¹³C NMR (CDC1₃, 75 MHz): δ = 204.1, 166.4, 156.5, 79.6, 49.9, 40.2, 30.9, 28.3.

Preparation of terf.-Butyl (2-(3-hydroxybutanamido)ethyl)carbamate via reduction of terf.-Butyl (2-(3-oxobutanamido)ethyl)carbamate.

NHBoc

C₁₁ H₂oN₂0₄ C-_|i H22N2O4

MW: 244,29 MW: 246,30

NaBH₄ (11.99 g, 317 mmol) was added in small portions to a solution of tert. -Butyl (2-(3- oxobutanamido)ethyl)carbamate (40.13 g, 164 mmol) in MeOH (667 mL) at 0 °C over a period of 2 hours. The reaction was quenched with NH₄C1 (10%) and diluted with CH₂CI₂ (2000 mL). The organic phase was separated and the solvent was removed under reduced pressure to give the crude product as an oil (47.33 g). The residue was dissolved in Et₂0 (267 mL) and the cloudy solution was refluxed for 2 hours and then cooled. The solid was filtered, washed with Et₂0 (53 mL) and dried under reduced pressure to give 40.2 g tert.- Butyl (2-(3-hydroxybutanamido)ethyl)carbamate (99% yield) as a solid.

1H NMR (CDCI3, 300 MHz): δ = 6.58 (br. s, 1H), 4.99 (br. s, 1H), 4.17 (br. s, 1H), 3.36 (m, 2H), 3.27 (m, 2H), 2.96 (very br. s, 1H), 2.34 (dd, J = 15.0, 2.6 Hz, 1H), 2.25 (dd, J = 15.1, 8.6 Hz, 1H), 1.43 (s, 9H), 1.21 (d, J= 6.2 Hz, 3H).

Preparation of Benzyl (2-((terf.-butoxycarbonyl)amino)ethyl)(3- hydroxybutanoyl)carbamate via Reduction and Cbz-Protection of terf.-Butyl (2-(3- hydroxybutanamido)ethyl)carbamate.

"l⁰" ², =

TFA (216.1 g, 1895 mmol) was added to a suspension of tert. -Butyl (2-(3- hydroxybutanamido)ethyl)carbamate (50.0 g, 203 mmol) and NaBH₄ (80.3 g, 2122 mmol) in 2-MeTHF (1300 mL) at room temperature over a period of 5 hours. The reaction was then cautiously quenched with H₂0 (500 mL). The two layers were separated, the organic phase was washed with H₂0 (150 mL) and dried over Na₂S0₄. The drying agent was filtered off and the solution was concentrated but not dried. The volume of the solution was approximately half of the original volume. 2-MeTHF was added in order to obtain a total weight of the solution of 573 g. NEt₃ (20 g, 198 mmol) was added followed by the slow addition of Cbz-Cl (29 mL, 203 mmol) over a period of 30 minutes at 0 °C. The reaction was quenched with citric acid (10%, 420 mL). The organic layer was separated and washed with NaHC0₃ (7.5%, 420 mL). The organic phase was concentrated under reduced pressure and dried in vacuo (< 10 mbar, 40 °C) to give crude Benzyl (2-((tert.- butoxycarbonyl)amino)ethyl)(3-hydroxybutanoyl)carbamate (69.1 g) as an oil.

The crude product was purified by column chromatography on silica gel with a heptane/ethyl acetate gradient as a solvent to give 49.0 g Benzyl (2- tert.- butoxycarbonyl)amino)ethyl)(3-hydroxybutanoyl)carbamate (63% yield over two steps) as an oil.

Preparation of Benzyl (2-((terf.-butoxycarbonyl)amino)ethyl)(3- oxobutanoyl)carbamate via TEMPO-Oxidation of Benzyl (2-((tert- butoxycarbonyl)amino)ethyl)(3-hydroxybutanoyl)carbamate .

C C MW: 366,45 MW: 364,44 A stirred solution of Benzyl (2-((tert.-butoxycarbonyl)amino)ethyl)(3- hydroxybutanoyl)carbamate (49.0 g, 128.8 mmol) in CH₂CI₂ (1000 mL) was cooled to 0 °C. KBr (15%, 76 mL) was added followed by NaHC0₃ (7.5%, 300 mL) and TEMPO (2.915 g, 18.6 mmol). A solution prepared from NaOCl (6-14%, 125 mL) and H₂0 (500mL) was added over a period of 90 minutes and the reaction mixture was stirred for 1 hour. The reaction was quenched with Na₂S0₃ (10%, 100 mL) and the organic phase was separated. The aqueous phase was extracted with CH₂C1₂ (320 mL) and the combined organic layers were washed with H₂0 (107 mL). The solution was concentrated under reduced pressure and dried in vacuo (<10 mbar, 40 °C) to give 49 g (2-((tert.- butoxycarbonyl)amino)ethyl)(3-oxobutanoyl)carbamate (100% yield) as an oil.

1H NMR (CDCI3, 300 MHz, hindered rotation is observed): δ = 7.26 (br. s, 1H), 5.03 (s, 2H), 5.00 (br. s, 0.5 H), 4.73 (br. s, 0.5H), 3.43 (t, J = 6.9 Hz, 2H), 3.31 (m, 2H), 3.18 (br. s, 2H), 2.70 (br. t, J = 6.2 Hz, 1H), 2.60 (br. t, J = 6.7 Hz, 1H), 2.06 (s, 1.5H), 2.00 (s, 1.5H), 1.34 (s, 9H). ¹³C NMR (CDC1₃, 75 MHz, hindered rotation is observed): δ = 207.0, 206.5, 156.1 , 155.6, 136.0, 128.1 , 127.7, 127.5, 78.8, 66.9, 47.3, 43.1 , 42.4, 41.8, 39.0, 29.8, 27.9.

Preparation of racemic Benzyl 5-methyl-l,4-diazepane-l-carboxylate via BOC- Cleavage and Reductive Amination of (2-((terf.-butoxycarbonyl)amino)ethyl)(3- oxobutanoyl)carbamate.

C19H28N2O5 C₁₄H₂ CIN203 C14H20N2O2 MW: 36 , MW: 300,78 MW: 2 8,32

(2-((tert.-butoxycarbonyl)amino)ethyl)(3-oxobutanoyl)carbamate (49.0 g, 134 mmol) was dissolved in methanolic HCl (1.25 M, 250 mL) and the solution was stirred for 2 hours at room temperature. HPLC indicated complete conversion of the starting material. The sol- vent was removed under reduced pressure to give crude benzyl (2-aminoethyl)(3- oxobutyl)carbamate hydrochloride (39.9 g, 99% yield) which was used in the next step without purification.

NaOAc (9.12 g, 111 mmol) was added to a solution of benzyl (2-aminoethyl)(3- oxobutyl)carbamate hydrochloride (39.9 g, 133 mmol) in CH₂CI₂ (1080 mL) and the solu- tion was cooled to 10 °C. AcOH (90 ML) was added followed by the addition of NaBH(OAc)3 (22.6 g, 107 mmol) in small portions over a period of 30 minutes. The reaction mixture was stirred for 30 minutes and then quenched with HCl (2.0 M, 181 mL). The pH value was adjusted to pH = 12.0 with NaOH (5.0 M) and the organic layer was separated. The aqueous phase was extracted twice with CH₂CI₂ (2 x 300 mL) and the combined organic layers were concentrated under reduced pressure to give crude Benzyl 5-methyl- 1,4-diazepane-l-carboxylate (32.5 g).

A solution of crude Benzyl 5 -methyl- 1,4-diazepane-l-carboxylate (32.5 g) im CH₂CI₂ (500 mL) was extracted four times with HCl (1.0 M, 4 x 500 mL). The aqueous layers were combined and the pH value was adjusted to pH = 12.0 with NaOH (5.0 M). The aqueous phase was extracted three times with CH₂CI₂ 3 x 500 mL) and the organic layers were combined. The solution was concentrated under reduced pressure to give 26.7 g Benzyl 5- methyl- 1,4-diazepane-l-carboxylate (80% yield over two steps) as an oil with a purity of 96 area% according to HPLC.

1H NMR (CDCI₃, 300 MHz, hindered rotation is observed): δ = 7.27 - 7.35 (m, 5H), 5.12 (m, 2H), 3.69 (m, 1H), 3.57 (m, 1H), 3.30 - 3.47 (m, 2H), 3.09 (m ~ tt, J = 12.4, 4.2 Hz, 1H), 2.66 - 2.86 (m, 2H), 1.78 - 1.93 (m, 1H), 1.72 (br. s, 1H), 1.36 - 1.51 (m, 1H), 1.11 (d, J = 6.3 Hz, 1.5H), 1.10 (d, J = 6.4 Hz, 1.5H). ¹³C NMR (CDC1₃, 75 MHz, hindered rotation is observed): δ = 155.8, 136.8, 136.7, 128.2, 127.7, 127.6, 127.5, 66.7, 54.6, 49.5, 49.2, 48.0, 47.9, 44.5, 44.5, 37.8, 37.7, 23.2, 23.1.

Formation of (R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA

DBTA

C14H20N2O2 C32H34N2O

MW: 248,32 MW: 606,62 small scale

A solution of DBTA (1.48 g, 4.13 mmol) in acetone (6.5 mL) was added to a solution of benzyl 5 -methyl- 1,4-diazepane-l-carboxylate (1.02 g, 4.11 mmol) and stirred at room tem- perature. A seeding crystal was added and the crystallization was stirred for 4 hours at room temperature and for 1 hour at 0 °C. The solid was filtered, washed with acetone (2.5 mL) and dried in vacuo to give 0.44 g benzyl 5 -methyl- 1,4-diazepane-l-carboxylate (18% yield) with an enantiomeric ration of e.r. = 96.7 : 3.3.

large scale

A solution of DBTA (5.24 g, 14.62 mmol) in acetone (25 mL) was added to a stirred solution of benzyl 5 -methyl- 1,4-diazepane-l-carboxylate (7.26 g, 29.24 mmol) in acetone (30 mL) at 40 °C. The onset of the crystallization occurred after 10 minutes. The crystallization was stirred at 40 °C for 4 hours and at room temperature over night. The solid was filtered, washed twice with acetone (2 x 8 mL) and dried under reduced pressure (<50 mbar, 45 °C) to give 5.50 g (R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA (31% yield) with an enantiomeric ratio of e.r. = 88.3 : 11.7.

Recrystallization of (R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA

Cbz~_N \ Cbz~_N

— "

C32H34N₂O₁₀ C32H34N₂O₁₀

(R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA (450 mg, 0.74 mmol) with an enantiomeric ration of e.r. = 88.3 : 1 1.7 was re-crystallized from EtOH (5 mL) by forming a solution at 60 °C and crystallizing at room temperature. The solid was filtered, washed twice with EtOH (2 x 2 mL) and dried to give (R)-benzyl 5 -methyl- 1,4-diazepane-l - carboxylate.DBTA (290 mg, 64% yield) with an enantiomeric ration of e.r. = 97.7 : 2.3.

Isolation of (R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate from (R)-benzyl 5- methyl- 1 ,4-diazepane- 1-carboxylate.DBT A.

C

MW: 606,62 MW: 248,32 A solution of (R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA (2.04 g, 3.36 mmol) in CH₂C1₂ (40 mL) was extracted with H₂0 at pH = 12.0 (adjusted with NaOH, 1.0 M). The organic layer was washed twice with H₂0 (2 x 20 mL), concentrated under reduced pressure and dried in vacuo to give benzyl 5 -methyl- 1,4-diazepane-l-carboxylate (1.02 g, quant, yield).

1H NMR (CDCI3, 300 MHz, hindered rotation is observed): δ = 7.28 - 7.36 (m, 5H), 5.13 (m, 2H), 3.54 - 3.78 (m, 2H), 3.32 - 3.49 (m, 2H), 3.1 1 (m ~ tt, J= 13.1, 3.5 Hz, 1H), 2.70 - 2.87 (m, 2H), 2.08 (br. s, 1H), 1.89 (m, 1H), 1.47 (m, 1H), 1.13 (d, J= 5.9 Hz, 1.5H.

The chirality in (R)-benzyl 5 -methyl- 1,4-diazepane-l-carboxylate was determined to be R according to the CIP system. The Chirality was determined by protecting the second amine group with Boc₂0, by measuring the specific rotation of the product and comparing it to literature values.

Preparation of (Z)-Methyl 3-((2-((terf.-Butoxycarbonyl)amino)ethyl)amino)but-2- enoate

C₇Hi₆N₂0₂ C₅H₈0₃ r.t. C ₂H₂₂N₂0₄

MW: 160,21 MW: 1 16,12 MW: 258,31

Boc-ethylenediamine (84.3 g, 500 mmol) was dissolved in CH₂C1₂ (110 mL), transferred into a 500 mL Schmizo and cooled to 10 °C. Silica gel (120 g) was added in portions and the slurry was diluted with CH₂C1₂ (50 mL). Methyl acetoacetate (54 mL, 500 mmol) was added, the reaction mixture was stirred at 20 °C and the reaction progress was monitored by GC. The reaction was judged complete after one hour. The silica gel was filtered off and the filter cake was washed with CH₂C1₂ (250 mL). The slightly yellow solution was concentrated under reduced pressure to give the enamine as slightly yellow oil (127.9 g).

1H NMR (300 MHz, CDC1₃): δ = 8.57 (br s, 1H), 4.84 (br s, 1H), 4.47 (s, 1H), 3.61 (s, 3H), 3.33 (m, 2H), 3.23 (m, 2H), 1.91 (s, 3H), 1.43 (s, 9H). ¹³C NMR (75 MHz, CDC1₃): δ = 170.9, 162.0, 155.9, 82.7, 79.6, 50.0, 42.8, 41.3, 28.3, 19.3. All data are in agreement with the data reported in literature (see J. Org. Chem. 2010, 75, 6023).

Preparation of Methyl 3-((2-((terf.-butoxycarbonyl)amino)ethyl)amino)butanoate via Hydrogenation

^12^22^2^4 ^12^24^2^4

MW: 258,31 MW: 260,33

A solution of the enamine (58.7 g, 227 mmol) in MeOH (650 mL) was hydrogenated in the presence of 73 g Pd/C at 55 °C at a pressure of 3 bar. The reaction was monitored by GC. After complete conversion (approximately 7 hours) the suspension was filtered over a K150 filter and the solid was washed with MeOH. The solution was concentrated under reduced pressure, taken up in MeOH (300 mL) and distilled under reduced pressure to give the β-aminoester (51.6 g, 87%) as oil.

1H NMR (300 MHz, CDC1₃): δ = 5.28 (br s, 1H, NH), 3.99 (br s, 1H, NH) 3.66 (s, 3H, OCH₃), 3.13 - 3.25 (overlapping m, 3H, CH₂ + CH), 2.78 (m, 2H, CH₂), 2.48 (m, 2H, CH₂), 1.41 (s, 9H, C(CH₃)₃), 1.15 (d, J= 6.3 Hz, 3H, CH₃). ¹³C NMR (75 MHz, CDC1₃): δ = 172.2, 156.1, 79.2, 51.6, 50.1, 45.9, 40.6, 39.8, 28.3, 19.7.

Preparation of Methyl 3-((2-((terf.-butoxycarbonyl)amino)ethyl)amino)butanoate with an Enantiomeric Excess of ee = 93% via Asymmetric Hydrogenation

ee = 93% 46.2mg (0.085 mmol) ferrocenyl ligand and 29.0 mg (0.077 mmol) [Rh(nbd)2]BF4 were placed in a lOmL Schlenk flask that was previously set under an atmosphere of argon. Then 6mL degassed 2,2,2-trifluoroethanol (TFE) was added and the resulting red solution stirred for 30 min. at 50°C. In a second Schlenk flask, 0.5g (1.94mmol) of enamine ((Z)- methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)but-2-enoate) was placed, followed by 14mL degassed TFE. The clear solution was stirred for 10 min. Then, both the substrate and the catalyst solution were transferred via syringe into a 50mL stainless steel reactor that was previously set under an atmosphere of argon. The reactor was sealed, purged with argon in three cycles (lbar/20bar) and finally, the argon replaced by hydrogen (4 cycles lbar/20bar). The reactor pressure was set to lObar hydrogen, heating to 50°C and stirring started. After 21hrs. reaction time, the autoclave was cooled to ambient temperature and the pressure released.

The crude product was analyzed by GC with respect to conversion and chemoselectivity and upon derivatization with 4-chlorobenzoylchloride by chiral HPLC method. The conversion after 21 hrs. was >99.5%, and product 2 (methyl 3-((2-((tert- butoxycarbonyl)amino)ethyl)amino)butanoate) was formed with approx. 60% chemoselec- tivity and 93% ee (first-eluting enantiomer).

Preparation of Methyl 3-((2-((terf.-butoxycarbonyl)amino)ethyl)amino)butanoate via Reduction

^12^22^2^4 ^12^24^2^4

MW: 258,31 MW: 260,33

NaBH₄ (33.0 g, 872 mmol) was added in small portions over a period of 90 minutes into vigorously stirred acetic acid (500 mL) and the internal temperature was kept between 15 - 20 °C. Vigorous gas formation was observed as well as the formation of a thick suspension halfway through the addition. MeCN (250 mL) was added, the suspension was stirred for 30 minutes and the internal temperature was adjusted to 0 - 5 °C. A solution of the enamine (113.0 g, 437 mmol) in MeCN (150 mL) was added over a period of 45 minutes at 0 - 5 °C followed by a MeCN-rinse (100 mL). The reaction mixture was stirred for 2.5 hours at 5 °C before being cautiously quenched with H₂0 (100 mL, gas formation). (At that stage the pH was adjusted to pH = 7.0 with NaOH (50%) and CH₂C1₂ (100 mL) was added which resulted in the formation of two phases. The two phases were stirred over night: holding point). The pH-value was adjusted to pH = 11.5 with NaOH (50%>). In order to avoid the formation of solids in the aqueous layer H₂0 (-800 mL) was added. The organic phase was separated and washed with H₂0. The combined aqueous phases were extracted twice with ethyl acetate (250 mL each). The combined organic phases were dried over Na₂S0₄, filtered and concentrated to give the aminoester (112. Og) as colorless oil.

The analytical data were in full agreement with the data obtained by hydrogenation.

Preparation of Methyl 3-((2-((terf.-butoxycarbonyl)amino)ethyl)amino)butanoate with an Enantiomeric Excess of ee = 33% via Chiral Resolution

Racemic aminoester was resolved with tartaric acid to give enantiomerically enriched ami- noester.

Preparation of 7-Methyl-l,4-diazepan-5-one:

4. H₂, Pd/CMeOH

^12^24^2^4 C₆H₁₂N₂0

MW: 260,33 MW: 128,17

Procedure "Cbz-protection": H₂0 (500 mL) was added to a solution of the beta-aminoester (78.0 g, 300 mmol) in EtOAc (1000 mL) at room temperature. Benyzl chloroformate (Cbz-Cl, 51.4 mL, 360 mmol) was added slowly and the pH-value was kept between pH = 8 - 9 by the addition of NaOH (10 M). The reaction was slightly exotherm and GC indicated complete conversion of the starting material after 30 minutes. The two phases were separated and the organic phase was washed with a saturated NaHC0₃ solution (300 mL). The solution was concentrated under reduced pressure to give the Cbz-protected amine quantitatively (128.4 g) as oil. The crude product was used in the next step without any further purification.

1H NMR (300 MHz, CDC1₃): δ = 7.33 - 7.39 (m, 6H, H_arom + NH), 5.13 (s, 2H, OCH₂), 4.32 (br s, 1H, CH), 3.61 (s, 3H, OCH₃), 3.21 - 3.35 (br m, 4H, CH₂, CH₂), 2.42 - 2.80 (series of br m, 2H, CH₂), 1.43 (s, 9H, C(CH₃)₃), 1.26 (br s, 3H, CH₃).

Procedure "Boc-deprotection":

HCl (37w%, 45 mL, 540 mmol) was added to a stirred solution of the Boc-protected amine (128.4 g, calcd. as 270 mmol) in MeOH (1200 mL) and the reaction mixture was stirred at 50 °C for two hours and at 80 °C for one hour. The reaction progress was monitored by HPLC and the reaction was judged complete after 4 hours. The reaction mixture was concentrated to a volume of approximately 250 mL. A solid precipitated during the MeOH- destillation. Acetone (1000 mL) was added drop wise and the solvent was removed completely. CH₂C1₂ (300 mL) was added and then removed by distillation. The product (amine in form of HCl salt, 116.7 g) was obtained as foam and used in the next step without any further purification.

Procedure "Cyclization":

NaOMe (51.2 g, 972 mmol) was added to a stirred solution of the amine. HCl salt (116.2 g, calculated as 243 mmol) im MeOH (1000 mL) at room temperature. An exotherm reaction was observed. The reaction mixture was stirred over night at room temperature. The solids were filtered off over a K150 filter and washed with MeOH (100 mL). The solution of the crude product was used directly in the next step without further purification.

A small aliquot was used for characterization. 1H NMR (300 MHz, CDC1₃): δ = 7.36 (m, 5H, H_arom.), 5.15 (s, 2H, OCH₂), 4.74 (br m, 2H, NH, CH), 4.25 (br s, 1H, CH_A), 3.34 (m, 1H, CHx), 3.15 (m, 2H, CH_B, CH_Y), 2.81 (d, J= 14.5 Hz, 1H, CH_P), 2.50 (dd, J= 14.5, 5.9 Hz, 1H, CH_Q), 1.26 (d, J= 7.0 Hz, 3H, CH₃).

Procedure "Cbz-deprotection":

The abovementioned solution of the Cbz-protected amine (calcd. as 219 mmol) in MeOH (1100 mL) was concentrated to a volume of approximately 700 mL. This solution was hy- drogenated in the presence of Pd/C (46 g, 10%Pd) at room temperature at a H₂-pressure of 2 bar. The hydrogenation was monitored by HPLC and judged complete after two hours. The suspension was filtered over a K150 filter and the filter cake was washed with MeOH. The solution of the crude product was concentrated under reduced pressure and the residue (71.4 g) was taken up in CH₂CI₂ (200 mL). The solution was stirred for 30 minutes and the remaining solids were filtered off. The solution was concentrated and the residue (30 g) started crystallizing upon standing at room temperature. MTBE (200 mL) was added and the suspension was stirred for one hour. The solid was filtered off, washed with MTBE and dried over night at 40 °C/2 mbar to give 7-methyl-l,4-diazepan-5-one (17.4 g, 62%) as colorless crystals.

1H NMR (300 MHz, CDC1₃): δ = 7.31 (br s, 1H, C(O)NH), 3.28 (m, 1H, CH_A), 2.90 - 3.14 (series of overlapping m, 3H, CH, CH_B, CH_X), 2.77 (m, 1H, CH_Y), 2.51 (dd, J = 14.1, 9.6 Hz, 1H, CH_P), 2.35 (apparent d, J = 14.3 Hz, 1H, CH_Q), 2.03 (br s, 1H, NH), 1.09 (d, J = 6.5 Hz, 3H, CH₃). ¹³C NMR (75 MHz, CDC1₃): δ = 177.3, 49.4, 47.2, 44.4, 23.6.

Chiral Resolution of 7-Methyl-l,4-diazepan-5-one:

Chiral resolutions were achieved with several chiral acids with varying degree of induction by performing a systematic screening. Here, the best hit will be described as a representative example. LTTA corresponds to the enantiomer (+)-Di-0,0'-toluyl-L-tartaric acid. A solution of the chiral acid (62.8 mg, 0.16 mmol) in MeOH (0.5 mL) and a solution of ra- cemic 7-methyl-l,4-diazepan-5-one (41.4 mg, 0.32 mmol) in MeOH (0.8 mL) were combined and allowed to crystallize over night. The solid was filtered and the enantiomeric excess was determined by HPLC. The enantiomeric ratio was > 40 : 1 (R : S) wherein, the absolute stereochemistry is determined according to literature proceedings.

Reaction of Methyl 3-((2-((terf.-butoxycarbonyl)amino)ethyl)amino)butanoate and 5- Methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzoic Acid:

Oxalyl chloride (14.26 g, 118.1 mmol) was added over a period of 14 minutes to a stirred suspension of 5-Methyl-2-(2H-l,2,3-triazol-2-yl)benzoic Acid (20.0 g, 98.4 mmol) in CH₂CI₂ (132 mL) and DMF (2.0 mL) at 1 °C. After complete addition the reaction mixture was stirred for 30 minutes at 5 °C. An addition funnel was charged with a solution of 3-((2- ((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate (24.4 g, 93.7 mmol) in CH₂CI₂ (340 mL) and NEt₃ (19.0 g, 187.4 mmol). The amine solution was added over a period of 40 minutes to the stirred acid chloride solution at a rate to keep the internal temperature < 10 °C. The reaction progress was monitored by HPLC and the reaction was judged complete after two hours. The reaction was quenched with H₂0 (250 mL) and the pH- value was adjusted to pH = 10.0 by the addition of NaOH (2.0 M).

The organic layer was separated and washed with H₂0 (250 mL) at a pH = 2.0 adjusted with HC1 (2.0 M). The organic phase was concentrated under reduced pressure. The residue was taken up in toluene (100 mL) and concentrated under reduced pressure to give 49.6 g residue. The residue was taken up in cyclohexane (~ 250 mL) and stirred for two hours at room temperature. The solid was filtered, washed twice with cyclohexane (2 x 20 mL) and dried (40 °C, < 5 mbar) to give the product (35.4 g, 84% yield) as a crystalline solid.

1H NMR (300 MHz, DMSO-D₆): δ = 6.77 - 8.07 (series of overlapping m, 6H), 3.88 - 4.37 (series of overlapping m, 1H), 3.42 - 3.66 (three s, 3H), 2.56 - 3.35 (series of overlapping m, 6H), 2.39 (three s, 3H), 0.82 - 1.40 (series of overlapping m, 12H).

Preparation of Methyl 3-(N-(2-aminoethyl)-5-methyl-2-(2H-l,2,3-triazol-2- yl)benzamido)butanoate Hydrochloride by Boc-Cleavage:

C₂₂H₃₁ N₅0₅ C₁₇H₂₄CIN₅0₃

MW: 445,51 MW: 381 ,86

HCI (1.25 M in MeOH, 136.3 mmol) was added to a solution of the Boc-protected amine (30.4 g, 68.2 mmol) in MeOH (304 mL) and the reaction mixture was refluxed. The reac- tion progress was monitored by HPLC and judged complete after 5.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in toluene (100 mL) and concentrated under reduced pressure to give 30.5 g foam. Crystallization from toluene and cyclohexane gave Methyl 3-(N-(2- aminoethyl)-5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzamido)butanoate Hydrochloride (25.1 g, 97%) as a crystalline solid.

1H NMR (300 MHz, D₂0): δ = 7.14 - 7.93 (series of overlapping m, 5H), 2.88 - 4.41 (series of overlapping m, 8H), 2.05 - 2.77 (series of overlapping m, 5H), 1.10 - 1.33 (series of d, 3H).

Preparation of 7-Methyl- l-(5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzoyl)- 1 ,4-diazepan- 5-one via Cyclization of Methyl 3-(N-(2-aminoethyl)-5-methyl-2-(2H-l,2,3-triazol-2- yl)benzamido)butanoate Hydrochloride:

C₁₇H₂₄CIN₅03 C16H19N5O2

MW: 381 ,86 MW: 313,35

NaOMe (6.0 g, 115.3 mmol) was added to a solution of Methyl 3-(N-(2-aminoethyl)-5- methyl-2-(2H-l,2,3-triazol-2-yl)benzamido)butanoate Hydrochloride (29.34 g, 76.8 mmol) in MeOH (380 mL) at room temperature and the reaction progress was monitored by HPLC. The reaction was judged complete after 1.5 hours. The suspension was diluted with CH₂CI₂ (380 mL) and H₂0 (380 mL) and the organic layer was separated. The aqueous layer was extracted twice with CH₂C1₂ (2 x 200 mL) and the combined organic phases were concentrated under reduced pressure to give a residue that was taken up in cyclohex- ane (100 mL), filtered and dried to give 7-Methyl- l-(5-methyl-2-(2H-l, 2, 3-triazo 1-2- yl)benzoyl)-l,4-diazepan-5-one (17.6 g, 85% yield) as a crystalline solid. A second crystallization from the mother liquor gave additional 7-Methyl- l-(5-methyl-2-(2H- 1,2, 3-triazo 1- 2-yl)benzoyl)-l,4-diazepan-5-one (1.7 g).

1H NMR (300 MHz, CDC1₃, suspension): δ = 7.76 - 7.90 (m, 3H), 6.94 - 7.36 (series of m, 3H), 5.35 (m, -0.5H), 4.89 (m, -0.5H), 3.95 - 4.09 (series of m, -0.5H), 3.21 - 3.64 (se- ries of overlapping m, 2H), 2.72 - 3.15 (series of overlapping m, -2.5H), 2.16 - 2.64 (series of m + s, 4H), 0.92 - 1.36 (series of d, 3H).

Preparation of 7-Methyl- l-(5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzoyl)- 1 ,4-diazepan- 5-one via Reaction of 7-Methyl- l,4-diazepan-5-one and 5-Methyl-2-(2H-l,2,3-triazol- 2-yl)benzoic Acid:

MW: 128,17 C₁₀H₉N₃O₂ CigHigN50₂

MW: 203,20 MW: 313,35

A solution of oxalyl chloride (1.08 mL, 12.6 mmol) in CH₂C1₂ (2 mL) was added over a period of 15 minutes to a suspension of 5-Methyl-2-(2H-l,2,3-triazol-2-yl)benzoic Acid (2.13 g, 10.5 mmol) in CH₂C1₂ (14 mL) and DMF (0.22 mL) at 0 - 2 °C. The resulting clear solution was stirred for 30 minutes at 5 °C. An addition funnel was charged with a solution of 7-Methyl- l,4-diazepan-5-one (1.34 g, 10.0 mmol) in CH₂C1₂ (11 mL) and NEt₃ (2.9 mL, 21 mmol) and the solution was added over a period of 20 minutes. The reaction mixture was stirred for one hour at 5 °C and the reaction progress was monitored by HPLC. The reaction was quenched by the slow addition of H₂0 (27 mL) and the two phas- es were stirred for 15 minutes. The phases were separated and the organic layer was dried over MgS0₄, filtered and concentrated under reduced pressure to give 3.3 g of a foam. The crude product was taken up in MeOH (7.5 mL) and the product was allowed to crystallize over night. The solid was filtered off, washed with MeOH and dried over night (40 °C, 2 mbar) to give 2.5 g (80% yield) 7-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl)- l,4-diazepan-5-one as a crystalline solid.

1H NMR (300 MHz, CDC1₃): δ= 7.77 - 7.91 (m, 3H), 6.85 - 7.37 (series of m, 3H), 5.36 (m, -0.5H), 4.90 (m, -0.5H), 3.93 - 4.13 (series of m, -0.5H), 3.21 - 3.64 (series of overlapping m, 2H, 2.16 - 3.16 (series of overlapping m, -6.5H), 0.92 - 1.37 (series of d, 3H). The analytical data are in full agreement with the data obtained via the other variant 1.

Preparation of (7-Methyl- 1 ,4-diazepan- l-yl)(5-methyl-2-(2H- 1 ,2,3-triazol-2- yl)phenyl)methanone via Reduction of 7-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)- 1 ,4-diazepan-5-one:

C16H 19N5O2 C₁₆H₂₁ N₅0

MW: 313,35 MW: 299,37 7-Methyl- l-(5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl)-l,4-diazepan-5-one (5.0 g, 15.9 mmol) was added to a suspension of NaBH₄ (6.03 g, 159.9 mmol) in 2-MeTHF (100 mL) and the suspension was warmed to 45 °C. TFA (24.6 mL, 318 mmol) was added via syringe pump over a period of 16 hours at 55°C. (In this case the reaction did not go to completion. Additional NaBH₄ and TFA had to be added). The reaction progress was moni- tored by HPLC and after complete conversion the reaction mixture was cooled to room temperature. The reaction was quenched by the addition of brine (500 mL). The organic phase was separated, washed with H₂0 (200 mL) and dried over MgS0₄. The drying agent was filtered and the solution was concentrated to give (7-Methyl- 1,4-diazepan-l -yl)(5 - methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone (5.59 g) as a white solid.

The crude product was taken up in a mixture (25 mL) of heptane/ethyl acetate/NEt₃ (1/1.5/0.1) and the solid was filtered to give (7-Methyl- 1,4-diazepan-l -yl)(5 -methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone (3.30 g, 69%) as a crystalline solid.

Preparation of Suvorexant from (7-Methyl-l,4-diazepan-l-yl)(5-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone and 2,5-Dichlorobenzoxazol

C₇H₃CI₂NO C₁₆H₂₁N₅0 C₂₃H₂₃CIN₆0₂

MW: 188,01 MW: 299,37 MW: 450,92

Oxalyl chloride (1.20 g, 9.4 mmol) was added dropwise to a stirred suspension of 2- mercapto-5-chlorobenzoxazol (1.28 g, 6.9 mmol) in CH₂C1₂ (37 mL) at < 20°C. DMF (4.59 g, 62.8 mmol) was added dropwise. A vigorous gas formation was observed and the suspension turned into a solution halfway throughout the addition. The reaction mixture was stirred for 20 minutes. Two additional aliquots oxalyl chloride (#1 : 0.20g, 1.35 mmol; #2: 0.40 g, 2.70 mmol) were added and the reaction mixture was stirred for 1.5 hours. HPLC indicated complete conversion of 2-mercapto-5-chlorobenzoxazol into 2,5- Dichlorobenzoxazol .

The solution of 2,5-Dichlorobenzoxazol was added to a solution of (7-Methyl-l ,4- diazepan-l-yl)(5-methyl-2-(2H-l ,2,3-triazol-2-yl)phenyl)methanone (1.88 g, 6.3 mmol) and NEt₃ (3.18 g, 6.3 mmol) in DMF (24 mL) at room temperature. The reaction mixture was then stirred at 70 °C for 19 hours and at 90 °C for 20 hours. The reaction mixture was then cooled to room temperature and quenched with a saturated solution of NaHC0₃ (50 mL). The organic phase was separated and washed with H₂0 (50 mL) followed by brine (50 mL). The organic phase was dried over MgS0₄, filtered and concentrated to give crude Suvorexant (3.58 g).

Synthesis of Suvorexant from compound of formula (A) wherein n=l, R¹ = H) (steps

(i) to (iv))

(i) 505.0 g (±)-7-methyl-l ,4-diazepan-5-one was dissolved in 4000 mL methanol at room temperature. 1088 g Ο,Ο'-di-toluyl-L-tartaric acid was added to the solution in one portion. Crystallization started spontaneously. A slight exotherm reaction was observed (T_max = 33 °C). The suspension was stirred for 4 hours at room temperature and for 20 hours at 0 °C. The suspension was filtered and washed three times with methanol (500 mL each). The solid was dried under reduced pressure at 40 °C at 30 mbar give 744.0 g (as is) salt.

(ii) A suspension of 40.6 g 5-methyl-2-(2H-l ,2,3-triazol-2-yl)benzoic acid in 280 mL CH₂C1₂ and 4.4 mL dimethylformamide was stirred at 0 °C. A solution of 18.8 mL oxalyl chloride in 40 mL CFi₂Cl₂ was added over a period of 15 minutes. The internal temperature rose to +5 °C and vigorous gas formation was observed. The resulting solution was stirred for 45 minutes at 5 °C. A suspension of 102.8 g tartaric acid salt of (R)-7-methyl-l ,4- diazepan-5-one of (i) in 600 mL CH₂CI₂ was stirred at 0 °C. 110.0 mL triethylamine was added and the internal temperature rose to T_max = +12 °C. The acid chloride solution was added to the solution of the ( ?)-7-methyl-l,4-diazepan-5-one over a period of 45 minutes (T_max = +5 °C) and the reaction progress was monitored by HPLC. The reaction was quenched with 540 mL H₂0. The phases were separated and the organic layer was washed with 300 mL H₂O. The organic layer was dried over MgS0₄, filtered and concentrated under reduced pressure to give 77.0 g residue which was dissolved at room temperature in 700 mL ethyl acetate and 350 mL diisopropyl ether. Crystallization started spontaneously. The suspension was stirred for 3 hours at room temperature and then filtered (G3). The solid was washed with diisopropyl ether and dried at 40 °C at 2 mbar overnight to give 50.0 g ( ?)-7-methyl- 1 -(5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzoyl)- 1 ,4-diazepan-5-one (80%).

(iii) A suspension of 36.7 g NaBH₄ in 1300 mL 2-methyltetrahydrofuran was stirred at 0 °C. 112.7 mL trifluoroacetic acid was added over a period of 2 hours (T_max = 7°C) and the resulting solution was stirred at room temperature for 1 hour. 60.8 g (i?)-7-methyl-l-(5- methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl)-l,4-diazepan-5-one of (ii) was added (gas formation) and the reaction mixture was stirred at 50 °C (T_max = 77 °C). The reaction progress was monitored by HPLC and the reaction mixture was stirred overnight. The reaction was judged complete when conversion > 80 %. The reaction was quenched with 650 mL H₂0. The reaction mixture was stirred for one hour at room temperature. Solids were filtered off (G3) and washed with 2-methyltetrahydrofuran. The aqueous phase was extracted with 650 mL CH₂CI₂ and the combined organic layers were dried over MgS0₄. The solution was filtered. 153.2 mL methanolic HC1 (1.25 M HC1 in methanol) was added and the solution was concentrated under reduced pressure. The residue was dissolved in 160 mL acetone and the solution was stirred at room temperature. Crystallization started spontaneously. The suspension was stirred for overnight at 4 °C. The solid was filtered, washed with acetone and dried at 40 °C at 2 mbar to give 36.7 g (i?)-(7-methyl-l,4-diazepan-l-yl)(5- methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone hydrochloride (56 %).

(iv) 47.0 g 5-chlorobenzo[d]oxazole-2-thiol were dissolved in 1300 mL CH₂CI₂ and 175 mL dimethylformamide at room temperature and stirring was continued until a clear solution was obtained. 26.3 mL Oxalyl chloride in 25 mL CH₂CI₂ was added over a period of 20 minutes (gas formation). The resulting 2,5-dichlorobenzo[<i]oxazole-solution was stirred for one hour at room temperature. To a suspension of 85.1 g (i?)-(7-methyl-l,4- diazepan-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone hydrochloride of (iii) in 915 mL dimethlyformamide was added 210.8 mL triethylamine at room temperature and the suspension was stirred for 10 minutes. ~ 1500 mL 2,5-dichlorobenzo[<i]oxazole- solution was transferred into an addition funnel and added over a period of 25 minutes to the ~ 1000 mL (i?)-(7-methyl-l,4-diazepan-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone-suspension at room temperature. The temperature of the reaction mixture increased (exotherm, T_max = 37 °C). The reaction mixture was stirred for 30 minutes at ambient temperature and the reaction progress was monitored by HPLC. The reaction mixture was added into a stirred reaction vessel containing 1140 mL H₂0. Stirring was continued for 5 minutes. The two phases were separated and the organic layer was washed with 568 mLH₂0. The organic phase was concentrated under reduced pressure to give 165.7 g residue (suvorexant crude). The crude product was dissolved in 275 mL ethyl acetate and 551 mL n-hexane. The solution was stirred and crystallization started spontaneously. The crystallization was stirred overnight at room temperature. The solid was fil- tered (G3) and washed with hexane. The product was dried overnight at 40 °C at 2 mbar to give 81.1 g suvorexant (yield: 76%, as is) with an assay of 99.6 area% (HPLC).

Claims

1. A rocess for the preparation of an acid salt (T) of a compound of formula (A)

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

wherein the acid salt (T) is the salt of a single stereoisomer of a chiral acid, preferably wherein the chiral acid salt is a tartaric acid derivative salt, preferably wherein the tartaric acid derivative salt is selected from the group consisting of 2,3-ditoluoyl tartaric acid salt, 2,3-dibenzoyl tartaric acid salt, 2,3-dianisoyl tartaric acid salt, 2,3- dibenzoyl tartaric acid mono(dimethylamide) salt and a mixture of two or more thereof, the process comprising

a) providing a compound of formula (A)

wherein the compound of formula (A) contains of from 20 to 75 % by weight of the compound of formula (la), based on the total weight of the sum of the compounds of formulas (la) and (lb), in a suitable solvent,

(b) adding a single stereoisomer of a chiral acid, preferably wherein the chiral acid is a tartaric acid derivative, wherein preferably the tartaric acid derivative is selected from the group consisting of 2,3-ditoluoyl tartaric acid, 2,3-dibenzoyl tartaric acid, 2,3-dianisoyl tartaric acid, 2,3-dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, thereby obtaining a mixture comprising a precipitated preferably crystallized acid salt (T) and the solvent, (c) preferably separating the precipitated, preferably crystallized, acid salt (T) from the mixture obtained in (b),

wherein the acid salt (T) contains at least 80 % by weight of the chiral acid salt of the compound of formula (la), based on the total weight of the acid salt of the compound of formula (A).

2. The process of claim 1, wherein when n=0 and

3. The process of claim 1, wherein when n=0 and R is not

4. The process of claim 1, wherein n=0 and R¹ is H or PG¹.

5. The process of claim 1 , wherein n= 1.

6. The process of any of claims 1 to 5, wherein step (b) comprises forming an acid salt (T*) of at least part of the compound of formula (A) by treating the compound of formula (A) with the chiral acid, and precipitating, preferably crystallizing, at least part of the acid salt (T*) formed, thereby obtaining a mixture comprising the precipitated, preferably crystallized, acid salt (T) and the solvent.

7. The process of any of claims 1 to 6, wherein the acid salt (T) of the compound formula (A) contains at least 85 % by weight, more preferably at least 90 % by weight, more preferably at least 95 % 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 chiral acid salt of the compound of formula (la), based on the total weight of the acid salt (T) of the compound of formula (A).

8. The process of any of claims 1 to 7, wherein n is 1 and the tartaric acid derivative is a di-toluoyl tartaric acid, more preferably L-di-toluoyl tartaric acid (LTTA).

9. The process of any of claims 1 to 8, wherein, n is 0 and the tartaric acid derivative is a di-benzoyl tartaric acid, more preferably D-di-benzoyl tartaric acid (DBTA).

10. The process of any of claims 1 to 9, wherein n is 1 and the suitable solvent is methanol.

11. The process of any of claims 1 to 9, wherein n is 0 and the suitable solvent is acetone.

12. The process of any of claims 1 to 11, wherein step (a) comprises (a') providing a compound of formula (II)

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^2a is a suitable protecting group,

(a' ') reacting the compound of formula (II) with a base and optionally reducing the compound to give the compound of formula (A).

The process of any of claims 1 to 11, wherein n is 0 and wherein R¹ is PG¹ or R^A, with R^A being

wherein preferably R¹ is PG¹, and wherein step (a) comprises

(aa) providing a compound of formula (II*)

wherein R² is a protecting group PG³, preferably a protecting group PG³ selected from the group consisting of Boc, Fmoc, trifluoroacetate, trichloroacetate, and phthalimide, preferably Boc,

(ab) converting compound (II)* to compound (III*)

O

_K , /\ ^ H-R²

N

R¹ (IIP),

removing R . 2 to a give a compound of formula (IV*)

(iv*),

subjecting the compound (IV*) to cyclization conditions, to give the compound of formula (A) with n = 0, and wherein R¹ is preferably Cbz, and wherein the cyclization conditions in (ad) preferably comprise reductive animation conditions.

14. The process of any of claims 1 to 13, wherein n is 0 and wherein R¹ is PG¹.

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

wherein n is 0, R¹ is selected from the group consisting of PG¹ and R^A, with R^A being

and wherein PG¹ is a suitable protecting group, preferably wherein R¹ is Cbz, the compound consisting of a mixture of the compounds (la) and (lb)

the process comprising

(aa) providing a compound of formula (II*)

(Π*),

(ab) converting compound (II)* to compound (III*)

O

.NH-R

ΊΜ^'

R¹ (HI*),

(ac) removing R a give a compound of formula (IV*)

(ad) subjecting the compound (IV*) to cyclization conditions,

to give the compound of formula (A) with n = 0,

and wherein the cyclization conditions in (ad) preferably comprise reductive tion conditions.

A process for the pre aration of suvorexant having the structure

the process comprising

preparing a acid salt (T of a compound of formula (A)

according to the method of any of claims 1 to 12,

(ii) transforming the acid salt to suvorexant.

The process of claim 16, wherein step (ii) comprises

of the compound of formula (A), preferably (AO-la)

wherein R¹ is preferably ¹ or

(ii-b) reacting the tartaric acid salt or the compound of (ii-a) with a compound of formula

wherein E is -COOH or a reactive carboxy group,

(ii-c) optionally removing PG¹, and attaching

to the compound of step (ii-b) in case R¹ is PG¹

wherein preferably when n=0 and R is — " ^"O then the tartaric acid de rivative is not D-di-benzoyl tartaric acid (DBTA) or wherein preferably when n=0

R¹ is not ^ 5^^O or wherein preferably when n=0, R¹ is H or PG¹.

A process for the preparation of a compound of formula (IV*)

O

R¹ (IV*),

the process comprising

(aa) providing a compound of formula (II*)

(ab) converting compound (II)* to compound (III*)

O

_K , /\ ^ H-R²

N

R¹ (III*),

(ac) removing R²,

to give the compound of formula (IV*)

O

.NH 2

R¹ (IV*),

preferably wherein step (aa) comprises

and a compound of formula (IX*)

_{U M} ^ NHR²

^H2^N ^ (XI*)

in a solvent; preferably a solvent selected from the group consisting of toluene, xylene, xylene, mesitylene and decaline, preferably xylene,

(aa2) subjecting the mixture of step (aal) to suitable reaction conditions, preferably heating the mixture,

to give the compound of formula (II*).

The process of claim 18

wherein step (aa) comprises

(yip) ^ (VIII*)

and a compound of formula (IX*)

u_M^ NHR²

^H2^N ^ (xi*)

to give the compound of formula (II*).

An acid salt (T) of a compound of formula (A), or an acid salt (T) of a compound of formula (A), obtained or obtainable by a process of any of claims 1 to 7, wherein the compound (A) has the structure

and wherein PG¹ is a suitable protecting group, and wherein n is 0 or 1 , wherein the acid salt (T) is the salt of a single stereoisomer of a chiral acid, preferably wherein the chiral acid salt is a tartaric acid derivative salt, preferably wherein the tartaric acid derivative salt is selected from the group consisting of 2,3-ditoluoyl tartaric acid salt, 2,3-dibenzoyl tartaric acid salt, 2,3-dianisoyl tartaric acid salt, 2,3-dibenzoyl tartaric acid mono(dimethylamide) salt and a mixture of two or more thereof , wherein the acid salt (T) contains at least 80 % by weight of the chiral acid salt of the compound of formula (la)

based on the total weight of the acid salt of the compound of formula (A), preferably wherein the acid salt (T) of the compound formula (A) contains at least 85 % by weight, more preferably at least 90 % by weight, more preferably at least 95 % 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 chiral acid salt of the compound of formula (la), based on the total weight of the acid salt (T) of the compound of formula (A).

The acid salt (T) of claim 20, wherein when n=0 and R is

, then the tartaric acid derivative is not D-di-benzoyl tartaric acid (DBTA).

22. The acid salt (T) of claim 20, wherein when n=0 and R is not

23. The acid salt (T) of claim 20, wherein n=l .

24. The acid salt (T) of claim 20, wherein n=0 and R¹ is H or PG^1'

25. The acid salt (T) of any of claims 20 to 24, wherein n is 1 and the tartaric acid derivative is a di-toluoyl tartaric acid, more preferably L-di-toluoyl tartaric acid (LTTA).

26. The acid salt (T) of any of claims 20 to 24, wherein n is 0 and the tartaric acid derivative is a di-benzoyl tartaric acid, more preferably D-di-benzoyl tartaric acid (DBTA).

27. A compound of formula (A) or a compound of formula (A), obtained or obtainable by the process according to claim 12, wherein compound (A) has the structure

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

the compound consisting of a mixture of the compounds of formulas (la) and (lb)

Use of an acid salt (T) of any of claims 20 to 26 for the preparation of suvorexant having the structure