WO2016020406A1 - Nouvelles voies de synthèse pour la préparation de suvorexant - Google Patents

Nouvelles voies de synthèse pour la préparation de suvorexant Download PDF

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WO2016020406A1
WO2016020406A1 PCT/EP2015/067996 EP2015067996W WO2016020406A1 WO 2016020406 A1 WO2016020406 A1 WO 2016020406A1 EP 2015067996 W EP2015067996 W EP 2015067996W WO 2016020406 A1 WO2016020406 A1 WO 2016020406A1
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compound
formula
group
ila
methyl
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PCT/EP2015/067996
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English (en)
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Roland Barth
Kathrin HÖFERL-PRANTZ
Frank Richter
Gerhard Widschwenter
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Sandoz Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a process for the preparation of a compound of formulae
  • the present invention relates to processes for the preparation of intermediate compounds useful in the synthesis of compounds of formula (A) and (Aa) and of suvorexant.
  • Orexin is a neurotransmitter that regulates wakefulness and appetite.
  • Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness.
  • Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behavior disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive feeding behaviors; binge/purge feeding behaviors; cardiovascular diseases; diabetes; appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprol
  • HIV post-chemotherapy pain
  • post-stroke pain post-operative pain
  • neuralgia conditions associated with visceral pain such as irritable bowel syndrome, and angina
  • migraine urinary bladder incontinence, e.g. urge incontinence
  • tolerance to narcotics or withdrawal from narcotics sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lag syndrome; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism- amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders and other diseases related to general orexin system dysfunction.
  • orexin receptor antagonists are capable of influencing at least some of the above described pathological conditions.
  • orexin receptor antagonists capable of promoting sleep in animals and humans are described in the art.
  • One example for such an orexin receptor antagonist is [(7R)-4-(5-chloro-l,3-benzoxazol-2-yl)-7-methyl-l,4- diazepan-l-yl][5-methyl-2-(2H-l ,2,3-triazol-2-yl)phenyl]methanone which has the structure according to Formula I
  • the first step of this synthesis involves a 1 ,4-addition of Boc-ethylenediamine to methyl vinylketone followed by a Cbz-protection of the free amine to give a Boc- protected intermediate.
  • the Boc-protecting group is then cleaved with HCI and a 7- membered ring is closed by a reductive amination reaction sequence to give a racemic compound which after re-protection of the free amine with a Boc-protective group is resolved by preparative chiral HPLC.
  • the resulting enantiomerically pure amine is then coupled with a triazole benzoic acid derivative under standard peptide coupling conditions.
  • a stereoselective Suvorexant synthesis includes a tandem enantioselective transamination/ring formation and is described in WO2013/169610.
  • the synthesis starts with the preparation of a mesylate under standard conditions which is then converted into an amine in the presence of a (R)-selective sitagliptin transaminase and the intermediately formed amine cyclizes to give the seven-membered diazepane ring.
  • This step requires a strict control of process parameters to suppress the formation of an undesired impurity (regioisomer). Further, a very specific and sensitive enzyme needs to be employed which again renders the process disadvantageous for the preparative scale.
  • the present invention regards a process for preparing a compound of formula (Ila')
  • 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
  • R la is H, R 1 , PG 1 , R A or PG la and R lb is H, or
  • R la is H and R lb is H, R 1 , PG 1 , R A or PG la ,
  • cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)
  • R 2a is H, R 2 , PG 2 , R B or PG 2a ,
  • PG la and PG 2a are, independently of each other, suitable protecting groups
  • R 1 is selected from the group consisting of H, PG 1 and R A ,
  • R 2 is selected from the group consisting of H, PG 2 and R B ,
  • PG 1 and PG 2 are, independently of each other, suitable protecting groups
  • the present invention relates to a process for preparing a compound of formula (Ila)
  • R la is H, R 1 , PG 1 , R A or PG la and wherein R 2a is H, PG 2 , R B or PG 2a and wherein PG la and PG 2a are, independently of each other, suitable protecting groups,
  • the present invention is directed to a process for the preparation of a compound of formula (II),
  • the present invention regards a process for the preparation of a compound of formula (Ila')
  • R E is selected from the group consisting of H, 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 la is R 1 , PG 1 , R A or PG la ' and R lb is H, in this case preferably R 1 not being H, or
  • R la is H
  • R lb is R 1 , PG 1 , R A or PG la in this case preferably R 1 not being H, or R la and R lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)
  • R 2a is H, PG 2 , R B or PG 2a '
  • PG la and PG 2a are, independently of each other, suitable protecting
  • R 1 is selected from the group consisting of H, PG 1 and R A
  • R 2 is selected from the group consisting of H, PG 2 and R B
  • the present invention is directed to a process for the preparation of a compound of formula (II),
  • the invention further regards compounds of formula (Ila') obtained or obtainable according to the process as disclosed above.
  • the invention further regards compound of formula (Ila') as such.
  • the invention further regards a compound of formula (Ila) obtained or obtainable according to the process as disclosed above.
  • the invention further regards a compound of formula (Ila) as such.
  • the invention further regards a compound of formula (II) obtained or obtainable according to the process as disclosed above.
  • the invention further regards a compound of formula (II) as such.
  • the invention further regards the use of a compound of formula (II) or of formula (Ila) or of formula (Ila') in the preparation of a compound of formula (A) or (Aa), preferably of suvorexant of formula (IX).
  • a compound of formula (II) or of formula (Ila) or of formula (Ila') in the preparation of a compound of formula (A) or (Aa), preferably of suvorexant of formula (IX).
  • the present invention is directed to two processes for the preparation of compound (Ila') or (Ila) which can be further reacted to obtain a compound (II).
  • the first process uses a ethylenediamine and derivative thereof as the staring material
  • the second process uses homoalanine and ester thereof as the starting material.
  • the compound of formula (Ila') provided in step (a3) of the ethylendiamine based process or in (a-ii) of the homoalanine based process has the structure
  • R la , R lb , R 2a and R E are as defined above.
  • step (a3) of the ethylendiamine process has the structure
  • R la , R 2a and R E are as defined above.
  • step (a4) has the structure
  • R 1 , R 2 and R E are as defined above
  • single isomer in this context is denoted to mean that the compound of formula (Ila' *) or the compound of formula (Ila*) or the compound of formula (II*) comprises less than 1 % by weight of compound (Ila' **) or (Ila**) or (II**), respectively, preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no compound of formula (Ila' *), (Ila*) or (II**) respectively based on the total weight of (Ila'*) and (Ila'**) or, (Ila*) and (Ila**), or (II*) and (II**) respectively.
  • step (a3) the provision preferably either comprises a chiral resolution step or an enantioselective reaction step, such as enantioselective reduction of the double bond present in compound (V')/(V).
  • step (a4) the provision preferably either comprises a chiral resolution step or an enantioselective reaction step, such as enantioselective reduction of the double bond present in compound (V')/(V).
  • the chiral resolution may be carried out by any suitable method known to those skilled in the art, such as resolution by crystallization or by chiral chromatography, such as chiral HPLC.
  • the chiral resolution during step (a3) or (a4) is carried out by crystallization employing an optical pure resolving agent, preferably an optical pure chiral acid.
  • the chiral resolution of compound (Ila') or (II), if carried out is carried out with a tartaric acid as chiral acid, preferably with tartaric acid.
  • 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. It is preferred that R E is alkyl, preferably Ci-C 6 alkyl, more preferably R E is methyl, ethyl or propyl, more preferably R E methyl.
  • R E when R E is alkyl, it is preferred that alkyl is Ci-C 6 alkyl, more preferably R E is methyl, ethyl or propyl, even more preferably R E methyl.
  • R la , R lb and R 1 when R E is alkyl, it is preferred that alkyl is Ci-C 6 alkyl, more preferably R E is methyl, ethyl or propyl, even more preferably R E methyl.
  • R la is H, R 1 , PG 1 , R A or PG la and R lb is H, or R la is H and R lb is H, R 1 , PG 1 , R A or PG la , or R la and R lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the grou consisting of phthalimido group of formula (p)
  • R la is H, R 1 , PG 1 , R A or PG la ' and R lb is H, or R la is H, and R lb is H, R 1 , PG 1 , R A or PG la wherein preferably,
  • R la is R 1 , PG 1 , R A or PG la ' and R lb is H, in this case preferably R 1 not being H, or
  • R la is H
  • R lb is R 1 , PG 1 , R A or PG la in this case preferably R 1 not being H
  • cyclic imide group is preferably selected from the group consisting of phthalimido group of formula
  • R la and R lb taken together with the N atom to which they are attached is an amino protecting group having the same role of group PG 1 or PG la as disclosed below.
  • R la is defined as H, PG 1 , R A or PG la in this case R lb is H.
  • PG la and PG 2a in the compound of formula (Ila') or (Ila) are independently of each other, suitable protecting groups.
  • suitable protecting group as used herein is denoted to encompass any amino protecting group.
  • protecting group 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 PG 1 include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl, 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-but
  • amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl, Cbz, PNZ, Alloc, Trifluoroacetate, Phthalimide and the like.
  • PG 1 is wherein PG 1 is selected from the group consisting of benzyl, t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and Phthalimide, more preferably PG1 is a Boc group or a Cbz group, more preferably Boc.
  • Preferred protecting groups for PG la include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl and the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t- butyldimethylsilyl and triisopropylsilyl.
  • carbamates such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and e
  • amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl and the like.
  • PG la is a Boc group or a Cbz group, more preferably Boc.
  • R 1 is selected from the group consisting of H, PG 1 and R A .
  • PG 1 is as defined above.
  • R 2a is H, R 2 , PG 2 , R B or PG 2a wherein R 2 is selected from the group consisting of H, PG 2 and R B .
  • PG 2a is suitable protecting groups, wherein "suitable protecting group” is as defined above.
  • PG 2 is suitable protecting groups, wherein "suitable protecting group” is as defined above.
  • Preferred protecting groups for PG 2a include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl and the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t-butyldimethylsilyl and triisopropylsilyl.
  • carbamates such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and
  • amino-protecting groups include Boc, Cbz (CBZ), Fmoc, benzyl, acetyl, benzoyl, trityl and the like.
  • PG 2a is a Boc group or a Cbz group, more preferably Cbz.
  • Preferred protecting groups for PG 2 include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl, 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 triisopropylsilyl.
  • carbamates such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbon
  • amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl, Cbz, PNZ, Alloc, Trifluoroacetate, Phthalimide and the like.
  • PG 1 is wherein PG 2 is selected from the group consisting of Benzyl, t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and Phthalimide, more preferably PG 2 is a Boc group or a Cbz group, more preferably Cbz.
  • R i a " ⁇ NHR 2a (m)) MN ⁇ NHR 2a (HI) are intermediates in the ethyldiamine process.
  • R la , R lb and R 2a are as defined above.
  • R la or R lb is not H or wherein when R la is H and R lb and then R 2a is not H.
  • Compound (1) is an homoalanine derivative of formula used in the homoalanine based process according to the present invention.
  • Compound (1) has formula (1)
  • R 2a and R E are as defined above.
  • Compound (2) is an intermediate of the homoalanine based process according present invention. It has formulae
  • R la and R lb are as defined above.
  • R la is H, R 1 , PG 1 , R A or PG la ' and R lb is H, or
  • R la is H, and R lb is H, R 1 , PG 1 , R A or PG la
  • R la is R 1 , PG 1 , R A or PG la ' and R lb is H, in this case preferably R 1 not being H, or
  • R la is H
  • R lb is R 1 , PG 1 , R A or PG la in this case preferably R 1 not being H
  • cyclic imide group is preferably selected from the group consisting of phthalimido group of formula
  • the cyclic imide formed by R la and R lb taken together with the N atom to which they are attached is an amino protecting group having the same role of group PG 1 or PG la as disclosed below.
  • the process of the present invention is directed to a process for preparing compounds (Ila'), (Ila) and compound (II).
  • process steps for the preparation of a compound of formula (II) are in some instances referred to as step "(a) providing a compound of formula (II)" or similar expressions.
  • the present invention is directed to a process for preparing a compound of formula
  • 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,
  • R la is H, R 1 , PG 1 , R A or PG la and R lb is H, or R la is H and R lb is H, R 1 , PG 1 , R A or PG la ,
  • cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)
  • R 2a is H, R 2 , PG 2 , R B or PG 2a ,
  • PG la and PG 2a are, independently of each other, suitable protecting groups
  • R 1 is selected from the group consisting of H, PG 1 and R A ,
  • R 2 is selected from the group consisting of H, PG 2 and R B ,
  • PG 1 and PG 2 are, independently of each other, suitable protecting groups
  • R is H and hence the compound of formula (Ila') is a compound of formula (Ha).
  • the compound of formula ( ⁇ ) is a compound of formula (III)
  • the process of the invention further optionally comprises
  • step (a4) is optional when R 2a is the same as R 2 and/or R la is the same as R , and/or R lb is the same as R 1 as it is explained below.
  • the present invention is hence, further directed to a process for the preparation of a compound of formula (II) and a compound obtained or obtainable by a method as disclosed above.
  • the method comprises
  • R la is H, R 1 , PG 1 , R A or PG la and wherein R 2a is H, PG 2 , R B or PG 2a and wherein PG la and PG 2a are, independently of each other, suitable protecting groups,
  • R 2a is H and R la or R lb is not H or when R la and R lb is H, R 2a is not H.
  • R a is H. It is preferred a process wherein in compounds ( ⁇ ), (III), (V), (V), (Ha') and (Ila) R a is H and R la is Boc.
  • R la is PG la and R 2a is H, wherein PG la is a suitable protecting group, preferably a Boc group, R lb is H; in (a3) R la is PG la and R 2a is H wherein PG la is a suitable protecting group, preferably a Boc group, R lb is H; and in (a4) R lb is H and R 2a is replaced with
  • R E is meth l
  • R 2 is
  • R 1 is H.
  • R 1 is H or Boc, preferably Boc and at each occurrence R E is preferably methyl.
  • R la is PG 1 , preferably Boc and R lb is H, or R la and R lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of hthalimido group of formula (p)
  • R E is methyl
  • R la is PG la , preferably Boc and R lb is H, or R la and R lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group (p) and succinimido group (s) and R 2a is H, wherein the process comprises
  • R 1 is H and R 2 is PG 2 wherein PG 2 is preferably Boc or Cbz, wherein PG la and PG 2 are orthogonal protecting groups, or
  • R la is PG la , preferably Boc or Cbz, and R 2a is H, wherein the process comprises
  • R 1 is H and R 2 is PG 2 wherein PG 2 is preferably Boc or Cbz, wherein PG la and PG 2 are orthogonal protecting groups.
  • R la is Boc or R la and R lb taken together with the N atom to which they are attached form phthalimido group or a succinimido group and R 2 is PG 2 wherein PG 2 is selected from the group consisting of Cbz, Bn, Boc and Fmoc, more preferably PG 2 is Cbz, wherein PG la and PG 2 are selected to be orthogonal protecting groups
  • step (al) a compound of formula (III) or ( ⁇ ) is reacted with a compound of formula (IV) or to give the compound of formula (V) or (V).
  • step (al) a compound of formula (III) is reacted with a compound of formula (IV) to give the compound of formula (V).
  • step (al) 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.
  • the temperature may be varied or held essentially constant.
  • an organic solvent is used in step (al), more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t- butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.
  • the reaction is carried out in dichloromethane.
  • (al) is carried out in the presence of a catalysing agent, such as a dehydrating reagent or an acidic catalyst.
  • a catalysing agent such as a dehydrating reagent or an acidic catalyst.
  • 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.
  • the catalysing agent is Si0 2 or a molecular sieve or a mixture thereof. More preferably, the catalysing agent Si0 2 .
  • the reaction mixture obtained in step (al) is subjected to a suitable work-up in step (a2), such as an isolation of the respective compound of formula (V) or (V).
  • a suitable work-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.
  • the reaction mixture is filtered to remove the Si0 2 and the solvent is removed, such as under reduced pressure.
  • compound (V) or (V) is further purified, e.g. by distillation.
  • step (a3) the compound of formula (V), preferably of formula (V) is reduced to give a compound having the structure (H a ).
  • 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 comprising
  • R la is H, R 1 , PG 1 , R A or PG la and wherein R 2a is H, PG 2 , R B or PG 2a and wherein PG la and PG 2a are, independently of each other, suitable protecting groups,
  • compound (Ila') or (Ila) consists of a mixture of (Ila'*) and (Ila'**) or, (Ila*) and (Ila**) as shown below
  • the reduction may be carried out by any suitable manner known to those skilled in the art.
  • 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.
  • 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 catalyst is a palladium catalyst, more preferably Pd/C. In case of Pd/C, the reaction is preferably carried out in a non-stereoselective manner.
  • non- stereoselective manner is denoted to mean that a racemic mixture of compounds (Ila'*) and (Ila'**) or, (Ila*) and (Ila**) is obtained.
  • the present invention also relates to a process, as described above, comprising the steps (al) to (a4), as described above, and wherein in step (a3), the compound is reduced with Pd/C.
  • 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.
  • the reaction is carried out at a temperature in the range of from 10 to 1000 °C, of from 10 to 100 °C, more preferably in the range of from 20 to 60 °C, more preferably at 40 to 60 °C.
  • 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.
  • 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, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.
  • the solvent is methanol or TFE.
  • step (a4) as disclosed below a mixture of (II*) and (II**) is provided, compound (IIa')/(IIa) also consists of a racemic mixture, i.e. a mixture of the com ounds (IIa'*)(IIa*) and (IIa'**)(IIa**)
  • step (a3) the compound (V) is stereoselectively reduced to give a compound of formula (Ila'*)
  • step (a3) the compound (V) is stereoselectively reduced to give a compound of formula (Ila*)
  • a chiral catalyst i.e. a metal catalyst comprising a chiral ligand is employed.
  • a metal catalyst and hydrogen is used.
  • the metal catalyst is preferably selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh and mixtures of two or more thereof.
  • the metal catalyst is preferably selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh, and mixtures of two or more thereof.
  • the catalyst comprises Fe and/or Rh.
  • the reaction is preferably carried out at a hydrogen pressure in the range of from 1 to 25 bar, more preferably, 2.5 to 10 bar. During the reaction, the pressure may be varied or held essentially constant.
  • 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.
  • 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.
  • 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, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.
  • the solvent is methanol or TFE.
  • R la is Boc
  • R lb is H
  • R 2a is H.
  • the process of the invention e.g. comprises reacting a compound of formula (III)
  • R la is PG la and wherein R 2a is H, wherein PG la is a suitable protecting group, preferably a Boc group,
  • E is -COOH or a reactive carboxy group, and replacing R la with H by removing the protecting group PG la .
  • the present invention relates to the preparation of a compound of formula (Ila') and to a compound (Ila') obtained or obtainable by said method, the method comprising
  • R la is H, R 1 , PG 1 , R A or PG la ,
  • R lb is H
  • cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)
  • R 2a is H, R 2 , PG 2 , R B or PG 2a ,
  • PG la and PG 2a are, independently of each other, suitable protecting groups
  • R 1 is selected from the group consisting of H, PG 1 and R A ,
  • R 2 is selected from the group consisting of H, PG 2 and R B ,
  • PG 1 and PG 2 are, independently of each other, suitable protecting groups
  • 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.
  • the present invention relates to the preparation of a compound of formula (Ila) and to a compound (Ila) obtained or obtainable by said method, the method comprising
  • R la is PG la and wherein R 2a is H, wherein PG la is a suitable protecting group, preferably a Boc group, (a2) optionally purifying the compound of formula (V),
  • the present invention relates to a compound of formula (Ila), in which R la is PG la and wherein R 2a is H, preferably R la is Boc.
  • the present invention also relates to the preparation of a compound of formula (II) and to a compound (II) obtained or obtainable by said method, the method comprising
  • R la is PG a and wherein R 2a is H, wherein PG la is a suitable protecting group, preferably a Boc group,
  • the present invention relates to a compound of formula (Ila), in which R la is H and wherein R a is
  • the process of the to the invention comprises (al) reacting a compound of formula (III)
  • R la is PG la and wherein R 2a is H, PG la is a suitable protecting group, preferably a Boc group,
  • R la is PG la and wherein R 2a is H replacing R 2a with a protecting group PG 2 and replacing R 2a with H by removing the protecting group PG la .
  • the present invention is further directed to a process for preparing compound of formula (Ila') and (II) using an homoalanine derivative as the stating material.
  • homoalanine is a commercially available starting material. It can be purchased both as a racemic compound or as enantiomerically pure compound. In the latter case the correct stereochemistry of the methyl group of compound (II) or (Ila') can be introduced since the beginning into the synthesis of compound of formula (Ila'*) or (Ila'**).
  • the compound of formula (Ila') or (II) can be separated into the two enantiomers as disclosed above in connection with the ethylenediamine based process of the invention.
  • the homoalanine based process comprises only two steps that can be advantageously carried out in one pot.
  • the present invention is directed to a process for the preparation of a compound of formula (Ila')
  • R E is selected from the group consisting of H, 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 la is H, R 1 , PG 1 , R A or PG la ' and R lb is H, or
  • R la is H, and R lb is H, R 1 , PG 1 , R A or PG la
  • R la is R 1 , PG 1 , R A or PG la ' and R lb is H, in this case preferably R 1 not being H, or
  • R la is H
  • R lb is R 1 , PG 1 , R A or PG la in this case preferably R 1 not being H
  • cyclic imide group is preferably selected from the group consisting of phthalimido group of formula
  • R 2a is H, PG 2 , R B or PG
  • PG la and PG 2a are, independently of each other, suitable protecting groups
  • R 1 is selected from the group consisting of H, PG 1 and R A
  • R 2 is selected from the group consisting of H, PG 2 and R B
  • PG 1 and PG 2 are, independently of each other, suitable protecting groups
  • the process further comprises
  • Step (a4) is carried out as disclosed below.
  • R la , R lb , R 1 , R 2 , R A , PG la , PG 1 , PG 2 , PG 2a , and R E they are defined as above and in the ethyldiamine based process of the invention.
  • R la is PG 1 , R A or PG la with R A being
  • cyclic imide group is preferably selected from the group consisting of phthalimido group of formula
  • R la and R lb taken together preferably they form a phthalimido group or a succinimido group.
  • R la is PG la and R 2a is H
  • PG la is a suitable protecting group, preferably a Boc group or R la and R lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group or succinimido group.
  • R la is PG 1 or PG la . More preferably, PG 1 or PG la is Boc. In this case R lb is H. Alternatively, it is preferred that R lb is PG 1 or PG la , more preferably, PG 1 or PG la is Boc. In this case R la is H. Alternatively it is preferred that R la and R lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of hthalimido group of formula (p)
  • R a is H
  • (a4) is carried out by replacing R a being H with
  • R la is PG la or PG 1 , preferably Boc and R lb is H, or R la and R lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group and succinimido group and R 2a is H.
  • R 2a H is replaced with PG 2 , wherein PG 2 is preferably Boc or Cbz and R la is replaced with H or R la taken together with R lb is replaced with hydrogens.
  • step (a4) comprises
  • step (a4-l) a compound is obtained wherein R 2a is PG 2 and wherein PG 2 is preferably Boc or Cbz.
  • PG 2 is chosen to be orthogonal to R la being PG 1 or PG la or to the imide group formed by R la and R lb taken together. This assures that in step (a4-2) when R la , or R la taken together with R lb is replaced with hydrogens, PG 2 is not removed.
  • the reaction is a reduction.
  • the reacting of (a-i) is selected from a reductive amination and hydrogenation, preferably reductive amination.
  • the reductive amination preferably is carried out using a reagent selected form the group consisting of NaBH 4 , NaBH 3 CN, NaBH(OAc) 3 , LiAlH 4 , more preferably NaBH(OAc) 3
  • an organic solvent is selected from the group consisting of tetrahydrofuran (THF), 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, even more preferably in a solvent selected from the group consisting of tetrahydrofuran (THF), methyltetrahydrofurane, methyltertbutylether, dichloromethane .
  • THF tetrahydrofuran
  • TFE trifluoroethanol
  • the reacting of (a-i) can be a hydrogenation reaction.
  • (a-i) it is carried out at a temperature in the range of- 10 to 1000 C, -10 to 100 C, more preferably in the range of from 10 to 70°C, even more preferably in the range of from 20 to 50°C.
  • the organic solvent is selected from the group consisting tetrahydrofuran (THF), 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 , ethyl acetate, isopropyl acetate and mixtures of two or more thereof, more preferably in tetrahydrofuran, ethyl acetate, methanol, ethanol, acetic acid and mixtures of two or more thereof, even more preferably in a solvent selected from the group consisting of
  • PG la is Boc or R la and R lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consistin of phthalimido group of formula (p)
  • step (a-ii) compound of formula (Ila') is purified.
  • Any purification method such as crystallization and distillation method is suitable for the purification of compound of formula (IF a). It is preferred that the obtained compound (Ila') is purified via distillation.
  • step (a3) of the first process and in step (a-i) or (a-ii) of the second process compound (Ila') is obtained.
  • Compound (Ila') obtained according to (a3) of the first ethylediamine process or according to (a-i) (a-ii) can be further reacted to compound (II) according to step (a4).
  • R la of compound (Ila') may be different from R 1 or may be the same.
  • R 2a in compound (Ila') may be different from R 2 or may be the same.
  • step (a4) is carried out.
  • step (a4) is omitted.
  • compound (Ila') or (Ila) may correspond to compound (II), compound (Ila'*) or (Ila*) may correspond to (II*) and compound (Ila'**) or (Ila**) may correspond to (II**) in case R la is equal to R 1 and in case R 2 is equal to R 2a .
  • step (a4) R la and/or R 2a is transformed in step (a4) to R 1 and R 2 , wherein this transformation may be carried out in one or in multiple steps, to give compound (II) or (II*), respectively. It is to be understood that in case (II) corresponds to (Ha') or (Ila) or, (II*) corresponds to (Ila'**) or (Ila'**), step (a4) is omitted.
  • step (a4) comprises
  • cyclic imide group is preferably selected from the group consisting of phthalimido group of formula (p) oe a succinimido group of formula (s) with R 1 and H
  • step (a4) comprises.
  • R la may be different from R 1 and/or R 2a may be different from R 2 .
  • articular the following embodiments are mentioned by way of example:
  • PG is preferably Boc and PG is preferably Cbz
  • step (a4) protecting groups are removed or attached to the molecule.
  • Methods for attaching and removing of a protecting group are known to those skilled in the art and depend on the respective protecting group employed.
  • Representative protecting groups for amino groups are well known to those skilled in the art and methods for attaching them to amino groups as well as removing them are described, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, N.Y., 1999, and references cited therein.
  • the protecting group is a Boc group
  • the removal is preferably carried out under acidic conditions. More preferably, the removal is carried out with HC1 or TFA.
  • the removal of such protecting groups may be carried out in any suitable solvent known to those skilled in the art.
  • the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.
  • the removal is carried out at a temperature in the range of from 0 to 40 °C, more preferably in the range of from 10 to 30°C, more preferably at room temperature. During the reaction, the temperature may be varied or held essentially constant.
  • the removal is preferably carried out under reductive conditions. More preferably, the removal is carried out with hydrogen and a metal catalyst, preferably a palladium catalyst, more preferably the protecting group is removed with Pd/C.
  • a metal catalyst preferably a palladium catalyst
  • the protecting group is removed with Pd/C.
  • the removal of such a protecting group may be carried out in any suitable solvent known to those skilled in the art.
  • the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof, and mixtures of two or more thereof.
  • 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,
  • the removal is carried out at a temperature in the range of from 0 to 60 °C, more preferably in the range of from 10 to 50 °C, more preferably at room temperature.
  • the temperature may be varied or held essentially constant.
  • the reaction is preferably carried out at a pressure in the range of from 1 to 3 bar, more preferably, 1.5 to 2.5 bar.
  • step (a4) the respective compound is reacted, i.e. coupled, with a compound of formula (XI), wherein E is -COOH or a reactive carboxy group
  • the coupling is preferably carried out in the presence of a suitable base, preferably an organic base, most preferably an amino group comprising base, most preferably a base selected from the group consisting of diisopropylamine (DIEA), triethylamine (TEA), N-methylmorpholine, N-methyl- imidazole, l,4-diazabicyclo[2.2.2]octane (DABCO), N-methylpiperidine, N- methylpyrrolidine, 2,6-lutidine, collidine, pyridine, 4-dimethylaminopyridine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).
  • a suitable base preferably an organic base, most preferably an amino group comprising base, most preferably a base selected from the group consisting of diis
  • the reaction is carried out in an organic solvent, such as N- methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, acetone, dimethyl acetamide (DMA), dimethyl formamide (DMF), formamide, tetrahydrofuran (THF), 1,4- dioxane, diethyl ether, tert.-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, tetrachloromethane and mixtures of two or more thereof. More preferably, the reaction is carried out in dichloromethane.
  • NMP N- methyl pyrrolidone
  • DMSO dimethyl sulfoxide
  • DMA dimethyl formamide
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • MTBE tert.-butyl methyl ether
  • DCM dichloromethane
  • chloroform tetrach
  • the temperature of the coupling reaction is preferably in the range of from 0 to 100 °C, more preferably in the range of from 5 to 50 °C, and especially preferably in the range of from 15 to 30 o0 C. During the course of the reaction, the temperature may be varied, preferably in the above given ranges, or held essentially constant.
  • step (a4) is carried out.
  • step (a4) comprises one or multiple steps, such a deprotection step and/or a protection step and/or a coupling step with a com ound of formula
  • Steps (al) to (a3), (al) to (a4), (a-i) to (a-ii), (a-i) to (a4) are indicated below in general as step (a) unless otherwise specified.
  • the process preferably comprises
  • step (a3) of the first process as disclosed above to give the compound of formula (Ila' *)/(IIa*) or (II*), respectively.
  • step (a) a compound having the structure (II*) is provided as single (isolated) isomer, as mentioned above, step (a) preferably comprises
  • step (a3) of the first process as disclosed above to give the compound of formula (IIa'*)/(IIa*) or (II*), respectively.
  • compound (II) may comprise a mixture of compounds (II*) and (II**)
  • a chiral resolution of (II) may be carried out. More preferably, in case a chiral resolution is carried out at this stage, R 2 is H, and R 1 is Boc. R E is preferably methyl.
  • the compound (II) contains of from 20 to 75 % by weight of the compound of formula (II*) based on the total weight of the sum of (II*) and (II**). This mixture is then resolved by chiral resolution to finally give, optionally after further steps, the compound
  • step (i) upon addition of the chiral acid in a suitable solvent, a chiral acid salt (S*) of at least part of the compound of formula (II) is formed and at least part of this chiral acid salt (S*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (S) and the solvent.
  • a chiral acid salt (S*) of at least part of the compound of formula (II) is formed and at least part of this chiral acid salt (S*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (S) and the solvent.
  • the chiral acid is preferably tartaric acid or a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, more preferably, the chiral acid is tartaric .
  • the compound of formula (II) employed in (i) contains of from 20 to 75 % by weight, more preferably of from 40 to 60 % by weight, of the compound of formula (II*) based on the total weight of the sum of (II*) and (II**).
  • step (i) at least part of the compound of formula (II) is transformed into the corresponding chiral acid salt, preferably tartaric acid salt (S*).
  • the chiral acid salt (S*) contains the chiral acid salt of the compound of formula (II*), 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 weigh, or in the range of from 45 to 55 % by weight, based on the total amount of the chiral acid salt (S*).
  • the precipitated, preferably crystallized, tartaric acid salt (S) of the compound of formula (II) contains at least 80 % by weight of chiral acid salt of the compound of formula (II*) based on the total weight of the chiral acid salt of the compound of formula (II).
  • the mixture obtained in step (i) may comprise further compounds, in particular non crystalline forms of the compound of formula (II) and salts thereof.
  • the mixture obtained in (i) comprises non-crystalline forms of the compound of formula (II**) and chiral acids salts thereof.
  • the chiral acid salt (S*) of the compound of formula (II) is denoted to encompass all chiral acid salts of compound (II) formed in step (i) including the chiral acid salt (S) which precipitates as well as all chiral acid salts formed which remain dissolved (S*-S).
  • the chiral acid salt (S) may comprise a mixture of chiral acid salt of compounds of formula (II*) and (II**).
  • any suitable organic solvent in which the compound of formula (II) is sufficiently soluble may be used.
  • the solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH2C12, ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketon, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof.
  • the solvent comprises methylisobutylketon, preferably is methylisobutylketon.
  • step (i) a further solvent may be added in order to precipitate, preferably crystallize, the chiral acid salt (S).
  • the mixture obtained in (i) preferably additionally comprises the 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 (II).
  • the compound of formula (II) 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.
  • the further solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH 2 CI 2 , 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.
  • the suitable solvent and the further solvent are the same, in particular, they both comprise methylisobutylketone, , preferably both are methylisobutylketone.
  • the present invention also relates to a process for the preparation of a chiral acid salt (S) of a compound of formula (II), as described above, and a chiral acid salt (S) of compound of formula (II), obtained or obtainable by said process, wherein step (i) comprises dissolving the compound of formula (II) 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 methylisobutylketone .
  • the compound of formula (II) is dissolved in the suitable solvent and the mixture is heated to a temperature in the range of from 30 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.
  • the temperature may be varied, constantly or stepwise, or held essentially constant.
  • the mixture is heated until a clear solution of the compound of formula (II) in the suitable solvent is obtained.
  • the mixture is afterwards cooled to room temperature.
  • the precipitation, preferably the crystallizing, in step (i) is preferably carried out at a temperature in the range of from 0 to 60 °C, wherein the temperature is preferably continuously or stepwise decreased during step (i).
  • the chiral acid may thus e.g. be added to a solution of the compound of formula (II) 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.
  • the mixture may again be heated or alternatively be cooled or the temperature may be held constant.
  • the mixture is cooled to a temperature in the range of from 0 to 50 °C, more preferably to a temperature in the range of from 0 to 40 °C, more preferably to a temperature in the range of from 10 to 30 °C.
  • the mixture obtained in step (i) consists of the chiral acid salt (S), optionally the unreacted chiral acid, optionally the unreacted compound of formula (II), precipitated chiral acid salts (salt (S*) minus the amount of precipitated chiral acid salt (S)), the suitable solvent and optionally the further suitable solvent.
  • step (ii) of the process of the invention the chiral acid salt (S) is separated from the mixture obtained in step (i).
  • the separation may be carried out by any suitable method known to those skilled in the art.
  • the separating in step (ii) is carried out by centrifugation or filtration, preferably filtration.
  • the separated salt may be subjected to a further treatment such as an after-treatment such as a purification step and/or lyophilization.
  • the obtained chiral acid salt (S) of the compound formula (II) contains at least 90 % 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, of the tartaric salt of the compound of formula (II*), based on the total weight of chiral acid salt of the compound of formula (II), i.e. based on the sum of (II**) and (II*). More preferably, the chiral acid salt (S) of the compound of formula (II) is the isolated chiral acid salt of the compound of formula (II*).
  • isolated chiral acid salt of the compound of formula (II*) in this context is denoted to mean that the salt of the compound of formula (II*) comprises less than 1 % by weight of the salt of compound (II**), preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no compound of formula (II**) based on the total weight of the salts of (II*) and (II**).
  • a chiral resolution of (IIa')/(IIa) may be carried out. More preferably, in case a chiral resolution is carried out at this stage, R 2a is H, and R la is Boc and R lb is H. R E is preferably methyl.
  • the compound (IIa')/(IIa) contains of from 20 to 75 % by weight % of the compound of formula (IIa'*)/(IIa*) based on the total weight of the sum of (Ila'*) and (IIa'**)/(IIa*) and (Ila**).
  • This mixture is then resolved by chiral resolution to finally give, optionally after further steps, the compound (IF*).
  • step (ia) upon addition of the chiral acid in a suitable solvent, a chiral acid salt (Sa'*) of at least part of the compound of formula (IIa')/(IIa) is formed, and at least part of this chiral acid salt (Sa'*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (S) and the solvent.
  • a chiral acid salt (Sa'*) of at least part of the compound of formula (IIa')/(IIa) is formed, and at least part of this chiral acid salt (Sa'*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (S) and the solvent.
  • the chiral acid is preferably tartaric acid or a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, more preferably, the chiral acid is tartaric.
  • the compound of formula (IIa')/(IIa) employed in (ia) contains of from 20 to 75 % by weight, more preferably of from 40 to 60 % by weight, of the compound of formula (Ila'*) based on the total weight of the sum of (Ila'*) and (IIa'**)/(IIa*) and (Ila**).
  • step (ia) at least part of the compound of formula (IIa')/(IIa) is transformed into the corresponding chiral acid salt, preferably tartaric acid salt (Sa'*).
  • the chiral acid salt (Sa'*) contains the chiral acid salt of the compound of formula (Ila'*), 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 (Sa'*).
  • (Sa'*) is precipitated, preferably crystallized.
  • This is preferably achieved, by contacting (treating) the compound of formula (II) in a suitable solvent with the chiral acid. Thereby a mixture comprising the crystallized chiral acid salt (Sa') of the compound of formula (IIa'*)/(IIa*) and the solvent is formed.
  • the precipitated, preferably crystallized, tartaric acid salt (Sa') of the compound of formula (IIa')/(IIa) contains at least 80 % by weight of chiral acid salt of the compound of formula (IIa'*)/(IIa*) based on the total weight of the chiral acid salt of the compound of formula (IIa')/(IIa).
  • the mixture obtained in step (ia) may comprise further compounds, in particular non-crystalline forms of the compound of formula (II) and salts thereof.
  • the mixture obtained in (ia) comprises non crystalline forms of the compound of formula (IIa**)/(IIa**)and chiral acid salts thereof.
  • the chiral acid salt (Sa*) of the compound of formula (Ila) is denoted to encompass all chiral acid salts of compound (Ila) formed in step (ia) including the chiral acid salt (Sa) which precipitates as well as all chiral acid salts formed which remain dissolved (Sa*-Sa).
  • the chiral acid salt (Sa) may comprise a mixture of chiral acid salt of compounds of formula (Ila'*) and (IIa'**)/(IIa*) and (Ila**).
  • any suitable organic solvent in which the compound of formula (Ila) is sufficiently soluble may be used.
  • the solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH 2 CI 2 , ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketon, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof.
  • the suitable solvent comprises methylisobutylketon, preferably is methylisobutylketon.
  • step (ia) a further solvent may be added in order to precipitate, preferably crystallize, the chiral acid salt (Sa').
  • the mixture obtained in step (i) preferably additionally comprises the 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 (IIa')(IIa).
  • the compound of formula (IIa')/(IIa) 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.
  • the further solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH 2 CI 2 , 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.
  • the further solvent comprises methylisobutylketone, preferably is methylisobutylketone.
  • the suitable solvent and the further solvent are the same, in particular, they both comprise methylisobutylketone, preferably they are both methylisobutylketone.
  • the present invention also relates to a process for the preparation of a chiral acid salt (Sa') of a compound of formula (IIa')/(IIa), as described above, and a chiral acid salt (Sa') of a compound of formula (IIa')/(IIa), obtained or obtainable by said process, wherein step (ia) comprises dissolving the compound of formula (IIa')/(IIa) 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 methylisobutylketone .
  • the compound of formula (IIa')/(IIa) is dissolved in the suitable solvent and the mixture is heated to a temperature in the range of from 30 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.
  • the temperature may be varied, constantly or stepwise, or be held essentially constant.
  • the mixture is heated until a clear solution of the compound of formula (IIa')/(IIa) in the suitable solvent is obtained.
  • the mixture is afterwards cooled to room temperature.
  • the precipitation, preferably the crystallizing, in (ia) 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 during step (ia).
  • the chiral acid may thus e.g. be added to a solution of the compound of formula (IIa')/(IIa) 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.
  • the mixture may again be heated or alternatively be cooled or the temperature may be held constant.
  • the mixture is cooled to a temperature in the range of from 0 to 80°C, more preferably to a temperature in the range of from 10 to 50 C, more preferably to a temperature in the range of from 15 to 35 C.
  • the mixture obtained in (ia) consists of the chiral acid salt (S), optionally unreacted chiral acid, optionally unreacted compound of formula (II), precipitated chiral acid salts (salt (Sa'*) minus the amount of precipitated chiral acid salt (Sa)), the suitable solvent and optionally the further suitable solvent.
  • step (iia) of the process of the invention the chiral acid salt (Sa) is separated from the mixture obtained in (ia).
  • the separation may be carried out by any suitable method known to those skilled in the art.
  • the separating in step (iia) is carried out by centrifugation or filtration, preferably filtration.
  • the separated salt may be subjected to a further treatment such as an after-treatment like a purification step and/or lyophilization.
  • the obtained chiral acid salt (Sa') of the compound of formula (IIa')/(IIa) contains at least 90 % 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, of the tartaric salt of the compound of formula (IIa'*)/(IIa*) based on the total weight of chiral acid salt of the compound of formula (II), i.e. based on the sum of (Iia'*) and (IIa'**)/(IIa*) and (Iia**). More preferably, the chiral acid salt (S) of the compound of formula (IIa')/(IIa) is the isolated chiral acid salt of the compound of formula (IIa'*)/(IIa*).
  • isolated chiral acid salt of the compound of formula (Iia'*) in this context is denoted to mean that the salt of the compound of formula (Iia'*) comprises less than 1 % by weight of the salt of compound (Iia'**), preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no compound of formula (Ila'**) based on the total weight of the salts of (Ila'*) and (Ila'**).
  • compound (II) has the same structure of compound (Ila') or (Ila).
  • the processes according to the present invention may further comprise
  • R 1 , R 2 , R la and R 2a are as defined above.
  • the com ound (A*) is a compound of formula
  • R 1 is selected from the group consisting of H, PG 1 and R A with R A being
  • R 2 is selected from the group consisting of H, PG 2 and R B with R B being
  • PG 1 and PG 2 are, independently of each other, suitable protecting groups, and wherein n is 0 or 1 , comprises
  • 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,
  • the providing a compound of formula (II) according to (a) is preferably carried out according to the ethyldiamine process or homoalanine process of the invention.
  • the com ound (A) has, e.g., the structure (la) or (lb)
  • R is as disclosed above.
  • the compound of formula (A) has, e.g., a structure selected from the group consisting of
  • R 1 is H.
  • R 2 is as described above.
  • the compound of formula (A) has, e.g., a structure selected from the group consisting of
  • R 1 and R 2 are both protecting groups
  • PG 1 and PG 2 preferably differ from each other.
  • R 1 and R 2 are preferably orthogonal protecting groups.
  • orthogonal protecting group refers to a protecting group that is chemically resistant under one set of selected conditions, but is liable under another set of conditions, i.e. under certain conditions either PG 1 is cleaved and PG 2 is not, or vice versa.
  • PG 1 is preferably Boc and PG 2 is preferably Cbz.
  • 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.
  • compound A e.g. has as structure selected from the structure shown in the table low:
  • the present invention also relates to a method for the preparation of a compound (A), as described above, and a compound obtained or obtainable by said process, wherein the compound has a structure selected from any one of the structures 1 to 24 shown above.
  • the present compounds of formula (II) or (Ila) are useful in the preparation of a compound of formula (A), preferably (IX) shown above (which corresponds to structure 21 shown above), the compound being obtained or obtainable by the above described process, wherein said compound comprises less than 5 % by weight, more preferably less than 2 % by weight, more preferably less than 1 % by weight, more preferably less than 100 ppm, of the regio-isomeric side roduct (IX-S) as impurity
  • the compound (IX) does not comprise the region-isomeric compound (IX-S) as impurity.
  • step (b) the compound of formula II
  • the reaction may be carried out in any suitable solvent known to those skilled in the art.
  • the cyclization reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of R E -OH, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof, with R E being as described above and below, preferably wherein R E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl.
  • 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 alkyl, more preferably wherein R E methyl, ethyl or propyl, more preferably wherein R E methyl.
  • the cyclization is carried out at a temperature in the range of from -20 to 80°C, more preferably in the range of from 0 to 50, more preferably in the range of from 20 to 30 °C. During the reaction, the temperature may be varied or held essentially constant.
  • a base selected from the group consisting of NaOR E , Na-tert.butoxid, K-tert.butoxid, NaNH 2 , DBU, Tetramethylguanidin, Na-CH 2 S(0)CH 3 and mixtures of two or more thereof is employed, with R E being selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R E alkyl, more preferably wherein R E methyl, ethyl or propyl, more preferably wherein R E methyl.
  • the base is 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.
  • the sequence of mixing the components of the reaction mixture is not subject to specific restrictions.
  • 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 h, more preferably in the range of from 0 to 5 h, more preferably in the range of from
  • step (b) 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").
  • step (b) the compound of formula (II) is reacted with a base to give, as intermediate product, the compound of formula (la), which is thereafter reduced to give, optionally after further steps, the compound (A).
  • a reduction of the carbonyl group is thus carried out.
  • the present invention also relates to a process, as described above, as well as to a compound obtained or obtainable by said process, wherein the compound of formula (A) has the structure of formula (lb), and wherein in step (b), upon reaction with the base, a compound of formula (la) is formed
  • step (b) further comprises reducing the compound of formula (Ia).
  • compound (la) may be isolated or may be directly reduced in situ to give the compound of formula (lb). If such isolation is carried out, this may be carried out by any method known to those skilled in the art. Such isolation may comprise one or more stages wherein preferably at least one stage comprises a purification, such as an extraction and/or a precipitation and/or filtration.
  • step (b) comprises
  • step (bl) 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, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.
  • a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.
  • 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.
  • step (bl) is carried out at a temperature in the range of from -20 to 80 °C, more preferably in the range of from 0 to 50, more preferably in the range of from 20 to 30 °C.
  • the temperature may be varied or held essentially constant.
  • step (b3) is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, nPrOH (n-propanol), i-PrOH (isopropanol), THF (tetrahydrofuran), 2-MeTHF (2-methyl- tetrahydrofuran), MTBE (Methyl-tert-butylether), DIPET (diisiopropylethylether) , toluene, acetonitrile, CH 2 CI 2 and mixtures of two or more thereof.
  • a solvent selected from the group consisting of methanol, ethanol, nPrOH (n-propanol), i-PrOH (isopropanol), THF (tetrahydrofuran), 2-MeTHF (2-methyl- tetrahydrofuran), MTBE (Methyl-tert-butylether), DIPET (diisioprop
  • step (b3) is carried out at a temperature in the range of from -20 °C to 110 °C.
  • the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH 4 , NaCNBH 3 , NaBH(OAc) 3 , LiAlH 4 , LiBH 4 and H 2 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 reducing agent is selected from the group consisting of NaBH 4 , NaCNBH 3 , NaBH(OAc) 3 , LiAlH 4 and LiBH 4 , more preferably the reducing agent is NaBH 4 , NaCNBH 3 or NaBH(OAc) 3, more preferably NaBH 4 .
  • the compound (A) has the structure (la*) or (lb*)
  • step (b) preferably compound (la*) or (lb*) is prepared.
  • step (b) of the process of the invention the com ound of formula (II)
  • compound (II) comprises the single bond shown as " ⁇ > ⁇ ", i.e. that compound (II) has either the structure
  • compound (A) has the structure (A*), such as (la*) or (lb*), preferably in step (a) compound (II) is provided in the correct stereochemistry, i.e. as compound (II*)
  • step (b) This compound is then employed in step (b) instead of the racemic mixture consisting of (II*) and (II**) shown above.
  • step (b) in the cyclization reaction of compound (II), a compound (A) consisting of a racemic mixture is obtained.
  • a chiral resolution of (A) us carried out. More preferabl , in this case, R 2 is H, and compound (A) is (Al),
  • the compound (Al) contains from 20 to 75 % by weight-% of the compound of formula (Al *) based on the total weight of the sum of (Al *) and (Al **), and wherein this mixture is then resolved by chiral resolution to finally give, optionally after further steps, the compound (A) in which R 2 is H.
  • (II) preferably separating the precipitated, preferably crystallized, chiral acid salt (T) of the compound of formula (Al) from the mixture obtained in (I), wherein the chiral acid salt (T) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al),
  • step (III) converting the chiral acid salt (T) to the free base.
  • a chiral acid salt (T*) of at least part of the compound of formula (II) is formed, and at least part of this chiral acid salt (T*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (T) and the solvent.
  • the chiral acid is preferably a single stereoisomer of a tartaric acid derivative, more 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.
  • the chiral acid is a di-benzoyl tartaric acid or a di-toluoyl tartaric acid.
  • Al is (la)
  • R 2 H.
  • the chiral acid is preferably or a di-toluoyl tartaric acid, more preferably L-di-toluoyl tartaric acid (LTTA).
  • LTTA L-di-toluoyl tartaric acid
  • the suitable solvent is preferably methanol.
  • the chiral acid is preferably a di-benzoyl tartaric acid, more preferably D-di-benzoyl tartaric acid (DBTA).
  • DBTA D-di-benzoyl tartaric acid
  • the suitable solvent is preferably acetone.
  • the compound (A) is preferably being used for the preparation of the compound of formula (IX) (Suvorexant) with a process comprising
  • the present invention relates to a process for the preparation of a compound of formula (IX) , wherein a compound of formula
  • 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,
  • step (a) compound (II) is provided according to the processes according to the present invention as disclosed above.
  • compound (la) with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being PG 2 , thus compound (la), with R 1 being H and with R 2 being
  • the present invention also relates to the use ooff tthhee ccoommppoouunndd ooff ffoorrmmuullia (la), preferably (la*), in which R 1 is H and R 2 is PG 2 , for the preparation of Suvorexant.
  • the present invention relates to a process for the preparation of a compound of formula (IX) and a compound of formula (IX) obtained or obtainable by said process comprising
  • 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 1 is H and R 2 is PG 2 ,
  • step (B) transforming the compound of step (A) into the compound of formula (IX), wherein preferably compound (II) I (a) is provided by processes according to the present invention as disclosed above
  • step (B) comprises
  • transition metal is preferably selected from the group consisting of Ir, Pt, Fe, Rh, Pd, Re, Ru, Ni and Co,
  • X* is a leaving group, preferably CI.
  • the present invention further relates to a compound obtained or obtainable by said process (this includes a salt thereof).
  • the present invention relates to a process for the preparation of a compound of formula (IX) , wherein a compound of formula
  • R E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R 1 E is alkyl, more preferably wherein R E is methyl, ethyl or propyl, more preferably wherein R E is methyl,
  • compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and with R 2 being PG 2 , thus compound (lb) with R 1 bein H and
  • the present invention also relates to the use of the compound of formula (lb), preferably (lb*), in which R 1 is H and R 2 is PG 2 , for the preparation of compound (IX Suvorexant)
  • the present invention relates to a process for the preparation of a compound of formula (IX) comprising
  • 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 methyl, wherein R 1 is H and R 2 is PG 2 ,
  • R 1 being H and with R 2 being PG 2 , preferably (la*) with R 1 being H and with R 2 being PG 2 , and reducing the resulting compound of formula (la), preferably (la*).
  • step (B) comprises
  • X* is a leaving group, preferably CI.
  • the present invention further relates to a compound obtained or obtainable by said process.
  • compound (A) has the structure (la), preferably (la*), with R 1 being H and with R 2 bein
  • Vila i.e. the structure (Vila), preferably (Vila*), with R 1 being H.
  • the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure (Vila), preferably (Vila*), with R 1 being H,
  • 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 2 is
  • the present invention also relates to the use of a compound (Vila), preferably
  • the present invention relates to a process for the preparation of a compound of formula (IX) comprising
  • R E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R E alkyl, more preferably wherein R E methyl, ethyl or propyl, more preferably wherein R E methyl, and wherein R 2 is
  • step (B) transforming the compound of step (A) into the compound of formula (IX).
  • step (B) further comprises
  • X* is a leaving group, preferably CI.
  • the present invention further relates to a compound obtained or obtainable by said process. Further, the present invention relates to a compound of formula (Vllb), preferably (Vllb*), as mentioned above. Further the present invention relates to the use of a compound (Vllb), preferably (Vllb*), as mentioned above.
  • compound (A) has the structure (lb), preferably (lb*), with R 1 being H and with R 2 being
  • Vllb i.e. the structure (Vllb), preferably (Vllb*), with R 1 being H.
  • the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure (Vila), preferably (Vila*), with R 1 being H,
  • 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 meth l, and wherein R 2 is
  • the present invention relates to a process for the preparation of a compound of formula (IX) comprising
  • 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 2 is
  • step (B) comprises
  • X* is a leaving group, preferably CI.
  • compound (A) has the structure (la), preferably (la*), with R 1 being R A and with R 2 bein PG 2 .
  • R A is
  • the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure
  • R 1 is R A with R A being
  • R 2 is PG 2 , the process comprising
  • 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,
  • R 1 is R A with R A bein
  • R 2 is PG 2 , preferably the compound of formula (la*), wherein R 1 is R A with R A being
  • R 2 is PG 2 ,
  • R 1 is R A with R A bein
  • R 2 is PG 2 , preferably the compound of formula (la*), wherein R 1 is R A with R A being
  • R 2 is PG 2 .
  • compound (Villa), more preferably compound (Villa*), is used for the preparation of Suvorexant.
  • the present invention also relates to the use of compound (Villa), more preferably of com ound (Villa*), for the preparation of Suvorexant
  • the present invention relates to a process for the preparation of a compound of formula (IX) comprising
  • 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, wherein R 1 is R A with R A being
  • R 2 is PG 2 , preferably the compound of formula (la*), wherein R 1 is R ⁇ with R A being
  • R 2 is PG 2 ,
  • step (B) further comprises
  • the present invention further relates to a compound obtained or obtainable by said process. Further, the present invention relates to a compound of formula (Villa), preferably (Villa*), as mentioned above. Further the present invention relates to the use of a compound (Villa), preferably (Villa*), as mentioned above.
  • compound (A) has the structure (lb), preferably (lb*), with R 1 being R A and with R 2 bein PG 2 .
  • R A is
  • the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure
  • R 1 is R A with R A being
  • R 2 is PG 2 , the process comprising providing a compound of formula II)
  • 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,
  • R 1 is R A with R A bein
  • R 2 is PG 2 , preferably the compound of formula (la*), wherein R 1 is R A with R A being
  • R 2 is PG 2 ,
  • R 1 is R A with R A bein
  • R 2 is PG 2 , preferably the compound of formula (lb*), wherein R 1 is R A with R A being
  • R 2 is PG 2 .
  • compound (Vlllb), more preferably compound (Vlllb*), is used for the preparation of compound (IX).
  • the present invention also relates to the use of compound (Vlllb), more preferably of compound (Vlllb*), for the preparation of compound (IX).
  • the present invention relates to a process for the preparation of the compound of formula (IX) comprising
  • 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, wherein R 1 is R A with R A being
  • R 2 is PG 2 , preferably the compound of formula (la*), wherein R 1 is R ⁇ with R A being
  • R 2 is PG 2 , (b) reacting the compound of formula (II), preferably (II*), with a base, to give the compound of formula (Villa), preferably (Villa*), and reducing the compound compound of formula (Villa), preferably (Villa*),
  • step (B) further comprises
  • E is -COOH or a reactive carboxy group.
  • the present invention further relates to a compound obtained or obtainable by said process. Further, the present invention relates to a compound of formula (Vlllb), preferably (Vlllb*), as mentioned above. Further the present invention relates to the use of a compound (Vlllb), preferably (Vlllb*), as mentioned above.
  • compound (A) has the structure (la), preferably (la*), with R 1 bein R A and with R 2 being R B
  • the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure
  • R 1 is R A and R 2 is R B ,
  • R 1 is R A and R 2 is R B ,
  • compound (IXa), more preferably compound (IXa*), is used for the preparation of compound (IX).
  • the present invention also relates to the use of compound (IXa), more preferably compound of IXa*), for the preparation of compound (IX)
  • the present invention relates to a process for the preparation of compound IX comprising
  • R 1 is R A and R 2 is R B ,
  • step (B) further comprises
  • the present invention further relates to a compound obtained or obtainable by said process. Further, the present invention relates to a compound of formula (IXa), preferably (IXa*), as mentioned above. Further the present invention relates to the use of a compound (IXa), preferably (IXa*), as mentioned above.
  • the protecting group PG 2 is removed.
  • the way of removing the protecting group PG 2 depends on the protecting group used. Suitable methods are known to those skilled in the art.
  • the removal of PG 2 is carried out under reductive conditions. More preferably, the removal is carried out with hydrogen and a metal catalyst, preferably a palladium catalyst, more preferably, the protecting group is removed with Pd/C.
  • the removal of group PG 2 may be carried out in any suitable solvent known to those skilled in the art.
  • the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, iPrOH, nPrOH, EtOAc, iPrOAc and mixtures of two or more thereof.
  • a solvent selected from the group consisting of methanol, ethanol, iPrOH, nPrOH, EtOAc, iPrOAc and mixtures of two or more thereof.
  • the removal of group PG 2 is carried out at a temperature in the range of from 0 °C to 100 °C, more preferably in the range of from 10 °C to 70 °C, more preferably at room temperature 20 °C to 50 °C.
  • the temperature may be varied or held essentially constant.
  • the reaction is preferably carried out at a pressure in the range of from 1 to 4 bar, more preferably, 1.0 to 2.5 bar.
  • the compound is preferably allowed to react for a time in the range of from 10 min to 180 min, more preferably in the range of from 20 to 120 min, more preferably in the range of from 30 to 60 min.
  • step (dl) the respective compound is reacted, i.e. coupled, with a compound of formula (XI), wherein E is -COOH or a reactive carboxy group, to give a compound of formula (Vila) in which R 1 is H, preferably a compound of formula (Vila*) in which R 1 is H.
  • reactive carboxy group as used in this context of the present invention is intended to mean an activated carboxy lie 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.
  • activated carboxylic acid derivative 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 ⁇ , ⁇ '- carbonyldiimidazole and the like, and esters derived from activation of the corresponding carboxylic acid with a coupling reagent.
  • 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 ⁇ , ⁇ '- carbony
  • Such coupling reagents include, but are not limited to, 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"-tetramethyluronium-2-fluoro- hexafluorophosphate); BOP (benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate); PyBOP (benzotriazol-l-yl-oxy-trispyrroli
  • EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, CDC (1-cyclohexyl- 3-(2-morpholinoethyl)carbodiimide), Pyclop, T3P, CDI, Mukayama's reagent, HODhbt, HAPyU, TAPipU, TPTU, TSTU, TNTU, TOTU, BroP, PyBroP, BOI, TOO, NEPIS, BBC, BDMP, BOMI, AOP, BDP, PyAOP, TDBTU, BOP-C1, CIP, DEPBT, Dpp-Cl, EEDQ, FDPP, HOTT, TOTT, PyCloP.
  • 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.
  • 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.
  • 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
  • EDC l-ethyl-3-(3- dimethylaminopropyl) carbodiimide 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.
  • EDC l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride
  • CDC l-cyclohexyl-3-(2- morpholinoethyl)
  • E is -COOH, as mentioned above, and the reaction includes the addition of a coupling reagent or a reagent that forms in situ an acid chlorid with E, such as oxalyl chloride.
  • the coupling with E being -COOH or a reactive carboxy group is preferably carried out in the presence of a suitable base, preferably an organic base, most preferably an amino group comprising base, most preferably a base selected from the group consisting of diisopropylamine (DIEA), triethylamine (TEA), N-methylmorpholine, N-methylimidazole, l,4-diazabicyclo[2.2.2]octane (DABCO), N-methylpiperidine, N-methylpyrrolidine, 2,6- lutidine, collidine, pyridine, 4-dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • a suitable base preferably an organic base, most preferably an amino group comprising base, most preferably a base selected from the group consisting of diisopropylamine (DIEA), triethylamine (TEA), N-methylmorpholine, N-methyl
  • the reaction is carried out in an organic solvent, such as N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, acetone, dimethyl acetamide (DMA), dimethyl formamide (DMF), formamide, tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, ter - butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, tetrachloromethane and mixtures of two or more thereof. More preferably, the reaction is carried out in dichloromethane.
  • NMP N-methyl pyrrolidone
  • DMSO dimethyl sulfoxide
  • DMA dimethyl formamide
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • MTBE ter - butyl methyl ether
  • DCM dichloromethane
  • chloroform tetrachloromethan
  • the temperature of the coupling reaction is preferably in the range of from 0 to 100 °C, more preferably in the range of from 5 to 50 °C, and especially preferably in the range of from 15 to 30 °C. During the course of the reaction, the temperature may be varied, preferably in the above given ranges, or held essentially constant.
  • step (el) the compound is reduced.
  • a reduction of the carbonyl group is thus carried out.
  • the reduction is preferably carried out as described with respect to step (b3) described hereinunder and above.
  • the reduction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE, DIPET, toluene, acetonitrile, CH 2 CI 2 and mixtures of two or more thereof.
  • step (b3) is carried out at a temperature in the range of from -20 °C to 110 °C.
  • step (el) is carried out at a temperature in the range of from -20 °C to 110 °C.
  • the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH 4 , NaCNBH 3 , NaBH(OAc) 3 , LiAlH 4 , LiBH 4 and H 2 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 reducing agent is selected from the group consisting of NaBH 4 , NaCNBH 3 , NaBH(OAc) 3 , LiAlH 4 and LiBH 4 , more preferably the reducing agent is NaBH 4 , NaCNBH 3 or NaBH(OAc) 3 , more preferably NaBH 4 .
  • step (fl) the respective compound is reacted with a compound of formula (XII)
  • 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.
  • 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, methyltertbutylether, diethylether, diisopropylether, toluol, acetonitrile and mixtures of two or more thereof.
  • a solvent selected from the group consisting of dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether
  • the reaction is carried out at a temperature in the range of from 0 to 80 0 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.
  • 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.
  • reaction mixture obtained is subjected to a suitable work-up, such as an isolation of the respective compound.
  • working up may comprise one or more stages wherein preferably at least one stage comprises purification, such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like.
  • purification such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like.
  • some reactions may be carried out with the crude intermediate products or even in situ.
  • compound (II) is provided in step (a) according the process of the invention as disclosed above.
  • the compound of formula (IX) obtained or obtainable by the above-described process or a pharmaceutical composition comprising this compound is useful in a method of antagonizing orexin receptor activity.
  • the present invention also describes the compound of formula (IX) obtained or obtainable by the above-described process or a pharmaceutical composition comprising this compound for use as antagonists of orexin receptor activity, in particular for use in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with orexin receptors, in particular for enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep; increasing stage 2 sleep; decreasing fragmentation of sleep patterns; treating insomnia; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a ma
  • the compound of formula (IX) obtained or obtainable by the above described process or a pharmaceutical composition comprising this compound is used for treating or preventing a sleep disorder, in particular for enhancing the quality of sleep or for treating insomnia in a mammalian patient, in particular, for treating or controlling obesity in a mammalian patient.
  • treatment and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such a disease or disorder.
  • R 2 is selected from the group consisting of H, PG 2 and R B with R 1 B being
  • n 0 or 1
  • 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,
  • step (b) upon reaction with the base a compound of formula (la) is formed
  • step (b) further comprises reducing the compound of formula (la).
  • step (b) further comprises reducing the compound of formula (la).
  • step (b) upon reaction with the base a compound of formula (la*) is formed
  • step (b) further comprises reducing the compound of formula (la*).
  • PG 1 is selected from the group consisting of Benzyl (Bn), t-butyloxycarbonyl (Boc), Cbz
  • PG 2 is selected from the group consisting of Benzyl, t-butyloxycarbonyl (Boc), Cbz
  • Rl is H
  • step (b) comprises
  • step (bl) is carried out at a temperature in the range of from -20°C to 80°C, more preferably in the range of from 0 to 50, more preferably in the range of from 20 to 30 °C.
  • the temperature may be varied or held essentially constant.
  • step (b3) the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH4, NaCNBFB, NaBH(OAc)3, LiAlH4, LiBH4 and H2 in the presence of at least one transition metal.
  • a reducing agent selected from the group consisting of NaBH4, NaCNBFB, NaBH(OAc)3, LiAlH4, LiBH4 and H2 in the presence of at least one transition metal.
  • compound (II) contains of from 20 to 75 % by weight % of the compound of formula (II*) based on the total weight of the sum of (II*) and (II**) and wherein mixture is resolved by chiral resolution to give the compound (II*).
  • R 1 is H and R 2 is PG 2 .
  • step (a) comprises
  • R la is H, R 1 , PG 1 , R A or PG la
  • R 2a is H, R 2 , PG 2 , R B or PG 2a and wherein PG la and PG 2a are, independently of each other, suitable protecting groups,
  • step (a3) a compound having the structure
  • (iia) preferably separating the precipitated, preferably crystallized, chiral acid salt (Sa) of the compound of formula (Iia) from the mixture obtained in (ia), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Iia*) based on the total weight of the chiral acid salt of the compound of formula (Iia),
  • step (a) comprises

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Abstract

La présente invention concerne un procédé pour la préparation d'un composé de formule (IIa') et (II). En outre, la présente invention concerne un composé de formule (IIa') et un composé de formule (II) ainsi que tous les intermédiaires préparés pendant le procédé de préparation du composé (IIa') et du composé (II).
PCT/EP2015/067996 2014-08-04 2015-08-04 Nouvelles voies de synthèse pour la préparation de suvorexant WO2016020406A1 (fr)

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CN111320616B (zh) * 2018-12-13 2023-02-17 上海医药工业研究院 一种苏沃雷生中间体的消旋化方法

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