Method for preparing n-substituted tetrahydrofuran-3-amines

Abstract

The present invention relates to a method for preparing a N-substituted tetrahydrofuran-3-amine of the formula (I) or a stereoisomer thereof where R2 is as defined in the claims and the description, by reacting maleic or fumaric acid or a suitable derivative thereof with an amine NH2R2 in a Michael addition reaction in which the amine is added to the C-C double bond of the maleic or fumaric acid or the suitable derivative thereof to afford an N-substituted aspartic acid or an acid derivative thereof, reducing the carboxylic groups thereof and subjecting the resulting diol to an intramolecular cyclic ether formation.

Description

[0001] Method for preparing N-substituted tetrahydrofuran-3-amines

[0002] The present invention relates to a method for preparing a N-substituted tetrahydrofu- ran-3-amine of the formula (I) or a stereoisomer thereof where R2is as defined below, by reacting maleic or fumaric acid or a suitable derivative thereof with an amine NH22in a Michael addition reaction in which the amine is added to the C-C double bond of the maleic or fumaric acid or the suitable derivative thereof to afford an N-substituted aspartic acid or an acid derivative thereof, reducing the carboxylic groups thereof and subjecting the resulting diol to an intramolecular cyclic ether formation.

[0003] TECHNICAL BACKGROUND

[0004] Tetrahydrofuran-3-amines, such as N-phenyl-tetrahydrofuran-3-amine, are valuable intermediates. N-phenyl-tetrahydrofuran-3-amine is for example used in the preparation of the physiological cooling agent (E)-3-(1 ,3-benzodioxol-5-yl)-N-phenyl-tetrahydrofu- ran-3-yl-propen-2-amide, which is described in WO 2019 / 043164 and WO 2022 / 207944. In the prior art, N-phenyl-tetrahydrofuran-3-amine is prepared by reacting dihydrofuran-3(2H)-one and aniline under reductive conditions. This synthetic path does however not work satisfactorily. Especially the high water-solubility of the di- hydrofuran-3(2H)-one precursor makes its preparation and isolation problematic. Various preparation methods for the dihydrofuranone are described in WO 2014 / 139080, such as oxidation of the corresponding alcohol or cyclization of the corresponding open-chained oxo-diol. All these methods usually require aqueous work-up followed by extraction of the product from the aqueous phase with an organic solvent. The high water solubility of the dihydrofuranone makes this route rather inefficient and cumbersome.

[0005] It was the object of the invention to provide an alternative synthetic route to N-substi- tuted tetrahydrofuran-3-amines, such as N-phenyl-tetrahydrofuran-3-amine, which does not have the drawback of the prior art preparation method. SUMMARY OF THE INVENTION

[0006] It was found that a reaction path involving aza-Michael addition of an amine NH2R2to maleic or fumaric acid or a suitable derivative thereof, reduction of the carboxylic groups in the resulting N-substituted aspartic acid (derivative) and subjection of the obtained diol to an intramolecular cyclic ether formation affords the desired N-substituted tetrahydrofuran-3-amine (I) in satisfactory yield and purity.

[0007] The invention relates thus to a method for preparing a N-substituted tetrahydrofuran-3- amine of the formula (I) or a stereoisomer thereof where

[0008] R2is Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Cs-Ce-cycloalkyl, phenyl or a 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, where the phenyl ring and the heterocyclic ring may carry 1 , 2, 3, 4 or 5 substituents R3; where each R3is independently selected from the group consisting of halogen, Ci-C4-alkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy-Ci-C4-alkyl; comprising

[0009] (i) reacting the compound (II) wherein

[0010] X1and X2are independently OH or OR1, where each R1is independently C1-C10- alkyl, phenyl or benzyl; or

[0011] X1and X2form together -O-, with an amine (III)

[0012] NH2R2 where R2is as defined above, to the compound (IV)

[0013] (ii) reducing the compound (IV) to the compound (V) and

[0014] (iii) subjecting the compound (V) to a cyclization reaction (intramolecular ether formation) to compound (I).

[0015] DETAILED DESCRIPTION OF THE INVENTION

[0016] Definitions

[0017] The waved line in the compound (II) shows that the C-C double bond can be substituted to give (Z) or (E) conformation. The compound (II) can thus be maleic acid or a derivative thereof (to be more precise a Ci-C -alkyl, phenyl or benzyl mono- or diester of maleic acid (where the diester can be symmetric (i.e. R1has the same meaning in the two OR1groups) or can be a mixed diester (i.e. R1has different meanings in the two OR1groups), where out of economic reasons symmetric diesters are preferred), or maleic anhydride); see formula (I I. a); or can be fumaric acid or a derivative thereof (to be more precise a Ci-Cw-alkyl, phenyl or benzyl mono- or diester of fumaric ester (where the diester can be symmetric (i.e. R1has the same meaning in the two OR1 groups) or can be a mixed diester (i.e. R1has a different meaning in the two OR1groups), where out of economic reasons symmetric diesters are preferred); in case of fumaric acid X1and X2cannot form together -O-); see formula (II. b):

[0018] The term "halogen" denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

[0019] The term "alkyl" is used in the proper sense and refers to saturated straight-chain (linear) or branched non-cyclic aliphatic hydrocarbon radicals having the indicated number of carbon atoms. Ci-C2-Alkyl denotes thus an alkyl radical with 1 to 2 carbon atoms. Examples are methyl and ethyl. Ci-C4-Alkyl denotes an alkyl radical with 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Ci-Ce-Alkyl denotes an alkyl radical with 1 to 6 carbon atoms. Examples are, in addition for those mentioned above for Ci-C4-alkyl, n-pentyl, 1-methylbutyl, 2-methyl- butyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1 , 1-dimethylpropyl, 1 ,2-dime- thylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1- dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 , 1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and other structural isomers thereof. Ci- Cs-Alkyl denotes an alkyl radical with 1 to 8 carbon atoms. Examples are, in addition for those mentioned above for Ci-Ce-alkyl, n-heptyl, n-octyl, 2-ethylhexyl and (other) structural isomers thereof. Ci-C -Alkyl denotes an alkyl radical with 1 to 10 carbon atoms. Examples are, in addition for those mentioned above for Ci-Cs-alkyl, n-nonyl, n- decyl, 2-propylheptyl and (other) structural isomers thereof. Ca-Cs-Alkyl denotes an alkyl radical with 3 to 5 carbon atoms. Examples are n-propyl, isopropyl, n-butyl, sec-bu- tyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dime- thylpropyl, 1-ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl and other structural isomers thereof.

[0020] The term "haloalkyl" denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms (= Ci-Ce-haloalkyl), more frequently 1 to 4 carbon atoms (= Ci-C4-haloalkyl), as defined above, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, bromomethyl, 1 -fluoroethyl, 2-fluo- roethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1-chloroethyl, 2-chloro- ethyl, 2, 2, -dichloroethyl, 2,2,2-trichloroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluo- roethyl, 2,2-dichloro-2-fluoroethyl, 1-bromoethyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoro- propyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1 , 1 , 1 -trifluoroprop-2- yl, 3-chloropropyl, and the like.

[0021] The term "cycloalkyl" as used herein denotes a monocyclic, saturated cycloaliphatic radical having usually from 3 to 6 carbon atoms (= Cs-Ce-cycloalkyl), preferably 5 or 6 carbon atoms (= Cs-Ce-cycloalkyl), as (only) ring members. Examples for Cs-Ce-cycloal- kyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples for Cs-Ce-cycloalkyl are cyclopentyl and cyclohexyl.

[0022] The term "alkoxy-alkyl" as used herein, refers to an alkyl group, as defined above, where one hydrogen atom is replaced by an alkoxy group. The term "Ci-C4-alkoxy-Ci- C4-alkyl" as used herein, refers to an alkyl group having 1 to 4 carbon atoms, as defined above, where one hydrogen atom is replaced by a Ci-C4-alkoxy group. Examples are methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butoxymethyl, sec-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, 1 -methoxyethyl, 1-ethoxyethyl,

[0023] 1-propoxyethyl, 1 -isopropoxyethyl, 1-n-butoxyethyl, 1-sec-butoxyethyl, 1-isobutoxy- ethyl, 1-tert-butoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxy- ethyl, 2-n-butoxyethyl, 2-sec-butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl, 1 -methoxypropyl, 1-ethoxypropyl, 1 -propoxypropyl, 1-isopropoxypropyl, 1-n-butoxypropyl, 1- sec-butoxypropyl, 1-isobutoxypropyl, 1-tert-butoxypropyl, 2-methoxypropyl, 2-ethoxy- propyl, 2-propoxypropyl, 2-isopropoxypropyl, 2-n-butoxypropyl, 2-sec-butoxypropyl, 2- isobutoxypropyl, 2-tert-butoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypro- pyl, 3-isopropoxypropyl, 3- n- butoxy propyl, 3-sec-butoxypropyl, 3-isobutoxypropyl, 3- tert- butoxy propyl, and the like. "Ci-C3-Alkoxy-C2-C3-alkyl" as used herein, refers to an alkyl group having 2 to 3 carbon atoms, as defined above, where one hydrogen atom is replaced by a Ci-Cs-alkoxy group. Examples are 1-methoxyethyl, 1-ethoxyethyl, 1- propoxyethyl, 1 -isopropoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-iso- propoxyethyl, 1-methoxypropyl, 1-ethoxypropyl, 1-propoxypropyl, 1-isopropoxypropyl,

[0024] 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl, 2-isopropoxypropyl, 3-methoxypro- pyl, 3-ethoxypropyl, 3-propoxypropyl, 3-isopropoxypropyl, and the like.

[0025] R2can be, inter alia, a 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members. An unsaturated heterocycle contains at least one C-C and / or C-N and / or N-N double bond(s). Partially unsaturated heterocyclic rings contain less than the maximum number of C-C and / or C-N and / or N-N double bond(s) allowed by the ring size. A fully (or maximally) unsaturated heterocycle contains as many conjugated C-C and / or C-N and / or N-N double bonds as allowed by the size(s) of the ring(s). Maximally unsaturated 5- or 6-membered heteromonocyclic rings are generally aromatic. Exceptions are maximally unsaturated 6-membered rings containing O and / or S as ring members, such as pyran and thiopyran, which are not aromatic.

[0026] Examples for 5- or 6-membered saturated heterocyclic rings containing 1 or 2 heteroatoms selected from N, O and S as ring members are: tetrahydrofuran-2-yl, tet- rahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 ,3-dioxolan-2-yl, 1 ,3-diox- olan-4-yl, 1 ,3-ditholan-2-yl, 1 ,3-ditholan-4-yl, 1 ,3-oxathiolan-2-yl, 1 ,3-oxathiolan-4-yl,

[0027] 1.3-oxathiolan-5-yl, pyrrolidin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrazolidin-1 -yl, pyra- zolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1 -yl, imidazolidin-2-yl, imidaz- olidin-4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-

[0028] 2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3- yl, thiazolidin-4-yl, thiazolidin-5-yl, isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4- yl, isothiazolidin-5-yl, 2-tetrahydropyranyl, 3- tetrahydropyranyl, 4-tetrahydropyranyl,

[0029] 1.3-dioxan-2-yl, 1 ,3-dioxan-4-yl, 1 ,3-dioxan-5-yl, 1 ,4-dioxan-2-yl, piperidin-1-yl, piperi- din-2-yl, piperidin-3-yl, piperidin-4-yl, hexahydropyridazin-1-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, hexahydropyrimidin-1-yl, hexahydropyrimidin-2-yl, hexahydro- pyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-1 -yl, piperazin-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4- yl, and the like;

[0030] Examples for 5- or 6-membered partially unsaturated heterocyclic rings containing 1 or 2 heteroatoms selected from N, O and S as ring members are: 2,3-dihydrofu- ran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,3-dihy- drothien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl, 2,5-dihydrothien-3-yl, 2-pyr- rolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-

[0031] 3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxa- zolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4- isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin- 5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol- 2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihy- dropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5- yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihy- dropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl,

[0032] 2.3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxa- zol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-di- hydrooxazol-4-yl, 3,6-dihydro-2H-pyran-2-, -3-, -4-, -5- or 6-yl, 3,4-dihydro-2H-pyran-2-, -3-, -4-, -5- or 6-yl, 3,6-dihydro-2H-thiopyran-2-, -3-, -4-, -5- or 6-yl, 3,4-dihydro-2H-thi- opyran-2-, -3-, -4-, -5- or 6-yl, 2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- or tetra- hydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- or tetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- or tetrahydropyrimidinyl, di- or tetrahydropyrazinyl; Examples for 5- or 6-membered fully unsaturated (all except for pyranyl and thiopyranyl being aromatic) heterocyclic rings containing 1 or 2 heteroatoms selected from N, O and S as ring members are: e.g. 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyr- rolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidaz- olyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxa- zolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-iso- thiazolyl, 5-isothiazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl, 4H-pyran-4- yl, 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thi- opyran-6-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl and 4H-thiopyran-4-yl.

[0033] Examples for 5- or 6-membered heteroaromatic rings containing 1 or 2 heteroatoms selected from N, O and S as ring members are thus 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyra- zolyl, 1 -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-ox- azolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-iso- thiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.

[0034] The term "stereoisomer" as used in context with the present invention relates specifically to optical isomers, such as enantiomers or diastereomers, the latter existing due to more than one stereogenic center in the molecule. The compounds of the formula (I) have at least one stereogenic center, namely the carbon atom of the tetrahydrofuran ring carrying the NHR2group. Another stereogenic center may be present in the radical R2, e.g. if this is or comprises an alkyl group with four or more carbon atoms with a stereogenic center, such as in sec-butyl (the carbon atom marked with an asterisk in the sec-butyl group -*CH(CH3)CH2CH3 being in here the stereogenic center), or a suitably substituted haloalkyl group, such as chlorofluoromethyl.

[0035] Embodiments (E.x) of the invention

[0036] General and preferred embodiments E.x are summarized in the following, non-exhaus- tive list. Further preferred embodiments become apparent from the paragraphs following this list.

[0037] E.1 . A method for preparing a N-substituted tetrahydrofuran-3-amine of the formula (I) where

[0038] R2is Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Cs-Ce-cycloalkyl, phenyl or a 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, where the phenyl ring and the heterocyclic ring may carry 1 , 2, 3, 4 or 5 substituents R3; where each R3is independently selected from the group consisting of halogen, Ci-C4-alkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy-Ci-C4-alkyl; comprising

[0039] (i) reacting the compound (II) wherein

[0040] X1and X2are independently OH or OR1, where each R1is independently Ci-C -alkyl, phenyl or benzyl; or

[0041] X1and X2form together -O-, with an amine (III)

[0042] NH2R2(III) where R2is as defined above, to the compound (IV)

[0043] (ii) reducing the compound (IV) to the compound (V) and

[0044] (iii) subjecting the compound (V) to a cyclization reaction to compound (I).

[0045] E.2. The method according to embodiment E.1 , where R2is Ci-Ce-alkyl, Ci-C4-alkoxy- Ci-C4-alkyl, Cs-Ce-cycloalkyl, phenyl or a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, where the phenyl ring and the heteroaromatic ring may carry 1 , 2 or 3 substituents R3.

[0046] E.3. The method according to embodiment E.2, where R2is Ci-Ce-alkyl, Ci-C4-alkoxy- Ci-C4-alkyl, Cs-Ce-cycloalkyl or phenyl, where the phenyl ring may carry 1 , 2 or 3 substituents R3.

[0047] E.4. The method according to embodiment E.2, where R2is Ci-Ce-alkyl, Ci-Cs-alkoxy- C2-C3-alkyl, Cs-Ce-cycloalkyl, phenyl or a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, where the phenyl ring and the heteroaromatic ring may carry 1 , 2 or 3 substituents R3.

[0048] E.5. The method according to embodiment E.4, where R2is Ci-Ce-alkyl, Ci-Cs-alkoxy- C2-C3-alkyl, Cs-Ce-cycloalkyl or phenyl, where the phenyl ring may carry 1 , 2 or 3 substituents R3.

[0049] E.6. The method according to embodiment E.4, where R2is Cs-Cs-alkyl, Ci-Cs-alkoxy- C2-C3-alkyl, Cs-Ce-cycloalkyl, phenyl or pyridyl.

[0050] E.7. The method according to embodiment E.6, where R2is Cs-Cs-alkyl, Ci-Cs-alkoxy- C2-C3-alkyl, Cs-Ce-cycloalkyl or phenyl.

[0051] E.8. The method according to any of embodiments E.1 to E.5, where R2is phenyl which may carry 1 , 2 or 3 substituents R3.

[0052] E.9. The method according to embodiment E.8, where R2is (unsubstituted) phenyl. E.10. The method according to any of the preceding embodiments, where the compound (II) is a compound (II. a) where X1and X2are OH or OR1, where R1is as defined in embodiment E.1.

[0053] E.11. The method according to embodiment E.10, where X1and X2are OH or OR1, where R1is Ci-C -alkyl.

[0054] E.12. The method according to embodiment E.11 , where X1and X2are OH or OR1, where R1is Ci-Cs-alkyl.

[0055] E.13. The method according to embodiment E.12, where X1and X2are OH or OR1, where R1is Ci-C4-alkyl; where R1is specifically ethyl.

[0056] E.14. The method according to any of embodiments E.1 to E.13, where X1and X2are OR1, where R1is as defined in embodiment E.1.

[0057] E.15. The method according to embodiment E.14, where X1and X2are OR1, where R1is Ci-Cw-alkyl.

[0058] E.16. The method according to embodiment E.15, where X1and X2are OR1, where R1is Ci-Cs-alkyl.

[0059] E.17. The method according to embodiment E.16, where X1and X2are OR1, where R1is Ci-C4-alkyl; where R1is specifically ethyl.

[0060] E.18. The method according to any of the preceding embodiments, where X1and X2have the same meaning, i.e. are both OH or are both OR1, where R1has the same meaning, or form both together -O-.

[0061] E.19. The method according to any embodiments E.1 to E.9 and E.14 to E.17, where the compound (II) is a compound (II. b) where X1and X2are OH or OR1, where R1is as defined in embodiment E.1. E.20. The method according to embodiment E.19, where R1is Ci-C -alkyl.

[0062] E.21. The method according to any of embodiments E.19 or E.20, where X1and X2are OR1, wherein R1is Ci-C4-alkyl; where R1is specifically ethyl.

[0063] E.22. The method according to any of embodiments E.19 to E.21 , where X1and X2have the same meaning, i.e. are both OH or are both OR1, where R1has the same meaning.

[0064] E.23. The method according to any of the preceding embodiments, where step (i) is carried out in the presence of an inorganic or organic acid (other than compound (II) (if this used at all in form of the acid)).

[0065] E.24. The method according to embodiment E.23, where step (i) is carried out in the presence of an organic acid.

[0066] E.25. The method according to embodiment E.24, where step (i) is carried out in the presence of a sulfonic acid.

[0067] E.26. The method according to embodiment E.25, where step (i) is carried out in the presence of methanesulfonic acid, trifluoromethanesulfonic acid or para-tol- uenesulfonic acid.

[0068] E.27. The method according to embodiment E.26, where step (i) is carried out in the presence of methanesulfonic acid or para-toluenesulfonic acid.

[0069] E.28. The method according to embodiment E.27, where step (i) is carried out in the presence of para-toluenesulfonic acid.

[0070] E.29. The method according to embodiment E.23, where step (i) is carried out in the presence of an inorganic acid.

[0071] E.30. The method according to embodiment E.29, where step (i) is carried out in the presence of HCI, phosphinic acid or sulfamic acid.

[0072] E.31. The method according to embodiment E.30, where step (i) is carried out in the presence of HCI.

[0073] E.32. The method according to any of embodiments E.23 to E.31 , where acid is used in an amount of from 0.005 mol to 10 mol, preferably from 0.01 to 5 mol, more preferably from 0.01 to 1 mol, even more preferably from 0.01 to 0.5 mol, mol, in particular from 0.01 to 0.1 mol, more particularly from 0.01 to 0.08 mol, per 1 mol of that starting compound [amine (III) or compound (II)] which is not used in excess [this is generally compound (II)] [if amine (III) or compound (II) are used in stoichiometric, i.e. equimolar amounts, the above amounts of the acid can of course be relative to any of the two compounds (II) or (III)].

[0074] E.33. The method according to embodiment E.32, where the acid is a carboxylic acid, and is used in an amount of from 1 mol to 10 mol, preferably from 2 mol to 10 mol, per 1 mol of that starting compound [amine (III) or compound (II)] which is not used in excess [this is generally compound (II)] [if amine (III) or compound (II) are used in stoichiometric, i.e. equimolar amounts, the above amounts of the acid can of course be relative to any of the two compounds (II) or (III)]. E.34. The method according to embodiment E.32, where the acid is an inorganic acid or a sulfonic acid, and is used in an amount of 0.005 mol to <1 mol, preferably from 0.01 to <1 mol, more preferably from 0.01 to 0.5 mol, in particular from 0.01 to 0.1 mol, more particularly from 0.01 to 0.08 mol, per 1 mol of that starting compound [amine (III) or compound (II)] which is not used in excess [this is generally compound (II)] [if amine (III) or compound (II) are used in stoichiometric, i.e. equimolar amounts, the above amounts of the acid can of course be relative to any of the two compounds (II) or (III)].

[0075] E.35. The method according to any of the preceding embodiments, where step (i) is carried out neat.

[0076] E.36. The method according to any of the preceding embodiments, where the compound (II) and the amine (III) are used in a molar ratio of from 5:1 to 1 :20, preferably from 2:1 to 1 :10, more preferably from 2:1 to 1 :5.

[0077] E.37. The method according to embodiment E.36, where the reaction in step (i) is carried out neat, and the compound (II) and the amine (III) are used in a molar ratio of from 1 :1 to 1 :20, preferably from 1 :1 to 1 :10, more preferably from 1 :1 to 1 :5, even more preferably from 1 :1 to 1 :3, in particular from 1 :1.1 to 1 :3, and specifically from 1 :1.1 to 1 :2.5.

[0078] E.38. The method according to any of embodiments E.1 to E.34 and E.36, where the reaction in step (i) is carried out in a solvent [other than compound (II) and amine (III)], and the compound (II) and the amine (III) are used in a molar ratio of from 5:1 to 1 :20, preferably from 2:1 to 1 :10, more preferably from 2:1 to 1 :5, in particular from 2:1 to 1 :2.

[0079] E.39. The method according to any of the preceding embodiments, where step (i) is carried out at from 10 to 150°C.

[0080] E.40. The method according to embodiment E.39, where step (i) is carried out at from 20 to 150°C.

[0081] E.41. The method according to embodiment E.40, where step (i) is carried out at from 100 to 150°C.

[0082] E.42. The method according to embodiment E.41 , where step (i) is carried out at from 110 to 140°C.

[0083] E.43. The method according to any of the preceding embodiments, where in step (ii) the compound (IV) is reduced to compound (V) with a complex hydride or a silane as reducing agent.

[0084] E.44. The method according to embodiment E.43, where in step (ii) the compound (IV) is reduced to compound (V) with a complex hydride.

[0085] E.45. The method according to embodiment E.44, where the complex hydride is selected from the group consisting of lithium aluminum hydride (LAH; UAIH4), sodium boron hydride (NaBH4), lithium triethylborohydride (superhydride; LiBH(CH2CH3)2), lithium tri-sec-butyl(hydrido)borate (L-selectride; LiBH(CH(CH3)CH2CH3)2), diisobutylaluminum hydride (DIBAL-H; ((CH3)2CHCH2)2AIH), and mixtures thereof.

[0086] E.46. The method according to embodiment E.45, where the complex hydride is selected from UAIH4 or NaBH4.

[0087] E.47. The method according to embodiment E.46, where the complex hydride is NaBH4.

[0088] E.48. The method according to embodiment E.43, where in step (ii) the compound (IV) is reduced to compound (V) with a silane.

[0089] E.49. The method according to any of embodiments E.1 to E.42, where in step (ii) the compound (IV) is reduced to compound (V) with hydrogen in the presence of a hydrogenation catalyst.

[0090] E.50. The method according to embodiment E.49, where the hydrogenation catalyst is a homogeneous hydrogenation catalyst.

[0091] E.51. The method according to embodiment E.50, where the homogeneous hydrogenation catalysts contains a transition metal, preferably a transition metal from group 7, 8, 9 or 10 of the Periodic Table of Elements.

[0092] E.52. The method according to embodiment E.51, where the homogeneous hydrogenation catalysts is a ruthenium-, manganese- or iron-based metal-complex with a multidentate phosphorus- and / or nitrogen-containing ligand.

[0093] E.53. The method according to embodiment E.52, where the homogeneous hydrogenation catalysts is a ruthenium-based metal-complex with a multidentate phosphorus- and / or nitrogen-containing ligand.

[0094] E.54. The method according to any of the preceding embodiments, where step (ii) is carried out in an organic solvent.

[0095] E.55. The method according to embodiment E.54, where the solvent is selected from cyclic ethers, aromatic solvents and mixtures thereof.

[0096] E.56. The method according to embodiment E.55, where the cyclic ethers are selected from tetra hydrofuran, 2-methyltetrahydrofuran (= 2-methyloxolane), 1,4-dioxane and mixtures thereof, and the aromatic solvents are selected from benzene, toluene, the xylenes and mixtures thereof.

[0097] E.57. The method according to embodiment E.56, where the cyclic ethers are selected from tetra hydrofuran, 2-methyltetrahydrofuran and mixtures thereof, and the aromatic solvent is toluene.

[0098] E.58. The method according to embodiment E.54, where in case that the reduction agent is or comprises NaBH4, the solvent comprises a Ci-C4-alkanol.

[0099] E.59. The method according to embodiment E.58, where in case that the reduction agent is or comprises NaBH4, the solvent comprises methanol, ethanol and / or isobutanol.

[0100] E.60. The method according to any of embodiments E.58 and E.59, where the solvent further comprises at least one organic solvent selected from cyclic ethers, aromatic solvents and mixtures thereof. E.61. The method according to embodiment E.60, where the cyclic ethers are selected from tetra hydrofuran, 2-methyltetrahydrofuran (= 2-methyloxolane), 1 ,4-dioxane and mixtures thereof, and the aromatic solvents are selected from benzene, toluene, the xylenes and mixtures thereof.

[0101] E.62. The method according to embodiment E.61 , where the cyclic ethers are selected from tetra hydrofuran, 2-methyltetrahydrofuran and mixtures thereof, and the aromatic solvent is toluene.

[0102] E.63. The method according to any of the preceding embodiments, where in case that in step (ii) the compound (IV) is reduced to compound (V) with NaBH4, the solvent comprises a Ci-C4-alkanol and 2-methyltetrahydrofuran.

[0103] E.64. The method according to any of the preceding embodiments, where step (iii) is carried out in acidic medium.

[0104] E.65. The method according to embodiment E.64, where step (iii) is carried out in the presence of an inorganic or organic acid.

[0105] E.66. The method according to embodiment E.65, where step (iii) is carried out in the presence of an inorganic acid selected from the group consisting of sulfuric acid, phosphoric acid, phosphonic acid, phosphinic acid and hydrochloric acid; and / or an organic acid selected from sulfonic acids, preferably from methanesulfonic acid, trifluoromethanesulfonic acid and para-toluenesulfonic acid.

[0106] E.67. The method according to embodiment E.66, where step (iii) is carried out in the presence of sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or para-toluenesulfonic acid.

[0107] E.68. The method according to embodiment E.67, where step (iii) is carried out in the presence of sulfuric acid.

[0108] E.69. The method according to any of embodiments E.64 to E.68, where the acid is used in stoichiometric amount or in molar excess, in each case relative to the amount of the compound (V).

[0109] E.70. The method according to any of embodiments E.64 to E.68, where the acid is used in catalytic amounts, relative to the amount of the compound (V).

[0110] E.71. The method according to any of the preceding embodiments, where step (iii) is carried out neat.

[0111] E.72. The method according to any of embodiments E.1 to E.70, where step (iii) is carried out in the presence of an organic solvent.

[0112] E.73. The method according to embodiment E.72, where the organic solvent is or comprises an aromatic organic solvent.

[0113] E.74. The method according to embodiment E.73, where the aromatic organic solvent is selected from benzene, toluene, the xylenes or mixtures thereof.

[0114] E.75. The method according to embodiment E.74, where the aromatic organic solvent is selected from xylenes.

[0115] E.76. The method according to any of the preceding embodiments, where step (iii) is carried out at 100 to 160°C. E.77. The method according to embodiment E.76, where step (iii) is carried out at 120 to 140°C.

[0116] The reaction sequence of the method of the invention can be depicted as follows:

[0117] Among compounds (II), due to easier availability, preference is given to symmetric compounds, i.e. to compounds (II) wherein X1and X2have the same meaning, i.e. both X1and X2are OH or both X1and X2are OR1wherein R1has the same meaning in X1and X2, or X1and X2form together -O- (compound (II) thus being in this case maleic anhydride).

[0118] Among compounds (II), preference is given to the acids and the esters, i.e. to compounds (II), wherein X1and X2are OH or OR1. Among the esters, preference is given to the diesters (i.e. X1and X2are both OR1), more preference to symmetric diesters (i.e. X1and X2are both OR1, where R1has the same meaning in X1and X2).

[0119] Due to easier availability, among the ester compounds (II) (i.e. compounds (II) wherein at least one, preferably both of X1and X2are OR1) preference is given to the alkyl esters. R1is thus preferably Ci-C -alkyl, more preferably Ci-Cs-alkyl, even more preferably Ci-Ce-alkyl, and in particular Ci-C4-alkyl, e.g. ethyl. When starting from maleic acid or maleic acid derivative (II. a), it was observed that in step (i) a part thereof is isomerized to the fumaric acid (derivative) (ll.b), which reacts further in the aza-Michael addition to (IV), indicating that fumaric acid or the ester thereof is an equally suitable starting material. Nevertheless, due to easier availability and better reactivity, starting compound (II) is preferably maleic acid or a maleic acid derivative (I I. a) wherein X1and X2are as defined above.

[0120] Among maleic acid and maleic acid derivatives (II. a), preference is given to maleic acid and maleic acid esters, i.e. to compounds (II. a), wherein X1and X2are OH or OR1, where R1is as defined above, Preferably, R1is Ci-C -alkyl, more preferably Ci-Cs-al- kyl, even more preferably Ci-Ce-alkyl, and in particular Ci-C4-alkyl, e.g. ethyl. Among maleic acid and maleic acid esters, preference is given to the esters, to be more precise to diesters (i.e. X1and X2are both OR1), to be even more precise to symmetric diesters (i.e. X1and X2are both OR1, where R1has the same meaning in X1and X2), among which alkyl esters are preferred. Specifically dimethyl maleate, diethyl maleate or di-(2-ethylhexyl) maleate is used. More specifically, diethyl maleate is used.

[0121] If fumaric acid or a fumaric acid ester (ll.b) is used, the same considerations as in context with maleic acid (derivatives) apply: in the esters, R1is preferably Ci-Cw-alkyl, more preferably Ci-Cs-alkyl, even more preferably Ci-Ce-alkyl, and in particular Ci-C4-alkyl. Among fumaric acid and fumaric acid esters, preference is given to the esters, to be more precise to diesters (i.e. X1and X2are both OR1), to be even more precise to symmetric diesters (i.e. X1and X2are both OR1, where R1has the same meaning in X1and X2), among which alkyl esters are preferred. Specifically diethyl fumarate is used.

[0122] In amine (III), R2is preferably Ci-Ce-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Cs-Ce-cycloalkyl, phenyl or a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, where the phenyl ring and the heteroaromatic ring may carry 1 , 2 or 3 substituents R3. More preferably, R2is Ci-Ce-alkyl, C1-C3- alkoxy-C2-C3-alkyl, Cs-Ce-cycloalkyl, phenyl or a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, where the phenyl ring and the heteroaromatic ring may carry 1 , 2 or 3 substituents R3, and is even more preferably Cs-Cs-alkyl, Ci-C3-alkoxy-C2-C3-alkyl, Cs-Ce-cycloalkyl, phenyl or pyridyl. In a specific embodiment, R2is phenyl which may carry 1 , 2 or 3 substituents R3(amine (III) being thus specifically aniline which may carry 1 , 2 or 3 substituents R3on the phenyl ring (such as in toluidine). In a very specific embodiment, R2is (unsubstituted) phenyl; i.e. amine (III) is very specifically aniline. The preferred, more preferred, even more preferred, specific and very specific meanings of R2apply of course to all downstream products, i.e. to compounds (IV), (V) and (I). R2is to stay unchanged in the course of the reaction steps.

[0123] Compound (II) and amine (III) are preferably used in a molar ratio of from 5:1 to 1 :20, more preferably from 2:1 to 1 :10, even more preferably from 2:1 to 1 :5. If the reaction is carried out neat (see below remarks), the amine (III) generally serves as diluent (provided it is liquid under the applied reaction conditions, of course) and is thus preferably used in at least equimolar amounts, more preferably in excess. In this case, compound (II) and amine (III) are preferably used in a molar ratio of from 1 :1 to 1 :20, e.g. 1 :1 to 1 :10, more preferably from 1 :1 to 1 :5, even more preferably from 1 :1 to 1 :3, in particular from 1 :1.1 to 1 :3, and specifically from 1 :1.1 to 1 :2.5. If a solvent [other than compound (II) and amine (III)] is used, the molar ratio of compound (II) and amine (III) is preferably from 5:1 to 1 :20, more preferably from 2:1 to 1 :10, even more preferably from 2:1 to 1 :5, in particular from 2:1 to 1 :2.

[0124] In one preferred embodiment, step (i) is carried out in the presence of an acid.

[0125] In another preferred embodiment, step (i) is not supplemented with an acid other than compound (II) (if this used at all in form of the acid).

[0126] Among these two options, preference is given to carry out the reaction in the presence of an acid (other than compound (II) of course (if this used at all in form of the acid)). To be more precise, the reaction is preferably carried out in the presence of an inorganic or organic acid or an acidic cation exchanger. Examples for suitable inorganic acids are HCI, HBr, HI, sulfuric acid, salts of hydrogensulfate (especially the Na or K salts), sulfamic acid, phosphoric acid, salts of dihydrogen phosphate (especially the Na or K salts), phosphonic acid, phosphinic acid and the like.

[0127] Examples for suitable organic acids are carboxylic acids, such as acetic acid, trifluoroacetic acid, propionic acid or oxalic acid, and sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or para-toluenesulfonic acid.

[0128] Suitable cationic exchangers are cationic exchangers in the H+form which have strongly acidic groups. The strongly acidic groups are generally sulfonic acid groups; they are generally bonded to a polymer matrix, which can be e.g. gel-like and / or macroporous. Preference is given to styrene (co)polymers containing sulfonic acid groups, specifically to styrene-divinyl benzene copolymers containing sulfonic acid groups. Commercial examples for such cationic exchangers are Lewatit® (Lanxess), Purolite® (The Purolite Company), Dowex® (Dow Chemical Company), Amberlite® (Rohm and Haas Company), Amberlyst® (Rohm and Haas Company). Preferred strongly acidic cation exchangers are: Lewatit® K 1221 , Lewatit® K 1461, Lewatit® K 2431 , Lewatit® K 2620, Lewatit® K 2621 , Lewatit® K 2629, Lewatit® K 2649, Amberlite® FPC 22, Amberlite® FPC 23, Amberlite® IR 120, Amberlyst® 131, Amberlyst® 15, Amberlyst® 31, Amberlyst® 35, Amberlyst® 36, Amberlyst® 39, Amberlyst® 46, Amberlyst® 70, Purolite® SGC650, Purolite® C1 OOH, Purolite® C 150 H, Dowex® 50X8, Serdolit® red and Nation® NR-50. Alternatively, the cation exchanger can be a perfluorinated ion exchange resin, sold e.g. under the Nation® brand of DuPont.

[0129] Especially if the reaction in step (i) is carried out neat, out of practical reasons, among inorganic acids, organic acids and cationic exchangers, preference is given to inorganic acids and organic acids.

[0130] Among inorganic acids, especially if the reaction in step (i) is carried out neat, preference is given to HCI, sulfamic acid and phosphinic acid, and in particular to HCI.

[0131] Among organic acids, especially if the reaction in step (i) is carried out neat, preference is given to sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or para-toluenesulfonic acid. Specifically, methanesulfonic acid or para-toluenesulfonic acid is used. More specifically, para-toluenesulfonic acid is used.

[0132] The acid is used in an amount of from 0.005 mol to 10 mol, preferably from 0.01 to 5 mol, more preferably from 0.01 to 1 mol, even more preferably from 0.01 to 0.5 mol, mol, in particular from 0.01 to 0.1 mol, more particularly from 0.01 to 0.08 mol, per 1 mol of that starting compound [amine (III) or compound (II)] which is not used in excess [this is generally compound (II)] [if amine (III) or compound (II) are used in stoichiometric, i.e. equimolar amounts, the above amounts of the acid can of course be relative to any of the two compounds (II) or (III)]. In case of carboxylic acids, at least equimolar amounts are more advantageous, whereas in case of inorganic acids or sulfonic acids, amounts of below 1 mol per mol of that starting compound [amine (III) or compound (II)] which is not used in excess [this is generally compound (II)] are sufficient and preferred. The given amounts relate to the acid molecule (the acid being in this case a discrete molecule, not a cationic exchanger), irrespective of the number of acidic protons which this can release. However, in case of strong acids which can release more than one proton, e.g. sulfuric acid or phosphorus acid, lesser amounts are of course sufficient as compared to acids which can release just one proton.

[0133] The reaction can be carried out in an organic solvent. Suitable solvents are for example hydrocarbons such as alkanes, e.g. pentane, hexane, heptane or petrol ether, cycloalkanes, e.g. cyclohexane, cycloheptane or cyclooctane, or aromatic hydrocarbons, such as benzene, toluene or the xylenes, halogenated alkanes, such as dichloromethane, trichloromethane, tetrachloromethane or tetrachloroethane, halogenated aromatics, such as chlorobenzene or the dichlorobenzenes, non-cyclic ethers, such as diethyl ether, dipropyl ether or methyl-tert-butyl ether, cyclic ethers, such as tetrahydrofuran, 2- methyltetrahydrofuran or 1,4-dioxane, ketones, such as acetone or ethylmethylketone, and mixtures of two or more of the afore-mentioned solvents.

[0134] Preferably, however, the reaction is carried out neat, i.e. without any (additional) solvent. In this case, amine (III) and also compound (II), especially if this is an ester which is liquid under the reaction conditions of step (i), generally serves as solvent / diluent. Depending on the nature and amount of acid used, this may also serve as solvent / diluent.

[0135] The reaction in step (i) is carried out at a temperature of preferably from 10 to 150°C, more preferably from 20 to 150°C; even more preferably from 100 to 150°C, in particular from 110 to 140°C.

[0136] The reaction time is preferably from 1 h to 70 h, more preferably from 3 h to 65 h, even more preferably from 10 h to 65 h, e.g. from 15 to 65 h, and is in particular from 15 h to 50 h.

[0137] The reaction in step (i) is generally carried out by mixing amine (III), compound (II) and, if applicable, an acid or a cation exchanger, bringing the reaction mixture to the desired temperature and reacting the mixture at the desired temperature for the required reaction time. The order of the addition of the reagents is not critical; these can be added simultaneously or sequentially in any order. The progress of the reaction can be monitored, if desired, e.g. by taking samples and analysing them via usual means, such as GC, DC or NMR.

[0138] After completion of the reaction, the reaction mixture can be worked-up by usual means and the product (IV) can be isolated and if desired also purified before being used in the subsequent step. It is however also possible to use the reaction mixture without any work-up in the next step. In this case however, it is expedient to remove any unreacted reagents, e.g. distillatively, before the reaction mixture is used in the next step.

[0139] If work-up is carried out, this can be done by usual means, such as quenching with water or an aqueous basic solution (especially if an acid has been used), optionally after dilution of the reaction with an organic solvent which has low miscibility with water, especially if the reaction has been carried out neat, and / or, if a cation exchanger has been used, filtering the reaction mixture; washing and drying the separated organic phase(s) and isolating the product, e.g. distillatively or by crystallization.

[0140] In step (ii), the compound (IV) obtained in step (i) is reduced to compound (V). The reduction agent has thus to be one which selectively reduces the carboxylic group [be it in the form of an acid group (i.e. C(O)X1and / or (CO)X2are C(O)OH), an ester group (i.e. C(O)X1and / or (CO)X2are C(O)OR1) or an anhydride group (i.e. C(O)X1and (CO)X2form together C(O)-O-C(O)] without affecting any (hetero)aromatic or unsaturated heterocyclic ring R2.

[0141] Suitable reduction agents for this purpose are for example complex hydrides or silanes, among which complex hydrides are preferred.

[0142] Examples for suitable complex hydrides are lithium aluminum hydride (LAH; LiAIH4), sodium boron hydride (NaBH4), lithium triethylborohydride (superhydride;

[0143] LiBH(CH2CH3)2), lithium tri-sec-butyl(hydrido)borate (L-selectride; LiBH(CH(CH3)CH2CH3)2), or diisobutylaluminum hydride (DIBAL-H; ((CH3)2CHCH2)2AIH).

[0144] Among these, preference is given to UAIH4 or NaBH4; and in particular to NaBH4.

[0145] The reduction agent is expediently used in such amounts that at least the equivalent amount of transferrable hydrogen atoms necessary for reducing the two ester groups in compound (IV) is present. In case of the preferred reduction agents UAIH4 or NaBH4, for instance, these are used in an amount of at least 1 mol per mol of compound (IV). Preferably, UAIH4 and NaBH4 are used in an amount of from 1 mol to 4 mol, more preferably from 1.2 mol to 3 mol; e.g. from 1.3 to 2.7 mol or 1 .5 to 2.5 mol, per 1 mol of compound (IV).

[0146] The reaction temperature for the reduction with a complex hydride is not critical. It is preferably in the range of 0 to 100°C. In case of UAIH4 lower temperatures, such as 0 to 30°C, or 0 to 20°C are sufficient, whereas in the case of NaBH4 higher temperatures, such as 40 to 100°C, or 50 to 90°C or 60 to 85°C are more expedient. The optimum reaction temperature for specific setups can be determined by the skilled person via simple preliminary tests.

[0147] Alternatively, compound (IV) can be reduced with hydrogen in the presence of a suitable hydrogenation catalyst.

[0148] Suitable hydrogenation catalysts can be heterogeneous or homogeneous. A sharp distinction between heterogeneous and homogeneous catalysts is difficult, but for the terms of the present invention, homogeneous catalysts are considered such where the catalyst is in the same phase as the reactants or products, whereas in heterogeneous catalysis, the phase of the catalyst differs from that of the reactants or products. A heterogeneous catalyst in terms of the present invention is thus a catalyst which is not soluble in the reaction medium. Heterogeneous hydrogenation catalysts that are used for the hydrogenation of esters to the corresponding alcohols most often contain a transition metal, preferably copper. Such catalysts are used technically on large scale for example in the hydrogenation of fatty acid esters to the corresponding alcohols.

[0149] Homogeneous catalysis is somewhat more suitable for esters than for acids or anhydrides, therefore in case of homogeneous catalysis the compound (IV) is preferably an ester, in particular a diester. The below remarks to the hydrogenation route using a homogeneous catalyst therefore specify the esters, although other compounds (IV) can also be used. In heterogeneous catalysis, there is no particular preference for specific compounds (IV).

[0150] Among heterogeneous and homogeneous hydrogenation catalysts, preference is given here to homogeneous hydrogenation catalysts because homogeneous catalysts can work at lower temperatures and pressures compared to the heterogeneous catalysts. Unless specified otherwise, the following remarks apply to homogeneous catalysis, whereas suitable reaction conditions for heterogeneous catalysis are known in the art and are described, for example, in Ullmann’s Encyclopaedia of Industrial Chemistry, 7thedition, Hydrogenation and Dehydrogenation Suitable homogeneous hydrogenation catalysts contain a transition metal, preferably a transition metal from group 7, 8, 9 or 10 of the Periodic Table of Elements. The group numbering relates to the IIIPAC nomenclature of 1985. Groups 7 to 10 are thus the Mn, Fe, Co and Ni groups. In particular, the use of ruthenium-, manganese- or ironbased metal-complexes with multidentate phosphorus, sulfur, NHC (N-heterocyclic carbene) or nitrogen-containing ligands as catalyst for the hydrogenation of esters to the corresponding alcohols is described in the prior art.

[0151] The mentioned ruthenium-, manganese- or iron-based metal-complexes are prepared by reaction of a metal precursor with the respective ligand. For the Ru-based complexes, the multidentate phosphorus, sulfur, NHC or nitrogen-containing ligands can have various structures. The first Ru-based catalysts with low activity for the hydrogenation of esters were PPP-coordinated Ru-complexes (described, for example, in Chem. Commun. 1998, 1367-1368). Later, various other ligand-systems with PNNP-, (PN)2-, PNP-, PNN-, PNNN-coordination in the Ru-complex were developed and led to more active catalysts. Examples for homogeneous Ru-complexes and the use as catalysts for ester hydrogenations with relevance for industrial use are Ru(PNN)(H)CO (described, for example, by Milstein et al. in Angew. Chem. 2006, 1113-1115), Ru-Macho (described, for example, in US 8,471 ,048), Ru(PNNP)CI2(described, for example, in US 7,989,665), Ru(PNN)CI2PPh3(described, for example, in US 11 ,708,316). An overview of Mn-based complexes that can be used as catalysts is described, for example, by Sortais et al. in Journal of Catalysis 2024, article 115334.

[0152] The amount of homogeneous catalyst to be used depends on factors including the reaction temperature that is necessary for a certain selectivity, the pressure, the intrinsic catalyst activity, and may be determined in the individual case by those skilled in the art. The homogeneous catalyst is generally used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.2 mol per mol of compound (IV), in particular 0.005 to 0.1 mol per mol of compound (IV), specifically 0.01 to 0.1 mol per mol of compound (IV). The amount of catalyst specified relates to the amount of active metal, i.e. to the catalytically active component of the catalyst.

[0153] The homogeneous hydrogenation process is preferably carried out at a temperature of 50 to 200°C, more preferably at <170° C and particularly preferably at <150° C, e.g. preferably from 50 to 170°C or from 50 to 150°C. The pressure in this case is preferably from 0.1 to 20 MPa abs, more preferably >1 MPa abs and particularly preferably >5 MPa abs, and preferably <15 MPa abs and particularly preferably <10 MPa abs, e.g. preferably from 1 to 15 MPa abs or from 5 to 10 MPa abs. The optimal pressure is a consequence of a decision and is in each case dependent on reaction rate and selectivity at the different pressures, available equipment, process safety and other factors. The reaction time of the homogeneous hydrogenation process or mean residence time in which the reaction mixture is present under the reaction conditions can also vary widely, but is typically in the range from 0.1 to 100 hours, preferably >1 hour and particularly preferably >2 hours, and preferably <80 hours and particularly preferably <60 hours, e.g. from 1-80 h or from 2 to 60 h. The Ru- or Mn-complex catalyzed homogeneous hydrogenation is generally positively influenced by the presence of a base and, as a result, significantly higher conversions are ultimately made possible. Therefore, in most cases it is advantageous to carry out the hydrogenation in the presence of a base. Examples of possible bases include alkoxides (generally alkali metal alkoxides), hydroxides (generally alkali metal hydroxides), alkali metal and alkaline earth metal carbonates, amides (generally alkali metal alkoxides), basic aluminum and silicon compounds and also hydrides (generally alkali metal hydrides). The bases used are particularly preferably alkoxides (generally alkali metal alkoxides) or amides, preferably sodium methoxide or potassium methoxide.

[0154] The reaction apparatus used in homogeneous hydrogenations may in principle be any reaction apparatus which is suitable for gas / liquid reactions under the specified temperature and the specified pressure. Suitable standard reactors for gas / liquid and for liq- uid / liquid reaction systems are described, for example, in K. D. Henkel, "Reactor Types and Their Industrial Applications", in Ullmann's Encyclopedia of Industrial Chemistry, 2005, Wiley- VCH Verlag GmbH & Co. KGaA, DOI: 10.1002 / 14356007. b04_087, chapter 3.3 "Reactors for gas-liquid reactions". Examples include stirred tank reactors, tubular reactors or bubble column reactors. Pressure-resistant stirred tanks are usually also referred to as autoclaves.

[0155] The reaction in step (ii) is preferably carried out in an organic solvent. Suitable solvents are for example hydrocarbons such as alkanes, e.g. pentane, hexane, heptane or petrol ether, cycloalkanes, e.g. cyclohexane, cycloheptane or cyclooctane, or aromatic hydrocarbons, such as benzene, toluene or the xylenes, halogenated alkanes, such as dichloromethane, trichloromethane, tetrachloromethane or tetrachloroethane, halogenated aromatics, such as chlorobenzene or the dichlorobenzenes, non-cyclic ethers, such as diethyl ether, dipropyl ether or methyl-tert-butyl ether, cyclic ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran or 1 ,4-dioxane, alkanols, in particular C1-C4- alkanols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol or tert-butanol, and mixtures of two or more of the afore-mentioned solvents. The optimum solvent depends on the specific reduction agent used and can be determined by the skilled person via simple preliminary tests.

[0156] In case of catalytic hydrogenation, while principally suitable, it preferred that the solvent be not halogenated. In case of heterogeneous catalysis, it is moreover also preferred that the solvent be not aromatic. In case of complex hydrides, for example, cyclic ethers, such as tetrahydrofuran, 2-me- thyltetrahydrofuran or 1 ,4-dioxane, aromatic hydrocarbons, such as benzene, toluene or the xylenes, Ci-C4-alkanols, such as methanol, ethanol, n-propanol, isopropanol, n- butanol, sec-butanol, isobutanol or tert-butanol, and mixtures of two or more of the afore-mentioned solvents are preferred.

[0157] In case of NaBH4, the solvent preferably comprises at least one Ci-C4-alkanol. More preferably, the solvent comprises one or more Ci-C4-alkanols, and at least one of an aromatic hydrocarbon and / or a cyclic ether. In particular, in case of NaBH4, the solvent comprises one or more Ci-C4-alkanols, and at least one of tetrahydrofuran, 2-methyl- tetrahydrofuran and / or toluene. In case of NaBH4, the solvent specifically comprises one or more Ci-C4-alkanols and 2-methyltetrahydrofuran.

[0158] The reaction in step (ii) is generally carried out by bringing compound (IV) into contact with the reduction agent. In case of complex hydrides or silanes, compound (IV) and the hydride are mixed, generally in a solvent (mixture). For instance, the reduction agent is placed in a solvent and the compound (IV) is added to this mixture, if desired also in a solvent, or, inversely, compound (IV) is dissolved in a solvent and the reduction agent is added thereto, if desired also in a solvent, or a solvent is provided and compound (IV) and the reduction agent are added simultaneously to the solvent. Addition can be carried in one portion, in several portions or in a continual manner. The mixture is then stirred at the desired temperature.

[0159] In case of reduction via hydrogenation, for instance, compound (IV) is mixed with the hydrogenation catalyst, generally in a solvent, the reaction mixture is brought to the desired temperature and hydrogen is introduced with the desired pressure.

[0160] After completion of the reaction, the reaction mixture is generally worked-up by usual means and product (V) can be isolated and if desired also purified before being used in the subsequent step.

[0161] In case of complex hydrides as reduction agent, the reaction mixture is generally quenched, e.g. with water or an aqueous basic solution, where before or after quenching, an organic solvent which has low miscibility with water may be added, which is expedient if the solvent used in the reduction has high miscibility with water; the organic phase is separated, if desired washed with water and / or brine, and the product is isolated therefrom, if desired, e.g. distillatively or by crystallization. In step (iii), the two OH groups in compound (V) undergo an intramolecular ether formation. The reaction conditions in this step correspond thus in general to known etherification conditions.

[0162] Accordingly, step (iii) is preferably carried out in acidic medium. To this purpose, the reaction is carried out in the presence or an inorganic or organic acid or an acidic cation exchanger.

[0163] Examples for suitable inorganic acids are HCI, HBr, HI, sulfuric acid, salts of hydrogensulfate (especially the Na or K salts), sulfamic acid, phosphoric acid, salts of dihydrogen phosphate (especially the Na or K salts), phosphonic acid, phosphinic acid and the like.

[0164] Examples for suitable organic acids are carboxylic acids, such as acetic acid, trifluoroacetic acid, propionic acid or oxalic acid, and sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or para-toluenesulfonic acid.

[0165] Suitable cationic exchangers are cationic exchangers in the H+form which have strongly acidic groups. The strongly acidic groups are generally sulfonic acid groups; they are generally bonded to a polymer matrix, which can be e.g. gel-like and / or macroporous. Preference is given to styrene (co)polymers containing sulfonic acid groups, specifically to styrene-divinyl benzene copolymers containing sulfonic acid groups. Commercial examples for such cationic exchangers are Lewatit® (Lanxess), Purolite® (The Purolite Company), Dowex® (Dow Chemical Company), Amberlite® (Rohm and Haas Company), Amberlyst® (Rohm and Haas Company). Preferred strongly acidic cation exchangers are: Lewatit® K 1221 , Lewatit® K 1461 , Lewatit® K 2431 , Lewatit® K 2620, Lewatit® K 2621 , Lewatit® K 2629, Lewatit® K 2649, Amberlite® FPC 22, Amberlite® FPC 23, Amberlite® IR 120, Amberlyst® 131 , Amberlyst® 15, Amberlyst® 31 , Amberlyst® 35, Amberlyst® 36, Amberlyst® 39, Amberlyst® 46, Amberlyst® 70, Purolite® SGC650, Purolite® C1 OOH, Purolite® C 150 H, Dowex® 50X8, Serdolit® red and Nation® NR-50. Alternatively, the cation exchanger can be a perfluorinated ion exchange resin, sold e.g. under the Nation® brand of DuPont.

[0166] Especially if the reaction in step (iii) is carried out neat, out of practical reasons, among inorganic acids, organic acids and cationic exchangers, preference is given to inorganic acids and organic acids.

[0167] Among inorganic acids, preference is given to sulfuric acid. Among organic acids, preference is given to sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or para-toluenesulfonic acid. Specifically, methanesulfonic acid or para-toluenesulfonic acid is used.

[0168] The acid is preferably used in at least equimolar amounts. Preferably, it is used in an amount of from 1 mol to 10 mol, more preferably from 1 to 5 mol, in particular from 1 to 3 mol, per 1 mol of compound (V). The given amounts relate to the acid molecule (the acid being in this case a discrete molecule, not a cationic exchanger), irrespective of the number of acidic protons which this can release.

[0169] Alternatively, the acid can be used in catalytic amounts, i.e. in less than 1 mol per mol of compound (V), e.g. in an amount of from 0.005 mol to 0.9 mol per mol of compound (V).

[0170] Preference is however given to using the acid in at least equimolar amounts.

[0171] The reaction can be carried out neat.

[0172] Alternatively, the reaction can be carried out in an organic solvent. Suitable solvents are for example hydrocarbons such as alkanes, e.g. pentane, hexane, heptane or petrol ether, cycloalkanes, e.g. cyclohexane, cycloheptane or cyclooctane, or aromatic hydrocarbons, such as benzene, toluene or the xylenes, halogenated alkanes, such as dichloromethane, trichloromethane, tetrachloromethane or tetrachloroethane, halogenated aromatics, such as chlorobenzene or the dichlorobenzenes, and mixtures of two or more of the afore-mentioned solvents. Among these, preference is given to the above-listed aromatic hydrocarbons, especially to the xylenes.

[0173] The reaction in step (iii) is carried out at a temperature of preferably from 100 to 160°C, more preferably from 120 to 140°C.

[0174] The reaction in step (iii) is generally carried out by bringing compound (V) into contact with an acid, if desired in a solvent. Generally, the acid is added to compound (V), expediently by and by, e.g. in several portions or continually. The mixture is then brought to the desired reaction temperature and stirred for the required reaction time. If the reaction is carried out neat, it is expedient to heat compound (V) to make it fluid before the acid is added.

[0175] If desired, reaction water formed in the etherification can be removed to promote the reaction, e.g. distillatively, especially by azeotropic distilliation with a suitable solvent or an entrainer, but this is not imperative. After completion of the reaction the mixture is generally worked up by usual means, such as quenching with water or an aqueous basic solution, extracting with an organic solvent which has low miscibility with water, especially if the reaction has been carried out neat or in a solvent with high water miscibility, and / or, if a cation exchanger has been used, filtering the reaction mixture; washing and drying the separated organic phase and isolating the product, e.g. distillatively.

[0176] The method as described above generally affords the compound (I) as a mixture of stereoisomers; in case of just one stereogenic center (= the carbon ring atom in the tetrahydrofuran ring carrying NHR2) in form of a racemate. Stereoisomers of the compound (I) can be obtained, for example, by suitable separation methods. Enantiomers of (I) or enantiomeric mixtures in which one of the enantiomers predominates can for example be obtained by preparative chiral HPLC or by other methods for racemic resolution known in the art.

[0177] The method of the invention uses readily available reagents and yields the amine (I) in satisfactory yields and purity. It does not require sophisticated reaction steps, and the intermediate products of steps (i) and (ii) can be used in the subsequent steps without cumbersome purification.

[0178] As said above, N-phenyl-tetrahydrofuran-3-amine, i.e. the compound (I) wherein R2is phenyl, is a valuable intermediate in the preparation of the physiological cooling agent (E)-3-(1 ,3-benzodioxol-5-yl)-N-phenyl-tetrahydrofuran-3-yl-propen-2-amide.

[0179] A further aspect of the invention is thus a downstream method for preparing said (E)-3- (1 ,3-benzodioxol-5-yl)-N-phenyl-tetrahydrofuran-3-yl-propen-2-amide of the formula (VI.1) or a stereoisomer thereof by reacting the compound (I) wherein R2is phenyl [termed below as (1.1)], as obtained in the method of the invention (the starting amine (III) being here aniline; termed below as (III.1)], with the acid or acid derivative of the formula (VII) where X is OH or a halide, preferably Cl, in an amidation reaction.

[0180] Suitable amidation conditions are known to those skilled in the art and are moreover described in WO 2022 / 207944. If an acid halide is used, the reaction is expediently carried out in the presence of a base.

[0181] The complete reaction sequence in this downstream method is as follows:

[0182] Another aspect of the invention is a more general downstream method for preparing (E)-3-(1 ,3-benzodioxol-5-yl)-N(R2)-tetrahydrofuran-3-yl-propen-2-amide of the formula (VI) or a stereoisomer thereof by reacting the compound (I) as obtained in the method of the invention with the acid or acid derivative of the formula (VII) where X is OH or a halide, preferably Cl, in an amidation reaction.

[0183] As said above, suitable amidation conditions are known to those skilled in the art and are moreover described in WO 2022 / 207944. If an acid halide is used, the reaction is expediently carried out in the presence of a base.

[0184] The complete reaction sequence in this more general downstream method is as follows:

[0185] To obtain a stereoisomer of the compound (VI) or (VI.1), either a stereoisomer of the compound (I) or (1.1) is used, or the compound (VI) or (VI.1) is subjected to a suitable separation method, e.g. preparative chiral HPLC, such as described in WO 2022 / 207944.

[0186] As far as they are novel, the invention also relates to the compounds (I), (IV) and (V) per se. They are useful intermediates in further conversions like that described above to compounds (VI). In particular, the invention relates to compounds (IV) wherein

[0187] - X1and X2are both OR1, where both R1are 2-ethylhexyl and R2has any of the above general or preferred meanings; or

[0188] - R2is isobutyl, 2-ethoxyethyl or 2-pyridyl and X1and X2have any of the above general or preferred meanings.

[0189] Specifically, the invention relates to compounds (IV), wherein

[0190] - X1and X2are both OR1, where both R1are 2-ethylhexyl, and R2is phenyl; or

[0191] - X1and X2are both OR1, where both R1are ethyl, and R2is isobutyl, 2-ethoxyethyl or 2-pyridyl.

[0192] In particular, the invention relates to compounds (V) wherein R2is 2-ethoxyethyl.

[0193] The invention will now be illustrated by the following examples.

[0194] EXAMPLES

[0195] 1H and13C NMR were recorded on a Bruker DRX-500-US 500 MHz spectrometer and referenced to the residual hydrogen or carbon resonance peak of the solvent DMSO-d6 or CDCI3.

[0196] In some instances, NMR spectra of crude products were recorded and may thus contain signals which do not belong to the desired compounds. The latter were nevertheless identified without doubt. Unless specified otherwise in the examples, GC analyses were performed by one of the following methods:

[0197] Method 1 using an Agilent 6890N equipped with a HP-5 column (30 m, 0.32 mm, 0.25 pm)

[0198] Temperature program: 60 °C

[0199] 8 K / min to 250 °C

[0200] Constant Flow: 0.8 mL / min

[0201] Carrier Gas: Nitrogen

[0202] Injector Temperature: 250 °C

[0203] Detector Temperature: 280 °C

[0204] Method 2 using an Agilent 7890A equipped with a DB1701 column (25 m, 0.32 mm,

[0205] 0.25 pm)

[0206] Temperature program: 50 °C

[0207] 10 K / min to 200 °C

[0208] 15 K / min to 275 °C

[0209] Constant Flow: 1.0 mL / min

[0210] Carrier Gas: Hydrogen

[0211] Injector Temperature: 250 °C

[0212] Detector Temperature: 320 °C

[0213] Method 3 using an Agilent 6890N equipped with a RXI-1MS column (30 m, 0.25 mm,

[0214] 0.25 pm)

[0215] Temperature program: 50 °C

[0216] 15 K / min to 280°C

[0217] Constant Flow: 0.7 mL / min

[0218] Carrier Gas: Nitrogen

[0219] Injector Temperature: 220 °C

[0220] Detector Temperature: 250 °C

[0221] Method 4 using an Agilent 6890N equipped with a DB1 column (30 m, 0.25 mm, 0.25 pm)

[0222] Temperature program: 40 °C

[0223] 8 K / min to 280°C

[0224] Constant Flow: 0.6 mL / min

[0225] Carrier Gas: Nitrogen

[0226] Injector Temperature: 250 °C

[0227] Detector Temperature: 300 °C Method 5 using an Agilent 7890A equipped with a DB1701 column (25 m, 0.32 mm, 0.25 pm)

[0228] Temperature program: 50 °C

[0229] 10 K / min to 280 °C

[0230] Constant Flow: 0.833 mL / min

[0231] Carrier Gas: Hydrogen

[0232] Injector Temperature: 220 °C

[0233] Detector Temperature: 300 °C

[0234] LCMS analysis was conducted as follows:

[0235] Instrument: Waters ACQUITY LIPLC

[0236] Column: YMC C18

[0237] Sample compartment temperature: ambient

[0238] Column temperature: ambient

[0239] Step (i): Aza-Michael Addition

[0240] Example i.1 : Amination of diethyl maleate with aniline to diethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= ethoxy)

[0241] Diethyl maleate (75 g, 0.436 mol, 1.00 equiv.) was added to acetic acid (225 mL). Aniline (81.1 g, 0.871 mol, 2.00 equiv.) was added over the course of 30 min. The reaction mixture was stirred at room temperature for 42 h. The reaction mixture was quenched by addition of saturated aqueous sodium carbonate solution (300 mL) and the phases were separated. The organic phase was washed twice with aqueous sodium carbonate solution (2x300 mL) and aqueous sodium chloride solution (100 mL), dried with sodium sulfate and concentrated in vacuum (60 °C, 5 mbar) to yield the crude product (142 g) in a purity of 35.1 GC-a%. The crude product was purified by further removal of light boilers (TSUmP= 72-160 °C 1.7-2.4 mbar) to yield the title compound (50.3 g) as a lightyellow solid in a purity of 97.1 GC-a% (the yield being thus 42.2%). GC method 1 was applied.

[0242] Example i.2: Amination of diethyl maleate with aniline to diethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= ethoxy)

[0243] Diethyl maleate (100 g, 0.581 mol, 1.00 equiv.), aniline (91.1 g, 0.971 mol, 1.50 equiv.) and p-toluenesulfonic acid monohydrate (2.21 g, 0.012 mol, 0.02 equiv.) were added to the reaction vessel and stirred at 120 °C for 58 h. The reaction mixture was quenched with aqueous sodium carbonate solution (30 mL), phases separated and the crude product purified by removal of light boilers (TSUmP= 109-155 °C 1.2 mbar) to yield the product (126 g) in a purity of 88.0 GC-a% (the yield being thus 72%) as a dark, partly crystalline liquid. GC method 1 was applied. Example i.3: Amination of diethyl maleate with aniline to diethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= ethoxy)

[0244] Diethyl maleate (250 g, 1.41 mol, 1.00 equiv.), aniline (262 g, 2.82 mol, 2.00 equiv.) and p-toluenesulfonic acid monohydrate (13.4 g, 0.0704 mol, 0.05 equiv.) were added to the reaction vessel and stirred at 120 °C for 48 h. Subsequently, the reaction mixture was concentrated in vacuum (130 °C, 20 mbar) to remove most of the unreacted aniline. The crude product (429 g) was obtained as a dark, partly crystalline liquid in a purity of 68.3 GC-a% (the yield being thus 78.4%) with 5.23 GC-a% residual aniline and 0.72 GC-a% residual diethyl fumarate. GO method 1 was applied. The crude product was used in subsequent reactions without purification.

[0245] Example i.4: Amination of diethyl maleate with aniline to diethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= ethoxy)

[0246] Diethyl maleate (100 g, 0.563 mol, 1.00 equiv.), aniline (78.7 g, 0.845 mol, 1.50 equiv.) and p-toluenesulfonic acid monohydrate (5.36 g, 28.2 mmol, 0.05 equiv.) were added to the reaction vessel and stirred at 120 °C for 24 h. Subsequently, the reaction mixture was concentrated in vacuum (130 °C, 20 mbar) to remove most of the unreacted aniline. The crude product (145 g) was obtained as a dark liquid in a purity of 77.2 GC-a% (the yield being thus 75%) with 7.68 GC-a% residual aniline and 6.93 GC-a% residual diethyl fumarate. GO method 1 was applied. The crude product was used in subsequent reactions without purification.

[0247] Example i.5: Amination of diethyl maleate with aniline to diethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= ethoxy)

[0248] Diethyl maleate (350 g, 1.97 mol, 1.00 equiv.), aniline (367 g, 3.94 mol, 2.00 equiv.) and p-toluenesulfonic acid monohydrate (18.8 g, 0.099 mol, 0.05 equiv.) were added to the reaction vessel and stirred at 120 °C for 48 h. Subsequently, the reaction mixture was concentrated in vacuum (130 °C, 20 mbar) to remove most of the unreacted aniline. 480 g of the crude residue were diluted with ethyl acetate (500 mL) washed twice with aqueous sodium carbonate solution (2x250 mL), dried over sodium sulfate and concentrated in vacuum to yield the crude product (458 g) as a dark, partly crystalline liquid in a purity of 80.2 GC-a% (the yield being thus 78.3%), 10.1 GC-a% residual aniline and 2.28 GC-a% residual diethyl fumarate. 311 g of the crude product were crystallized in cyclohexane (311 mL) by heating the mixture to 60 °C, followed by a slow decrease of the temperature to 8 °C. Filtration, washing with cyclohexane (200 mL) and drying yielded the product (168 g) as a light gray solid in a purity of 97.8 GC-a%. GO method 2 was applied. The product was used in the subsequent step without additional purification.

[0249] 1H NMR (500 MHz, DMSO-d6) 8 = 7.08 (t, J = 7.9 Hz, 2H), 6.65 - 6.56 (m, 3H), 5.95 (d, J = 9.2 Hz, 1 H), 4.38 (dt, J = 9.0, 6.7 Hz, 1 H), 4.13 - 4.02 (m, 4H), 2.89 - 2.68 (m, 2H), 1.16 (dt, J = 11.9, 7.1 Hz, 6H).13C NMR (126 MHz, DMSO-d6) 5 = 172.15, 170.10, 147.25, 128.91 , 116.89, 112.77, 60.61 , 60.32, 52.50, 36.82, 14.01.

[0250] MS (GC-EI): [M+H]+- = 266.2 m / z

[0251] Melting Point: 51°C

[0252] Example i.6: Amination of diethyl maleate with aniline to diethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= ethoxy)

[0253] Diethyl maleate (350 g, 1.97 mol, 1.00 equiv.), aniline (367 g, 3.94 mol, 2.00 equiv.) and p-toluenesulfonic acid monohydrate (18.8 g, 0.099 mol, 0.05 equiv.) were added to the reaction vessel and stirred at 120 °C for 48 h. Subsequently, the reaction mixture was concentrated in vacuum (130 °C, 20 mbar) to remove most of the unreacted aniline. The crude product (579 g) was obtained as a dark, partly crystalline liquid in a purity of 78.2 GC-a% (the yield being thus 86.7%) with 12.1 GC-a% residual aniline and 2.31 GC-a% residual diethyl fumarate. GO method 1 was applied. The crude product was used in the subsequent step without purification.

[0254] Example i.7: Amination of diethyl maleate with aniline to diethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= ethoxy)

[0255] Diethyl maleate (250 g, 1.41 mol, 1.00 equiv.), aniline (197 g, 2.11 mol, 1.50 equiv.) and methanesulfonic acid (6.77 g, 0.0704 mol, 0.05 equiv.) were added to the reaction vessel and stirred at 120 °C for 62 h. The reaction was quenched with aqueous sodium carbonate solution (50 mL) and the phases separated to yield the crude product (446 g) in a purity of 43.7 GC-a% (the yield being thus 52.2%) with 33.4 GC-a% residual aniline and 17.2 GC-a% residual diethyl fumarate. The crude product was purified by distillation (Thead = 73-137 °C, 5.2-1.4 mbar) to yield the product (169 g) in a purity of -98.9 GC-a% (the overall yield being thus 44.7%). GO method 1 was applied.

[0256] Example i.8: Amination of diethyl maleate with aniline to diethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= ethoxy)

[0257] In a simplified set-up, three more acid catalysts were screened for their usefulness. To this purpose, diethyl maleate (97%, 9.53 g, 53.7 mmol, 1.00 equiv.), aniline (10.0 g, 107 mmol, 2.00 equiv.) and an acidic catalyst (0.05 equiv.) were added to a flask and stirred at 120 °C for 48 h. After 48 h the progress of the reaction was assessed by diluting a sample (0.5 mL) of the reaction mixture with ethyl acetate (3 mL) and quenching it with saturated aqueous sodium carbonate solution (1 mL). The product was analyzed via GO. GO method 1 was applied.

[0258] GO analysis in the course of the reaction showed that a part of diethyl maleate isomerizes to diethyl fumarate, which then also reacts to the desired product.

[0259] Example i.9: Amination of dimethylmaleate with aniline to dimethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= methoxy)

[0260] Dimethyl maleate (50 g, 367 mmol, 1.00 equiv.), aniline (65.6 g, 694 mmol, 2.00 equiv.) and p-toluenesulfonic acid monohydrate (3.30 g, 17.0 mmol, 0.05 equiv.) were added to the reaction vessel and stirred at 120 °C for 24 h. The reaction mixture was quenched with aqueous sodium carbonate solution (50 mL), ethyl acetate (150 mL) was added, phases separated and the organic phase dried over Na2SC>4 and concentrated in vacuum (5 mbar) at 60 °C to yield the crude product (99.3 g) in a purity of 48.5 GC-a% (the crude yield being thus 58.5%) with 32.5 GC-a% residual aniline and 2.52 GC-a% residual dimethyl fumarate. The crude product was purified by distillation (Thead = 148-145 °C, 2.4-2.7 mbar) to yield dimethyl N-phenylaspartate as a pale yellow, viscous liquid (27.2 g) in a purity of -98.2 GC-a% (the yield being thus 32.5%). GO method 2 was applied.

[0261] 1H NMR (500 MHz, CDCI3) 8 = 7.22 - 7.16 (m, 2H), 6.77 (t, J = 7.4 Hz, 1 H), 6.70 - 6.62 (m, 2H), 4.47 (t, J = 5.7 Hz, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 2.89 (dd, J = 5.6, 2.3 Hz, 2H).

[0262] 13C NMR (126 MHz, CDCI3) 8 = 172.90, 171.11 , 146.26, 129.47, 118.87, 113.82, 53.46, 52.71 , 52.12, 37.24.

[0263] Example i.10: Amination of bis(2-ethylhexyl) maleate with aniline to bis(2-ethylhexyl) N- phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= 2-ethylhexyloxy) Bis(2-ethylhexyl) maleate (100 g, 294 mmol, 1.00 equiv.), aniline (54.7 g, 587 mmol, 2.00 equiv.) and p-toluenesulfonic acid monohydrate (2.79 g, 14.7 mmol, 0.05 equiv.) were added to the reaction vessel and stirred at 120 °C for 48 h. The reaction mixture was quenched with aqueous sodium carbonate solution (25 mL), ethyl acetate (70 mL) was added, phases separated and the organic phase dried over Na2SO4 and concentrated in vacuum (3 mbar) at 60-70 °C to yield the crude product (120.8 g) as a mixture of diastereomers in a purity of 68.4 GC-a% (the yield being thus 65.1%) with 8.1 GC- a% residual aniline and 22.3 GC-a% residual bis(2-ethylhexyl) fumarate. GO method 5 was applied.

[0264] 1H NMR (500 MHz, DMSO) 8 = 6.25 - 6.18 (m, 2H), 5.79 - 5.74 (m, 2H), 5.09 (d, J = 9.3 Hz, 1 H), 3.54 (dt, J = 9.1 , 6.8 Hz, 1 H), 3.16 - 3.03 (m, 4H), 2.08 - 1.82 (m, 2H), 0.69 - 0.25 (m), 0.08 - -0.14 (m).13C NMR (126 MHz, DMSO) 5 = 172.24, 170.07, 170.06, 147.26, 147.25, 128.79, 128.77, 116.87, 112.75, 66.37, 66.36, 66.32, 66.30, 52.53, 52.50, 38.19, 38.18, 38.15, 38.11 , 36.88, 29.80, 29.77, 29.72, 29.70, 28.38, 28.36, 28.35, 28.34, 23.22, 23.19, 23.15, 23.11 , 23.09, 22.42, 22.41 , 13.88, 13.86, 10.79, 10.77.

[0265] Example i.11 : Amination of diethyl fumarate with aniline to diethyl N-phenylaspartate (compound (IV) wherein R2= phenyl and X1and X2= ethoxy)

[0266] Diethyl fumarate (40.0 g, 232 mmol, 1.00 equiv.), aniline (43.3 g, 465 mmol, 2.00 equiv.) and p-toluenesulfonic acid monohydrate (2.21 g, 11.6 mmol, 0.05 equiv.) were added to the reaction vessel and stirred at 120 °C for 48 h. The reaction mixture was quenched with aqueous sodium carbonate solution (25 mL), ethyl acetate (70 mL) was added, phases separated and the organic phase dried over Na2SC>4 and concentrated in vacuum (3 mbar) at 60 °C to yield the crude product (77.7 g) in a purity of 60.9 GC-a% (the yield being thus 76.8%) with 30.2 GC-a% residual aniline and 1.29 GC-a% residual diethyl fumarate. GO method 5 was applied.

[0267] Example i.12: Amination of diethyl maleate with cyclohexylamine to diethyl 2-(cyclohex- ylamino)butanedioate (compound (IV) wherein R2= cyclohexyl and X1and X2= ethoxy) A 50 mL three-necked round bottomed flask was sequentially charged with diethyl maleate (5.00 g, 29.0 mmol, 1.0 equiv.), cyclohexylamine (5.76 g, 58.1 mmol, 2.0 equiv.), and p-toluenesulfonic acid monohydrate (0.280 g, 1.45 mmol, 0.05 equiv.). The flask was equipped with a reflux condenser. Then the resulting mixture was heated at 120 °C for 18 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium carbonate solution (2 * 10 mL), dried over sodium sulfate and concentrated under reduced pressure to yield a brown oily residue (8.14 g). The crude residue was subjected to silica gel column chromatography (0-30% ethyl acetate / n- heptane) to afford diethyl 2-(cyclohexylamino)butanedioate (5.44 g, 69%) as a yellow oil.

[0268] 1H NMR (500 MHz, DMSO) 8 = 4.22 (q, J = 7.1 Hz, 2H), 4.17(q, J = 7.1 Hz, 2H), 3.75 (t, J = 6.8 Hz, 1 H), 2.73 (dd, J = 15.6, 6.4 Hz, 1 H), 2.64-2.59 (m, 1 H), 2.05 (br s, 1 H), 1.92-1.89 (m, 1 H), 1.81-1.74 (m, 3H), 1.65-1.62 (m, 1 H), 1.37-1.02 (m, 12H).

[0269] 13C NMR (126 MHz, DMSO) 8 = 173.60, 170.36, 60.20, 59.95, 54.50, 54.06, 38.25, 33.44, 32.23, 25.70, 24.27, 23.97, 14.02, 13.99.

[0270] Example i.13: Amination of diethyl maleate with 2-ethoxyethylamine to diethyl 2-(2-eth- oxyethylamino)butanedioate (compound (IV) wherein R2= 2-ethoxyethyl and X1and X2= ethoxy)

[0271] A 50 mL three-necked round bottomed flask was sequentially charged with diethyl maleate (3.00 g, 17.4 mmol, 1.0 equiv.), 2-ethoxyethylamine (3.11 g, 34.8 mmol, 2.0 equiv.), and p-toluenesulfonic acid monohydrate (0.166 g, 0.871 mmol, 0.05 equiv.). The flask was equipped with a reflux condenser. Then the resulting mixture was heated at 120 °C for 18 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium carbonate solution (2 * 10 mL), dried over sodium sulfate and concentrated under reduced pressure to yield diethyl 2-(2-ethoxyethylamino)bu- tanedioate (3.36 g, 74% crude yield) as a brown viscous liquid. The liquid was used for the subsequent step without any further purification.

[0272] 1H NMR (300 MHz, DMSO) 8 = 4.09 (q, J = 7.1 Hz, 2H), 4.04(q, J = 7.1 Hz, 2H), 3.54- 3.51 (m, 1 H), 3.46-3.35 (m, 6H), 2.76-2.64 (m, 1H), 2.61-2.52 (m, 2H), 2.14 (br s, 1 H), 1.21-1.05 (m, 9H).

[0273] 13C NMR (75 MHz, DMSO) 8 = 173.02, 170.44, 69.68, 65.30, 60.26, 60.01, 57.37, 46.69, 37.54, 15.09, 14.05, 14.01.

[0274] MS (LCMS-ESI): calcd for C12H24NO5 [M+H]+262.2, found 262.4.

[0275] Example i.14: Amination of diethyl maleate with pyridin-2-ylamine to diethyl 2-(2-pyri- dylamino)butanedioate (compound (IV) wherein R2= pyridin-2-yl and X1and X2= ethoxy)

[0276] A 50 mL three-necked round bottomed flask was sequentially charged with diethyl maleate (5.00 g, 29.0 mmol, 1.0 equiv.), 2-aminopyridine (3.00 g, 31.9 mmol, 1.1 equiv.). The flask was equipped with a reflux condenser. Then the resulting mixture was heated at 120 °C for 3 h. Then, the reaction mixture was cooled to room temperature following which the crude residue was subjected to silica gel column chromatography (30-65% ethyl acetate / n-heptane) to afford diethyl 2-(2-pyridylamino)butanedioate (0.739 g, 10%) as a colorless oil.

[0277] 1H NMR (300 MHz, DMSO) 8 = 7.95 (ddd, J = 5.0, 1.9, 0.9 Hz, 1 H), 7.39 (ddd, J = 9.0, 7.0, 1.9 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 6.58 (dt, J = 8.4, 1.0 Hz, 1H), 6.53 (ddd, J = 7.1 , 5.1 , 1.0 Hz, 1 H), 4.89-4.82 (m, 1H), 4.12-4.01 (m, 4H), 2.84 (dd, J = 13.9, 5.9 Hz, 1H), 2.75 (dd, J = 16.0, 7.4 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H).

[0278] 13C NMR (75 MHz, DMSO) 8 = 172.14, 170.26, 157.53, 147.14, 136.75, 112.60, 109.16, 60.46, 60.25, 50.28, 36.53, 14.02, 13.99.

[0279] MS (LCMS-ESI): calcd for C13H19N2O4 [M+H]+267.1, found 267.4.

[0280] Example i.15: Amination of diethyl maleate with 2-methylpropan-1 -amine (isobutylamine) to diethyl 2-(isobutylamino)butanedioate (compound (IV) wherein R2= isobutyl and X1and X2= ethoxy)

[0281] A 10 mL crimp-capped vial was sequentially charged with diethyl maleate (0.500 g, 2.90 mmol, 1.0 equiv.), isobutylamine (0.425 g, 5.81 mmol, 2.0 equiv.), and p-tol- uenesulfonic acid monohydrate (0.028 g, 0.15 mmol, 0.05 equiv.). Then the resulting mixture was heated at 120 °C for 18 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (2 mL), washed with saturated aqueous sodium carbonate solution (3 x 1.5 mL), dried over sodium sulfate and concentrated under reduced pressure to yield a brown oily residue (0.502 g). The crude residue was subjected to silica gel column chromatography (0-30% ethyl acetate / n-heptane) to afford diethyl 2-(isobutylamino)butanedioate (0.21 g, 42%) as a brown oil.

[0282] 1H NMR (300 MHz, DMSO) 8 = 4.10 (q, J = 7.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.48 (t, J = 6.8 Hz, 1 H), 2.64 (dd, J = 15.6, 6.6 Hz, 1 H), 2.51 (dd, J = 15.6, 7.1 Hz, 1 H), 2.36 (dd, J = 11.2, 6.9 Hz, 1 H), 2.03 (br s, 1 H), 1.57 (hept, J = 6.6 Hz, 1 H), 1.18 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H), 0.83 (dd, J = 6.6, 1.3 Hz, 6H).

[0283] 13C NMR (75 MHz, DMSO) 8 = 173.14, 170.42, 60.15, 59.95, 57.60, 55.10, 37.55, 28.07, 20.48, 20.35, 14.06, 13.99.

[0284] MS (GCMS): calcd for C12H23NO4 [M]+245.3, found 245.1.

[0285] Step (ii): Reduction of (IV) to (V)

[0286] Example ii.1 : Reduction of diethyl N-phenylaspartate to 2-(phenylamino)-1 ,4-butanediol (compound (V) wherein R2= phenyl)

[0287] N-phenyl-aspartic acid diethyl ester (30.0 g, 113 mmol, 1.00 equiv.) from step (i) was added to tetrahydrofuran (145 mL) and cooled to 5 °C. Lithium aluminum hydride solution (1 M in THF, 226 mL, 226 mmol, 2.00 equiv.) was added slowly within 90 minutes. The reaction mixture is cooled to 0 °C and quenched by careful addition of water (25.8 mL), aqueous sodium hydroxide solution (15%, 8.60 mL) and another portion of water (25.8 mL). The mixture is stirred for 30 minutes at 25 °C. Then, magnesium sulfate (38.7 g) is added. The mixture is filtered and the residue washed with 2-methoxy-2- methylpropane (100 mL). The filtrated is concentrated in vacuum (50 °C, 1 mbar) to yield the title compound (14.9 g) as a yellow solid in a purity of 90.4 GC-a% (the yield being thus 65.9%). GO method 1 was applied.

[0288] Example ii.2: Reduction of diethyl N-phenylaspartate to 2-(phenylamino)-1 ,4-butanediol (compound (V) wherein R2= phenyl)

[0289] Sodium borohydride (21.3 g, 0.563 mol, 2.0 equiv.) was added to tetrahydrofuran (200 mL). At 66 °C, N-phenyl-aspartic acid diethyl ester (74.7 GC-a%, 120 g, 0.281 mol, 1.00 equiv.) from step (i) diluted in methanol (82 mL) and tetrahydrofuran (50 mL) was added within 75 minutes. The reaction mixture was stirred at 65 °C for 2 hours. The reaction mixture was cooled to 25 °C and quenched with water (290 mL), diluted with ethyl acetate (150 mL) and aqueous sodium chloride solution (150 mL) was added.

[0290] The phases were separated and the aqueous phase was extracted thrice with ethyl acetate (3x150 mL). The combined organic phases were concentrated in vacuum (50 °C, 2 mbar) to yield the crude product (51 .2 g) in a purity of 84.5 GC-a% (the yield being thus 85.1 %). GO method 3 was applied. Example ii.3: Reduction of diethyl N-phenylaspartate to 2-(phenylamino)-1,4-butanediol (compound (V) wherein R2= phenyl)

[0291] Sodium borohydride (16.0 g, 0.422 mol, 1.5 equiv.) was added to tetrahydrofuran (150 mL). At 66 °C, N-phenyl-aspartic acid diethyl ester (74.7 GC-a%, 120 g, 0.281 mol, 1.00 equiv.) from step (i) diluted in methanol (62 mL) and tetrahydrofuran (50 mL) was added within 60 minutes. The reaction mixture was stirred at 68 °C for 22 hours. The reaction mixture was cooled to 25 °C and quenched with water (218 mL), diluted with ethyl acetate (150 mL) and aqueous sodium chloride solution (150 mL) was added. The phases were separated and the aqueous phase was extracted twice with ethyl acetate (2x150 mL). The combined organic phases were concentrated in vacuum (50 °C, 2 mbar) to yield the crude product (58 g) in a purity of 62.8 GC-a% (the yield being thus 71.6%). GO method 3 was applied.

[0292] Example ii.4: Reduction of diethyl N-phenylaspartate to 2-(phenylamino)-1,4-butanediol (compound (V) wherein R2= phenyl)

[0293] Sodium borohydride (29.2 g, 0.773 mol, 2.5 equiv.) was added to tetrahydrofuran (150 mL). At 74 °C, N-phenyl-aspartic acid diethyl ester (68.3 GC-a%, 120 g, 0.309 mol, 1.00 equiv.) from example i.3 diluted in ethanol (128 mL) and tetrahydrofuran (50 mL) was added within 60 minutes. The reaction mixture was stirred at 72 °C for 5 hours. The reaction mixture was cooled to 40 °C and quenched with water (375 mL), diluted with ethyl acetate (180 mL) and aqueous sodium chloride solution (180 mL) was added. The phases were separated and the aqueous phase was extracted twice with ethyl acetate (2x180 mL). The combined organic phases were concentrated in vacuum (50 °C, 2 mbar) to yield the crude product (89.9 g). GO method 3 was applied. The crude product was used in subsequent reactions without purification.

[0294] Example ii.5: Reduction of diethyl N-phenylaspartate from example i.7 to 2-(phenyla- mino)-1,4-butanediol (compound (V) wherein R2= phenyl)

[0295] Sodium borohydride (8.56 g, 0.226 mol, 2.0 equiv.) was added to tetrahydrofuran (250 mL). At 66 °C, N-phenyl-aspartic acid diethyl ester (-98.9 GC-a%, 30 g, 0.113 mol, 1.00 equiv.) from example i.7 diluted in methanol (33 mL) was added within 45 minutes. The reaction mixture was stirred at 65 °C for 3 hours. The reaction mixture was cooled to 25 °C and quenched with water (117 mL). The phases were separated and the organic phase was diluted with ethyl acetate (200 mL) and washed with saturated sodium chloride solution (100 mL). The aqueous phase was extracted twice with ethyl acetate (2x 100 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuum (50 °C, 2 mbar) to yield the product (20.3 g) as a white solid in a purity of 98 GC-a% (the yield being thus 97.1%). GO method 3 was applied. The crude product was used in the subsequent step without purification. Example ii.6: Reduction of diethyl N-phenylaspartate to 2-(phenylamino)-1,4-butanediol (compound (V) wherein R2= phenyl)

[0296] Sodium borohydride (14.6 g, 0.386 mol, 2.5 equiv.) was added to 2-methyloxolane (150 mL). At 74 °C, N-phenyl-aspartic acid diethyl ester (68.3 GC-a%, 60 g, 0.154 mol, 1.00 equiv.) from example i.3 diluted in methanol (64 mL) and 2-methyloxolane (50 mL) was added within 80 minutes. The reaction mixture was stirred at 75 °C for 3 hours. The reaction mixture was cooled to 40 °C and quenched with water (170 mL). The phases were separated and the organic phase was washed with saturated sodium chloride solution (100 mL). The combined organic phase was concentrated in vacuum (50 °C, 3 mbar) to yield the title compound (39.4 g) as a light brown solid in a purity of 65.9 GC- a% (the yield being thus 93.1%). GO method 4 was applied. The crude product was used in the subsequent step without purification.

[0297] Example ii.7: Reduction of diethyl N-phenylaspartate to 2-(phenylamino)-1,4-butanediol (compound (V) wherein R2= phenyl)

[0298] Sodium borohydride (16.5 g, 0.437 mol, 2.5 equiv.) was added to toluene (150 mL). At 76 °C, N-phenyl-aspartic acid diethyl ester (77.2 GC-a%, 60 g, 0.175 mol, 1.00 equiv.) from example i.4 diluted in methanol (64 mL) and toluene (50 mL) was added within 80 minutes. The reaction mixture was stirred at 74-81 °C for 4 hours. The reaction mixture was cooled to 40 °C and quenched with water (425 mL) and extracted thrice with toluene (3x150 mL). Additionally, aqueous phase was extracted four times with ethyl acetate (4x150 mL). The combined toluene phases were concentrated in vacuum (50 °C, 2 mbar) to yield a brown viscous product (9.1 g) in a purity of 28.4 GC-a%. The combined ethyl acetate phases were concentrated in vacuum (50 °C, 2 mbar) to yield the product (22.3 g) as a beige solid in a purity of 97.3 GC-a% (the yield being thus 68.5%). GO method 3 was applied.

[0299] Example ii.8: Reduction of diethyl N-phenylaspartate to 2-(phenylamino)-1,4-butanediol (compound (V) wherein R2= phenyl)

[0300] Sodium borohydride (41.8 g, 1.11 mol, 2.5 equiv.) was added to 2-methyloxolane (150 mL). At 74 °C, N-phenyl-aspartic acid diethyl ester (78.2 GC-a%, 150 g, 0.442 mol, 1.00 equiv.) from example i.6 diluted in methanol (160 mL) and 2-methyloxolane (50 mL) was added within 150 minutes. The reaction mixture was stirred at 80 °C for 5 hours. The reaction mixture was cooled to 40 °C and quenched with water (425 mL). The phases were separated and the organic phase was washed with saturated sodium chloride solution (250 mL). The combined aqueous phases were extracted with 2- methyloxolane (200 mL) and the combined organic phases concentrated in vacuum (50 °C, 3 mbar) to yield the title compound (99.5 g) as a brown solid in a purity of 77.2 GC- a% (the yield being thus 96%). GO method 2 was applied. The crude product was used in the subsequent step without purification. Example ii.9: Reduction of diethyl N-phenylaspartate to 2-(phenylamino)-1,4-butanediol (compound (V) wherein R2= phenyl)

[0301] Sodium borohydride (27.9 g, 0.738 mol, 2.5 equiv.) was added to 2-methyloxolane (100 mL). At 71 °C, N-phenyl-aspartic acid diethyl ester (97.8 GC-a%, 80 g, 0.295 mol, 1.00 equiv.) from example i.5 diluted in ethanol (85.4 mL) and 2-methyloxolane (100 mL) was added within 90 minutes. The reaction mixture was stirred at 69 °C for 4 hours. The reaction mixture was cooled to 40 °C and quenched with water (226 mL). The phases were separated and the organic phase was washed with saturated sodium chloride solution (133 mL). The combined aqueous phases were extracted with 2- methyloxolane (150 mL) and the combined organic phases concentrated in vacuum (50 °C, 2 mbar) to yield the title compound (55.3 g) as a brown solid in a purity of >95mol% (determined by NMR) (the yield being >98.4%). GC method 2 was applied. The crude product was used in the subsequent step without purification.

[0302] 1H NMR (500 MHz, DMSO) 8 = 7.74 (dd, J = 8.5, 7.3 Hz, 2H), 7.33 - 7.27 (m, 2H), 7.18 (t, J = 7.2 Hz, 1 H), 5.90 (d, J = 8.1 Hz, 1H), 5.41 (d, J = 4.9 Hz, 1H), 5.23 (t, J = 4.6 Hz, 1H), 4.32 - 3.94 (m, 5H), 2.56 - 2.20 (m, 2H).

[0303] 13C NMR (126 MHz, DMSO) 8 = 148.68, 128.96 (2C), 115.33, 112.41 (2C), 63.12, 58.25, 51.33, 34.94.

[0304] MS (GC-EI): [M]+* = 181.1 m / z

[0305] Melting Point: 88-89 °C

[0306] Example ii.10: Reduction of diethyl N-phenylaspartate to 2-(phenylamino)-1 ,4-butane- diol (compound (V) wherein R2= phenyl)

[0307] Sodium borohydride (27.9 g, 0.738 mol, 2.5 equiv.) was added to 2-methyloxolane (100 mL). At 71 °C, N-phenyl-aspartic acid diethyl ester (97.8 GC-a%, 80 g, 0.295 mol, 1.00 equiv.) from example i.5 diluted in isobutanol (85.4 mL) and 2-methyloxolane (100 mL) was added within 90 minutes. The reaction mixture was stirred at 80 °C for 6 hours. The reaction mixture was cooled to 40 °C and quenched with water (226 mL). The phases were separated and the organic phase was washed with saturated sodium chloride solution (133 mL). The combined aqueous phases were extracted with 2- methyloxolane (150 mL) and the combined organic phases concentrated in vacuum (50 °C, 2 mbar) to yield the title compound (56.9 g) as a brown solid in a purity of 91.9 GC- a% (the yield being thus 97.9%). GC method 2 was applied.

[0308] Example ii.11 : Reduction of dimethyl N-phenylaspartate to 2-(phenylamino)-1 ,4-bu- tanediol (compound (V) wherein R2= phenyl)

[0309] Sodium borohydride (6.34 g, 169 mmol, 2.5 equiv.) was added to 2-methyloxolane (20 mL). At 71 °C, dimethyl N-phenylaspartate (98.2 GC-a%, 16.0 g, 67.4 mmol, 1.00 equiv.) from example i.9 diluted in ethanol (17 mL) and 2-methyloxolane (20 mL) was added within 40 minutes. The reaction mixture was stirred at 68-62 °C for 3 hours. The reaction mixture was cooled to room temperature and quenched with water (45 mL). The phases were separated and the organic phase was washed with saturated sodium chloride solution (25 mL). The combined aqueous phases were extracted with 2- methyloxolane (15 mL) and the combined organic phases concentrated in vacuum (60 °C, 5 mbar) to yield the title compound (11 .8 g) as a solid in a purity of 97.4 GC-a% (the yield being thus 94.2%). GO method 5 was applied.

[0310] Example ii.12: Reduction of bis(2-ethylhexyl) N-phenylaspartate to 2-(phenylamino)- 1 ,4-butanediol (compound (V) wherein R2= phenyl)

[0311] Sodium borohydride (3.49 g, 92.4 mmol, 2.5 equiv.) was added to 2-methyloxolane (20 mL). At 71 °C, bis(2-ethylhexyl) phenylaspartate (68.4 GC-a%, 16 g, 36.9 mmol, 1.00 equiv.) from example i.10 diluted in ethanol (17 mL) and 2-methyloxolane (20 mL) was added within 30 minutes. The reaction mixture was stirred at 65 °C for 3 hours. The reaction mixture was cooled room temperature and quenched with water (45 mL). The phases were separated and the organic phase was washed with saturated sodium chloride solution (25 mL). The combined aqueous phases were extracted with 2- methyloxolane (15 mL) and the combined organic phases concentrated in vacuum (60 °C, 5 mbar) to yield the title compound (14.0 g) in a purity of 21.6 GC-a% (the yield being thus 45.2%) with 6.9 GC-a% residual aniline and 68.1 GC-a% residual 2- ethylhexan-1-ol. GO method 5 was applied.

[0312] Examples ii.13, ii.14 and ii.15: Reduction of diethyl N-phenylaspartate to 2-(phenyla- mino)-1 ,4-butanediol (compound (V) wherein R2= phenyl) via hydrogenation in the presence of a hydrogenation catalyst

[0313] In these examples a catalyst of one of the following formulae was used:

[0314] Example ii.13:

[0315] Ru-complex 1 (46 mg, 0.057 mmol, 0.3 mol%), N-phenyl-aspartic acid diethyl ester (5.0 g, 18.8 mmol, 1.00 equiv.) and sodium methanolate (51 mg, 0.9 mmol, 5 mol%) were placed in a 100 mL autoclave under inert atmosphere and 40 mL of dry tetrahydrofuran were added. The autoclave was sealed, a hydrogen pressure of 6.0 MPa abs applied, and heated to 135°C at 700 rpm. After reaching the temperature, a hydrogen pressure of 8.0 MPa abs was set. After 48 h of reaction time, the autoclave was cooled to room temperature and the solution obtained was analyzed by GO. GC-analysis [DB-5 column (60 m x 0.25 mm / 1 .0 pm; 15 min at 80°C then with 15°C / min to 250°C; flow: 1.9 mL / min; nitrogen as carrier gas)] showed a conversion of >99% and a selectivity of 90% for the diol.

[0316] Example ii.14:

[0317] Ru-complex 2 (6.9 mg, 0.011 mmol, 0.3 mol%), N-phenyl-aspartic acid diethyl ester (1.0 g, 3.77 mmol, 1.00 equiv.) and sodium methanolate (10 mg, 0.19 mmol, 5 mol%) were placed in a 100 mL autoclave under inert atmosphere and 20 mL of dry tetrahydrofuran were added. The autoclave was sealed, a hydrogen pressure of 6.0 MPa abs applied, and heated to 135°C at 700 rpm. After reaching the temperature, a hydrogen pressure of 8.0 MPa abs was set. After 20 h of reaction time, the autoclave was cooled to room temperature and the solution obtained was analyzed by GC. GC-analysis [DB- 5 column (60 m x 0.25 mm / 1.0 pm; 15 min at 80°C then with 15°C / min to 250°C; flow: 1.9 mL / min; nitrogen as carrier gas)] showed a conversion of >99% and a selectivity of 80% for the diol.

[0318] Example ii.15:

[0319] Ru-complex 1 (123 mg, 0.15 mmol, 0.2 mol%), N-phenyl-aspartic acid diethyl ester (20.0 g, 75.2 mmol, 1.00 equiv.) and sodium methanolate (200 mg, 0.36 mmol, 5 mol%) were placed in a 100 mL autoclave under inert atmosphere and 40 mL of dry toluene were added. The autoclave was sealed, a hydrogen pressure of 6.0 MPa abs applied, and heated to 135°C at 700 rpm. After reaching the temperature, a hydrogen pressure of 8.0 MPa abs was set. After 20 h of reaction time, the autoclave was cooled to room temperature and the solution obtained was analyzed by GC. GC-analysis [DB- 5 column (60 m x 0.25 mm / 1.0 m; 15 min at 80° C then with 15° C / min to 250° C; flow: 1.9 mL / min; nitrogen as carrier gas)] showed a conversion of >99% and a selectivity of 91% for the diol.

[0320] Example ii.16: Reduction of diethyl 2-(cyclohexylamino)butanedioate to 2-(cyclohexyla- mino)butane-1 ,4-diol (compound (V) wherein R2= cyclohexyl)

[0321] In a 50 mL three-necked round bottomed flask, a solution of the crude diethyl 2-(cyclo- hexylamino)butanedioate (0.500 g, 1.84 mmol, 1.0 equiv.) from example i.12 in THF (3 mL) was cooled to 5 °C under an atmosphere of nitrogen. A 2.0 M solution of lithium aluminum hydride (1.8 mL, 3.69 mmol, 2.0 equiv.) in THF was added dropwise to the precooled solution over 5 min. Then the resulting mixture was stirred for 90 min at that temperature. Then the reaction mixture was cooled to 0 °C and quenched by careful addition of water (0.15 mL), aqueous sodium hydroxide solution (15%, 0.15 mL) and another portion of water (0.45 mL). The mixture was stirred for 30 minutes at room temperature. Then, sodium sulfate (0.630 g) is added. The mixture was filtered through a pad of Celite and the residue washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to yield 2-(cyclohexylamino)butane-1 ,4-diol (0.334 g, 97% crude yield) as a viscous brownish liquid. The liquid was used for the subsequent step without any further purification.

[0322] 1H NMR (500 MHz, DMSO) 5 = 3.50 (t, J = 6.3 Hz, 2H), 3.32 (dd, J = 10.6, 5.3 Hz, 1 H), 3.25 (dd, J = 10.6, 5.0 Hz, 1 H), 2.76-2.64 (m, 1 H), 2.49-2.41 (m, 1 H), 1.82-1.36 (m, 10H), 1.27-0.90 (m, 9H).

[0323] MS (LCMS-ESI): calcd for C10H22NO2 [M+H]+ 188.2, found 188.4; calcd for C10H21NO1 [M-H2O+H]+171.2, found 171.1.

[0324] Example ii.17: Reduction of diethyl 2-(2-ethoxyethylamino)butanedioate to 2-(2-ethoxy- ethylamino)butane-1 ,4-diol (compound (V) wherein R2= 2-ethoxyethyl)

[0325] In a 50 mL three-necked round bottomed flask, a solution of the crude diethyl 2-(2-eth- oxyethylamino)butanedioate (2.33 g, 8.93 mmol, 1.0 equiv.) from example i.13 in THF (15 mL) was cooled to 5 °C under an atmosphere of nitrogen. A 2.0 M solution of lithium aluminum hydride (9.0 mL, 18 mmol, 2.0 equiv.) in THF was added dropwise to the precooled solution over 10 min. Then the resulting mixture was stirred for 90 min at that temperature. Then the reaction mixture was cooled to 0 °C and quenched by careful addition of water (0.70 mL), aqueous sodium hydroxide solution (15%, 0.70 mL) and another portion of water (2.1 mL). The mixture was stirred for 30 minutes at room temperature. Then, sodium sulfate (3.00 g) is added. The mixture was filtered through a pad of Celite and the residue washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to yield 2-(2-ethoxyethylamino)butane-1 ,4-diol (1.47 g, 93% crude yield) as a viscous brownish liquid. The liquid was used for the subsequent step without any further purification.

[0326] 1H NMR (300 MHz, DMSO) 8 = 3.50-3.34 (m, 9H), 2.71-2.44 (m, 4H), 1.55-1.41 (m, 1 H), 1.10 (t, J = 7.0 Hz, 3H).

[0327] MS (LCMS-ESI): calcd for C8H2oN03[M+H]+178.1 , found 178.3.

[0328] Example ii.18: Reduction of diethyl 2-(2-pyridylamino)butanedioate to 2-(2-pyridyla- mino)butane-1 ,4-diol (compound (V) wherein R2= 2-pyridyl)

[0329] In a 50 mL three-necked round bottomed flask, a solution of the crude diethyl 2-(2-pyri- dylamino)butanedioate (0.587 g, 2.20 mmol, 1.0 equiv.) from example i.14 in THF (4 mL) was cooled to 5 °C under an atmosphere of nitrogen. A 2.0 M solution of lithium aluminum hydride (2.2 mL, 4.41 mmol, 2.0 equiv.) in THF was added dropwise to the precooled solution over 5 min. Then the resulting mixture was stirred for 90 min at that temperature. Then the reaction mixture was cooled to 0 °C and quenched by careful addition of water (0.17 mL), aqueous sodium hydroxide solution (15%, 0.17 mL) and another portion of water (0.50 mL). The mixture was stirred for 30 minutes at room temperature. Then, sodium sulfate (0.753 g) is added. The mixture was filtered through a pad of Celite and the residue washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to yield 2-(2-pyridylamino)butane-1 ,4-diol (0.395 g, 98% crude yield) as a pale yellow oil. The oil was used for the subsequent step without any further purification.

[0330] 1H NMR (300 MHz, DMSO) 8 = 7.90 (ddd, J = 5.0, 1.9, 0.6 Hz, 1 H), 7.32 (ddd, J = 8.6, 7.0, 2.0 Hz, 1 H), 6.49 (dt, J = 8.5, 1.0 Hz, 1 H), 6.42 (ddd, J = 7.0, 5.0, 0.9 Hz, 1 H), 6.20 (d, J = 8.0 Hz, 1 H), 4.72 (t, J = 5.5 Hz, 1 H), 4.57 (t, J = 5.3 Hz, 1 H), 4.38 (t, J = 5.2 Hz, 1 H), 3.49-3.37 (m, 6H).

[0331] MS (LCMS-ESI): calcd for C9Hi5N2O2[M+H]+183.1 , found 183.3; calcd for C9HnN2[M- 2H2O+H]+147.1 , found 147.2.

[0332] Example ii.19: Reduction of diethyl 2-(isobutylamino)butanedioate to 2-(isobutyla- mino)butane-1 ,4-diol (compound (V) wherein R2= isobutyl)

[0333] In a 100 mL three-necked round bottomed flask, a solution of the crude diethyl 2-(iso- butylamino)butanedioate (4.43 g, 18.1 mmol, 1.0 equiv.) from example i.15 in THF (22 mL) was cooled to 5 °C under an atmosphere of nitrogen. A 2.0 M solution of lithium aluminum hydride (18 mL, 36 mmol, 2.0 equiv.) in THF was added dropwise to the precooled solution over 15 min. Then the resulting mixture was stirred for 90 min at that temperature. Then the reaction mixture was cooled to 0 °C and quenched by careful addition of water (1.3 mL), aqueous sodium hydroxide solution (15%, 1.3 mL) and another portion of water (3.9 mL). The mixture was stirred for 30 minutes at room temperature. Then, sodium sulfate (0.630 g) was added. The mixture was filtered through a pad of Celite and the residue washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure to yield 2-(isobutylamino)butane-1 ,4-diol (2.69 g, 92% crude yield) as a viscous orange liquid. The liquid was used for the subsequent step without any further purification.

[0334] 1H NMR (300 MHz, DMSO) 8 = 3.50 (td, J = 6.3, 1.8 Hz, 2H), 3.36 (dd, J = 10.6, 5.1 , 1 H), 3.28 (dd, J = 10.6, 5.1 Hz, 1 H), 2.58-2.52 (m, 1 H), 2.37 (dd, J = 11.3, 6.6 Hz, 1 H), 2.29 (dd, J = 11.3, 6.6 Hz, 1 H), 1.59 (hept, J = 6.7 Hz, 1 H), 1.51-1.41 (m, 2H), 0.86 (dd, J = 6.6, 1.2 Hz, 6H).

[0335] MS (LCMS-ESI): calcd for C8H20NO2[M+H]+162.1 , found 162.4.

[0336] Example iii.1 : Preparation of N-phenyl-tetrahydrofuran-3-amine (compound (I) wherein R2= phenyl)

[0337] 2-(Phenylamino)-1 ,4-butanediol (10.2 g, 38.5 mmol, 1.00 equiv.) from example ii.4 and methanesulfonic acid (11.1 g, 115 mmol, 3.00 equiv.) were mixed and stirred at 130 °C for 6 h. After cooling, water (12 mL) and aqueous sodium hydroxide solution (50%, 9.78 g) were added and the mixture was extracted four times with ethyl acetate (4x12 mL). The combined organic phases were concentrated in vacuum (50 °C, 1 mbar) to yield the crude product (7.4 g) as a brown liquid in a purity of 73.9 GC-a% (the yield being thus 87.1%). GC method 3 was applied. Example iii.2: Preparation of N-phenyl-tetrahydrofuran-3-amine (compound (I) wherein R2= phenyl)

[0338] 2-(Phenylamino)-1,4-butanediol (65.9 GC-a% purity, 8.8 g, 32.0 mmol, 1.00 equiv.) from example ii.6 and sulfuric acid (96%, 9.81 g, 96.1 mmol, 3.00 equiv.) were mixed and stirred at 130 °C for 3 h. After cooling, water (12 mL) and aqueous sodium hydroxide solution (50%, 17.9 g) were added and the mixture was extracted thrice with ethyl acetate (3x12 mL). The combined organic phases were concentrated in vacuum (50 °C, 2 mbar) to yield the crude product (6.0 g) as a brown liquid in a purity of 68.2 GC- a% (the yield being thus 78.4%). GO method 4 was applied.

[0339] Example iii.3: Preparation of N-phenyl-tetrahydrofuran-3-amine (compound (I) wherein R2= phenyl)

[0340] 2-(Phenylamino)-1,4-butanediol (90.4 GC-a% purity, 1.0 g, 4.99 mmol, 1.00 equiv.) and p-toluenesulfonic acid monohydrate (1.97 g, 10.4 mmol, 2.08 equiv.) were added to xylenes (5 mL) and stirred at 155 °C for 22 h. A sample of the organic phase was added to sodium carbonate and diluted with methanol. Conversion was shown with 93.5 GC- a% of the desired product. GC method 1 was applied.

[0341] Example iii.4: Preparation of N-phenyl-tetrahydrofuran-3-amine (compound (I) wherein R2= phenyl)

[0342] 2-(Phenylamino)-1,4-butanediol (15.0 g, 55.7 mmol, 1.00 equiv.) from example ii.4 was added to xylenes (75 mL) and heated to 83 °C. Methanesulfonic acid (16.1 g, 167 mmol, 3.00 equiv.) was added within 10 minutes and the mixture was stirred at 130 °C for 5 hours. After cooling, aqueous sodium hydroxide solution (50%, 14.2 g) and water (17.6 mL) were added and the phases separated. The aqueous phase was extracted thrice with xylenes (3x20 mL) and the combined organic phases were concentrated in vacuum (50 °C, 2 mbar) to yield the crude product (10.0 g) as a brown liquid in a purity of 73.1 GC-a% (the yield being thus 80.5%). GC method 4 was applied.

[0343] Example iii.5: Preparation of N-phenyl-tetrahydrofuran-3-amine (compound (I) wherein R2= phenyl)

[0344] To a melting of 2-(phenylamino)-1,4-butanediol (77.2 GC-a% purity, 91.5 g, 390 mmol, 1.00 equiv.) from example ii.8 at 78 °C, sulfuric acid (96%, 59.7 g, 584 mmol, 1.50 equiv.) was added slowly. The temperature was not allowed to exceed 113 °C. After addition, the mixture was stirred at 130 °C for 4 hours. After cooling, water (110 mL), aqueous sodium hydroxide solution (50%, 72 mL) and ethyl acetate (110 mL) were added. Additional water (200 mL) was added, and the phase separated. The aqueous phase was extracted thrice with ethyl acetate (3x110 mL). The combined organic phases were concentrated in vacuum (50 °C, 1 mbar) to yield the crude product (76.1 g) as a brown liquid in a purity of 70.4 GC-a% (the yield being thus 84.3%). GC method 2 was applied. The crude product was purified by distillation with a 30 cm column with wire mesh rings according to the table below to yield the pure product.

[0345] Example iii.6: Preparation of N-phenyl-tetrahydrofuran-3-amine (compound (I) wherein R2= phenyl)

[0346] To a melting of 2-(phenylamino)-1 ,4-butanediol (98.1 GC-a% purity, 51.2 g, 277 mmol, 1.00 equiv.) from example ii.9 at 87 °C, sulfuric acid (96%, 42.5 g, 416 mmol, 1.50 equiv.) was added slowly. The temperature was not allowed to exceed 122 °C. After addition, the mixture was stirred at 130 °C for 4 hours. After cooling, water (61.4 mL), aqueous sodium hydroxide solution (50%, 51.2 mL) and ethyl acetate (85 mL) were added. Additional water (150 mL) was added, and the phase separated. The aqueous phase was extracted twice with ethyl acetate (2x85 mL). The combined organic phases were concentrated in vacuum (50 °C, 2 mbar) to yield the crude product (44.1 g) as a brown liquid in a purity of 90.2 GC-a% (the yield being thus 88.1%). GO method 2 was applied. The crude product was purified by distillation with a 30 cm column with wire mesh rings according to the table below to yield the pure product.

[0347] 1H NMR (500 MHz, DMSO) 8 = 7.13 - 7.04 (m, 2H), 6.63 - 6.52 (m, 3H), 5.97 - 5.77 (m, 1 H), 3.95 (ddd, J = 9.8, 7.3, 3.7 Hz, 1 H), 3.90 - 3.78 (m, 2H), 3.72 (td, J = 8.2, 5.5 Hz, 1 H), 3.53 (dd, J = 8.7, 3.7 Hz, 1 H), 2.15 (dq, J = 12.5, 7.3 Hz, 1 H), 1.76 (dddd, J = 12.6, 7.4, 5.5, 3.8 Hz, 1 H).

[0348] 13C NMR (126 MHz, DMSO) 8 = 147.99, 128.92 (2C), 115.91 , 112.52 (2C), 72.59, 66.47, 52.90, 32.60.

[0349] MS (GC-EI): [M]+* = 163.2 m / z Example iii.7: Preparation of N-cyclohexyl-tetrahydrofuran-3-amine (compound (I) wherein R2= cyclohexyl)

[0350] A 25 mL three-necked round bottomed flask was charged with 2-(cyclohexylamino)bu- tane-1 ,4-diol (0.146 g, 0.780 mmol, 1.0 equiv.) from example ii.16. The flask was equipped with a reflux condenser and xylenes (2 mL) was added into it to dissolve the compound. Methanesulfonic acid (0.15 mL, 2.3 mmol, 3.0 equiv.) was dropwise added to this solution over 5 min at 83 °C. Post addition, the reaction mixture was heated to 130 °C for 5 h. After cooling, an aqueous sodium hydroxide solution (50%, 0.2 mL) and water (5 mL) were added to the reaction mixture and the two phases were separated. The aqueous phase was extracted with xylenes (3 x 5 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield the crude product (0.139 g) as a dark brown oil. The residue was subjected to silica gel column chromatography (0-5% methanol / dichloromethane) to afford N-cyclo- hexyltetrahydrofuran-3-amine (0.120 g, 91%) as a brown oil.

[0351] 1H NMR (500 MHz, DMSO) 8 = 3.76-3.57 (m, 3H), 3.43-3.35 (m, 1 H), 3.29 (dd, J = 8.2, 5.0 Hz, 1 H), 2.36 (tt, J = 10.1 , 3.7 Hz, 1 H), 2.00-1.89 (m, 1 H), 1.83-1.49 (m, 7H), 1.27-0.88 (m, 5H).

[0352] 13C NMR (126 MHz, DMSO) 8 = 73.15, 66.36, 54.95, 54.62, 33.42, 33.24, 33.18, 25.85, 24.58, 24.52.

[0353] MS (LCMS-ESI): calcd for Ci0H20NO [M+H]+170.2, found 170.4.

[0354] Example iii.8: Preparation of N-(2-ethoxyethyl)-tetrahydrofuran-3-amine (compound (I) wherein R2= 2-ethoxyethyl)

[0355] A 25 mL three-necked round bottomed flask was charged with 2-(2-ethoxyethyla- mino)butane-1 ,4-diol (0.143 g, 0.807 mmol, 1.0 equiv.) from example ii.17. The flask was equipped with a reflux condenser and xylenes (2 mL) was added into it to dissolve the compound. Methanesulfonic acid (0.16 mL, 2.4 mmol, 3.0 equiv.) was dropwise added to this solution over 5 min at 83 °C. Post addition, the reaction mixture was heated to 130 °C for 5 h. After cooling, an aqueous sodium hydroxide solution (50%, 0.2 mL) and water (5 mL) were added to the reaction mixture and the two phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 5 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield the crude product (0.109 g) as a dark brown oil. The residue was subjected to silica gel column chromatography (0-3% methanol / dichloromethane) to afford N-(2-ethoxyethyl)tetrahydrofuran-3-amine (0.082 g, 64%) as a brown oil.1H NMR (300 MHz, DMSO) 8 = 3.76-3.58 (m, 3H), 3.45-3.35 (m, 6H), 3.31-3.24 (m, 1 H), 2.70-2.58 (m, 2H), 2.01-1.88 (m, 1 H), 1.67-1.57 (m, 1 H), 1.10 (t, J = 7.0 Hz, 3H).13C NMR (126 MHz, DMSO) 8 = 72.50, 69.49, 66.37, 65.41 , 58.07, 47.31 , 32.47, 15.11. MS (LCMS-ESI): calcd for C8Hi8NO2 [M+H]+160.1 , found 160.4. Example iii.9: Preparation of N-tetrahydrofuran-3-yl-pyridin-2-amine (compound (I) wherein R2= 2-pyridyl)

[0356] A 25 mL three-necked round bottomed flask was charged with 2-(2-pyridylamino)bu- tane-1,4-diol (0.365 g, 2.00 mmol, 1.0 equiv.) from example ii.18. The flask was equipped with a reflux condenser and xylenes (5 mL) was added into it to dissolve the compound. Methanesulfonic acid (0.39 mL, 6.0 mmol, 3.0 equiv.) was drop-wise added to this solution over 5 min at 83 °C. Post addition, the reaction mixture was heated to 130 °C for 5 h. After cooling, an aqueous sodium hydroxide solution (50%, 0.5 mL) and water (5 mL) were added to the reaction mixture and the two phases were separated. The aqueous phase was extracted with ethyl acetate (3 * 10 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield the crude product (0.186 g) as a dark brown oil. The residue was subjected to silica gel column chromatography (70-100% ethyl acetate / n-heptane) to afford N-tetrahydrofuran-3-ylpyridin-2-amine (0.156 g, 47%) as a yellow viscous liquid, which slowly solidified upon storing in a refrigerator at 4 °C to give a pale yellow waxy solid.

[0357] 1H NMR (500 MHz, DMSO) 8 = 7.96 (dd, J = 5.9, 1.7 Hz, 1 H), 7.35 (ddd, J = 8.8, 7.3, 2.0 Hz, 1 H), 6.69 (d, J = 6.2 Hz, 1H), 6.48-6.45 (m, 2H), 4.36-4.31 (m, 1H), 3.86 (dd, J = 8.7, 5.9 Hz, 1 H), 3.82 (dd, J = 15.5, 7.3 Hz, 1H), 3.70 (td, J = 8.1 , 5.6 Hz, 1H), 3.50 (dd, J = 8.7, 4.0 Hz, 1H), 2.15 (ddd, J = 15.0, 12.5, 7.5 Hz, 1H), 1.80-1.74 (m, 1 H).

[0358] 13C NMR (126 MHz, DMSO) 8 = 158.36, 147.49, 136.49, 111.66, 108.60, 72.99, 66.38, 51.19, 32.49.

[0359] MS (LCMS-ESI): calcd for C9Hi3N2O [M+H]+165.1, found 165.2.

[0360] Example iii.10: Preparation of N-isobutyl-tetrahydrofuran-3-amine (compound (I) wherein R2= isobutyl)

[0361] A 50 mL three-necked round bottomed flask was charged with 2-(isobutylamino)bu- tane-1,4-diol (1.00 g, 6.2 mmol, 1.0 equiv.) from example ii.19. The flask was equipped with a reflux condenser and xylenes (5 mL) was added into it to dissolve the compound. Methanesulfonic acid (1.2 mL, 18 mmol, 3.0 equiv.) was dropwise added to this solution over 5 min at 83 °C. Post addition, the reaction mixture was heated to 130 °C for 5 h. After cooling, an aqueous sodium hydroxide solution (50%, 1.0 mL) and water (1.25 mL) were added to the reaction mixture and the two phases were separated. The aqueous phase was extracted with xylenes (3 x 5 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield the crude product N-isobutyltetrahydrofuran-3-amine (0.195 g) as a brown oil.1H NMR (300 MHz, DMSO) 8 = 3.76-3.5 (m, 2H), 3.36 (dd, J = 8.5, 4.5 Hz, 1H), 3.24- 3.17 (m, 1 H), 2.33-2.21 (m, 2H), 2.17-2.09 (m, 1H), 1.97-1.86 (m, 1 H), 1.70-1.53 (m, 2H), 0.85 (dd, J = Q.Q Hz, 6H).

[0362] MS (LCMS-ESI): calcd for C8Hi8NO [M+H]+ 144.1 , found 144.3.

Claims

Claims1. A method for preparing a N-substituted tetrahydrofuran-3-amine of the formula (I) or a stereoisomer thereofwhereR2is Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Cs-Ce-cycloalkyl, phenyl or a 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, where the phenyl ring and the heterocyclic ring may carry 1 , 2, 3, 4 or 5 substituents R3; where each R3is independently selected from the group consisting of halogen, Ci-C4-alkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy-Ci-C4-alkyl; comprising(i) reacting the compound (II)whereinX1and X2are independently OH or OR1, where each R1is independently Ci-C -alkyl, phenyl or benzyl; orX1and X2form together -O-, with an amine (III)NH2R2(III) where R2is as defined above,to the compound (IV)(ii) reducing the compound (IV) to the compound (V)and(iii) subjecting the compound (V) to a cyclization reaction to compound (I).

2. The method according to claim 1 , where R2is Ci-Ce-alkyl, Ci-C3-alkoxy-C2-C3- alkyl, Cs-Ce-cycloalkyl, phenyl or a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, where the phenyl ring and the heteroaromatic ring may carry 1 , 2 or 3 substituents R3; where R2is preferably Ci-Ce-alkyl, Ci-C3-alkoxy-C2-C3-alkyl, Cs-Ce-cycloalkyl or phenyl.

3. The method according to claim 2, where R2is Cs-Cs-alkyl, Ci-C3-alkoxy-C2-C3- alkyl, Cs-Ce-cycloalkyl, phenyl or pyridyl, and is preferably Cs-Cs-alkyl, C1-C3- alkoxy-C2-C3-alkyl, Cs-Ce-cycloalkyl or phenyl.

4. The method according to claim 2, where R2is phenyl which may carry 1 , 2 or 3 substituents R3, where R2is preferably (unsubstituted) phenyl.

5. The method according to any of the preceding claims, where X1and X2are OH or OR1, preferably OR1.

6. The method according to any of the preceding claims, where R1is Ci-C -alkyl.

7. The method according to any of the preceding claims, where the compound (II) is a compound (II. a)where X1and X2are OH or OR1, where R1is as defined in claim 1 and is preferably Ci-Cw-alkyl; where preferably X1and X2are OR1, wherein R1is Ci-Cw-alkyl.

8. The method according to any of claims 1 to 6, where the compound (II) is a compound (II. b)where X1and X2are OH or OR1, where R1is as defined in claim 1 and is preferably Ci-Cw-alkyl; where preferably X1and X2are OR1, wherein R1is Ci-C4-alkyl.

9. The method according to any of the preceding claims, where step (i) is carried out in the presence of an inorganic or organic acid.

10. The method according to claim 9, where step (i) is carried out in the presence of an organic acid, preferably of a sulfonic acid, more preferably of methanesulfonic acid, trifluoromethanesulfonic acid or para-toluenesulfonic acid.11 . The method according to any of the preceding claims, where step (i) is carried out neat.

12. The method according to any of the preceding claims, where step (i) is carried out at a temperature of from 10 to 150°C, preferably from 20 to 150°C.

13. The method according to claim 12, where step (i) is carried out at a temperature of from 100 to 150°C, preferably from 110 to 140°C.

14. The method according to any of the preceding claims, where in step (ii) the compound (IV) is reduced to compound (V) with a complex hydride or a silane as reducing agent, preferably with a complex hydride, more preferably with a complex hydride selected from lithium aluminum hydride (LAH; UAIH4), sodium boron hydride (NaBH4), lithium triethylborohydride (superhydride; LiBH(CH2CH3)2), lithium tri-sec-butyl(hydrido)borate (L-selectride; LiBH(CH(CH3)CH2CH3)2), or diisobutylaluminum hydride (DIBAL-H; ((CH3)2CHCH2)2AIH).

15. The method according to claim 14, where in step (ii) the compound (IV) is reduced to compound (V) with UAIH4 or NaBH4; preferably with NaBH4.

16. The method according to any of claims 1 to 13, where in step (ii) the compound (IV) is reduced to compound (V) with hydrogen in the presence of a hydrogenation catalyst, preferably of a homogeneous hydrogenation catalyst.

17. The method according to any of the preceding claims, where step (ii) is carried out in an organic solvent, where in case that the reduction agent is or comprises NaBH4, the solvent comprises a Ci-C4-alkanol.

18. The method according to any of the preceding claims, where step (iii) is carried out in acidic medium, preferably in the presence of an inorganic or organic acid.

19. The method according to claim 18, where step (iii) is carried out in the presence of an inorganic acid selected from the group consisting of sulfuric acid, phosphoric acid, phosphonic acid and hydrochloric acid; and / or an organic acid selected from sulfonic acids, preferably from methanesulfonic acid, trifluoromethanesulfonic acid and para-toluenesulfonic acid; where step (iii) is preferably carried out in the presence of sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or para-toluenesulfonic acid.

20. The method according to any of claims 18 or 19, where the acid is used in equimolar amount relative to the amount of the compound (V) or in molar excess.21 . The method according to any of the preceding claims, where step (iii) is carried out neat.

22. The method according to any of claims 1 to 20, where step (iii) is carried out in the presence of an organic solvent, preferably an aromatic organic solvent.

23. The method according to any of the preceding claims, where step (iii) is carried out at 100 to 160°C, preferably at 120 to 140°C.

24. A compound of formula (IV)wherein- X1and X2are OR1, where R1is 2-ethylhexyl, and R2is as defined in any of claims 1 to 4 and is preferably phenyl; or- R2is isobutyl, 2-ethoxyethyl or 2-pyridyl, and X1and X2are as defined in any of claims 1 , 5 or 6, and are preferably OR1, where R1is ethyl.

25. A compound of formula (V)wherein R2is 2-ethoxyethyl.

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