Process for preparing substituted amino alcohols

Abstract

The present invention relates to a method for preparing a compound of formula (I), which comprises at least the following process steps: a) reacting a compound of formula (II) with hydrogen and water in the presence of at least one homogeneous transition metal catalyst TMC 1.

Description

[0001] The present invention relates to a method for preparing a compound of formula (I),

[0002]

[0003] At least the following process steps are included:

[0004] a) reacting a compound of formula (II) with hydrogen and water in the presence of at least one homogeneous transition metal catalyst TMC 1,

[0005]

[0006] Compounds of formula (I), hereinafter also referred to as substituted amino alcohols of formula (I) of the present invention, are valuable compounds for industrial preparation. For example, 2-amino-2-methyl-1-propanol is a useful organic base for neutralization and solubilization applications, for use in toiletries and cosmetics, for use as a dispersant in combination with fatty acids, for use as a formaldehyde scavenger and wetting agent, as described in NitroCompounds, Aliphatic, Ullmann's Encyclopedia of Industrial Chemistry, DOI: 10.1002 / 14356007.a17_401.pub2.

[0007] Currently, substituted amino alcohols of formula (I) are prepared in the art by nitrating alkanes, followed by Henry reaction with formaldehyde and then reduction to amino alcohols, as exemplified for 2-amino-2-methyl-1-propanol in Nitro Compounds, Aliphatic, Ullmann's Encyclopedia of Industrial Chemistry, DOI: 10.1002 / 14356007.a17_401.pub2 and WO2009 / 129097A1:

[0008]

[0009] This approach has some serious disadvantages: firstly, the nitration of the paraffin is not very selective, and several other nitroalkanes are formed as by-products, such as nitromethane, nitroethane or 1-nitropropane, which have to be separated and reduce the yield of the propane used, as described in Nitro Compounds, Aliphatic, Ullmann's Encyclopedia of Industrial Chemistry, DOI: 10.1002 / 14356007.a17_401.pub2. In addition, due to the low selectivity in the nitration of paraffins, this process does not allow the synthesis of more complex amino alcohols of formula (I). Another major disadvantage is the problems in the nitration / workup, since many nitroalkanes are shock-sensitive and can explode if not properly handled.

[0010] The reductive hydrolysis of aliphatic nitriles by using transition metal catalysts and the reductive hydrolysis of aromatic aliphatic nitriles by using ruthenium or nickel catalysts is described, wherein the nitriles are hydrogenated in the presence of water with formation of ammonia as a by-product:

[0011]

[0012] This transition metal-catalyzed reductive hydrolysis of nitrile groups is described in, for example, a) Catalysis Communications, 2004, 5, 237-238; b) Chinese Journal of Catalysis, 2004, 25, 611-614; c) Bulletin dela Societe chimique France, 1969, 1, 126-127; d) US 5741955; e) ChemCatChem, 2017, 9, 4175-4178. However, none of these reports describe the synthesis of substituted amino alcohols of formula (I).

[0013] The use of reductive nitrile hydrolysis for the synthesis of substituted amino alcohols of formula (I) has the disadvantage that the closest starting material aminonitriles are not stable under the conditions required for reductive nitrile hydrolysis. In the presence of water necessary for reductive nitrile hydrolysis, at elevated temperatures of 80-150° C., the free aminonitriles are hydrolyzed in a reverse Strecker reaction, thus not forming the desired amino alcohol:

[0014]

[0015] On the other hand, if the amino functionality in the aminonitrile is protected as an HCl salt, hydrolysis of the nitrile group to an amino acid generally occurs, as described in European Journal of Organic Chemistry, 2008, 350-355:

[0016]

[0017] In order to overcome these problems, suitable protecting groups are needed, which can also be easily introduced and removed. For example, N-formylamine can in principle be deprotected by hydrogenation using a homogeneous hydrogenation catalyst based on iron or ruthenium, thereby forming free amine and methanol, for example as described in a) ACS Catalysis, 2016, 6, 6377-6383; b) Journal of the American Chemical Society, 2017, 139, 2549-2552. However, this strategy has not been applied to the synthesis of amino alcohols of formula (I) so far.

[0018] Protection of the amine functional group as an amide can be easily achieved. For example, the corresponding N-formyl-α-aminonitrile can be easily obtained by reaction of cyanohydrin with formamide in acetic acid solvent as described in Liebigs Annalen der Chemie, 1970, 735, 27-34:

[0019]

[0020] N-Formyl-α-aminonitrile can also be synthesized by reacting α-aminonitrile with formate or mixed formic acid / acetic anhydride, as described in a) Chemische Berichte, 1987, 120, 1-4; b) Chemistry-A European Journal, 2016, 22, 7352-7356; c) Sel.Org.React.Database (SORD), 1978, 20121004:

[0021]

[0022] EP 0562345 A2 describes the hydrogenation of N-formyl-α-aminonitriles under anhydrous conditions using heterogeneous transition metal catalysts, but using this protocol no amino alcohols of the formula (I) are formed, but rather substituted imidazoles are the main products, since the nitrile is hydrogenated continuously to the amine and subsequently cyclized.

[0023] Starting from this prior art, it is an object of the present invention to provide a technically and economically advantageous process for preparing amino alcohols of the formula (I).

[0024] This object is achieved by a method for preparing a compound of formula (I):

[0025]

[0026] in:

[0027] R1 is hydrogen or an organic group having 1 to 40 carbon atoms,

[0028] R 2 is an organic group having 1 to 40 carbon atoms,

[0029] or R 1 and R 2 Together with the atoms to which they are attached, they form a divalent organic group having 1 to 40 carbon atoms,

[0030] It includes at least the following process steps:

[0031] a) reacting a compound of formula (II) with hydrogen and water in the presence of at least one homogeneous transition metal catalyst TMC 1:

[0032]

[0033] in:

[0034] R1 and R 2 has the same meaning as in formula (I), and

[0035] R 3 is hydrogen or an organic group having 1 to 40 carbon atoms.

[0036] Surprisingly found that, when formula (II) compound, hereinafter also referred to as protected aminonitrile, particularly the aminonitrile of formyl protection is used under the condition of transition metal catalyzed reductive nitrile hydrolysis, reaction is carried out with high selectivity, and amine can use the same catalyst by formyl hydrogenation to methanol and deprotection.If other carboxylic acids are used for amino protection, then they are also reduced to corresponding alcohol and removed (for example, acetic ester is to ethanol).Use this scheme, do not produce salt during deprotection.Another advantage of the method is compared with the nitro route of above-mentioned prior art, and the substrate scope of formula (I) compound (also referred to as the substituted amino alcohol of formula (I)) is significantly wider, because cyanohydrin and aminonitrile can easily be obtained by ketone and aldehyde of wide range.

[0037] Unless otherwise specified, the substituents of the present invention are defined as follows:

[0038] The term "organic group having 1 to 40 carbon atoms" as used herein refers to, for example, a C1-C 40 Alkyl, C1-C 40 Substituted alkyl, C1-C 10 Fluorinated alkyl, C1-C 12 Alkoxy, saturated C3-C 20 Heterocyclic group, C6-C 40 Aryl, C2-C 40 Heteroaryl, C6-C 10Fluorinated aryl, C6-C 10 Aryloxy, silyl having 3-24 carbon atoms, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C7-C 40 Arylalkyl or C8-C 40 Arylalkenyl. Organic radicals are derived in each case from organic compounds. Thus, the organic compound methanol can in principle give rise to three different organic radicals having one carbon atom, namely methyl (H3C-), methoxy (H3C-O-) and hydroxymethyl (HOC(H2)-). Thus, the term "organic radical having 1 to 40 carbon atoms" also includes, in addition to alkoxy, for example dialkylamino, monoalkylamino or alkylthio.

[0039] In this specification, when the variable R is defined in the formula provided x When used in the context of a group, the term group can be used interchangeably with the term group.

[0040] The term "alkyl" as used herein includes straight chain or mono- or poly-branched saturated hydrocarbons, which may also be cyclic. 18 Alkyl, for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopentyl, cyclohexyl, isopropyl, isobutyl, isopentyl, isohexyl, sec-butyl or tert-butyl.

[0041] The term "alkenyl" as used herein includes straight chain or singly or multiply branched hydrocarbons having one or more CC double bonds, which may be cumulative or alternating.

[0042] The term "saturated heterocyclic group" as used herein refers to, for example, monocyclic or polycyclic, substituted or unsubstituted aliphatic or partially unsaturated hydrocarbon groups, in which one or more carbon atoms, CH groups and / or CH2 groups have been replaced by heteroatoms, preferably selected from the elements O, S, N and P. Preferred examples of substituted or unsubstituted saturated heterocyclic groups are pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl and the like, and methyl, ethyl, propyl, isopropyl and tert-butyl substituted derivatives thereof.

[0043] The term "aryl" as used herein refers to, for example, aromatic and optionally fused polyaromatic hydrocarbon groups, which may be straight-chain or branched C1-C 18 Alkyl, C1-C 18 Alkoxy, C2-C 10The substituted aryl radicals are mono- or polysubstituted with alkenyl or halogen, in particular fluorine. Preferred examples of substituted and unsubstituted aryl radicals are in particular phenyl, pentafluorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-n-propylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 1-naphthyl, 9-anthryl, 9-phenanthrenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl or 4-trifluoromethylphenyl.

[0044] The term "heteroaryl" as used herein refers to aromatic hydrocarbon groups, for example, in which one or more carbon atoms or CH groups are replaced by nitrogen, phosphorus, oxygen or sulfur atoms or combinations thereof. These groups may be, like aryl groups, optionally replaced by straight or branched C1-C 18 Alkyl, C2-C 10 Alkenyl or halogen, especially fluorine mono- or poly-substituted. Preferred examples are furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl, pyrazinyl, etc., and methyl, ethyl, propyl, isopropyl and tert-butyl substituted derivatives thereof.

[0045] The term "aralkyl" as used herein refers to a substituent containing an aromatic group, such as an aryl group, which is attached to the rest of the molecule via an alkyl chain. Preferred examples are benzyl, substituted benzyl, phenethyl, substituted phenethyl, and the like.

[0046] The terms fluoroalkyl and fluoroaryl mean that at least one hydrogen atom, preferably more than one and up to all hydrogen atoms of the corresponding group have been replaced by fluorine atoms. Examples of preferred fluorine-containing groups are trifluoromethyl, 2,2,2-trifluoroethyl, pentafluorophenyl, 4-trifluoromethylphenyl, 4-perfluorotert-butylphenyl, etc.

[0047] R in Formula I and II 1 is hydrogen or an organic group having 1 to 40 carbon atoms, preferably hydrogen, an acyclic or cyclic substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted C7-C 12 Aralkyl is especially hydrogen or methyl, especially methyl.

[0048] R in Formula I and II 2 is an organic group having 1 to 40 carbon atoms, preferably an acyclic or cyclic substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted C7-C 12 Aralkyl, in particular methyl.

[0049] Or, R 1 and R 2Together with the atoms to which they are attached, they form a divalent organic group having 1 to 40 carbon atoms. 1 and R 2 A divalent organic group selected from -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2NHCH2CH2- and -CH2CH2OCH2CH2- is formed.

[0050] R in formula (II) 3 is hydrogen or an organic group having 1 to 40 carbon atoms, preferably hydrogen, an acyclic or cyclic substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted C7-C 12 Aralkyl, especially R 3 For hydrogen.

[0051] In one embodiment of the invention, the process according to the invention is characterized in that R 3 For hydrogen.

[0052] In the process of the present invention, the compound of formula (II) is reacted with hydrogen and water in the presence of at least one homogeneous transition metal catalyst TMC 1 (hereinafter also referred to as hydrogenation catalyst or simply as transition metal catalyst TMC 1).

[0053] The homogeneous transition metal catalyst TMC 1 comprises a transition metal selected from metals of Group 7, 8, 9 or 10 of the IUPAC Periodic Table of the Elements, such as Mn, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd or Pt, preferably Ru.

[0054] In one embodiment of the present invention, the process according to the invention is characterized in that the homogeneous transition metal catalyst TMC 1 comprises a transition metal selected from the group consisting of metals of Groups 7, 8, 9 and 10 of the IUPAC Periodic Table of the Elements, for example Mn, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd or Pt, preferably ruthenium, rhodium, iridium, nickel, platinum and palladium, in particular Ru.

[0055] In one embodiment of the present invention, the process according to the invention is characterized in that the transition metal of the transition metal catalyst TMC 1 is Ru.

[0056] In one embodiment of the present invention, the process according to the invention is characterized in that the transition metal catalyst TMC 1 is a homogeneous catalyst, wherein the transition metal of the transition metal catalyst TMC 1 is Ru.

[0057] The hydrogenation catalyst of the process of the present invention can be used in the form of a preformed metal complex comprising a metal compound and one or more ligands. Alternatively, the catalytic system is formed in situ in the reaction mixture by combining a metal compound (also referred to herein as a precatalyst) with one or more suitable ligands to form a catalytically active metal complex in the reaction mixture.

[0058] Suitable precatalysts are selected from neutral metal complexes, oxides and salts of ruthenium. Examples of ruthenium compounds that can be used as precatalysts are [Ru(p-cymene)Cl2]2, [Ru(benzene)Cl2] n 、[Ru(CO)2Cl2] n , [Ru(CO)3Cl2]2, [Ru(COD)(allyl)], [RuCl3·H2O], [Ru(acetylacetone)3], [Ru(DMSO)4Cl2], [Ru(PPh3)3Cl2], [Ru(cyclopentadienyl)(PPh3)2Cl], [Ru(cyclopentadienyl)(CO)2Cl], [Ru(cyclopentadienyl)(CO)2H], [Ru(cyclopentadienyl)(CO)2]2, [Ru(pentamethylcyclopentadienyl) (CO)2Cl], [Ru(pentamethylcyclopentadienyl)(CO)2H], [Ru(pentamethylcyclopentadienyl)(CO)2]2, [Ru(indenyl)(CO)2Cl], [Ru(indenyl)(CO)2H], [Ru(indenyl)(CO)2]2, bis(cyclopentene), [Ru(2,2'-bipyridine)2(Cl)2·H2O], [Ru(COD)(Cl)2H]2, [Ru(pentamethylcyclopentadienyl)(COD)Cl], [Ru3(CO) 12 ] and [Ru(tetraphenylhydroxycyclopentadienyl)(CO)2H].

[0059] For the hydrogenation according to the process of the invention, it is possible to use any complexing ligands known in the art, in particular those known to be useful for ruthenium-catalyzed hydrogenations.

[0060] Suitable ligands for the catalytic system for the hydrogenation according to the process of the invention are, for example, the mono-, di-, tri- and tetradentate phosphines of the formulae IV and V shown below:

[0061]

[0062] in:

[0063] n is 0 or 1;

[0064] R 4 To R 12 are independently unsubstituted or at least monosubstituted C1-C 10Alkyl, C1-C4 alkyl diphenylphosphine (-C1-C4 alkyl-P(phenyl)2), C3-C 10 Cycloalkyl, C3-C4-C6 ... 10 Heterocyclic, C5-C 14 an aromatic group or a C5-C ... 10 Heteroaryl,

[0065] Wherein the substituent is selected from: F, Cl, Br, OH, CN, NH2 and C1-C 10 alkyl;

[0066] A is:

[0067] i) a bridging group selected from unsubstituted or at least monosubstituted N, O, P, C1-C6 alkanes, C3-C 10 Cycloalkane, C3-C4-C6 ... 10 Heterocycloalkanes, C5-C 14 Aromatic compounds and C5-C6 heteroaromatic compounds containing at least one heteroatom selected from N, O and S,

[0068] The substituent is selected from: C1-C4 alkyl, phenyl, F, Cl, Br, OH, OR 16 、NH2、NHR 16 or N(R 16 )2,

[0069] Where R 16 Selected from C1-C 10 Alkyl and C5-C 10 aryl; or

[0070] ii) a bridging group of formula (VI) or (VII):

[0071]

[0072] m, q are independently 0, 1, 2, 3 or 4;

[0073] R 13 , R 14 Independently selected from C1-C 10 Alkyl, F, Cl, Br, OH, OR 15 、NH2、NHR 15 and N(R 15 )2,

[0074] Where R 15 Selected from C1-C 10 Alkyl and C5-C 10 Aryl;

[0075] X 1 , X 2 are independently NH, O or S;

[0076] X 3 For bond, NH, NR 16 , O, S or CR 17 R 18 ;

[0077] R 16 is unsubstituted or at least monosubstituted C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C3-C4-C6 ... 10 Heterocyclic, C5-C 14 an aromatic group or a C5-C ... 10 Heteroaryl,

[0078] Wherein the substituent is selected from: F, Cl, Br, OH, CN, NH2 and C1-C 10 alkyl;

[0079] R 17 , R 18 are independently unsubstituted or at least monosubstituted C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkoxy, a C3-C4-cycloalkyl group containing at least one heteroatom selected from N, O and S 10 Heterocyclic, C5-C 14 Aryl, C5-C 14 an aryloxy group or a C5-C 10 Heteroaryl,

[0080] Wherein the substituent is selected from: F, Cl, Br, OH, CN, NH2 and C1-C 10 alkyl;

[0081] Y 1 , Y 2 , Y 3 independently of one another a bond, an unsubstituted or at least monosubstituted methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene,

[0082] Wherein the substituent is selected from: F, Cl, Br, OH, OR 15 、CN、NH2、NHR 15 、N(R 15 )2 and C1-C 10 alkyl,

[0083] Where R 15 Selected from C1-C 10 Alkyl and C5-C 10 Aryl.

[0084] A is a bridging group. A is selected from unsubstituted or at least monosubstituted C1-C6 alkanes, C3-C 10 Cycloalkanes, C3-C 10 Heterocycloalkanes, C5-C 14 In the case of aromatic compounds and C5-C6 heteroaromatic compounds (n=0), the two hydrogen atoms of the bridging group are replaced by the adjacent substituent Y 1 and Y 2 For the case of (n=1), the three hydrogen atoms of the bridging group are replaced by the adjacent substituent Y 1 , Y 2 and Y 3 The three keys are replaced.

[0085] When A is P (phosphorus), phosphorus forms a bond with the adjacent substituent Y when (n=0) 1 and Y 2 and one bond to a substituent selected from C1-C4 alkyl and phenyl. For the case (n=1), phosphorus forms a bond with the adjacent substituent Y 1 , Y 2 and Y 3 Three keys.

[0086] When A is N (nitrogen), the nitrogen forms a bond with the adjacent substituent Y when (n=0) 1 and Y 2 and one bond to a substituent selected from C1-C4 alkyl and phenyl. For the case (n=1), the nitrogen forms a bond with the adjacent substituent Y 1 , Y 2 and Y 3 Three keys.

[0087] When A is O (oxygen), n = 0. Oxygen forms a bond with the adjacent substituent Y. 1 and Y 2 two keys.

[0088] Preference is given to complex catalysts comprising at least one element selected from ruthenium and iridium.

[0089] In a preferred embodiment, the process of the invention is carried out in the presence of at least one complex catalyst comprising at least one element selected from Groups 8, 9 and 10 of the Periodic Table of the Elements and at least one phosphorus donor ligand of the general formula (V), wherein:

[0090] n is 0 or 1;

[0091] R 7 To R 12 are independently unsubstituted C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C3-C4-C6 ... 10 Heterocyclic group, C5-C 14 an aromatic group or a C5-C ... 10 heteroaryl;

[0092] A is:

[0093] i) a bridging group selected from unsubstituted C1-C6 alkanes, C3-C 10 Cycloalkane, C3-C4-C6 ... 10 Heterocycloalkanes, C5-C 14 Aromatic compounds and C5-C6 heteroaromatic compounds containing at least one heteroatom selected from N, O and S; or

[0094] ii) a bridging group of formula (VI) or (VII):

[0095]

[0096] m, q are independently 0, 1, 2, 3 or 4;

[0097] R 13 , R 14 Independently selected from C1-C 10 Alkyl, F, Cl, Br, OH, OR 15 、NH2、NHR 15 and N(R 15 )2;

[0098] Where R 15 Selected from C1-C 10 Alkyl and C5-C 10 Aryl;

[0099] X 1 , X 2 are independently NH, O or S;

[0100] X 3 For bond, NH, NR 16 , O, S or CR 17 R 18 ;

[0101] R 16 For unsubstituted C1-C 10 Alkyl, C3-C10 Cycloalkyl, C3-C4-C6 ... 10 Heterocyclic, C5-C 14 an aromatic group or a C5-C ... 10 heteroaryl;

[0102] R 17 , R 18 are independently unsubstituted C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkoxy, a C3-C4-cycloalkyl group containing at least one heteroatom selected from N, O and S 10 Heterocyclic, C5-C 14 Aryl, C5-C 14 an aryloxy group or a C5-C 10 heteroaryl;

[0103] Y 1 , Y 2 , Y 3 are independently of one another a bond, an unsubstituted methylene, an ethylene, a trimethylene, a tetramethylene, a pentamethylene or a hexamethylene.

[0104] In another preferred embodiment, the process according to the invention is carried out in the presence of at least one complex catalyst comprising at least one element selected from Groups 8, 9 and 10 of the Periodic Table of the Elements and at least one phosphorus donor ligand of the general formula (VIII),

[0105]

[0106] in:

[0107] R 7 To R 10 are independently unsubstituted or at least monosubstituted C1-C 10 Alkyl, C1-C4 alkyl diphenylphosphine (-C1-C4 alkyl-P(phenyl)2), C3-C 10 Cycloalkyl, C3-C4-C6 ... 10 Heterocyclic, C5-C 14 an aryl group and a C5-C5 10 heteroaryl;

[0108] Wherein the substituent is selected from: F, Cl, Br, OH, CN, NH2 and C1-C 10 alkyl;

[0109] A is:

[0110] i) a bridging group selected from unsubstituted or at least monosubstituted N, O, P, C1-C6 alkanes, C3-C 10 Cycloalkane, C3-C4-C6 ... 10 Heterocycloalkanes, C5-C 14 Aromatic compounds and C5-C6 heteroaromatic compounds containing at least one heteroatom selected from N, O and S,

[0111] The substituent is selected from: C1-C4 alkyl, phenyl, F, Cl, Br, OH, OR 15 、NH2、NHR 15 or N(R 15 )2;

[0112] Where R 15 Selected from C1-C 10 Alkyl and C5-C 10 aryl; or

[0113] ii) a bridging group of formula (VI) or (VII):

[0114]

[0115] m, q are independently 0, 1, 2, 3 or 4;

[0116] R 13 , R 14 Independently selected from C1-C 10 Alkyl, F, Cl, Br, OH, OR 15 、NH2、NHR 15 and N(R 15 )2;

[0117] Where R 15 Selected from C1-C 10 Alkyl and C5-C 10 Aryl;

[0118] X 1 , X 2 are independently NH, O or S;

[0119] X 3 For bond, NH, NR 16 , O, S or CR 17 R 18 ;

[0120] R 16 is unsubstituted or at least monosubstituted C1-C 10 Alkyl, C3-C 10Cycloalkyl, C3-C4-C6 ... 10 Heterocyclic, C5-C 14 Aryl or containing at least one heteroatom selected from N, O and S C5-C 10 heteroaryl;

[0121] Wherein the substituent is selected from: F, Cl, Br, OH, CN, NH2 and C1-C 10 alkyl;

[0122] R 17 , R 18 are independently unsubstituted or at least monosubstituted C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkoxy, a C3-C4-cycloalkyl group containing at least one heteroatom selected from N, O and S 10 Heterocyclic, C5-C 14 Aryl, C5-C 14 an aryloxy group or a C5-C 10 heteroaryl;

[0123] Wherein the substituent is selected from: F, Cl, Br, OH, CN, NH2 and C1-C 10 alkyl;

[0124] Y 1 , Y 2 independently of one another a bond, unsubstituted or at least monosubstituted methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene;

[0125] Wherein the substituent is selected from: F, Cl, Br, OH, OR 15 、CN、NH2、NHR 15 、N(R 15 )2 and C1-C 10 alkyl;

[0126] Where R 15 Selected from C1-C 10 Alkyl and C5-C 10 Aryl.

[0127] In another preferred embodiment, the process according to the invention is carried out in the presence of at least one complex catalyst comprising at least one element selected from Groups 8, 9 and 10 of the Periodic Table of the Elements and at least one phosphorus-donor ligand of the general formula (IX),

[0128]

[0129] in:

[0130] R 7 To R 12 are independently unsubstituted or at least monosubstituted C1-C 10 Alkyl, C1-C4 alkyl diphenylphosphine, C3-C 10 Cycloalkyl, C3-C4-C6 ... 10 Heterocyclic, C5-C 14 an aromatic group or a C5-C ... 10 heteroaryl;

[0131] Wherein the substituent is selected from: F, Cl, Br, OH, CN, NH2 and C1-C 10 alkyl;

[0132] A is a bridging group selected from unsubstituted or at least monosubstituted N, P, C1-C6 alkane, C3-C 10 Cycloalkane, C3-C4-C6 ... 10 Heterocycloalkanes, C5-C 14 Aromatic compounds and C5-C6 heteroaromatic compounds containing at least one heteroatom selected from N, O and S;

[0133] The substituent is selected from: C1-C4 alkyl, phenyl, F, Cl, Br, OH, OR 15 、NH2、NHR 15 or N(R 15 )2;

[0134] Where R 15 Selected from C1-C 10 Alkyl and C5-C 10 Aryl;

[0135] Y 1 , Y 2 , Y 3 are independently of one another a bond, an unsubstituted or at least monosubstituted methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene,

[0136] Wherein the substituent is selected from: F, Cl, Br, OH, OR 15 、CN、NH2、NHR 15 、N(R 15 )2 and C1-C 10 alkyl,

[0137] Where R 15 Selected from C1-C 10 Alkyl and C5-C 10 Aryl.

[0138] In another preferred embodiment, the process according to the invention is carried out in the presence of at least one complex catalyst comprising at least one element selected from Groups 8, 9 and 10 of the Periodic Table of the Elements and at least one phosphorus donor ligand of the general formula (VIII), wherein:

[0139] R 7 To R 10 are independently methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl or base;

[0140] A is:

[0141] i) a bridging group selected from methane, ethane, propane, butane, cyclohexane, benzene, naphthalene and anthracene; or

[0142] ii) a bridging group of formula (X) or (XI):

[0143]

[0144] X 1 , X 2 are independently NH, O or S;

[0145] X 3 is a bond, NH, O, S or CR 17 R 18 ;

[0146] R 17 , R 18 are independently unsubstituted C1-C 10 alkyl;

[0147] Y 1 , Y 2 are independently a bond, a methylene group or an ethylene group.

[0148] In a particularly preferred embodiment, the process according to the invention is carried out in the presence of at least one complex catalyst comprising at least one element selected from Groups 8, 9 and 10 of the Periodic Table of the Elements and at least one phosphorus donor ligand of the general formula (XII) or (XIII):

[0149]

[0150] For m, q, R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , X 1 , X 2 and X3 , the definitions and preferences listed above may apply.

[0151] In one embodiment, the process of the present invention is carried out in the presence of at least one transition metal complex catalyst, and the monodentate ligand of formula IV is preferably wherein R 5a , R 5b and R 6 Each of which is phenyl or alkyl optionally substituted with 1 or 2 C1-C4 alkyl groups, and wherein R 7 , R 8 and R 9 Each is a C5-C8 cycloalkyl or a C2-C 10 Alkyl groups, especially straight chain unbranched normal C2-C 10 Those of alkyl groups. 5a To R 6 Preferably, the group R 5a To R 6 are identical and are selected from the substituents mentioned herein, in particular from those indicated as preferred. Examples of preferred monodentate ligands IV are triphenylphosphine (TPP), triethylphosphine, tri-n-butylphosphine, tri-n-octylphosphine and tricyclohexylphosphine.

[0152] In another embodiment, the process of the present invention is carried out in the presence of at least one transition metal complex catalyst and at least one phosphorus donor ligand selected from 1,2-bis(diphenylphosphino)ethane (dppe), 1,2-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)butane (dppb), 2,3-bis(dicyclohexylphosphino)ethane (DCPE), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), bis(2-diphenylphosphinoethyl)phenylphosphine and 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos).

[0153] In another particularly preferred embodiment, the process according to the invention is carried out in the presence of a complex catalyst comprising ruthenium and at least one phosphorus donor ligand selected from 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), bis(2-diphenylphosphinoethyl)phenylphosphine and 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos).

[0154] In another particularly preferred embodiment, the process of the invention is carried out in the presence of a complex catalyst comprising iridium and at least one phosphorus donor ligand selected from 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), bis(2-diphenylphosphinoethyl)phenylphosphine and 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos).

[0155] In the context of the present invention, C1-C 10 Alkyl is understood to mean branched, unbranched, saturated and unsaturated groups. Alkyl groups having 1 to 6 carbon atoms (C1-C6 alkyl) are preferred. Alkyl groups having 1 to 4 carbon atoms (C1-C4 alkyl) are more preferred.

[0156] Examples of saturated alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

[0157] Examples of unsaturated alkyl (alkenyl, alkynyl) groups are vinyl, allyl, butenyl, ethynyl and propynyl.

[0158] C1-C 10 The alkyl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of F, Cl, Br, hydroxyl (OH), C1-C 10 Alkoxy, C5-C 10 Aryloxy, C5-C 10 Alkyl aryloxy, containing at least one heteroatom selected from N, O, S C5-C 10 Heteroaryloxy, oxo, C3-C 10 Cycloalkyl, phenyl, C5-C6 containing at least one heteroatom selected from N, O, S 10 Heteroaryl, C5-C 10 Heterocyclyl, naphthyl, amino, C1-C 10 Alkylamino, C5-C 10 Arylamino, a C5-C 10 Heteroarylamino, C1-C 10 -dialkylamino, C 10 -C 12 -diarylamino, C 10 -C 20 Alkyl aryl amino, C1-C 10 Acyl, C1-C 10 Acyloxy, NO2, C1-C 10 Carboxyl, carbamoyl, carboxamide, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfonylamino, thiol, C1-C 10Alkylthio, C5-C 10 Arylthio or C1-C 10 Alkylsulfonyl.

[0159] C1-C above 10 The definition of alkyl applies correspondingly to C1-C 30 Alkyl and C1-C6 alkane.

[0160] C3-C 10 Cycloalkyl is understood in this case to mean saturated, unsaturated monocyclic and polycyclic radicals. 10 Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The cycloalkyl group may be unsubstituted or substituted with one or more C1-C12 radicals as described above. 10 The alkyl group is substituted with a substituent as defined above.

[0161] The active hydrogenation catalyst can be generated in situ in the reaction mixture by adding the ligand to the above precursors. The molar ratio of transition metal to ligand is 2:1 to 1:50, preferably 1:1 to 1:10, and most preferably 1:2 to 1:5.

[0162] In addition to one or more ligands selected from the above-mentioned ligand group, the catalytic system of the method of the present invention may also comprise at least one other ligand selected from halides, amides, carboxylates, acetylacetonates, aryl- or alkyl-sulfonates, hydrides, CO, olefins, dienes, cycloolefins, nitriles, aromatic compounds and heteroaromatic compounds, ethers, PF3, phospholes, phosphabenzenes and mono-, di- and multidentate phosphinates, phosphites, phosphoramidites and phosphites ligands. Preferably, the catalyst also contains CO as a ligand.

[0163] The active catalyst can also be preformed in a dedicated synthesis step. Suitable preformed catalysts may be [Ru(PPh3)3(CO)(H)Cl], [Ru(PPh3)3(CO)Cl2], [Ru(PPh3)3(CO)(H)2], [Ru(binap)(Cl)2], [Ru(PMe3)4(H)2], [Ru(PEt3)4(H)2], [Ru(Pn-Pr3)4(H)2], [Ru(Pn-Bu3)4(H)2], [Ru(Pn-Octyl3)4(H) 2], [Ru(Pn-Bu3)4(H)2], [Ru(PnOctyl3)4(H)2], [Ru(PPh3)3(CO)(H)Cl] and [Ru(PPh3)3(CO)(H)2], preferably [Ru(PPh3)3(CO)(H)Cl], [Ru(PPh3)3(CO)Cl2], [Ru(PPh3)3(CO)(H)2, and the most preferred active catalyst is [Ru(PPh3)3(CO)(H)Cl].

[0164] In one embodiment of the present invention, the process of the present invention is characterized in that the homogeneous transition metal catalyst TMC 1 is selected from [Ru(PPh3)3(CO)(H)Cl], [Ru(PPh3)3(CO)Cl2], [Ru(PPh3)3(CO)(H)2], [Ru(binap)(Cl)2], [Ru(PMe3)4(H)2], [Ru(PEt3)4(H)2], [Ru(Pn-Pr3)4(H)2], [Ru(Pn-Bu3)4(H)2], [Ru(Pn-Octyl3)4(H)2 ], [Ru(Pn-Bu3)4(H)2], [Ru(PnOctyl3)4(H)2], [Ru(PPh3)3(CO)(H)Cl] and [Ru(PPh3)3(CO)(H)2], preferably [Ru(PPh3)3(CO)(H)Cl], [Ru(PPh3)3(CO)Cl2], [Ru(PPh3)3(CO)(H)2, and most preferably [Ru(PPh3)3(CO)(H)Cl].

[0165] If a preformed active catalyst is used, it may also be beneficial to add additional ligand of formula IV or V to the reaction mixture.

[0166] In the process of the present invention, the amount of transition metal catalyst TMC 1 used can vary within a wide range based on the amount of compound of formula (II) (also referred to as protected amino nitrile of formula (II)). Typically, the transition metal catalyst TMC 1 is used in a substoichiometric amount relative to the protected amino nitrile of formula (II). Typically, the amount of transition metal catalyst TMC 1 does not exceed 50 mol%, often does not exceed 20 mol%, in particular does not exceed 10 mol% or does not exceed 5 mol%, based on the amount of protected amino nitrile of formula (II). The transition metal catalyst TMC 1 is preferably used in the process of the present invention in an amount of 0.001-50 mol%, often 0.001-20 mol%, in particular 0.005-5 mol%, based on the amount of protected amino nitrile of formula (II). Preferably, a transition metal catalyst TMC 1 in an amount of 0.01-5 mol% is used. All amounts of the transition metal complex catalyst TMC 1 shown are calculated as transition metal and based on the amount of the compound of formula (II).

[0167] In one embodiment of the present invention, the process according to the invention is characterized in that the homogeneous transition metal catalyst TMC 1 is used in an amount of 0.001 to 20 mol %, calculated as transition metal and based on the amount of compound of the formula (II) used in the process.

[0168] The reaction of the compound of the formula (II) with hydrogen and water can in principle be carried out by all methods known to the person skilled in the art which are suitable for the reaction of protected aminonitriles with H2 in the presence of water.

[0169] The hydrogen (H2) used for the reduction reaction can be used in pure form or, if desired, in a mixture with other preferably inert gases such as nitrogen or argon. Preference is given to using H2 in undiluted form.

[0170] The hydrogen gas may be applied discontinuously or continuously, for example by bubbling H2 gas through the reaction mixture.

[0171] The reaction is generally carried out at a H2 pressure of 0.1-400 bar, preferably 5-200 bar, more preferably 10-180 bar.

[0172] In one embodiment of the present invention, the process according to the invention is characterized in that the reaction between the compound of formula (II), water and hydrogen is carried out at a pressure of 10 to 180 bar.

[0173] In one embodiment of the invention, the inventive method is characterized in that hydrogenation is carried out under different H pressures. Preferably, first, at 1-80 bar, preferably at a lower H pressure of 10-80 bar, the nitrile functional group is completely reductively hydrolyzed to an alcohol functional group. Then, the H pressure is increased to 90-200 bar, preferably 100-180 bar, to deprotect the amine group completely by the hydrogenation of the amide group.

[0174] In the presence of inert salts such as NaCl, (NH4)2SO4 or (NH4)H2PO4 from the synthesis of the starting compound of formula (I), the reductive hydrolysis of the nitrile is generally not affected by these salts.

[0175] The reaction can in principle be carried out continuously, semi-continuously or discontinuously. A continuous process is preferred.

[0176] The reaction can in principle be carried out in all reactors known to the person skilled in the art for reactions of this type, so the person skilled in the art will select the reactor accordingly. Suitable reactors are described and reviewed in the relevant prior art, for example in the suitable monographs and references mentioned in US 6639114 B2, column 16, lines 45-49. Preferably, for the reaction, an autoclave which may have an internal stirrer and an inner lining is used.

[0177] The process of the present invention can be carried out in a wide temperature range. Preferably, the reaction is carried out at a temperature of 20-200°C, more preferably 50-180°C, especially 100-170°C.

[0178] In one embodiment of the present invention, the process according to the invention is characterized in that the process is carried out at a temperature of 50-180°C, preferably 100-170°C.

[0179] The reductive hydrolysis of the nitrile is carried out in the presence of water. The reaction can be carried out in water as a solvent or in combination with a solvent. In the reductive hydrolysis of the nitrile, a water-solvent mixture is preferably used. Suitable solvents are selected from aliphatic hydrocarbons, aromatic hydrocarbons, ethers or alcohols and mixtures thereof. Preferred solvents are:

[0180] - aliphatic hydrocarbons, for example pentane, hexane, heptane, octane or cyclohexane;

[0181] - aromatic hydrocarbons, such as benzene, toluene, xylene, ethylbenzene, or trifluorotoluene;

[0182] - ethers, for example dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dibutyl ether, methyl tert-butyl ether, diisopropyl ether, dimethoxyethane or diglyme and other glymes (ethers of various oligomers and polymers of propylene glycol and ethylene glycol);

[0183] - Alcohols, for example methanol, ethanol, 2-propanol, 1-butanol, isobutanol, tert-butanol, pentanol, hexanol, ethylhexanol, octanol, methoxyethanol, ethylene glycol, diethylene glycol, triethylene glycol and higher polyethylene glycols.

[0184] Preference is given to using solvents selected from the group consisting of ethers and alcohols, preferably dioxane, tetrahydrofuran, glyme, methanol and ethanol.

[0185] In one embodiment of the present invention, the process according to the invention is characterized in that the reaction between the compound of formula (II), water and hydrogen is carried out in the presence of a solvent selected from ethers and alcohols, preferably dioxane, tetrahydrofuran, glyme, methanol and ethanol.

[0186] If desired, mixtures of two or more of the abovementioned solvents can also be used.

[0187] When additional solvent is used, the molar ratio of water to solvent is from 50:1 to 1:50, preferably from 2:1 to 1:30, and most preferably from 2:1 to 1:10.

[0188] Alternatively, the process of the present invention can be carried out in the absence of any of the above-mentioned organic solvents, ie, so-called neat conditions, preferably in the presence of a compound of formula (I) and water as solvents.

[0189] The composition obtained in the nitrile reductive hydrolysis of the present invention comprises compound of formula (I), amino alcohol. The aftertreatment of the reaction mixture of the inventive method and the separation of amino alcohol of formula (I) are carried out in a conventional manner, for example, by filtering, extracting aftertreatment or by distillation, for example, under reduced pressure. By using these measures or their combination, compound of formula (I) can be obtained with enough purity, without the need for additional purification steps. Alternatively, further purification can be completed by methods commonly used in this area, for example chromatography or distillation.

[0190] In one embodiment of the present invention, the process according to the invention is characterized in that after the reductive hydrolysis of the nitrile, the compound of the formula (I) is separated from the transition metal catalyst by distillation.

[0191] The distillation residue generally still contains the transition metal catalyst in active form, which can be used again in a new nitrile reductive hydrolysis step, i.e. a new process step a) or b). As long as the distillation conditions, in particular the temperature treatment, are not too harsh, the transition metal catalyst remains active. When a high-boiling solvent is used, only the compounds of the formulae (I), (II) and (III) and water can be distilled off, while the catalyst remains dissolved in the high-boiling solvent.

[0192] In one embodiment of the present invention, the process according to the invention is characterized in that the homogeneous transition metal catalyst TMC 1 is recycled by removing the compound of the formula (I) and other volatile compounds in the reaction mixture by distillation.

[0193] The composition obtained in the reductive hydrolysis of the nitrile of the present invention comprises a compound of formula (I), which is a substituted amino alcohol. In the case where complete deprotection of the amino functional group is not achieved in the reductive hydrolysis of the nitrile, the composition may also comprise a compound of formula (III), hereinafter also referred to as an amine-protected amino alcohol:

[0194]

[0195] Further deprotection of the protected amino alcohol of formula (III) to the desired amino alcohol of formula (I) can be easily achieved by acid hydrolysis or further reductive deprotection of the amine.

[0196] In one embodiment of the present invention, the process according to the invention is characterized in that the nitrogen-carbon bond of the amide group -N(H)-C(=O)- of the compound of formula (III) formed as an intermediate in process step a)

[0197]

[0198] The cracking is carried out in a second process step, comprising:

[0199] b) by hydrolysis, preferably by acid hydrolysis, of the amide group -NH-C(=O)-R 3 Converted to amino -NH2 or its corresponding ammonium NH3 + , or through the hemiaminal -NH-CH(-OH)-R 3 In the formation of amino-NH2 and primary alcohol HO-CH2-R 3 Under the conditions of 3 Hydrogenation followed by the formation of the aldehyde HC(=O)-R 3 Further hydrogenation to primary alcohol HO-CH2-R 3 .

[0200] The second process step can be carried out directly with the reaction mixture obtained in process step a) of the process of the present invention without previously isolating the intermediate of formula (III) from the desired product of formula (I). Process step b) can also be carried out after isolating the compound of formula (III) from the reaction mixture obtained in process step a) of the process of the present invention.

[0201] The conditions for the hydrolysis of amides to the parent carboxylic acid and the corresponding amine are well known to those skilled in the art. The hydrolysis of the amide group is usually carried out by using a strong acid (e.g. hydrochloric acid or sulfuric acid) or a strong base (e.g. sodium hydroxide), preferably in both cases in combination with heating.

[0202] Alternatively, the amide group of the compound of formula (III) can be cleaved by hydrogenation, preferably by applying an increased H2 pressure or an increased temperature compared to process step a), or by adding a second transition metal catalyst TMC2, which is preferably more active than transition metal catalyst TMC1.

[0203] Suitable for amide group -NH-C(=O)-R 3 Transition metal catalysts for hydrogenation are known to those skilled in the art. 3 The very active transition metal catalyst TMC 2 for hydrogenation is a transition metal catalyst comprising a transition metal M selected from metals of groups 7, 8, 9 and 10 of the periodic table of the elements of IUPAC, in particular Ru, and a tridentate ligand of formula XIV, XV or XVI:

[0204]

[0205] Preferably, in process step b) the same transition metal catalyst is used as in process step a), but the H2 pressure and / or the temperature are increased.

[0206] The protected amino nitrile of formula (II) as a starting material can be prepared according to R 3 and can be prepared in different ways using precursors. R in formula (II) 3 is hydrogen or an organic group having 1 to 40 carbon atoms, preferably hydrogen, an acyclic or cyclic, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted C7-C 12 Aralkyl, especially R 3 For hydrogen.

[0207]

[0208] The formyl-protected amino nitrile (R 3 =H) can be achieved in different ways.

[0209] Starting from cyanohydrins (which are readily obtained by reaction of the corresponding ketones or aldehydes with HCN), protected aminonitriles of the formula (II) are obtained by reaction with formamide in an acidic medium such as AcOH (cf. Liebigs Annalen der Chemie, 1970, 735, 27-34):

[0210]

[0211] N-Formyl-α-amino nitrile can also be synthesized by reacting α-amino nitrile with formate or mixed formic acid / acetic anhydride (see: a) Chemische Berichte, 1987, 120, 1-4; b) Chemistry-A European Journal, 2016, 22, 7352-7356; c) Sel.Org.React.Database (SORD), 1978, 20121004). The corresponding amino nitrile is easily obtained by reacting the corresponding cyanohydrin with NH3 and / or NH4Cl.

[0212]

[0213] In a similar manner, protected aminonitriles of formula (II) having other carboxylic acid esters as protecting groups, such as acetyl (R 3 =CH3). For example, the acetyl-protected aminonitrile of formula (I) can be prepared by reacting the aminonitrile with acetic anhydride or acyl chloride:

[0214]

[0215] The present invention is illustrated by the following examples, but these examples do not limit the present invention.

[0216] Unless expressly stated otherwise, figures expressed in percentages are each based on % by weight.

[0217] General

[0218] All chemicals and solvents were purchased from Sigma-Aldrich or ABCR and used without further purification.

[0219] 1 H and 13 C NMR spectra were recorded on a Bruker Avance 200 MHz spectrometer and referenced to the residual protons of the solvent ( 1 H) or carbon ( 13 C) Resonance peaks. Chemical shifts (δ) are reported in ppm.

[0220] 1. Synthesis of protected amino nitrile, compound of formula (II):

[0221] 1.1 Synthesis of N-(1-cyanocyclohexyl)formamide

[0222]

[0223] 1-Hydroxycyclohexane-1-carbonitrile (1.252 g, 10.0 mmol), formamide (1.19 mL, 30 mmol) and acetic acid (0.57 mL, 10 mmol) were added to an approximately 20 mL pressure tube (Ace tube). The tube was then purged with argon and sealed. It was then placed in a 120 ° C preheated oil bath and the mixture was stirred at this temperature for 4 hours. The crude material was purified by flash chromatography (SiO2, DCM / MeOH 1:0 to 50:1) to obtain 1.439 g (95% yield) of the desired product as an off-white solid (GC analysis purity of 96%). CDCl3-d 1 H NMR showed a 3.5:1 mixture of isomers. Major isomer: 1 HNMR (200 MHz, CDCl3) δ 8.18 (s, 1H), 5.65 (s, 1H), 2.52-2.29 (m, 2H), 1.92-1.62 (m, J = 6.0 Hz, 8H). Minor isomers: 1 H NMR (200MHz, CDCl3) δ8.51 (d, J=11.8Hz, 1H), 6.11 (s, 1H), 2.27-2.09 (m, J=6.4Hz, 2H), 1.92-1.62 (m, J=6.0Hz, 8H).

[0224] 1.2 Synthesis of N-(1-cyanocyclohexyl)acetamide

[0225]

[0226] To the aminonitrile (474mg, 3.62mmol) and trimethylamine (0.6mL, 4.28mmol) of stirring anhydrous Et o (6mL) solution (cooling in ice bath), acetyl chloride (0.3mL, 4.28mmol) was added dropwise with a syringe. Remove bath, and the reaction was stirred at room temperature for 3.5 hours. Then, the mixture was filtered through a porous glass funnel (medium porosity), and Et o was discarded. Use second filter bottle, filter cake was washed 4 times with EtOAc. Collect EtOAc extract and evaporate, thereby obtain 311.7mg (52% yield) target compound, it is a white solid, does not need to be purified for subsequent reaction. 1 HNMR (200MHz, CDCl3) δ7.08 (s, 1H), 2.40-2.19 (m, 2H), 1.96 (s, 3H), 1.80-1.40 (m, 8H).

[0227] 1.3 Synthesis of N-(1-cyano-1-methylethyl)acetamide

[0228]

[0229] 2-amino-2-methylpropionitrile (300mg, 3.57mmol) is added in the double-necked round-bottom flask of 100mL drying and is dissolved in anhydrous EtOAc (14mL).Add KCO(615mg, 4.44mmol), then add AcO(0.4mL, 4.28mmol).The heterogeneous mixture is stirred 20 hours at room temperature and argon atmosphere.Then, filter the crude product, wash the residue with EtOAc.Then the resulting solution is concentrated under vacuum.By flash chromatography (SiO, petroleum ether / EA / acetone 10:10:1) purifying, thus obtain 150.7mg (33% yield) required product, it is off-white solid. 1 H NMR (200MHz, CDCl3) δ5.78 (s, 1H), 2.01 (s, 3H), 1.70 (s, 6H).

[0230] 1.4 Synthesis of N-(1-cyano-1-methylethyl)formamide

[0231]

[0232] Acetone cyanohydrin (2.55 g, 30.0 mmol), formamide (4.05 g, 90 mmol) and acetic acid (1.7 mL, 30 mmol) were added to an approximately 20 mL pressure tube (Ace tube). The tube was then purged with argon and sealed. It was then placed in a 125° C. preheated oil bath and the mixture was stirred at that temperature for 4 hours. The reaction was cooled to room temperature. 30 mL of benzene was added and the resulting mixture was concentrated in vacuo and purified by flash chromatography (SiO , CH Cl / MeOH 1:0 to 50:1 as eluent) without further treatment. The product was dried in vacuo to remove residual volatiles and separated as a yellow oil to give 1.837 g (91% yield, 9:1 mixture of isomers). 1 H NMR (200 MHz, CDCl3) δ 8.17 (s, 1H), 6.00 (s, 1H), 1.74 (s, 6H). The signals of the minor isomers are all superimposed, except 1 H NMR (200 MHz, CDCl3) δ 8.48 (d, J = 11.8 Hz, 1H).

[0233] 1.5 Synthesis of N-(1-cyano-1,2-dimethylpropyl)formamide

[0234]

[0235] 1.5.1 Standard Procedure for Formyl-Protected Amino Nitriles of Formula (II):

[0236] Freshly prepared acetic acid-formic anhydride* (1.44 mL, 10 mmol) was added to a stirred solution of aminonitrile (2 mmol) in THF (9 mL) at room temperature under an argon atmosphere. The resulting mixture was stirred for 65 hours under these conditions. The reaction was then treated with saturated aqueous sodium bicarbonate (2×30 mL) and subsequently extracted with dichloromethane (3×50 mL). The organic extract was dried over Na2SO4, evaporated, and the residue was purified by flash column chromatography on silica gel using MeOH / CH2Cl2 (4%) as eluent.

[0237] *Acetic acid-formic anhydride: In a MW vial equipped with a stir bar, 2 mL of Ac2O and 0.88 mL of formic acid were added, sealed and placed under argon. The resulting solution was stirred at 60°C for 1.5 hours. The mixture was cooled to room temperature and used in the subsequent step without further treatment.

[0238] Starting from 2-amino-2,3-dimethylbutyronitrile (224.3 mg, 2 mmol); a pale yellow oil was isolated (243 mg, 87% yield) as a 3:1 mixture of isomers. Major isomer: 1 HNMR (200 MHz, CDCl3) δ 8.20 (s, 1H), 5.64 (s, 1H), 2.37 (app dt, J = 13.6, 6.8 Hz, 1H), 1.68 (s, 3H), 1.20-1.02 (m, 6H). Minor isomers: 1 HNMR (200MHz, CDCl3) δ8.48 (d, J=11.7Hz, 1H), 6.13 (s, 1H), 2.00 (app dt, J=14.6, 7.4Hz, 1H), 1.61 (s, 3H), 1.20-1.02 (m, 6H).

[0239] 1.6 Synthesis of N-(1-cyano-1-ethylpropyl)formamide

[0240]

[0241] Synthesized according to the standard procedure of the formyl-protected amino nitrile of formula (II) of Example 1.5.1.

[0242] Starting from 2-amino-2-ethylbutyronitrile (224.3 mg, 2 mmol); a pale yellow oil was isolated (245 mg, 88% yield) as a 3:1 mixture of isomers. Major isomer: 1HNMR (200 MHz, CDCl3) δ 8.19 (s, 1H), 5.73 (s, 1H), 2.06 (app qd, J = 7.8, 6.7 Hz, 4H), 1.20-0.99 (m, J = 10.8, 7.4 Hz, 6H). Minor isomers: 1 HNMR (200MHz, CDCl3) δ8.44 (d, J=11.7Hz, 1H), 6.54 (s, 1H), 1.97-1.76 (m, J=19.4, 10.9, 6.3Hz, 4H), 1.20-0.99 (m, J=10.8, 7.4Hz, 6H).

[0243] 2. Synthesis of the compound of formula (I) by reductive hydrolysis of the compound of formula (II)

[0244] 2.1 Scheme for the reductive nitrile hydrolysis of protected amino nitrile of formula (II)

[0245] 2.1.1 Synthesis of (1-aminocyclohexyl)methanol

[0246]

[0247] To a ca. 40 mL Premex autoclave (equipped with a Teflon insert) was added RuHCl(CO)(PPh3)3 (47.6 mg, 0.05 mmol), nitrile (152.2 mg, 1 mmol), 1,4-dioxane (7.0 mL) and H2O (7.0 mL) in air. After closing the reaction vessel, the system was purged first with nitrogen (3x) and then with hydrogen (3x). Finally, the autoclave was pressurized with hydrogen (45 bar) and heated at 140 °C. Note: At this temperature, the internal pressure increased to 60 bar. The mixture was stirred under these conditions for 20 hours. The reaction was then cooled in a water bath and carefully decompressed, and the organic phase was extracted with EtOAc (3×25 mL), washed with brine and dried over Na2SO4. Filtered through a short cotton pad and concentrated in vacuo. CDCl3-d 1 H-NMR analysis showed that only the deprotected product was formed (>99% conversion). 1 H NMR (200MHz, CDCl3) δ3.32 (s, 1H), 2.09 (br.s, 2H), 1.59-1.31 (m, J=19.1, 11.0Hz, 8H).

[0248] 2.2 Evaluation of the conditions for preparing 2-amino-2-methylpropanol (2-AMP):

[0249] 2.2.1 Standard Procedure:

[0250] To an approximately 40 mL Premex autoclave (equipped with a Teflon insert) was added RuHCl(CO)(PPh3)3 (3 mol%), nitrile 1 (1 mmol) and the indicated solvent (7.0 mL) in air. After closing the reaction vessel, the system was purged first with nitrogen (3x) and then with hydrogen (3x). Finally, the autoclave was pressurized with the indicated hydrogen pressure (x bar) and heated at 140°C. The mixture was stirred under the same conditions for the indicated time. The reaction was then cooled in a water bath and carefully depressurized, and the crude mixture was collected in a round bottom flask and concentrated in vacuo. The ratios between the product mixtures were determined by 1 H-NMR measurement, wherein MeOD-d4 was used as solvent.

[0251]

[0252]

[0253] cm = complex mixture, primary and secondary amines also detected; tr = trace

[0254] 2.2.2 Evaluation of ligands:

[0255] To an approximately 40 mL Premex autoclave (equipped with a Teflon insert) were added the ruthenium complex (5 mol%) and the corresponding ligand (10 mol%), nitrile 1 (1 mmol) and dioxane (7.0 mL) in air. After closing the reaction vessel, the system was purged first with nitrogen (3x) and then with hydrogen (3x). Finally, the autoclave was pressurized with the indicated hydrogen pressure (45-50 bar) and heated at 140°C. The mixture was stirred for 18 hours. The reaction was then cooled in a water bath and carefully decompressed, the crude mixture was collected in a round-bottom flask and concentrated under vacuum. The ratio between the product mixtures was determined by 1 H-NMR measurement used MeOD-d4 as solvent and hexamethylbenzene as internal standard.

[0256]

[0257]

[0258]

[0259] 2.2.2.1 Evaluation of different metals and ligands for reductive nitrile hydrolysis

[0260]

[0261] Catalyst, ligand, additive, protected aminonitrile 1 (0.5 mmol) and solvent were added to an approximately 40 mL Premex autoclave (equipped with a Teflon insert). After closing the reaction vessel, the system was purged first with nitrogen (5x) and then with hydrogen (3x). Finally, the autoclave was pressurized with hydrogen (55 bar) and heated at the indicated temperature (140°C). The mixture was then stirred for 18 hours under the same conditions. The reactants were then cooled in a water bath and carefully decompressed. Finally, the reaction mixture was stirred for 18 hours under the same conditions. The reaction mixture was ... 1 The crude product was analyzed for quantification by H NMR (0.05 M in CDCl 3 ) using hexamethylbenzene as an internal standard.

[0262]

[0263]

[0264] 2.2.3 Evaluation of pressure impact

[0265] For the experiment under higher pressure, a 160 mL stainless steel autoclave without Teflon lining was used, which was equipped with a magnetically coupled overhead stirrer with inclined blades, an electric heating jacket and H2 inlet. A solution of 0.6 g (0.005 mol) of nitrile 1 in 25.7 g of dioxane and 4.3 g of water was added to an autoclave beaker, 0.153 g of RuHCl (CO) (PPh3) 3 (3 mol%) was added, the autoclave was closed and purged with argon. Then, the autoclave was pressurized to 20 bar at room temperature with hydrogen and stirring, and the autoclave was heated to 150 ° C. The pressure was adjusted to 55 bar at this temperature by adding hydrogen to the autoclave, and the mixture was stirred for 24 hours. After this time, it was cooled to room temperature and decompressed. Samples were taken and analyzed as described below (sample 1). Thereafter, the autoclave was pressurized to 20 bar again, heated to 150 ° C and the pressure was increased to 135 bar. The mixture was stirred under these conditions for a further 24 hours and then another sample (Sample 2) was taken in a similar manner as before.

[0266] The samples were analyzed by gas chromatography using a column of type RTX5 Amine, 30 m long, 0.32 mm diameter, 1.5 μm layer thickness, FID detector. Temperature program: injection at 60°C, heating to 280°C at 4°C / min, holding at 280°C for 15 min, results given in area percent, excluding solvent signals and no water detected.

[0267] sample 2-AMP Nitrile 1 N-Formyl-2-AMP 1 58,3 3,9 22,0 2 74,3 1,5 7,8

[0268] The purity of the starting nitrile 1 measured by GC was 84% ​​(area %). Therefore, up to about 84% of the desired product peak area is expected, which is good compared to the measured amount (74.3% of 2-AMP). The selectivity calculated based on 84% of the initial peak area of ​​the raw material is 89% for sample 2. Sample 2 was also analyzed using an internal standard (diglyme) to quantify the mass of the product formed. The crude product solution was found to contain 1.16% by mass of 2-AMP, which corresponds to a molar yield of 73% for the product 2-AMP; and 0.16% of N-formyl-2-AMP, which corresponds to a molar yield of 8% for N-formyl-2-AMP.

[0269] Therefore, it was shown that higher pressure favored the deprotection of the amino group, as the ratio of 3:2 was much higher than that obtained previously in higher yield (about 9.5:1, combined yield of 81%).

[0270] In the same apparatus, according to the same procedure, at two different pressure levels, triphos and xantphos ligands were also tested using 3 mol % of the catalyst (RuHCl(CO)(PPh3)3 / ligand 1:1). The experiments were carried out at 140°C for 24 hours. The purity of the starting nitrile was taken into account in the calculation of the yield (triphos 95%, xantphos 91%).

[0271] Triphos:

[0272]

[0273] Xantphos

[0274]

[0275] Thus, it is shown again that in the case of multidentate ligands, higher pressures also favor the deprotection of the amino group, since the 3:2 ratio is much higher than that previously obtained in higher yields (about 5.5:1 for triphos, 85% combined yield; 14.6:1 for xantphos, 60% combined yield).

[0276] 2.2.4 Evaluation of salt impact:

[0277] Standard procedure: To an approximately 40 mL Premex autoclave (equipped with a Teflon insert) were added the indicated additives (1 equiv), RuHCl(CO)(PPh3)3 (X mol %), nitrile 1 (1 mmol), dioxane (6.0 mL) and H2O (1.0 mL) in air. After closing the reaction vessel, the system was purged first with nitrogen (3x) and then with hydrogen (3x). Finally, the autoclave was pressurized with hydrogen (55 bar) and heated at 140°C. Note: At this temperature, the internal pressure increased to 70 bar. The mixture was stirred for 17 hours. The reaction was then cooled in a water bath and carefully depressurized, the crude mixture was collected in a round-bottom flask and concentrated in vacuo. 0.3 mmol hexamethylcyclotrisiloxane or 1 mmol Cl2CH2CH2Cl2 (used as internal standard) was added to the crude mixture to determine the concentration in MeOD-d4. 1 H-NMR yield.

[0278]

[0279] mol%[Ru] additive Conversion rate (%) 2 (yield, %) 3 (yield, %) 4 (yield, %) 2 — 90 86 3 — 2 NaCl 83 26 — 57 3 <![CDATA[(NH4)2SO4]]> >99 53 — 30 3 <![CDATA[Na2SO4]]> >99 50 28 — 3 <![CDATA[(NH4)H2PO4]]> >99 60 — 29 3 <![CDATA[Yb(OTf)3*]]> <75％ 70 — —

[0280] *In this case, only 5 mol% of additive was used.

[0281]

[0282] 1 H NMR (200MHz, MeOD) δ 3.28 (s, 2H), 1.06 (s, 6H).

[0283]

[0284] Separated as a 2.5:1 isomer mixture: Major isomer: 1 H NMR (200 MHz, MeOD) δ 7.92 (s, 1H), 3.58 (s, 2H), 1.30 (d, J = 0.6 Hz, 6H). Minor isomers: 1 HNMR (200MHz, MeOD) δ 8.21 (s, 1H), 3.39 (s, 2H), 1.27 (d, J = 0.7Hz, 6H).

[0285]

[0286] 1 H NMR (200MHz, MeOD) δ3.48 (s, 1H), 1.29 (s, 1H).

[0287] 2.2.5 Separation into HCl adducts:

[0288] Method A)

[0289]

[0290] RuHCl(CO)(PPh3)3(3mol%), nitrile 1(1mmol), dioxane (6.0mL) and H2O(1.0mL) were added to about 40mL Premex autoclave (equipped with Teflon insert) in air. After closing the reaction vessel, the system was purged with nitrogen (3x) and then with hydrogen (3x). Finally, the autoclave was pressurized with hydrogen (45 bar) and heated at 140°C. Note: at this temperature, the internal pressure was raised to 60 bar. The mixture was stirred for 18 hours. Then, the reactant was cooled in a water bath and carefully decompressed, and the crude mixture was collected in a round-bottom flask and concentrated in vacuo. Subsequently, it was dissolved in 1mL EtOH. 0.1mL concentrated HCl (36%) was added to the solution. The resulting mixture was stirred at room temperature for 18 hours. Then, the mixture was concentrated under reduced pressure, washed with Et2O(x3), and dried in vacuo. The isolated product was an off-white solid (67.1mg, 54% yield for two steps). 1 HNMR (200MHz, D2O) δ3.55 (s, 2H), 1.31 (s, 6H).

[0291] Method B)

[0292]

[0293] RuHCl(CO)(PPh3)3 (3 mol%), nitrile 1 (1 mmol), dioxane (6.0 mL) and H2O (1.0 mL) were added to about 40 mL Premex autoclave (equipped with Teflon insert) in air. After closing the reaction vessel, the system was purged with nitrogen (3x) and then with hydrogen (3x). Finally, the autoclave was pressurized with hydrogen (55 bar) and heated at 140°C. Note: at this temperature, the internal pressure increased to 60 bar. The mixture was stirred for 18 hours. Then, the reactants were cooled in a water bath and carefully decompressed, and the crude mixture was collected in a round-bottom flask and concentrated in vacuo. Subsequently, it was dissolved in 2.5 mL MeOH. 2.5 mL 2M HCl aqueous solution was added to the solution. The mixture was stirred at 80°C for 18 hours. Then, the mixture was concentrated under reduced pressure, washed with Et2O (x3), and dried in vacuo. The product was isolated as an off-white solid (74.2 mg, 59% yield over two steps). 1 H NMR (200MHz, D2O) δ3.55 (s, 2H), 1.31 (s, 6H).

[0294] 2.2.6 Separation into HCl adducts, substrate range:

[0295] According to procedures 1.3 or 1.4, 1.51, the corresponding formyl-protected amino nitrile is prepared. The reaction on the substrate range is carried out as follows: RuHCl(CO)(PPh3)3(5mol%), formyl-protected amino nitrile (1mmol), dioxane (6.0mL) and H2O(1.0mL) are added to about 40mL Pre-Mex autoclave (equipped with Teflon insert) in air. After closing the reaction vessel, the system is purged with nitrogen (3x) and then with hydrogen (3x). Finally, the autoclave is pressurized with hydrogen (55 bar) and heated at 140°C. Note: at this temperature, the internal pressure rises to 60 bar. The mixture is stirred for 18 hours. Then, the reaction is cooled in a water bath and carefully decompressed, and the crude mixture is collected in a round-bottom flask and concentrated in vacuo. Subsequently, it is dissolved in 2.5mL MeOH. 2.5mL 2M HCl aqueous solution is added to the solution. The mixture is stirred at 80°C for 18 hours. The mixture was then concentrated under reduced pressure, washed with Et2O (x3) and dried in vacuo to afford the corresponding amino alcohol as its HCl salt.

[0296] The product yield was determined by 1 Determined by H-NMR spectroscopy.

[0297]

[0298] 2..2.3 Comparative Example:

[0299] Stability of Unprotected Aminonitriles in the Presence of Water at Elevated Temperatures:

[0300] 2-Amino-2-methyl-propionitrile was dissolved in D2O / MeOH-d4 (1:1) in a J-Young NMR tube and heated at 140°C for 2 hours. 1 H-NMR analysis of the reaction mixture. Hydrolysis of the aminonitrile to ketone, HCN and NH3 was detected, indicating that the unprotected aminonitrile is unstable under the conditions required for reductive nitrile hydrolysis. Therefore, the amine functional group must be protected.

[0301]

[0302] To a ca. 40 mL Premex autoclave (equipped with a Teflon insert) was added RuHCl(CO)(PPh3)3 (48.1 mg, 0.05 mmol), 1-aminocyclohexane-1-carbonitrile (124.2 mg, 1 mmol), 1,4-dioxane (7.0 mL) and H2O (7.0 mL) in air. The mixture was gently degassed with argon. After closing the reaction vessel, the system was purged first with nitrogen (3x) and then with hydrogen (3x). Finally, the autoclave was pressurized with hydrogen (43 bar) and heated at 140°C. Note: At this temperature, the internal pressure increased to 60 bar. The mixture was stirred under these conditions for 17.5 hours. The reaction was then cooled in a water bath and carefully decompressed, and the organic phase was extracted with EtOAc (3×25 mL), washed with brine and dried over Na2SO4. Filtered through a short cotton pad and concentrated in vacuo. CDCl3-d 1 H-NMR analysis showed that no expected product was formed.

[0303] Therefore, this experiment shows that the reductive hydrolysis of the nitrile group occurs faster than the deprotection of the formylamino group.

Claims

1. A method for preparing a compound of formula (I), in: R 1 is hydrogen, acyclic or cyclic unsubstituted C1-C 10 Alkyl, unsubstituted C6-C 10 Aryl or unsubstituted C7-C 12 Aralkyl, R 2 is an acyclic or cyclic unsubstituted C1-C 10 Alkyl, unsubstituted C6-C 10 Aryl or unsubstituted C7-C 12 Aralkyl, or R 1 and R 2 Together with the atoms connecting them, they form a divalent C1-C 18 alkyl, -CH2CH2NHCH2CH2- and -CH2CH2OCH2CH2-, It includes at least the following process steps: a) reacting a compound of formula (II) with hydrogen and water in the presence of at least one homogeneous transition metal catalyst TMC 1 and in the presence of a solvent selected from ethers: in: R 1 and R 2 has the same meaning as in formula (I), and R 3 is hydrogen or an acyclic or cyclic unsubstituted C1-C 10 alkyl, Wherein TMC 1 is a complex catalyst comprising ruthenium and at least one phosphorus donor ligand, wherein the phosphorus donor ligand is selected from 1,1,1-tris(diphenylphosphinomethyl)ethane.

2. The method according to claim 1, wherein R 3 For hydrogen.

3. The process according to claim 1, wherein the homogeneous transition metal catalyst TMC 1 is selected from the group consisting of [Ru(PPh3)3(CO)(H)Cl], [Ru(PPh3)3(CO)Cl2], [Ru(PPh3)3(CO)(H)2], [Ru(binap)(Cl)2], [Ru(PMe3)4(H)2], [Ru(PEt3)4(H)2], [Ru(Pn-Pr3)4(H)2], [Ru(Pn-Bu3)4(H)2], [Ru(Pn-Octyl3)4(H)2], [Ru(Pn-Bu3)4(H)2], [Ru(PnOctyl3)4(H)2], [Ru(PPh3)3(CO)(H)Cl], [Ru(PPh3)3(CO)(H)2], Ru-MACHO, and [Ru(PPh3)3(CO)(H)Cl], which is combined with 1,1,1-tris(diphenylphosphinomethyl)ethane.

4. The process according to claim 2, wherein the homogeneous transition metal catalyst TMC 1 is selected from the group consisting of [Ru(PPh3)3(CO)(H)Cl], [Ru(PPh3)3(CO)Cl2], [Ru(PPh3)3(CO)(H)2], [Ru(binap)(Cl)2], [Ru(PMe3)4(H)2], [Ru(PEt3)4(H)2], [Ru(Pn-Pr3)4(H)2], [Ru(Pn-Bu3)4(H)2], [Ru(Pn-Octyl3)4(H)2], [Ru(Pn-Bu3)4(H)2], [Ru(PnOctyl3)4(H)2], [Ru(PPh3)3(CO)(H)Cl], [Ru(PPh3)3(CO)(H)2], Ru-MACHO, and [Ru(PPh3)3(CO)(H)Cl], which is combined with 1,1,1-tris(diphenylphosphinomethyl)ethane.

5. The process according to claim 1, wherein the homogeneous transition metal catalyst TMC 1 is used in an amount of 0.001 to 20 mol %, calculated as transition metal and based on the amount of compound of the formula (II) used in the process.

6. The process according to claim 2, wherein the homogeneous transition metal catalyst TMC 1 is used in an amount of 0.001 to 20 mol %, calculated as transition metal and based on the amount of compound of the formula (II) used in the process.

7. The process according to claim 3, wherein the homogeneous transition metal catalyst TMC 1 is used in an amount of 0.001 to 20 mol %, calculated as transition metal and based on the amount of compound of the formula (II) used in the process.

8. The process according to claim 4, wherein the homogeneous transition metal catalyst TMC 1 is used in an amount of 0.001 to 20 mol %, calculated as transition metal and based on the amount of compound of the formula (II) used in the process.

9. The process according to any one of claims 1 to 8, wherein the reaction between the compound of formula (II), water and hydrogen is carried out at a pressure of 10 to 180 bar.

10. The process according to any one of claims 1 to 8, wherein the reaction between the compound of formula (II), water and hydrogen is carried out at a temperature of 50 to 180°C.

11. The process according to claim 9, wherein the reaction between the compound of formula (II), water and hydrogen is carried out at a temperature of 50-180°C.

12. The process according to any one of claims 1 to 8, wherein the solvent is selected from dioxane, tetrahydrofuran and glyme.

13. The method of claim 11, wherein the solvent is selected from the group consisting of dioxane, tetrahydrofuran and glyme.

14. The process according to claim 1, wherein the homogeneous transition metal catalyst TMC 1 is recycled by removing the compound of formula (II) and other volatile compounds in the reaction mixture by distillation.

15. The process according to claim 13, wherein the homogeneous transition metal catalyst TMC 1 is recycled by removing the compound of formula (II) and other volatile compounds in the reaction mixture by distillation.

16. The process according to claim 1, wherein the hydrogenation is carried out under different H2 pressures, first at a lower H2 pressure of 1-80 bar to reduce the nitrile groups and then the H2 pressure is increased to 90-200 bar to reduce the amide groups.

17. The process according to claim 15, wherein the hydrogenation is carried out under different H2 pressures, first at a lower H2 pressure of 1-80 bar to reduce the nitrile groups, and then the H2 pressure is increased to 90-200 bar to reduce the amide groups.

18. The process according to any one of claims 1 to 8, wherein in process step a) a compound of formula (III) is formed as an intermediate product and the nitrogen-carbon bond of the amide group -N(H)-C(=O)- of the compound of formula (III) is Breaking in the following second process step: b) by forming an amino group -NH2 and a primary alcohol HO-CH2-R 3 Hydrolyze or hydrogenate the amide group -NH-C(=O)-R 3 , the amide group -NH-C(=O)-R 3 Converted to amino group -NH2 or its corresponding ammonium group -NH3 + .

19. The process of claim 17, wherein in process step a) a compound of formula (III) is formed as an intermediate product, and the nitrogen-carbon bond of the amide group -N(H)-C(=O)- of the compound of formula (III) is Breaking in the following second process step: b) by forming an amino group -NH2 and a primary alcohol HO-CH2-R 3 Hydrolyze or hydrogenate the amide group -NH-C(=O)-R 3 , the amide group -NH-C(=O)-R 3 Converted to amino group -NH2 or its corresponding ammonium group -NH3 + .

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