Improved process for deprotection of N-formyl protected amines

Abstract

The invention relates to a method for converting an N-formyl-protected amine into the corresponding deprotected amine, characterized in that the N-formyl-protected amine is deprotected by decomposing the formyl into carbon dioxide and hydrogen in the presence of water and a dehydrogenation catalyst and at a temperature in the range of 10 DEG C to 300 DEG C. The process can be used to effectively deprotect an N-formyl-protected amino alcohol intermediate in a process for preparing an amino alcohol by reductive hydrolysis of a nitrile functional group starting from an N-formyl-protected amino nitrile followed by deprotection of the N-formyl-protected amino alcohol intermediate.

Description

[0001] The present invention relates to a method for converting an N-formyl protected amine into the corresponding deprotected amine, characterized in that the N-formyl protected amine is deprotected by decomposing the formyl group into carbon dioxide and hydrogen in the presence of water and a dehydrogenation catalyst and at a temperature in the range of 10 °C to 300 °C. This method can be used to effectively deprotect an N-formyl protected amino alcohol intermediate in a method for preparing an amino alcohol starting from an N-formyl protected amino nitrile by reductive hydrolysis of the nitrile functional group followed by deprotection of the N-formyl protected amino alcohol intermediate.

[0002] According to the amino alcohol having the formula (I),

[0003]

[0004] wherein R1 and R2 are independently of each other hydrogen or an alkyl group having 1 to 4 carbon atoms, such as 2-amino-2-methyl-1-propanol (R1, R2 = methyl), are valuable compounds in the chemical industry, these compounds are useful organic bases for neutralization and solubilization applications, are used in toiletries and cosmetics, are used as dispersants in combination with fatty acids, are used as formaldehyde scavengers and wetting agents.

[0005] Currently, such amino alcohols are technically produced by nitration of alkanes followed by a Henry reaction with formaldehyde and subsequent reduction to the amino alcohol, as shown by the following reaction scheme.

[0006]

[0007] However, the nitration step of this synthetic route is not very selective and it is associated with safety issues because some nitroalkanes are shock-sensitive and may explode when not properly handled.

[0008] To address these drawbacks, WO 2020 / 094454 A recently proposed a synthetic route based on reductive nitrile hydrolysis of the corresponding nitrile compound. The central step of this method is the reductive hydrolysis of the nitrile group of the starting compound. As shown in the following reaction scheme, the nitrile is hydrogenated in the presence of a homogeneous transition metal catalyst and water to form the corresponding alcohol and ammonia as a by-product.

[0009]

[0010] In this method, it is not possible to start the reaction directly with the corresponding amino nitrile because under these reaction conditions, such amino nitriles decompose in a reverse Strecker reaction as shown by the following reaction scheme.

[0011]

[0012] Thus, according to WO 2020 / 094454 A, N-formyl-protected aminonitriles are used as starting compounds, and such N-formyl-aminonitriles are (i) directly converted into the desired aminoalcohol in a one-step process, or (ii) converted in a two-step process to form the corresponding N-formyl-aminoalcohol as an intermediate, which is deprotected to the desired aminoalcohol in a separate second step, as follows.

[0013]

[0014] The reductive hydrolysis of the nitrile group to form the corresponding alcohol group in the first step of the one-step or two-step process is preferably carried out with a homogeneous transition metal catalyst in the presence of hydrogen and water. Under suitable conditions, the homogeneous transition metal catalyst also catalyzes the cleavage of the formyl group, however usually with lower efficiency. Therefore, the two-step process allows for a more efficient use of the homogeneous transition metal catalyst.

[0015] According to WO 2020 / 094454 A, the deprotection of the amino group in the two-step process can be carried out by hydrolysis or hydrogenation using a hydrolysis or hydrogenation catalyst. The hydrolysis of the N-formyl-protected amine functional group in the presence of water is usually catalyzed by the addition of a strong base or more preferably a strong acid such as sulfuric acid or hydrochloric acid, and results in the release of formic acid or its salt and the deprotected amine functional group (possibly in protonated form as an ammonium group). The hydrogenation of the N-formyl-protected amine functional group in the presence of hydrogen is catalyzed by hydrogenation catalysts known in the art, and results in the release of methanol and the deprotected amine functional group. Disadvantageously, in such hydrolysis, the addition of the strong acid or strong base requires subsequent neutralization of them and separation of the resulting salts. In addition, formic acid is released as an unwanted by-product. The use of strong acids or strong bases and the release of formic acid also promote corrosion of the apparatus. Cleavage by hydrogenation again requires the use of hydrogen and associated overpressure equipment.

[0016] The object of the present invention is to provide a favorable alternative for the deprotection of N-formyl-protected amino groups by hydrolysis or hydrogenation, which alternative does not have the above-mentioned disadvantages.

[0017] Therefore, the present invention relates to a method for converting an N-formyl-protected amine into the corresponding deprotected amine, characterized in that the N-formyl-protected amine is deprotected by decomposing the formyl group into carbon dioxide and hydrogen in the presence of water and a dehydrogenation catalyst and at a temperature in the range of 10 °C to 300 °C.

[0018] In this method, the formic acid released in the middle is directly decomposed into carbon dioxide and hydrogen, which shifts the equilibrium of the reaction towards the formation of the deprotected amine functional group. Therefore, this method should be considered as simultaneously releasing formic acid and dehydrogenating it to carbon dioxide.

[0019]

[0020] The method of the present invention for converting an N - formyl - protected amine to the corresponding de - protected amine is applicable to the de - protection of any N - formyl - protected aliphatic (linear, branched or cyclic) or aromatic primary or secondary amine (including aliphatic or aromatic amines showing one or more other functional groups as substituents). Thus, the N - formyl - protected amine is preferably an N - formyl - protected aliphatic or aromatic primary amine, which shows one or more substituents selected from the group consisting of: hydroxyl, amino (primary, secondary or tertiary), ether functional group, thiol group, thioether functional group, ester functional group, alkoxy, nitro, halogen (chlorine, fluorine, bromine or iodine) substituents, nitrile group, ketone functional group and aldehyde group. More preferably, the N - formyl - protected amine is an N - formyl - protected aliphatic or aromatic primary amine, which shows no substituents or shows no substituents other than one or more hydroxyl groups. Particularly preferably, the N - formyl - protected amine is an N - formyl - protected aliphatic primary amine, which shows one or more hydroxyl groups at the 2 - (β), 3 - (γ) or 4 - (δ) position relative to the carbon atom bearing the N - formyl (1 - position). Even more particularly preferably, the N - formyl - protected amine is an N - formyl - protected aliphatic primary amine, which shows one or more hydroxyl groups at the 2 - (β) position relative to the carbon atom bearing the N - formyl. Most particularly preferably, the N - formyl - protected amine is an N - formyl - protected amino - alcohol compound of formula I

[0021]

[0022] wherein R1 and R2 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms.

[0023] In a specific embodiment, the method of the present invention for converting an N - formyl - protected amine to the corresponding de - protected amine is incorporated into a method for manufacturing an amino - alcohol compound of formula II

[0024]

[0025] wherein R1 and R2 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, and the method is characterized in that

[0026] (i) In a first step, an N - formyl - protected amino - nitrile compound of formula III

[0027]

[0028] wherein R1 and R2 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, is converted by reductive hydrolysis in the presence of water, hydrogen and a homogeneous transition - metal catalyst to the corresponding N - formyl - protected amino - alcohol compound of formula I,

[0029] (ii) In a subsequent step, the resulting N-formyl protected amino alcohol compound of formula I is deprotected by the method according to the invention for converting an N-formyl protected amine into the corresponding deprotected amine, optionally after intermediate purification of the resulting N-formyl protected amino alcohol compound of formula I from the reaction mixture of the first step.

[0030] Accordingly, in a specific embodiment, the present invention also relates to a method for manufacturing an amino alcohol compound of formula II

[0031]

[0032] wherein R1 and R2 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms,

[0033] The method comprises the following steps

[0034] a) Applying hydrogen to a reaction mixture comprising an N-formyl protected amino nitrile compound of formula III,

[0035]

[0036] a homogeneous transition metal catalyst and water to at least partially convert the compound of formula III into the corresponding N-formyl protected amino alcohol compound of formula I,

[0037]

[0038] a1) Optionally separating at least a portion of the N-formyl protected amino alcohol compound of formula I produced in step a) from the remainder of the reaction mixture of step a), and

[0039] b) Converting the N-formyl protected amino alcohol compound of formula I produced in step a) or the purified N-formyl protected amino alcohol compound of formula I produced in optional step a1) into the corresponding deprotected amino alcohol of formula II,

[0040] The method is characterized in that

[0041] the N-formyl protected amino alcohol compound of formula I is deprotected by decomposing the formyl group into carbon dioxide and hydrogen in the presence of water and a dehydrogenation catalyst and at a temperature in the range from 10 °C to 300 °C.

[0042] In a specific embodiment of the process according to the invention for preparing an amino alcohol compound of formula II starting from an N-formyl-protected aminonitrile compound of formula III, purification in step a1) is mandatory. Preferably, the purification in step a1) comprises separating off any hydrogen remaining from step a).

[0043] Preferably, the process according to the invention for preparing an amino alcohol compound of formula II starting from an N-formyl-protected aminonitrile compound of formula III is carried out using a compound of formula III in which the residues R1 and R2 are both methyl. In this case, the compound of formula III is N-(2-cyano-propan-2-yl)formamide, and the process leads to the formation of 2-amino-2-methyl-1-propanol as the compound of formula II.

[0044] The N-formyl-protected aminonitrile compound of formula III is obtainable, for example, by reaction of the corresponding cyanohydrin with formamide in acetic acid as described in WO 2020 / 094454 A.

[0045] Preferably, the deprotection of the N-formyl-protected amine by catalytic decomposition of the formyl group into carbon dioxide and hydrogen in the process according to the invention is carried out without addition of hydrogen.

[0046] Preferably, the dehydrogenation catalyst used in the process according to the invention is a heterogeneous catalyst, preferably used in the form of a fixed-bed catalyst. Such heterogeneous dehydrogenation catalysts are well known to the person skilled in the art.

[0047] Preferred dehydrogenation catalysts are heterogeneous catalysts having an active material selected from the group consisting of: Pt, Pd, Rh, Ru, Ag, Au, Cu, Ni, Co, Fe, Cr, Mo, W and V, in metallic form or as a compound (such as an oxide or sulfide), including mixtures of such active materials. Particularly preferably, the active material is selected from Pt, Pd, Ag, Cu, Ni, more preferably from Pd, Ag, Cu, Ni. Preferred dehydrogenation catalysts are heterogeneous catalysts having the active material provided on a support material, which support material is preferably selected from the group consisting of: activated carbon, alumina, titanium dioxide, zirconium dioxide, silica, niobium oxide, vanadium oxide or mixtures thereof, more preferably from the group consisting of alumina, silica, zirconium dioxide or mixtures thereof. Preferably, such heterogeneous dehydrogenation catalysts have a BET surface area in the range from 1 to 200 m 2 in the range, more preferably in the range from 10 to 150 m 2 and are used with a catalyst loading in the range from 0.01 to 3 kg / L / h, more preferably in the range from 0.1 to 1 kg / L / h.

[0048] The catalytic deprotection of N - formyl - protected amines according to the invention is carried out in the presence of water at a temperature in the range of 10 °C to 300 °C, preferably in the range of 25 °C to 270 °C, more preferably in the range of 50 °C to 250 °C, and particularly preferably in the range of 100 °C to 230 °C, and at a pressure preferably in the range of 0.1 to 300 bara, more preferably in the range of 0.5 to 200 bara, and particularly preferably in the range of 1 to 150 bara. In a specific embodiment, the method of the invention can be carried out at ambient pressure.

[0049] The catalytic deprotection of N - formyl - protected amines according to the invention is carried out in the presence of water, and preferably the weight ratio of water to the N - formyl - protected amine is in the range of 0.1:1 to 100:1, more preferably 1:1 to 50:1, and particularly preferably 2:1 to 20:1.

[0050] As used herein, the term "alkyl" refers to a straight - chain, branched - chain or cyclic hydrocarbon group without any heteroatoms and is preferably saturated, such as an ethyl residue. As used herein, the term "aryl" refers to a hydrocarbon group without any heteroatoms but optionally substituted by one or more alkyl groups, such as a phenyl residue or a tolyl residue. As used herein, the term "arylalkyl" refers to a residue containing an aryl group, the aryl of which is connected to the rest of the molecule via an alkyl chain having at least one carbon atom, such as a benzyl residue. As used herein, the term "heteroatom" refers to any atom other than a carbon atom or a hydrogen atom.

[0051] The method of the invention can be carried out continuously, semi - continuously (semi - batch) or discontinuously (batch). A continuous method is preferred.

[0052] Preferably, in step a) of the method according to the invention for manufacturing an amino alcohol compound of formula II starting from an N - formyl - protected aminonitrile compound of formula III, the homogeneous transition metal catalyst is a coordination complex composed of a ligand and one or more ruthenium coordination centers. In addition, the homogeneous transition metal catalyst preferably contains at least one tridentate ligand having 3 phosphine atoms. Preferably, the tridentate ligand is a ligand of formula IV or V,

[0053]

[0054] Wherein A is a trivalent alkyl group having 1 to 10 carbon atoms, each Q is independently a divalent alkyl group having 1 to 10 carbon atoms, and each R3 is independently an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms or an arylalkyl group having 6 to 12 carbon atoms. Preferably, the A residue is a trivalent alkyl group having 1 to 10 carbon atoms. Preferably, the Q residue is a divalent alkyl group having 1 to 6 carbon atoms, and preferably the two Q residues of the tridentate phosphine of formula V are the same. Preferably, the R3 residue is an aryl group having 6 to 10 carbon atoms, and preferably all R3 residues of the toothed phosphine of formula IV or V are the same. Particularly preferably, such tridentate phosphine ligands are selected from the group consisting of: 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos), 1,1,1-tris(bis(3,5-dimethylphenyl)phosphinomethyl)ethane (triphos-xyl), 1,1,1-tris(bis(o-tolyl)phosphinomethyl)ethane (triphos-tol), and bis(2-diphenylphosphinoethyl)phenylphosphine (dppepp). The most preferred obligatory ligand of the homogeneous transition metal catalyst is 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos). In addition to such tridentate ligands, the homogeneous transition metal catalyst comprises one or more additional ligands, preferably selected from the group consisting of: triphenylphosphine (TPP), bis(diphenylphosphine)ethane (dppe), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (xanthphos), Cl−, H−, CN - , acetoacetate, methallyl, 1,5-cyclooctadiene, and CO. Particularly preferred additional ligands are Cl - and H - . Particularly preferred transition metal catalysts comprise no more than one CO ligand, more preferably no CO ligand among the additional ligands. Particularly preferred homogeneous transition metal catalysts for step a) of the process for manufacturing an amino alcohol compound of formula II are selected from the group consisting of: [Ru2(Triphos)2(μ-Cl3)]Cl, [Ru2(μ-Cl3)(triphos)]Cl, [Ru(triphos)(CO)(H)2], and [Ru(triphos)(methallyl)].

[0055] The homogeneous transition metal catalysts of the present invention can be prepared by contacting a precursor containing a transition metal (ruthenium) with the desired ligand. Suitable precursors are ruthenium salts, preferably chloride salts, in which the ruthenium cation is complexed with the desired ligand, or different ruthenium complexes (such as commercially available complexes) in which the original ligand is at least partially replaced by the desired ligand through a ligand substitution reaction.

[0056] The homogeneous transition metal catalyst of the present invention can be prepared by a separate method or in situ within step a), for example, by adding a Ru-containing precursor RuCl3 x 3H2O and the ligand 1,1,1-tris(diphenylphosphinomethyl)ethane to the reaction mixture of step a).

[0057] The reductive hydrolysis of step a) is preferably carried out at a temperature in the range of 20 °C to 200 °C, more preferably 50 °C to 180 °C, and especially 100 °C to 170 °C. The hydrogen pressure used in this step a) is preferably in the range of 0.1 to 400 bar, more preferably 5 to 200 bar, especially 5 to 80 bar. The reductive hydrolysis of step a) is carried out in the presence of water. Preferably, based on the total reaction mixture, the water content in the reaction mixture of step a) is in the range of 1% to 50% by weight, more preferably in the range of 1% to 30% by weight, and most preferably in the range of 1% to 20% by weight. Preferably, the reductive hydrolysis of step a) is carried out in the presence of a solvent such as an ether, an alcohol or an amide. It is preferred to use a solvent having a relatively high boiling point, for example, a boiling point higher than that of the amino alcohol compound of formula I produced by the method of the present invention.

[0058] The steps of the method of the present invention can be carried out in a batch method or in a continuous method, and each such step is carried out in a single reactor or in a set of two or more continuous reactors.

[0059] Examples

[0060] The N-formyl protected amine functional group of N-(1-hydroxy-2-methyl-propan-2-yl)formamide is cleaved by catalytic decomposition of the formyl group into carbon dioxide and hydrogen, resulting in the formation of 2-amino-2-methyl-1-propanol.

[0061] A solution of 15 g of N-(1-hydroxy-2-methylpropan-2-yl)formamide in 38.3 g of water and 50 g of tetraethylene glycol dimethyl ether (a solution with 15% by weight of formyl-protected amine) was continuously pumped through an oil-heated (220 °C) tubular reactor equipped with 23 mL (16.7 g) of a heterogeneous palladium-based dehydrogenation catalyst (0.75% by weight, palladium on alumina spheres, BASF SE). The pressure inside the reactor was controlled at 20 bar absolute by a RECO valve. Quantitative analysis of the reactor effluent by gas chromatography showed a 9.95% content of 2-amino-2-methyl-1-propanol and a 0.6% content of N-(1-hydroxy-2-methylpropan-2-yl)formamide. This corresponds to a conversion of 96% and a chemical yield of 87%. At a catalyst volume of 23 mL and an amount of N-(1-hydroxy-2-methylpropan-2-yl)formamide applied to the reactor of 5.7 g / h, a space-time yield of 0.25 kg / L / h was achieved.

Claims

1. A method for converting an N - formyl - protected amine to the corresponding deprotected amine, characterized by deprotecting the N - formyl - protected amine by decomposing the formyl group into carbon dioxide and hydrogen in the presence of water and a dehydrogenation catalyst and at a temperature in the range of 10 °C to 300 °C.

2. The method according to claim 1, wherein, The dehydrogenation catalyst is a heterogeneous catalyst having an active material selected from the group consisting of: Pt, Pd, Rh, Ru, Ag, Au, Cu, Ni, Co, Fe, Cr, Mo, W, and V, in metallic form or as a compound, including mixtures of such active materials.

3. The method according to claim 2, wherein The heterogeneous dehydrogenation catalyst has the active material provided on a support material selected from the group consisting of: activated carbon, alumina, titanium dioxide, zirconium dioxide, silica, niobium oxide, vanadium oxide, or mixtures thereof.

4. The method according to any one of claims 1 to 3, wherein The weight ratio of water to the N - formyl - protected amine is in the range of 0.1:1 to 100:

1.

5. The method according to any one of claims 1 to 4, wherein The deprotection of the N - formyl - protected amine is carried out without the addition of hydrogen.

6. The method according to any one of claims 1 to 5, wherein The N - formyl - protected amine is an N - formyl - protected aliphatic primary amine having one or more hydroxyl groups at the 2 - (β), 3 - (γ), or 4 - (δ) position relative to the carbon atom bearing the N - formyl (1 - position).

7. The method according to any one of claims 1 to 5, wherein, The N - formyl - protected amine is an N - formyl - protected aliphatic primary amine having one or more hydroxyl groups at the 2 - (β) position relative to the carbon atom bearing the N - formyl.

8. The method according to any one of claims 1 to 5, wherein, The N - formyl - protected amine is an N - formyl - protected amino - alcohol compound of formula I, wherein R1 and R2 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms.

9. A method for manufacturing an amino - alcohol compound of formula II wherein R1 and R2 are each independently hydrogen or an alkyl group having 1 to 4 carbon atoms, The method comprises the following steps a) Applying hydrogen to a reaction mixture comprising an N - formyl - protected amino - nitrile compound of formula III, a homogeneous transition - metal catalyst, and water to convert at least part of the compound of formula III to the corresponding N - formyl - protected amino - alcohol compound of formula I, a1) Optionally separating at least part of the N - formyl - protected amino - alcohol compound of formula I produced in step a) from the remainder of the reaction mixture of step a), and b) Converting the N - formyl - protected amino - alcohol compound of formula I produced in step a) or the purified N - formyl - protected amino - alcohol compound of formula I produced in optional step a1) to the corresponding deprotected amino - alcohol of formula II according to the method of claim 8.

10. The method according to claim 9, wherein, The purification in step a1) is mandatory.

11. The method according to claim 10, wherein, The purification in step a1) includes separating any remaining hydrogen from step a).

12. The method according to any one of claims 9 to 11, wherein, The residues R1 and R2 are both methyl.

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