HK1115867A - Process for the preparation of 1-aminopiperidine derivatives - Google Patents

Description

Process for preparing 1-aminopiperidine derivatives

The invention relates to a method for producing compounds of general formula (I)

Hydrazine derivatives of formula (I) are valuable intermediates for the preparation of biologically active molecules. Thus, the compounds of the general formula (I) are used for the synthesis of CB₁Antagonists, e.g. Rimonabant^®(EP 656354; Shim et al, J.Med.chem.2002, 45, 1447-.

For example, the preparation of 1-aminopiperidine is well known to those skilled in the art. Thus, Auelbekov et al and Seebach et al propose the reduction of 1-nitroso-piperidines to amino derivatives in the presence of Zn/AcOH (Khimiko-Farmatseviskii Zhurnal, 1985, 19, 829-32; Synthesis, 1979, 6, 423-4). Jain et al describe the reaction of piperidine with chloramine to produce the corresponding hydrazine derivative (Proceedings-Indian academic of Science, chemical sciences1985, 95, 381-9).

The synthetic routes proposed above only allow the preparation of the envisaged compounds using chemicals which cannot be applied on an industrial scale without the measures of special protection devices. The use of Zn/acetic acid mixtures as reducing agents is disadvantageous in view of the heterogeneity of the reaction and the necessity to use an excess of Zn in the reaction. The work-up of the reaction batch is generally complicated. 1-nitrosopiperidine is a very strong carcinogen and its disposal also poses major technical problems. Although chloramine is a widely used agent for disinfecting drinking water, its use in concentrated form is also problematic for industrial safety. Special safety precautions must be taken to avoid plant and environmental pollution by the gases, since at higher concentrations it is harmful to the lungs.

It is therefore an object of the present invention to provide an alternative process for preparing compounds of the general formula (I). In particular, the process is advantageous for large scale applications compared to prior art processes. Moreover, the process can be carried out in a chemical plant without great expenditure and is superior to the known processes from an economic and ecological point of view.

The object of the invention is achieved according to the claims.

As a result, the above objects are extremely surprisingly achieved in the process for preparing the compounds of the general formula (I) described below, but with advantages not inferior to those described above,

wherein

n can be 0, 1,

p can be 0, 1, 2, 3,

x may be CR¹R¹、O、NR²、NR¹、S，

R¹Independently of one another, may be H, (C)₁-C₈) Alkyl radicals, (C)₁-C₈) -alkoxy, (C)₁-C₈) Alkoxyalkyl (C)₃-C₈) -cycloalkyl, (C)₆-C₁₈) -aryl, (C)₇-C₁₉) Aralkyl, (C)₃-C₁₈) -heteroaryl, (C)₄-C₁₉) -heteroarylalkyl, ((C)₁-C₈) -alkyl groups)_1-3-(C₃-C₈) -cycloalkyl, ((C)₁-C₈) -alkyl groups)_1-3-(C₆-C₁₈) Aryl, ((C)₁-C₈) -alkyl groups)_1-3-(C₃-C₁₈) -a heteroaryl group,

R²is H or an N-protecting group which can be cleaved under acidic or basic conditions,

the process starts from a dicarbonyl compound of the general formula (II),

x, R therein¹N, p may have the above-mentioned meanings,

reacting the compound of formula (II) with one equivalent of a hydrazine derivative of the general formula (III),

wherein R is²Is an N-protecting group which can be cleaved under acidic or basic conditions,

the compound formed is subsequently hydrogenated in the presence of a transition metal, and the radical R is optionally carried out under acidic or basic conditions²Dissociation of (3). The process according to the invention can be used starting from the dicarbonyl compounds described above to>Hydrazine derivatives of general formula (I) were prepared in 76% yield.

In principle, the person skilled in the art can use all starting compounds of the general formulae (II) or (III) which he wants to obtain for the above synthesis within the scope of the invention. Here, he himself judges on the basis of the reactivity of the compounds used, preferably those which are capable of participating in the reaction but are inert under the reaction conditions, so that the production of by-products is suppressed as much as possible during the reaction. With respect to the parameter n, those compounds of the formula (II) which form a five-or six-membered ring are preferably selected by the person skilled in the art. The parameter p is preferably 0. Advantageously, the X group is CH₂Or O. In a preferred embodiment, R¹Is H, (C)₁-C₈) -alkyl or (C)₆-C₁₈) -an aryl group. R²Is an N-protecting group such as formyl, acetyl, propionyl, benzoyl, arylcarbonyl, aralkylcarbonyl or alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Z, Boc, phenoxycarbonyl.

Very particular preference is given to processes in which compounds of the formula (II) or (III) in which n ═ 1, p ═ 0, X ═ CH₂，R²Is acetyl orA methoxycarbonyl group.

For the hydrogenation reaction, the skilled person can use transition metals suitable for this purpose. These transition metals used in the hydrogenation reaction may be in the form of known homogeneous soluble transition metal complexes containing metals such as Ru, Rh, Pt, Pd as central atoms or in the form of heterogeneous soluble and optionally supported transition metals. Transition metal complexes which are preferably used can be found in the literature (Katalytische Hydriierung im Organisch-Chemischen Laboratoriaum [ catalytic hydrogenation in organic chemistry laboratories ]]Zymalkowski, Ferdinand Enke VerlagStuttgart, 1965). Very particular preference is given to using those catalysts which contain Pt or Pd. A very particularly preferred heterogeneously soluble transition metal as catalyst is Pd/C, PtO₂、Pt/C。

The hydrogenation reaction mentioned can be carried out using H₂The hydrogenation of the gas is carried out or as a transfer hydrogenation. These methods are likewise known to the person skilled in the art ("Asymmetric transfer hydrogenation of the C ═ O and C ═ N bonds", M.Wills et al, Tetrahedron: Asymmetry1999, 10, 2045; "Asymmetric transfer hydrogenation by chiral ruthenium complexes" R.Noyori et al, Acc.chem.Res.1997, 30, 97; "Asymmetry catalyst in organic Synthesis", R.Noyori, John Wiley&Sons, new york, 1994, 123; "Transition Metals for Organic Synthesis", M.Beller, C.Bolm, ed.Wiley-VCH, Weinheim, 1998, Vol.2, 97; "Comprehensive asymmetry catalvis", Jacobsen, E.N., Pfaltz, A., Yamamoto, H. ed., Springer-Verlag, 1999). The hydrogen pressure for the reaction of the present invention can be arbitrarily selected by those skilled in the art. Preference is given to pressures of from 1 to 100 bar, more preferably from 1 to 50 bar and very particularly preferably from 1 to 30 bar. Particularly preferably from 1 to 20 bar.

The transition metal complexes mentioned are used in the reaction in amounts of from 0.1 to 10 mol%, based on the compound (II). The amount is preferably from 0.5 to 7.5 mol%, more preferably from 1.0 to 5.0 mol% and very particularly preferably from 2.0 to 3.0 mol%. The person skilled in the art will, in itself, select the amount to be used in view of the reaction economy, which means: as little expensive catalyst as possible is used, while the yield is as optimal as possible.

Cleavage of the protecting group R2 is optionally carried out. This is preferably carried out in an acidic or basic aqueous solution. For this purpose, inorganic acids are more advantageously dissolved in water or solutions of inorganic bases in water are used to cleave protecting groups. According to the invention, an "aqueous solution" refers to a homogeneous aqueous solution (>50 mol%) of an inorganic acid or an inorganic base as the main component of the mixture. Suitable inorganic acids are, in particular, acids such as hydrochloric acid, sulfuric acid or phosphoric acid. The inorganic base may be selected from alkali metal carbonates, alkali metal hydroxides, especially lithium hydroxide, sodium hydroxide and potassium hydroxide.

The temperature during the reaction may be between RT and 140 ℃. Temperatures of 80 ℃ to 140 ℃ are preferably set, particularly preferably temperatures of 100 ℃ to 130 ℃.

The person skilled in the art is free to choose whether he wishes to carry out the individual reaction steps sequentially or together in one pot. However, preference is given to processes in which the reaction of the compound of the formula (II) with the compound of the formula (III) and the hydrogenation of the compounds formed therefrom is carried out as a one-pot reaction. Optionally, the entire reaction can also be carried out in one pot. According to the invention, the overall reaction here refers to the preparation of the compounds of the general formula (III), the reaction of the compounds of the general formula (III) with the compounds of the general formula (II), the hydrogenation of the intermediates formed, and optionally the cleavage of the N-protecting group (cf. example 2). The compounds of the general formula (I) are thus obtained in a simple manner and this is particularly easy to carry out on an industrial scale.

Suitable solvents for the reaction according to the invention are essentially water, alcohols, ethers or mixtures thereof. Preference is given to using water in the presence of an alcohol (methanol or ethanol). The reaction can be carried out homogeneously as a single phase or in two phases, however homogeneous processes are preferred. Work-up of the reaction mixture is carried out by distillation, extraction and/or crystallization of the product of the formula (III) according to methods known to the person skilled in the art.

The invention also relates to intermediate compounds of the general formula (V).

In these intermediate compounds, n is 0, 1, p may be 0, 1, 2, 3, and X may be CR, as described above for the compounds of formula (I)¹R¹、O、NR²、NR¹、S，R¹Is H, (C)₁-C₈) Alkyl radicals, (C)₁-C₈) -alkoxy, (C)₁-C₈) Alkoxyalkyl (C)₃-C₈) -cycloalkyl, (C)₆-C₁₈) -aryl, (C)₇-C₁₉) Aralkyl, (C)₃-C₁₈) -heteroaryl, (C)₄-C₁₉) -heteroarylalkyl, ((C)₁-C₈) -alkyl groups)_1-3-(C₃-C₈) -cycloalkyl, ((C)₁-C₈) -alkyl groups)_1-3-(C₆-C₁₈) Aryl, ((C)₁-C₈) -alkyl groups)_1-3-(C₃-C₁₈) -heteroaryl, R²Is H or an N-protecting group which can be cleaved under acidic or basic conditions.

Very particular preference is given to the following compounds:

the reaction according to the invention can be carried out, for example, by reacting an aqueous solution of a dicarbonyl compound (II), for example glutaraldehyde, with a compound of the general formula (III), for example acetohydrazide. The aqueous (glutaraldehyde) solution is treated with compound (II) optionally dissolved in a solvent such as ethanol and added to the autoclave in the presence of a catalyst (e.g. 5% Pd/C). After the hydrogenation at 20 bar hydrogen pressure and a temperature of 80 ℃ the reaction is generally complete after 1 hour. The compound of the general formula (III) obtained, in this case 1-acetamidopiperidine, can be worked up in a manner known to the person skilled in the art and isolated by distillation.

Subsequently, the cleavage of the N-protecting group can be carried out as described. The work-up of the formed dissociation solution is preferably carried out by separating the phases and extracting the reaction mixture with a suitable organic solvent suitable for this purpose for the person skilled in the art. These phases are then combined, from which R is separated off, for example by distillation²Compounds of general formula (III) as H. Overall yield of the reactions described herein>76％。

The following reaction scheme again illustrates the process:

(C₁-C₈) Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, and all bonding isomers thereof. It can be (C)₁-C₈) Haloalkyl, OH, halogen, NH₂Mono-or polysubstituted.

(C₁-C₈) Alkoxy is (C) bonded to the molecule under consideration via an oxygen atom₁-C₈) -an alkyl group.

(C₁-C₈) The alkoxyalkyl radical being (C) containing an oxygen atom₁-C₈) -an alkyl group.

(C₃-C₈) Cycloalkyl is intended to mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

(C₆-C₁₈) Aryl means an aromatic radical having 6 to 18C atoms. In particular, groups (compounds) such as phenyl, naphthyl, anthryl, phenanthryl, biphenyl are included. It can be (C)₁-C₈) -alkoxy, (C)₁-C₈) Haloalkyl, OH, halogen, NH₂、S-(C₁-C₈) -alkyl mono-or polysubstituted.

(C₇-C₁₉) -aralkyl is through (C)₁-C₈) -alkyl bonded to molecule (C)₆-C₁₈) -an aryl group.

(C₁-C₈) Haloalkyl is (C) substituted by one or more halogen atoms₁-C₈) -an alkyl group. Possible halogen atoms are in particular chlorine and fluorine.

In the context of the present invention, (C)₃-C₁₈) Heteroaryl is a five-, six-or seven-membered aromatic ring system of 3 to 18C atoms, which contains heteroatoms such as nitrogen, oxygen or sulfur in the ring. Said heteroaryl is, in particular, for example, 1-, 2-, 3-furyl, 1-, 2-, 3-pyrrolyl, 1-, 2-, 3-thienyl, 2-, 3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, 5-imidazolyl, acridinyl, quinolinyl, phenanthridinyl, 2-, 4-, 5-, 6-pyrimidinyl. These radicals may be substituted by (C)₁-C₈) -alkoxy, (C)₁-C₈) Haloalkyl, OH, halogen, NH₂、NO₂、SH、S-(C₁-C₈) -alkyl mono-or polysubstituted.

(C₄-C₁₉) By heteroaralkyl is meant a radical corresponding to (C)₇-C₁₉) -heteroaromatic systems of aralkyl groups.

Halogen is fluorine, chlorine, bromine, iodine.

The N-protecting group is defined according to the invention as follows. It may be arbitrarily selected as long as the group contains a carbonyl functional group and is bonded to a nitrogen atom via the carbonyl group. Such Groups are well known to those skilled in the art (Greene, T.W., Protective Groups in Organic Synthesis, J.Wiley & Sons, 1981). In particular, in the context of the present invention, it is understood that it is selected from the following groups: formyl, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, Z, Fmoc, phthaloyl.

In the context of the present invention, there are a plurality of radicals R present in the molecule¹In this case, each may be different.

Experimental part

Procedure

280.4g (1.4mol) of aqueous glutaraldehyde (50% by weight in water) and 115.2g (1.4mol) of solid acetohydrazide are dissolved in 1400ml of ethanol and stirred for 30 minutes at RT. The solution was charged to a 2L autoclave and treated with 14.0g of commercially available wet Pd/C (5%). A hydrogen pressure of 20 bar was set and the mixture was then hydrogenated at 80 ℃. After about 4-5h the necessary amount of hydrogen was absorbed, the reaction mixture was cooled to RT and the autoclave was depressurized. The catalyst is filtered off. The filtrate was distilled in vacuo to remove ethanol. To completely remove the ethanol, water was added again and distilled again. Under argon, 252.0g (6.3mol) of solid NaOH were added. The reaction mixture was refluxed at a temperature of 128-130 ℃ for 4 h. The agitator was turned off. The product is deposited as an oil phase. The oil phase is separated off and distilled at 100-50 mbar and a bath temperature of 90 ℃.

Yield: 125.7g of product having a water content of 6.85% by weight. This corresponds to 117.1g of 100% strength product-83.5% of theory-NMR OK.

One-pot method scheme

Procedure

A solution of 1mol of ethyl acetate and 1mol of hydrazine hydrate is refluxed for 10 h. The mixture was cooled to 50 ℃ and 1mol of an aqueous glutaraldehyde solution was added. After addition of 3 mol% Pd/C (5%), flushing with nitrogen, closure of the autoclave and injection of 20 bar of hydrogen. The mixture was heated to 80 ℃ and hydrogenated under a constant hydrogen pressure of 20 bar. The reaction was complete after 2 h. The mixture was cooled to RT, reduced pressure and the catalyst was filtered off. The filtrate was distilled under vacuum to reduce the amount of ethanol, and then 4.5mol of concentrated sodium hydroxide solution was added. The mixture was refluxed for 4 h. After cooling to RT, the work-up was carried out as described above. Yield: 75 percent of

Procedure

1081.1g (5.4mol) of aqueous glutaraldehyde (50% by weight in water) and 486.0g (5.4mol) of methyl carbazate were dissolved in 10L of ethanol. During this time, the reaction mixture was heated to 50 ℃. Stirred at the same temperature for 30 minutes. The reaction mixture was charged into a 20L autoclave. 150g of wet Pd/C (5%) catalyst were added and the reaction mixture was hydrogenated at 80 ℃ and 20 bar of hydrogen. After 8h, the absorption of hydrogen was complete. The autoclave was cooled to RT and depressurized. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was dried under vacuum at 50 ℃ overnight.

Yield: 821.8g (98.7% of theory); 1-methoxycarbonyl-piperidines

Procedure

216g (1.4mol) of 1-methoxycarbonylpiperidine are hydrolyzed in 500ml of 48% strength NaOH over a period of 5 h. After the stirrer was switched off, the phases were separated and the organic phase was distilled under vacuum (100-50 mbar; 85-90 ℃).

Yield: 112g (80%).

Claims (10)

1. A process for the preparation of a compound of formula (I),

wherein

n can be 0, 1,

p can be 0, 1, 2, 3,

x may be CR¹R¹、O、NR²、NR¹、S，

R¹Independently of one another, may be H, (C)₁-C₈) Alkyl radicals, (C)₁-C₈) -alkoxy, (C)₁-C₈) Alkoxyalkyl (C)₃-C₈) -cycloalkyl, (C)₆-C₁₈) -aryl, (C)₇-C₁₉) Aralkyl, (C)₃-C₁₈) -heteroaryl, (C)₄-C₁₉) -heteroarylalkyl, ((C)₁-C₈) -alkyl groups)_1-3-(C₃-C₈) -cycloalkyl, ((C)₁-C₈) -alkyl groups)_1-3-(C₆-C₁₈) Aryl, ((C)₁-C₈) -alkyl groups)_1-3-(C₃-C₁₈) -heteroaryl, R²Is H or an N-protecting group which can be cleaved under acidic or basic conditions,

the process starts from a dicarbonyl compound of the general formula (II),

x, R therein¹N, p may have the above-mentioned meanings,

reacting the compound of formula (II) with one equivalent of a hydrazine derivative of the general formula (III),

wherein R is²Is an N-protecting group which can be cleaved under acidic or basic conditions,

the resulting compound is subsequently hydrogenated in the presence of a transition metal and R is optionally dissociated under acidic or basic conditions²。

2. A process according to claim 1, characterized in that a compound of formula (II) or (III) is used, wherein n ═ 1, p ═ 0, and X ═ CH₂，R²Acetyl or methoxycarbonyl.

3. The process as claimed in one or more of the preceding claims, characterized in that the transition metal used is a Pt-or Pd-containing compound.

4. The process according to one or more of the preceding claims, characterized in that said hydrogenation reaction uses H₂Gas or as a transfer hydrogenation reaction.

5. The process as claimed in one or more of the preceding claims, characterized in that the transition metal complex is used in an amount of from 0.1 to 10 mol%, based on the amount of compound (II).

6. The process according to one or more of the preceding claims, characterized in that for the radical R²The dissociation of (2) is carried out using a solution of an inorganic acid in water or a solution of an inorganic base in water.

7. The process according to one or more of the preceding claims, with the proviso that the process involves a hydrogenation reaction using hydrogen, characterized in that the hydrogenation reaction is carried out at a pressure of 1 to 20 bar.

8. The process according to one or more of the preceding claims, characterized in that it is carried out between RT and 140 ℃.

9. Process according to claim 1 and/or 2, characterized in that the reaction of the compound of formula (II) with the compound of formula (III) and the hydrogenation of the compound formed are carried out in a one-pot reaction.

10. An intermediate compound of formula (V)

Wherein

m, n independently of one another can be 0, 1, 2 or 3, where n and m cannot simultaneously be 0,

p can be 0, 1, 2, 3,

x may be CR¹R¹、O、NR²、NR¹、S，

R¹Independently of one another, may be H, (C)₁-C₈) Alkyl radicals, (C)₁-C₈) -alkoxy, (C)₁-C₈) Alkoxyalkyl (C)₃-C₈) -cycloalkyl, (C)₆-C₁₈) -aryl, (C)₇-C₁₉) Aralkyl, (C)₃-C₁₈) -heteroaryl, (C)₄-C₁₉) -heteroarylalkyl, ((C)₁-C₈) -alkyl groups)_1-3-(C₃-C₈) -cycloalkyl, ((C)₁-C₈) -alkyl groups)_1-3-(C₆-C₁₈) Aryl, ((C)₁-C₈) -alkyl groups)_1-3-(C₃-C₁₈) -a heteroaryl group,

R²is H or an N-protecting group which can be cleaved under acidic or basic conditions.