HK1087111B - Process for the preparation of nicotinaldehydes - Google Patents

Description

Process for preparing nicotinaldehydes

The present invention relates to a process for the preparation of nicotinaldehydes by reduction of the corresponding nicotinic acid morpholinamides.

Nicotinaldehydes are important intermediates or end products in industrial organic chemistry. Appropriately substituted derivatives, such as arylnicotinaldehydes, are in particular important intermediates for the synthesis of high value-added end products, or are themselves such end products, in particular for crop protection, for example fungicides, insecticides, herbicides or pesticides, or for the preparation of highly pharmaceutically active substances. Thus, economic methods for large scale production of these compounds have been of interest.

Aldehydes are generally difficult to obtain as unstable oxidation states between alcohols and carboxylic acids. Aromatic aldehydes are particularly susceptible to oxidation to the corresponding carboxylic acids or disproportionation under basic conditions to yield alcohols and carboxylic acids. In the reductive preparation of nicotinaldehyde derivatives, the reduction of dihydropyridines takes place as an additional side reaction. There are preparation methods known from the literature which describe the selective reduction of carboxylic acid derivatives up to the aldehyde stage. These processes generally require cooling of the reaction mixture in order to minimize over-reduction. Specific methods for reducing nicotinic acid derivatives are also known. Thus, for example, DE-A10005150 describes a process for preparing 5-arylnicotinaldehydes by reducing the corresponding 5-arylnicotinic acids by means of catalytic hydrogenation.

The reduction of nicotinamide by lithium aluminum hydride is described in j.am.chem.soc.81, p.502(1959) by h.c.brown and a.tsukamoto. However, low reaction temperatures are described as indispensable here, the yields being below 90% of theory. Other known methods for preparing nicotinaldehydes by reduction are shown below.

No.	Number of reaction steps	Nicotinic acid derivatives	Reducing agent	Reaction conditions	Yield of	Literature
							1	2	Diethyl amides	Cp2Zr(H)Cl	Room temperature 15min	99％	J.Am.Chem.Soc.48(2000)11995-11996
2	3	Nitrile	DiBAH (diisobutylaluminum hydride)	Toluene-50 deg.C for 2.5hr	96％	J.Org.Chem.64，26(1999)9658-9667
							3	3	Nitrile	K pentyl- (9) -borabicyclononane	THF 25℃	96％	Tetrahedron Letters30，28(1989)3677-3680
4	3	Nitrile	DiBAH	Toluene-12 deg.C	70％	J.Med.Chem.36，8(1993)953-966
							5	2	Hydrazides	NaIO4	water/NH3	70％	J.Am.Chem.Soc.74(1952)5796
6	3	N-formanilide	LiAlH4	THF 0℃	65％	Angew.Chemie 65(1953)525
							7	3	Nitrile	DiBAH	THF 0℃	62％	J.Med.Chem.35，21(1992)3784-3791
8	3	Sulphonylhydrazide	Na2CO3	Ethylene glycol at 160 DEG C	61％	J.Am.Chem.Soc.80(1958)862
							9	3	Nitrile	DiBAH	THF	61％	J.Med.Chem.34，9(1991)2922-2925
10	2	Primary amides	LiAlH(NEt2)3	Room temperature 12hr	53％	THL 32，41(1991)6903-6904
							11	2	N-methoxy-N-methylamides	DiBAH	THF-100℃	51％	Heterocycles 53(2000)2183-2190

It can be seen that the known processes either require expensive reagents (examples No.1, 3, 10), use starting materials which are not available in industrial quantities (examples No.1, 3, 11), can only be carried out with nitriles which themselves have to be prepared in three steps (examples No.2, 3, 4, 7, 9), or require low temperatures (examples No.2, 4, 11). From a yield point of view, only examples No.1, 2 and 3 are economically valuable. If reagent costs are considered, only the process of example No.2 is feasible. However, the latter requires three reaction steps starting with nicotinic acid and relies on the maintenance of low temperatures.

Surprisingly, the inventors of the present patent application have now found that nicotinaldehydes can be obtained by reduction under standard conditions (room temperature, atmospheric pressure) with virtually quantitative yields if the starting material employed is the corresponding morpholinamide. The morpholine amides of nicotinic acid and its derivatives are previously unknown aldehyde precursors.

The invention thus relates to a process for preparing nicotinaldehydes, characterized in that the starting material used for the reduction is the corresponding morpholinamide. The process is preferably carried out at room temperature and without pressure (at atmospheric pressure).

The reducing agents preferred according to the invention are lithium aluminum alkoxides hydride which contain one to three alkoxy groups. The general formula is LiAlH_(4-n)(OR)_nWherein n may be 1, 2 or 3. Suitable groups are straight or branched chain aliphatic groups such as methyl, ethyl and t-butyl. In particular, LiAlH (OEt) is chosen₃The reduction was successful. Also suitable as reducing agents for the preparation process according to the invention are the rather inexpensive LiAlH₃(OEt)。

In a preferred embodiment, nicotinic acid morpholinamides of the formula I

Wherein

R¹’、R¹"each independently of the other denotes H, Hal, A, OA, CH₂R²Or Ar, in the presence of a catalyst,

R²represents OA or NA₂，

A represents an unbranched or branched alkyl radical having 1 to 10C atoms, in which one or two CH' s₂A group may be replaced by an O or S atom and/or a-CH ═ CH-group and/or 1 to 7H atoms may be replaced by F,

ar represents an unsaturated, partially or fully saturated, mono-or polycyclic, carbocyclic or heterocyclic ring system containing the heteroatom O, N, S, which is unsubstituted or substituted by Hal, A, OA, NA₂、NO₂、NASO₂A、SO₂NA、SO₂A is mono-or polysubstituted, and

hal represents F, Cl, Br or I,

reduced as a starting material to nicotinaldehydes of formula II

Here, the above groups preferably have the following meanings:

R¹’、R¹"each independently of the other denotes H, Hal, A, OA, CH₂R²Or Ar, wherein A, Ar, Hal and R²Has one of the following meanings. R¹’、R¹"is especially hydrogen, methoxy, ethoxy, propoxy, butoxy, fluorine, chlorine, bromine, iodine, phenyl or o-, m-or p-substituted phenyl. R¹' particularly preferably p-fluorophenyl or bromo, R¹"while hydrogen.

Hal represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

R²Represents OA or NA₂Wherein A has the meaning indicated above and below.

A represents an alkyl group, unbranched (linear) or branched, having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10C atoms.

A preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1, 2-, 1, 3-, 2, 2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1, 2, 2-trimethylpropyl, furthermore, for example, trifluoromethyl is preferred.

A very particularly preferably represents alkyl having 1 to 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1-trifluoroethyl.

Furthermore, a represents cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 2, 6, 6-trimethylbicyclo [3.1.1] heptyl, but likewise mono-or bicyclic terpenes, preferably p-menthane, menthol, pinane, bornane or camphor, including each of the known stereoisomeric forms, or adamantyl. As far as camphor is concerned, it means L-camphor and D-camphor.

Ar represents an unsaturated, partially or fully saturated, mono-or polycyclic, carbocyclic or heterocyclic ring system containing the heteroatom O, N, S, which is unsubstituted or substituted by Hal, A, OA, NA₂、NO₂、NASO₂A、SO₂NA、SO₂A is mono-or polysubstituted. Preferred ring systems are unsubstituted or substituted phenyl, naphthyl or biphenyl, particularly preferably phenyl, o-, m-or p-tolyl, o-, m-or p-cyanophenyl, o-, m-or p-methoxyphenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, furthermore preferably 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-difluorophenyl, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dichlorophenyl, 2, 3-, 2, 4-, 2, 5-, alpha-hydroxyphenyl, phenylthio, o-, m-or p-bromophenyl, o-, m-cyanophenyl, o-, 2, 6-, 3, 4-or 3, 5-dibromophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl.

Particularly preferred starting materials for the aldehyde synthesis according to the invention are 5- (4-fluorophenyl) nicotinic acid morpholinamide and 5-bromonicotinic acid morpholinamide.

The invention therefore also relates to the use of nicotinic acid morpholinamides, preferably 5- (4-fluorophenyl) nicotinic acid morpholinamide or 5-bromonicotinic acid morpholinamide, for preparing the corresponding nicotinaldehydes.

The invention furthermore relates to 5- (4-fluorophenyl) nicotinic acid morpholinamides and 5-bromonicotinic acid morpholinamides as starting materials for the synthesis according to the invention.

The reaction according to the invention is generally carried out in an inert solvent. Examples of inert solvents suitable for the above reaction are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol dimethyl ether (diglyme); or a mixture of said solvents. Ethers, especially tetrahydrofuran, are particularly preferred.

The amount of solvent is not critical and in general from 5g to 500g, preferably from 10g to 100g, of solvent may be added per g of starting material.

Depending on the conditions used, the reaction temperature of the above-mentioned reaction is between about-10 ℃ and 200 ℃, generally between-10 ℃ and 100 ℃, in particular between 0 ℃ and 50 ℃, but preferably between 10 ℃ and 40 ℃, particularly preferably at room temperature.

Depending on the conditions used, the reaction time is between a few seconds and several hours, preferably between 1 minute and 3 hours. However, the reaction according to the invention will generally be very complete after 0.1 to 1.5 hours.

For the purposes of the present invention, "conditions used" are intended to indicate the substitution pattern of nicotinic acid morpholinamide, the type and amount of solvent, the type and amount of reducing agent, the duration of the reaction, the reaction temperature and further details of the reaction carried out, for example the stirrer speed of the reaction vessel or other attributes.

In general, the end of the reduction of the aldehyde of the invention is determined by a suitable analytical method, such as thin layer chromatography or HPLC, terminating the reduction.

After removal of the solvent by means of conventional work-up steps, for example addition of water or acid to the reaction mixture and extraction, the nicotinaldehydes according to the invention can be obtained. It may be advantageous to subsequently perform distillation or crystallization for further purification of the product.

The nicotinic acid morpholinamides used as starting materials for the process of the invention can be prepared by processes known per se, as described in the literature (for example standard works, such as Houben-Weyl, Methoden der organischen Chemie (methods of organic chemistry), Georg-Thieme-Verlag, Stuttgart), in particular under reaction conditions known to be suitable for the reaction in question. However, variants known per se, which are not mentioned here in detail, can also be used.

In general, the following procedure is followed: conversion of nicotinic acid to the acid chloride using a suitable reagent, such as thionyl chloride, followed by reaction with the desired amine gives the amide.

In order to protect the substituents from undesired reactions during the reaction according to the invention and/or subsequent work-up steps, protective groups are employed, if appropriate, and are removed again after reduction of nicotinic acid morpholinamide. Methods of use of protecting groups such as Theodora w.green, Peter g.m.wuts: protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons (1999).

Without further implementation, it is assumed that a person skilled in the art will be able to apply the above description in its broadest scope. The preferred embodiments should therefore be regarded as illustrative disclosure only, and not as restrictive in any way.

Example 1: preparation of 5- (4-fluorophenyl) nicotinaldehyde from 5- (4-fluorophenyl) pyridine-3-carboxylic acid morpholinamide

(a) Synthesis of precursor 5- (4-fluorophenyl) pyridine-3-carboxylic acid

First, 5- (4-fluorophenyl) pyridine-3-carboxylic acid was prepared by Suzuki coupling (n.miyaura, a.suzuki, chem.rev.95, 2457(1995)), and 5-bromonicotinic acid was reacted with p-fluorobenzboronic acid (all commercially available) under reaction conditions known per se to give 5- (4-fluorophenyl) pyridine-3-carboxylic acid.

(b1) Synthesis of 5- (4-fluorophenyl) pyridine-3-carboxylic acid morpholinamide-Change 1

25.6g of 5- (4-fluorophenyl) pyridine-3-carboxylic acid are initially taken in 200ml of toluene, and 25.1g of thionyl chloride are then added at room temperature. The mixture was then heated at 90 ℃ for 18 hours, followed by distillation to remove unreacted thionyl chloride and some solvent. After the volume distilled off was made up with toluene, 12.4g of morpholine were added at 80 to 100 ℃ and the reaction mixture was cooled after 2 hours. Sodium hydroxide solution was added to adjust the pH to 8 and the product was isolated by extraction with toluene. After decolorization with activated carbon and removal of the solvent by distillation, 27.7g of 5- (4-fluorophenyl) pyridine-3-carboxylic acid morpholinamide remain as a solid (melting point: 100-.

(b2) Synthesis of 5- (4-fluorophenyl) pyridine-3-carboxylic acid morpholinamide-variant 2

To a solution of 14.3g 5-bromonicotinic acid morpholinamide in 100g THF was added 1.2g Pd [ P (Ph)₃]₄And 7.6g of p-fluorobenzeneboronic acid. Subsequently 8.0g of Na are added dropwise₂CO₃While stirring at 65 ℃. After 16 hours, the reaction mixture was cooled and evaporated in a rotary evaporator. The residue was dissolved in dichloromethane, activated carbon was added and the mixture was filtered. The filtrate is extracted repeatedly with water and evaporated in a rotary evaporator to give 15.7g of a residue which, according to HPLC, contains 89% of 5- (4-fluorophenyl) pyridine-3-carboxylic acid morpholinamide (net yield: 93% of theory). Recrystallization from ethyl acetate gave 8.0g of 5- (4-fluorophenyl) pyridine-3-carboxylic acid morpholinamide with an HPLC purity of 99.6% (53.3% of theory).

(c) Preparation of 5- (4-fluorophenyl) nicotinaldehyde

6.0g of 5- (4-fluorophenyl) pyridine-3-carboxylic acid morpholinamide from example 1(b) are dissolved in 30ml of THF, 57g of 13.6% LiAlH (OEt) are added over the course of 10 minutes at 30 ℃ to 35 ℃)₃A THF solution of (1). After 1 hour, 30ml of 12.5% sulfuric acid were added and the organic phase was separated off. The aqueous phase is adjusted to pH 1 with sulfuric acid and extracted several times with methyl tert-butyl ether. The organic phases are then combined, extracted once with water and then evaporated, leaving 4.3g of a residue having a content of 5- (4-fluorophenyl) pyridine-3-carbaldehyde of 97% by weight (yield: 98% of theory).

Example 2 (comparative example to example 1, using piperidine amide instead of morpholine amide): preparation of 5- (4-fluorophenyl) nicotinaldehyde from 5- (4-fluorophenyl) pyridine-3-carboxylic acid piperidinamide

36.7g of 10% LiAlH₄The solution was diluted with 75g of THF, and a mixture of 8.88g of ethyl acetate and 75g of THF was added at 0 ℃. A solution of 6.8g of 5- (4-fluorophenyl) pyridine-3-carboxylic acid piperidineamide in 24.7ml THF is added at-7 ℃. After 3 hours, the mixture was added to 190g of 10% sulfuric acid. The pH was adjusted to 3 with sodium hydroxide solution and then THF was substantially removed by distillation. Extraction with methyl tert-butyl ether and evaporation left 2.6g of solid (content 67 area%, corresponding to HPLC)36% of theory).

Example 3: preparation of 5-bromonicotinaldehyde from 5-bromopyridine-3-carboxylic acid morpholinamide

(a) Synthesis of 5-bromopyridine-3-carboxylic acid morpholinamide

50.4g of 5-bromonicotinic acid and 87.5g of morpholine are heated to reflux in 200ml of xylene, and the water formed is distilled off. After cooling, the reaction mixture was extracted three times with 10% sodium hydroxide solution and then twice with water. After removal of the xylene by distillation, the residue was recrystallized from ethyl acetate. The yield after drying was 19.2g (28.3% of theory). Melting point 80 ℃.

(b) Preparation of 5-bromonicotinaldehyde

1.75g of lithium aluminum hydride powder are suspended in 64g of THF. A mixture of 5.9g of ethyl acetate and 28g of THF is subsequently added dropwise with cooling. After 30 minutes, the reaction mixture is added dropwise at 0 ℃ to 10 ℃ to a solution of 5.0g of 5-bromopyridine-3-carboxylic acid morpholinamide from example 3(a) in 30g of THF (this corresponds to a 150% excess of reducing agent). After 1 hour, the reaction mixture is poured into 35ml of 12% sulfuric acid and the organic phase is evaporated to dryness. Recrystallization from MTB ether and drying gave 1.91g of product (55.7% of theory). Melting point 95 ℃.

As can be seen from the comparison of the reaction yields of each of examples 1 and 2, the use of nicotinic acid piperidine amide results in a significantly worse reaction, an alternative nicotinamide, but structurally close to morpholine amide. In contrast, the use of morpholine amides enables better yields to be achieved even with a large excess of reducing agent (example 3) in the correct stoichiometric amount (example 2), where piperidine is used as the amine component.

Claims (6)

1. A process for the reductive preparation of nicotinaldehydes, characterized in that the starting material used for the reduction is nicotinic acid morpholinamide of the formula I

Wherein

R¹’、R¹", each independently of the other, denotes H, Hal, A, OA, CH₂R²Or Ar, in the presence of a catalyst,

R²represents OA or NA₂，

A represents an unbranched or branched alkyl radical having 1 to 10C atoms, in which one or two CH' s₂The radicals are optionally replaced by O or S atoms and/or-CH ═ CH-groups and/or 1 to 7H atoms are optionally replaced by F,

ar represents an unsaturated, partially or fully saturated, mono-or polycyclic carbocyclic or heterocyclic ring system containing the heteroatom O, N, S, which is unsubstituted or substituted by Hal, A, OA, NA₂、NO₂、NASO₂A、SO₂NA、SO₂A is mono-or polysubstituted, and

hal represents F, Cl, Br or I.

2. The process according to claim 1, wherein the starting material is 5- (4-fluorophenyl) nicotinic acid morpholinamide.

3. A process according to claim 1, characterized in that the starting material used is 5-bromopyridine-3-carboxylic acid morpholinamide.

4. Process according to any one of claims 1 to 3, characterized in that the reducing agent used is LiAlH (OEt)₃、LiAlH₂(OEt)₂Or LiAlH₃(OEt)。

5. Use of nicotinic acid morpholinamides of the formula I according to claim 1 for the reductive preparation of the corresponding nicotinaldehydes.

6. 5- (4-fluorophenyl) nicotinic acid morpholinamide.