Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-06
2004-03-09
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S318000, C546S319000, C546S339000, C546S341000
Reexamination Certificate
active
06703509
ABSTRACT:
The invention relates to a process for the preparation of 5-arylnicotinaldehydes by reduction of the corresponding 5-arylnicotinic acids by catalytic hydrogenation in the presence of carboxylic anhydrides in which the catalyst used is a palladium/ligand complex, characterized in that the molar ratio between palladium and ligand is from 1:5 to 1:15 in the case of monodentate ligands and from 1:2.5 to 1:7.5 in the case of bidentate ligands.
5-Arylnicotinaldehydes are important intermediates and end products in industrial organic chemistry. Appropriately substituted derivatives are, in particular, valuable intermediates in the synthesis of highly value-added end products or are themselves such end products, in particular for crop protection, such as, for example, fungicides, insecticides, herbicides or pesticides, or for the preparation of substances having high pharmaceutical activity. Production of the corresponding 5-arylnicotinaldehydes on an industrial scale makes highly economical and environmentally friendly preparation necessary.
The 5-arylnicotinaldehydes are distinguished by an unexpected sensitivity to oxidation and disproportionation. Consequently, the methods described in the literature for the preparation of these compounds by chemoselective reduction of aromatic acids or their esters or by oxidation of aromatic alcohols cannot be applied to a satisfactory extent to the corresponding 5-arylnicotinic acid or the corresponding 5-arylnicotinyl alcohol.
Methods for the reduction of nicotinic acid are known. Thus, for example, the reduction of nicotinic acid by palladium-catalysed hydrogenation is described in Chemistry Letters 1998, 1143-1144. The process disclosed therein is carried out in the presence of pivalic anhydride (trimethylacetic anhydride), giving, in the case of unsubstituted nicotinic acid, the corresponding aldehyde in good yields.
However, if substituted nicotinic acids and in particular aromatic-substituted nicotinic acids are employed in this process, considerable losses of yield occur. In addition, the use of pivalic acid is associated with considerable costs, and consequently this process is not suitable for industrial application.
The object on which the invention is based was to discover a process for the preparation of 5-arylnicotinaldehydes which makes inexpensive and environmentally friendly access even to this class of substances possible without the above-mentioned disadvantages.
Surprisingly, it has now been found that 5-arylnicotinaldehydes can be obtained by reduction of the corresponding 5-arylnicotinic acids by catalytic hydrogenation in the presence of carboxylic anhydrides in which the catalyst used is a palladium/ligand complex if a molar ratio between palladium and ligand of from 1:5 to 1:15 is observed in the case of monodentate ligands and of from 1:2.5 to 1:7.5 in the case of bidentate ligands.
The measure according to the invention also allows the use of other carboxylic anhydrides which are less expensive than pivalic anhydride and which, without an excess of ligand, give only a low yield of product.
The invention thus relates to a process for the preparation of 5-arylnicotinaldehydes by reduction of the corresponding 5-arylnicotinic acids by catalytic hydrogenation in the presence of carboxylic anhydrides in which the catalyst used is a palladium/ligand complex, characterized in that the molar ratio between palladium and ligand is from 1:5 to 1:15 in the case of monodentate ligands and from 1:2.5 to 1:7.5 in the case of bidentate ligands.
The invention preferably relates, in particular, to a process for the preparation of 5-arylnicotinaldehydes of the formula I
in which
A is a phenyl radical or naphthyl radical, each of which is unsubstituted or monosubstituted or polysubstituted by R, F, Cl, Br, I, —CN, —NO
2
, —CF
3
, —OCF
3
, —OCHF
2
, —OCF
2
CF
3
, —OCHFCF
3
or —OH and in which, in addition, one or more CH groups may be replaced by N, and
R is H, a straight-chain or branched alkyl radical having 1 to 15 carbon atoms which is monosubstituted by —CF
3
or at least monosubstituted by fluorine, where, in addition, one or more CH
2
groups in these radicals may each, independently of one another, be replaced by —S—, —O—, —O—CO—, —CO—O— or —CH═CH— in such a way that heteroatoms are not directly adjacent,
by reduction of the corresponding 5-arylnicotinic acids by catalytic hydrogenation in the presence of carboxylic anhydrides in which the catalyst used is a palladium/ligand complex, characterized in that the molar ratio between palladium and ligand is from 1:5 to 1:15 in the case of monodentate ligands and from 1:2.5 to 1:7.5 in the case of bidentate ligands.
The invention furthermore relates to the use of the 5-arylnicotinaldehydes for the preparation of N-alkylated amines by reaction of the 5-arylnicotinaldehydes with primary amines to give the corresponding imines, followed by reduction. The reaction of the aldehydes with the amines and also the reduction of the imines can be carried out by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart, or Organikum [Organic Chemistry], 17
th
Edition, VEB Deutscher Verlag der Wissenschaften, Berlin, 1988), to be precise under reaction conditions which are known and are suitable for the said reactions.
The compounds of the formula I are, in particular, highly suitable for the preparation of N-alkylated amines of the formula X:
In which
R′ and R″, independently of one another, are as defined for R or are F, Cl, Br, I, —CN, —NO
2
, —CF
3
, —OCF
3
, —OCHF
2
, —OCF
2
CF
3
, —OCHFCF
3
or —OH, and A is as defined above, by reaction of the corresponding amines and reduction of the resultant imines by conventional reduction processes, in particular by catalytic hydrogenation or by using borohydrides, such as, for example, sodium borohydride.
Similar compounds are already known from EP 0707007.
Preference is given to the use of the aldehyde of the formula I in which A is 4-fluorophenyl for the preparation of (R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman by reaction with R-chromanamine and reduction of the resultant imine.
In the preferred compounds of the formulae above and below, R is H, an alkyl or alkoxy group having 1 to 10 carbon atoms or an alkenyl group having 2 to 7 carbon atoms.
A is preferably a phenyl group, a phenyl group which is monosubstituted or disubstituted by F, a 4-fluorophenyl group, a pyrimidyl, a pyridyl, a pyrazyl or a pyridazyl group, in particular a 4-fluorophenyl group.
Preference is given to compounds which contain at least one of the preferred radicals.
If R is an alkyl group, in which, in addition, one CH
2
group (alkoxy or oxaalkyl) may be replaced by an O atom, it may be straight-chain or branched. It preferably has 2, 3, 4, 5, 6, 7, 8, 9 or 12 carbon atoms and accordingly is preferably ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy, furthermore also undecyl, dodecyl, undecyloxy, dodecyloxy, 2-oxapropyl (=2-methoxymethyl), 2-oxabutyl (=methoxyethyl) or 3-oxabutyl (=2-ethoxymethyl), 2-, 3- or 4-oxapentyl, 2-, 3-, 4- or 5-oxahexyl, or 2-, 3-, 4-, 5- or 6-oxaheptyl. Particular preference is given to hexyl, pentyl, butyl, n-butyl, propyl, i-propyl, methyl and ethyl, in particular propyl and pentyl; particularly preferred alkoxy groups are hexyloxy, pentoxy, n-butoxy, propoxy, i-propoxy, methoxy and ethoxy, in particular ethoxy and n-butoxy. Compounds of the formulae above and below which have branched wing groups R may be of importance. Branched groups of this type generally contain not more than two chain branches. R is preferably a straight-chain group or a branched group having not more than one chain branch.
Preferred branched radicals are isopropyl, 2-butyl (=1-methylpropyl), isobutyl (=3-methylpropyl), tert-butyl,
Bathe Andreas
Bokel Heinz
Keil Thomas
Knieriemen Ralf
Murmann Christoph
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
Seaman D. Margaret
LandOfFree
Method for producing 5-aryl nicotinaldehydes does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for producing 5-aryl nicotinaldehydes, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for producing 5-aryl nicotinaldehydes will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3264984