A process for the alpha-monoalkyaltion of arylacertonitriles, arylacetoesters and arylacetic acids with dialkyl carbonates in the liquid phase, in the presence of bases at temperatures ranging from 100 to about 270 °C

M. Selva

P. C. Loosen

P. Tundo

Archivio Ricerca Ca'Foscari


Claims: US5278333  (A) ― 1994-01-11
Process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters and
arylacetic acids  
Claims of US5278333 (A)
The EPO does not accept any responsibility for the accuracy of data and information
originating from other authorities than the EPO; in particular, the EPO does not
guarantee that they are complete, up-to-date or fit for specific purposes.
We claim:
1. Process for the preparation of an .alpha.-substituted compound of the formula:
##STR2## in which Ar is phenyl, naphthyl, or thienyl, each of which is unsubstituted for
substituted with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo,
carboxy, alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy group, arylcarbonyl, or
cyano, X' is --CN or --COOR, and R is alkyl of 1 to 4 carbon atoms,
which comprises heating a reaction mixture consisting essentially of (i) an acetic acid
derivative of the formula:
Ar--CH2 --X
in which Ar is as previously defined and X is --CN, --COOH, or --COOR, in which R is as
previously defined, (ii) from 1 to 50 molar equivalents, per mole of acetic acid derivative,
of a dialkyl carbonate of the formula ROCOOR, in which R is as previously defined, and
(iii) from 0.005 to 5 molar equivalents, per mole of acetic acid derivative, of a base,
in liquid phase at temperatures of from about 100 DEG C. to about 270 DEG C.
2. The process according to claim 1 wherein the dialkyl carbonate is dimethyl carbonate.
3. The process according to claim 1 wherein the dialkyl carbonate is diethyl carbonate.
4. The process according to claim 1 wherein the base is an alkali earth metal carbonate
or bicarbonate.
5. The process according to claim 1 wherein the reaction mixture is heated at
temperatures of from about 120 DEG C. to about 250 DEG C.
6. The process according to claim 1 wherein Ar is phenyl, 3-methoxycarbonylphenyl,
3-benzoylphenyl, or 6-methoxynaphth-2-yl.
Last updated: 14.03.2012  Worldwide Database  5.7.38; 92p
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Description: US5278333  (A) ― 1994-01-11
Process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters and
arylacetic acids  
Description of US5278333 (A)
The EPO does not accept any responsibility for the accuracy of data and information
originating from other authorities than the EPO; in particular, the EPO does not
guarantee that they are complete, up-to-date or fit for specific purposes.
The present invention relates to a process for the .alpha.-monoalkylation of
arylacetonitriles, arylacetoesters and arylacetic acids of formula (I), to obtain
.alpha.-aryl-.alpha.-alkyl-acetonitriles or .alpha.-aryl-.alpha.-alkyl-acetoesters of formula
(II), using dialkyl carbonates in liquid phase, according to the following scheme:
##STR1## wherein Ar is an aromatic or hetero-aromatic ring, for example a phenyl,
naphthyl, thiophene ring and the like, optionally having one or more substituents, such
as C1 -C4 alkyl, C1 -C4 alkoxy, halogens, carboxy, C1 -C4 alkoxycarbonyl, arylcarbonyl,
nitrile groups,
X is a CN, COOR or COOH group,
X' is a CN or COOR group,
R is a C1 -C4 alkyl group, preferably methyl or ethyl.
The resulting compounds of formula (II) are useful intermediates; in particular, they are
useful to prepare, by means of simple hydrolysis of the CN or COOR groups,
.alpha.-arylpropionic acids, some of which are important from the therapeutical point of
view: see, for instance, ibuprofen, naproxen, ketoprofen, fluorbiprofen and the like.
According to the prior art techniques, particularly, the main processes for the preparation
of arylpropionic acid comprise: (1) direct or indirect methylation of the corresponding
arylacetic acid derivatives; (2) in the case of ketoprofen, introduction of the carbonyl
function on the aromatic ring; (3) introduction of the propionic group as such; (4)
rearrangements of propiophenones (the relevant literature being extremely wide: see, for
instance, U.S. Pat. No. 3,641,127, DOS 2,646,792, DOS 2,744,832, U.S. Pat. Nos.
3,959,364, 3,720,708).
.alpha.-Arylpropionic acids (particularly those useful as antiinflammatory drugs), are
important from the economic point of view, therefore even complex preparation
processes can be industrially interesting, whenever they yield products which are pure
or can easily be purified.
The process which is apparently the simplest consists in the selective introduction of a
methyl group on the reactive methylene of an arylacetonitrile. Said reaction was studied
accurately also under phase-transfer catalysis conditions (M. Mikolajczyk et al.,
Tetrahedron Lett. 3757 (1975), but it always gave reaction mixtures; in fact, even in the
presence of unconverted reagent, the formation of the dimethyl derivative could not be
avoided, which makes the separation of the monomethyl derivative difficult and
expensive.
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On the contrary, no alkylation reactions of arylacetoesters are disclosed: in fact, in this
case, the --CH2 -- group is not acidic enough, therefore the carbanion forms with
difficulty, and anyhow the ester will be hydrolyzed under phase-transfer conditions.
However, arylacetoesters are known to act as intermediates for the above mentioned
antiinflammatory drugs when they are transformed, by means of strong bases, such as
sodium hydride, into the corresponding anions which are then treated with methyl
iodide. Nevertheless, the monomethylation selectivity is never high: see, for example,
monomethylation of methyl (6-methoxy-2-naphthyl)acetate to methyl 2-(6-methoxy-
2-naphthyl)propionate (U.S. Pat. No. 3,896,157).
Recently, dialkyl carbonates have been reported to act as alkylation agents on phenols,
mercaptans, amines, arylacetonitriles and other CH-acid compounds (P. Tundo et al.,
Ind. Eng. Chem. Res. 28, 881 (1989)). The reaction is carried out continuously on a
column containing catalytic amounts of the base and the phase-transfer catalyst and it
proceeds without base consumption since the acidity is removed from the reaction
mixture in form of CO2, due to the instability of the O-alkylcarbonic acids, which
represent the leaving group of the dialkyl carbonates during the methylation reaction.
The continuous alkylation of methyl-phenylacetate has also been described (Italian
patent appl. n DEG 20159A/90), but this reaction proceeds markedly more slowly than
that to the corresponding nitriles. The reported conversions are of 60% only.
However, continuous reactions in vapour phase, such as those disclosed in EP 240,863
and U.S. Pat. No. 4,894,471, and in Italian Pat. appl. 20159A/90, cannot be used in case
of high-boiling products, since such products are difficult to vapourize: the high boiling
point of many arylacetonitriles and arylacetoesters can lead to the decomposition
thereof, due to the extended time at high temperature on the fix bed in which the
reaction takes place.
Now it has surprisingly been found that .alpha.-monoalkylation of arylacetonitriles,
arylacetoesters and arylacetic acids with dialkyl carbonates proceeds in a highly
satisfactory way from the point of view of both selectivity and yields also when such a
reaction is carried out in the liquid phase, in batch processes, which obviously do not
suffer from the problem of the vapourizing of the high-boiling substrates, which are
liable to heat-decomposition. The high selectivity with respect to monoalkyl derivatives
achieved by the invention is definitely unforeseeable, since said monoalkyl derivatives,
on the contrary to what happens in case of the vapour phase process disclosed in the
above cited EP 240,863, U.S. Pat. No. 4,894,471 and It. Pat. appl. 20159A/90, remain for
a long time in the reaction medium, in the presence of an alkylating agent and under
conditions which are foreseen to be suitable for the formation of the undesired dialkyl
derivatives: in fact, a very high selectivity (>99%, as evident from the following examples)
is achieved in the presence of a very high dialkyl carbonate excess (from 10 to 50 moles
for mole of compound I), which is actually used as the reaction solvent. When X, in
formula I, is COOH, the reaction according to the invention occurs with initial formation
of arylacetoester Ar--CH2 --COOR (U. Romano, Chimica oggi, 1984, 37), which is
subsequently mono-alkylated at the .alpha.-position.
A further characteristic distinguishing the batch process of the present invention from
the one in vapour phase of the prior art resides in the fact that the reaction can be
carried out in absence of the phase-transfer catalyst which is essential in the vapour
phase. On the contrary, the presence of bases, such as alkali metal carbonates, for
example K2 CO3, is necessary. The base amount can range from catalytic to
stoichiometric amounts, or even excess amounts to the stoichiometric ratio (related to
compound I). Since the temperatures required to obtain good results in "normal" times
from the industrial point of view are generally higher than 100 DEG C., and since
dimethyl carbonate (DMC) boils under said temperature range, the monomethylation
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reaction is carried out in apparatuses capable of bearing the required pressures, which,
o the other hand, are relatively mild, generally not exceeding 15-25 bars.
It should be noted that monoalkylation of compounds I batchwise, according to the
invention, is a much simpler process than that in vapour phase which, as it happens
with all the continuous processes, requires a precise optimisation, particularly as far as
the flow rate of the reagents is concerned. According to the present invention, on the
contrary, it is sufficient to place compound I, the dialkyl carbonate and the base (in a
molar ratio from 1:1:0.005 to 1:50:5) in the reactor and to heat the mixture to
temperatures ranging from about 100 DEG C. to about 270 DEG C., preferably from
about 120 DEG C. to about 250 DEG C., for times varying from about 2 hours to about
40 hours. After that, the reaction mixture can be worked up conventionally, by filtering
the solid residue (usually K2 CO3), recovering the dialkyl carbonate excess and isolating
the desired product by distillation or crystallization.
The following Examples further illustrate the invention.
EXAMPLE 1
2-(3-Methoxycarbonyl-phenyl)propionitrile
The reaction for the selective methylation is carried out placing into a 250 ml (.phi.i =45
mm) stainless steel autoclave a mixture of (3-methoxycarbonylphenyl)acetonitrile (10 g,
96% purity), dimethyl carbonate (86 ml) and K2 CO3 (12 g), in the 1:18:2 molar ratio. Air
is replaced by a N2 stream; then the mixture is heated at a temperature of 180 DEG C.,
with stirring. During the reaction, which is completed within 6 hours, the pressure raises
from 7 bars, reached at the working temperature, to about 12 bars after 5 hours of
isothermal heating. After cooling K2 CO3 is filtered off, DMC is recovered and the
residue is distilled (b.p. 0.078=109 DEG-110 DEG C.) to obtain 8.3 g of
2-(3-methoxycarbonyl-phenyl)propionitrile which is 99,5% pure (78% yield) (>99%
selectivity in monomethylation).
The same result is obtained, under the same conditions, by decreasing the K2 CO3
amount to 1/10th of that described above.
From the resulting product, the corresponding 3-(1-cyanoethyl)benzoic acid is obtained
by means of selective alkali hydrolysis, which is a known intermediate for the
preparation of ketoprofen.
EXAMPLE 2
2-(3-Methoxycarbonyl-phenyl)butyronitrile
The procedure of example (1) is followed, using diethyl carbonate instead of dimethyl
carbonate. The reaction, which is completed within about 24 hours, takes place at a
pressure ranging from 3 bars, which is the value achieved at the working pressure, to
about 7 bars.
The title product is obtained in a 80% yield; the monomethylation selectivity being >99%.
EXAMPLE 3
2-(3-Benzoyl-phenyl)propionitrile
A mixture of (3-benzoylphenyl)acetonitrile (1 g), dimethyl carbonate (15 ml) and K2 CO3
(3 g) in the 1:40:5 molar ratio, is reacted in a steel autoclave at the temperature of 140
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DEG C. for 10 hours and 30 minutes. After recovering DMC, 0.85 g of the title product
are obtained, with a monomethylation selectivity >99% (80% yield), which is hydrolyzed
to obtain ketoprofen by known methods.
EXAMPLE 4
2-Phenylpropionitrile
The procedure of example (1) is followed, using phenylacetonitrile, dimethyl carbonate
and a catalytic amount of alkali carbonate in a 1:18:0.05 molar ratio. Li2 CO3, Na2 CO3,
K2 CO3 and Cs2 CO3 were used respectively, to obtain the following results:
______________________________________
reaction
time conversion
monomethylation
base (h) (%) selectivity
______________________________________
Li2 CO3
7.5 5
Na2 CO3
8.75 89 >99%
K2 CO3
7.5 98 >99%
Cs2 CO3
5.0 99 >99%
______________________________________
EXAMPLE 5
a) Monomethylation of methyl (6-methoxy-2-naphthyl)acetate
The reaction for the selective methylation is carried out placing a mixture of methyl
(6-methoxy-2-naphthyl)acetate (U.S. Pat. No. 3,896,157; 2 g), dimethyl carbonate (10
ml) and K2 CO3 (0.9 g), in the 1:15:1.5 molar ratio into a 250 ml (.phi.i =45 mm)
stainless steel autoclave. Air is replaced by a N2 stream; then the mixture is heated to
210 DEG C., with stirring. During the reaction, which is completed within 6 hours, the
pressure rises from 18 bars, which are achieved at the working temperature, to about 20
bars after 5 hours of isothermal heating. K2 CO3 is filtered off and the residue is
hydrolyzed directly.
Alternatively, the reaction for the selective methylation can be carried out by reacting a
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mixture of (6-methoxy-2-naphthyl)acetic acid, dimethyl carbonate and K2 CO3, in the
1:20:2 molar ratio, in autoclave at a temperature of 220 DEG C. The reaction is
completed within about 8 hours. (In this case DMC acts first as a methylating agent for
the carboxylic group, through an already known reaction; then the monomethylation
reaction takes place on the resulting ester).
b) Hydrolysis of methyl 2-(methoxy-2-naphthyl)propionate
The reaction product is refluxed in 100 ml of 5% NaOH for 1 hour and 30 minutes. The
precipitate is neutralized and filtered, to obtain 1.8 g of Naproxen. Yield (starting from
the not methylated ester): 90%.
EXAMPLE 6
Flurbiprofen
Following the procedure of example (5), a mixture of 2 g of methyl (2-fluoro-
4-biphenyl)acetate (U.S. Pat. No. 3,755,427), 14 ml of dimethyl carbonate and 1.7 g of
K2 CO3, in a 1:20:1.5 molar ratio, is reacted in autoclave at a temperature of 210 DEG
C.; the reaction is completed within 6 hours. The resulting product, methyl .alpha.-(2-
fluoro-4-biphenyl)propionate, is hydrolyzed with 100 ml of 5% NaOH, as in example 5, to
give .alpha.-(2-fluoro-4-biphenyl)propionic acid (Flurbiprofen) with 100 ml of 5% NaOH,
as in example 5. Yield (starting from the not methylated ester): 85%.
EXAMPLE 7
Ibuprofen
Following the procedure of example 1, a mixture of 2 g of methyl
(4-isobutylphenyl)acetate (EP 347,939), 16 ml of dimethyl carbonate and 2 g of K2 CO3,
in a 1:20:1.5 molar ratio, is reacted in autoclave at a temperature of 210 DEG C. The
reaction is completed within about 8 hours. The product, methyl .alpha.-(4-
isobutylphenyl)propionate, is hydrolyzed to .alpha.-(4-isobutyl)propionic acid (Ibuprofen)
as in the examples above. Yield (starting from the not methylated ester): 90%.
EXAMPLE 8
.alpha.-Phenylpropionic acid
Following the procedure of examples 5-7, a mixture of 2 g of methyl phenylacetate, 23
ml of dimethyl carbonate, 2.8 g of K2 CO3, in a 1:20:1.5 molar ratio, is reacted in
autoclave at a temperature of 210 DEG C. for 8 hours. The product, methyl
.alpha.-phenylpropionate, is hydrolyzed to .alpha.-phenylpropionic acid according to the
procedure of example 5. Yield 85%.
.alpha.-Phenylmethylpropionate can be obtained under similar conditions, by reacting a
mixture of phenylacetic acid, dimethyl carbonate and K2 CO3, in a 1:20:2 molar ratio, in
autoclave at a temperature of 225 DEG C., for 15 hours.
EXAMPLE 9
Ethyl .alpha.-phenylbutyrate
A mixture of 2 g of ethyl phenylacetate, 30 ml of diethyl carbonate, 2.5 g of K2 CO3, in
the 1:20:1.5 molar ratio, is reacted in autoclave at 225 DEG C. After 14 hours, a 30%
conversion is achieved, with formation of ethyl .alpha.-phenylbutyrate as the mono-C-
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ethylation product.
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Process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters and arylacetic acids

Archivio Istituzionale della Ricerca

A process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters and arylacetic acids.

TUNDO, Pietro

SELVA, Maurizio

Archivio istituzionale della ricerca - Università degli Studi di Venezia Ca' Foscari

Description: EP0525506  (A2) ― 1993-02-03A process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters andarylacetic acids.  Description of EP0525506 (A2)The EPO does not accept any responsibility for the accuracy of data and informationoriginating from other authorities than the EPO; in particular, the EPO does notguarantee that they are complete, up-to-date or fit for specific purposes.[0001] The present invention relates to a process for the a-monoalkylation ofarylacetonitriles, arylacetoesters and arylacetic acids of formula (I), to obtain a-aryl-a-alkyl-acetonitriles or a-aryl-a-alkyl-acetoesters of formula (II), using dialkyl carbonatesin liquid phase, according to the following scheme:wherein Ar is an aromatic or hetero-aromatic ring, for example a phenyl, naphthyl,thiophene ring and the like, optionally having one or more substituents, such as C1-C4alkyl, C1-C4 alkoxy, halogens, carboxy, C1-C4 alkoxycarbonyl, arylcarbonyl, nitrilegroups,X is a CN, COOR or COOH group,X' is a CN or COOR group,R is a C, -C4. alkyl group, preferably methyl or ethyl.[0002] The resulting compounds of formula (II) are useful intermediates; in particular,they are useful to prepare, by means of simple hydrolysis of the CN or COOR groups,a-arylpropionic acids, some of which are important from the therapeutical point of view:see, for instance, ibuprofen, naproxen, ketoprofen, fluorbiprofen and the like.[0003] According to the prior art techniques, particularly, the main processes for thepreparation of arylpropionic acid comprise: (1) direct or indirect methylation of thecorresponding arylacetic acid derivatives; (2) in the case of ketoprofen, introduction ofthe carbonyl function on the aromatic ring; (3) introduction of the propionic group assuch; (4) rearrangements of propiophenones (the relevant literature being extremelywide: see, for instance, USP 3,641,127, DOS 2,646,792, DOS 2,744,832, USP3,959,364, USP 3,720,708).[0004] a-Arylpropionic acids (particularly those useful as antiinflammatory drugs), areimportant from the economic point of view, therefore even complex preparationprocesses can be industrially interesting, whenever they yield products which are pureor can easily be purified.[0005] The process which is apparently the simplest consists in the selectiveintroduction of a methyl group on the reactive methylene of an arylacetonitrile. Saidreaction was studied accurately also under phase-transfer catalysis conditions (M.Mikolajczyk et al., Tetrahedron Lett. 3757 (1975), but it always gave reaction mixtures; infact, even in the presence of unconverted reagent, the formation of the dimethylderivative could not be avoided, which makes the separation of the monomethylderivative difficult and expensive.EspacenetEspacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...1 di 5 03/07/2012 16:36[0006] On the contrary, no alkylation reactions of arylacetoesters are disclosed: in fact,in this case, the -CH2- group is not acidic enough, therefore the carbanion forms withdifficulty, and anyhow the ester will be hydrolyzed under phase-transfer conditions.However, arylacetoesters are known to act as intermediates for the above mentionedantiinflammatory drugs when they are transformed, by means of strong bases, such assodium hydride, into the corresponding anions which are then treated with methyliodide. Nevertheless, the monomethylation selectivity is never high: see, for example,monomethylation of methyl (6-methoxy-2-naphthyl)acetate to methyl 2-(6-methoxy-2-naphthyl)propionate (USP 3,896,157).[0007] Recently, dialkyl carbonates have been reported to act as alkylation agents onphenols, mercaptans, amines, arylacetonitriles and other CH-acid compounds[0008] (P. Tundo et al., Ind. Eng. Chem. Res. 28, 881 (1989)).[0009] The reaction is carried out continuously on a column containing catalytic amountsof the base and the phase-transfer catalyst and it proceeds without base consumptionsince the acidity is removed from the reaction mixture in form of C02, due to theinstability of the O-alkylcarbonic acids, which represent the leaving group of the dialkylcarbonates during the methylation reaction.[0010] The continuous alkylation of methyl-phenylacetate has also been described(Italian patent appl. n 20159A/90), but this reaction proceeds markedly more slowly thanthat to the corresponding nitriles. The reported conversions are of 60% only.[0011] However, continuous reactions in vapour phase, such as those disclosed in EP240,863 and USP 4,894,471, and in Italian Pat. appl. 20159A/90, cannot be used in caseof high-boiling products, since such products are difficult to vapourize: the high boilingpoint of many arylacetonitriles and arylacetoesters can lead to the decompositionthereof, due to the extended time at high temperature on the fix bed in which thereaction takes place.[0012] Now it has surprisingly been found that a-monoalkylation of arylacetonitriles,arylacetoesters and arylacetic acids with dialkyl carbonates proceeds in a highlysatisfactory way from the point of view of both selectivity and yields also when such areaction is carried out in the liquid phase, in batch processes, which obviously do notsuffer from the problem of the vapourizing of the high-boiling substrates, which areliable to heat-decomposition. The high selectivity with respect to monoalkyl derivativesachieved by the invention is definitely unforeseeable, since said monoalkyl derivatives,on the contrary to what happens in case of the vapour phase process disclosed in theabove cited EP 240,863, USP 4,894,471 and It. Pat. appl. 20159A/90, remain for a longtime in the reaction medium, in the presence of an alkylating agent and underconditions which are foreseen to be suitable for the formation of the undesired dialkylderivatives: in fact, a very high selectivity (>99%, as evident from the following examples)is achieved in the presence of a very high dialkyl carbonate excess (from 10 to 50 molesfor mole of compound I), which is actually used as the reaction solvent. When X, informula I, is COOH, the reaction according to the invention occurs with initial formationof arylacetoester Ar-CH2-COOR (U. Romano, Chimica oggi, 1984, 37), which issubsequently mono-alkylated at the a-position.[0013] A further characteristic distinguishing the batch process of the present inventionfrom the one in vapour phase of the prior art resides in the fact that the reaction can becarried out in absence of the phase-transfer catalyst which is essential in the vapourphase. On the contrary, the presence of bases, such as alkali metal carbonates, forexample K2C03, is necessary. The base amount can range from catalytic toEspacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...2 di 5 03/07/2012 16:36stoichiometric amounts, or even excess amounts to the stoichiometric ratio (related tocompound I). Since the temperatures required to obtain good results in "normal" timesfrom the industrial point of view are generally higher than 100[deg.]C, and sincedimethyl carbonate (DMC) boils under said temperature range, the monomethylationreaction is carried out in apparatuses capable of bearing the required pressures, which,on the other hand, are relatively mild, generally non exceeding 15-25 bars.[0014] It should be noted that monoalkylation of compounds I batchwise, according tothe invention, is a much simpler process than that in vapour phase which, as it happenswith all the continuous processes, requires a precise optimisation, particularly as far asthe flow rate of the reagents is concerned. According to the present invention, on thecontrary, it is sufficient to place compound I, the dialkyl carbonate and the base (in amolar ratio from 1:1:0.005 to 1:50:5) in the reactor and to heat the mixture totemperatures ranging from about 100 [deg.] C to about 270 C, preferably from about120 [deg.]C to about 250 C, for times varying from about 2 hours to about 40 hours.After that, the reaction mixture can be worked up conventionally, by filtering the solidresidue (usually K2C03), recovering the dialkyl carbonate excess and isolating thedesired product by distillation or crystallization.[0015] The following Examples further illustrate the invention.Example 12-(3-Methoxycarbonyl-phenyl)propionitrile[0016] The reaction for the selective methylation is carried out placing into a 250 ml (O =45 mm) stainless steel autoclave a mixture of (3-methoxycarbonyl-phenyl)acetonitrile (10g, 96% purity), dimethyl carbonate (86 ml) and K2C03 (12 g), in the 1:18:2 molar ratio.Air is replaced by a N2 stream; then the mixture is heated at a temperature of180[deg.]C, with stirring. During the reaction, which is completed within 6 hours, thepressure raises from 7 bars, reached at the working temperature, to about 12 bars after5 hours of isothermal heating. After cooling K2C03 is filtered off, DMC is recovered andthe residue is distilled (b.p. 0.08 = 109-110[deg.]C) to obtain 8.3 g of2-(3-methoxycarbonyl-phenyl)propionitrile which is 99,5% pure (78% yield) (>99%selectivity in monomethylation).[0017] The same result is obtained, under the same conditions, by decreasing theK2C03 amount to 1/1 Oth of that described above.[0018] From the resulting product, the corresponding 3-(1-cyanoethyl)benzoic acid isobtained by means of selective alkali hydrolysis, which is a known intermediate for thepreparation of ketoprofen.Example 22-(3-Methoxycarbonyl-phenyl)butyronitrile[0019] The procedure of example (1) is followed, using diethyl carbonate instead ofdimethyl carbonate. The reaction, which is completed within about 24 hours, takes placeat a pressure ranging from 3 bars, which is the value achieved at the working pressure,to about 7 bars.[0020] The title product is obtained in a 80% yield; the monomethylation selectivity being>99%.Example 3Espacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...3 di 5 03/07/2012 16:362-(3-Benzoyl-phenyl)propionitrile[0021] A mixture of (3-benzoylphenyl)acetonitrile (1 g), dimethyl carbonate (15 ml) andK2C03 (3 g) in the 1:40:5 molar ratio, is reacted in a steel autoclave at the temperatureof 140 [deg.]C for 10 hours and 30 minutes. After recovering DMC, 0.85 g of the titleproduct are obtained, with a monomethylation selectivity >99% (80% yield), which ishydrolyzed to obtain ketoprofen by known methods.Example 42-Phenylpropionitrile[0022] The procedure of example (1) is followed, using phenylacetonitrile, dimethylcarbonate and a catalytic amount of alkali carbonate in a 1:18:0.05 molar ratio. Li2C03,Na2CO3, K2C03 and Cs2 C03 were used respectively, to obtain the following results:Example 5Naproxena) Monomethylation of methyl (6-methoxy-2-naphthyl)acetate[0023] The reaction for the selective methylation is carried out placing a mixture ofmethyl- (6-methoxy-2-naphthyl)acetate (USP 3,896,157; 2 g), dimethyl carbonate (10 ml)and K2C03 (0.9 g), in the 1:15:1.5 molar ratio into a 250 ml (Oi = 45 mm) stainless steelautoclave. Air is replaced by a N2 stream; then the mixture is heated to 210[deg.]C, withstirring. During the reaction, which is completed within 6 hours, the pressure rises from18 bars, which are achieved at the working temperature, to about 20 bars after 5 hoursof isothermal heating. K2C03 is filtered off and the residue is hydrolyzed directly.[0024] Alternatively, the reaction for the selective methylation can be carried out byreacting a mixture of (6-methoxy-2-naphthyl)acetic acid, dimethyl carbonate and K2C03,in the 1:20:2 molar ratio, in autoclave at a temperature of 220 [deg.] C. The reaction iscompleted within about 8 hours. (In this case DMC acts first as a methylating agent forthe carboxylic group, through an already known reaction; then the monomethylationreaction takes place on the resulting ester).b) Hydrolysis of methyl 2(methoxy-2-naphthyl)pro-pionate[0025] The reaction product is refluxed in 100 ml of 5% NaOH for 1 hour and 30minutes. The precipitate is neutralized and filtered, to obtain 1.8 g of Naproxen. Yield(starting from the not methylated ester): 90%.Example 6Flurbiprofen[0026] Following the procedure of example (5), a mixture of 2 g of methyl (2-fluoro-4-biphenyl)acetate (USP 3,755,427), 14 ml of dimethyl carbonate and 1.7 g of K2C03, ina 1:20:1.5 molar ratio, is reacted in autoclave at a temperature of 210[deg.]C; thereaction is completed within 6 hours. The resulting product, methyl a-(2-fluoro-4-biphenyl)propionate, is hydrolyzed with 100 ml of 5% NaOH, as in example 5, to givea-(2-fluoro-4-biphenyl)propionic acid (Flurbiprofen) with 100 ml of 5% NaOH, as inexample 5. Yield (starting from the not methylated ester): 85%.Espacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...4 di 5 03/07/2012 16:36Example 7Ibuprofen[0027] Following the procedure of example 1, a mixture of 2 g of methyl(4-isobutylphenyl)acetate (EP 347,939), 16 ml of dimethyl carbonate and 2 g of K2C03,in a 1:20:1.5 molar ratio, is reacted in autoclave at a temperature of 210[deg.]C. Thereaction is completed within about 8 hours. The product, methyla-(4-isobutylphenyl)propionate, is hydrolyzed to a-(4-isobutyl)propionic acid (Ibuprofen)as in the examples above. Yield (starting from the not methylated ester): 90%.Example 8a-Phenylpropionic acid[0028] Following the procedure of examples 5-7, a mixture of 2 g of methylphenylacetate, 23 ml of dimethyl carbonate, 2.8 g of K2 C03, in a 1:20:1.5 molar ratio, isreacted in autoclave at a temperature of 210[deg.]C for 8 hours. The product, methyla-phenylpropionate, is hydrolyzed to a-phenylpropionic acid according to the procedureof example 5. Yield 85%. a-Phenylmethylpropionate can be obtained under similarconditions, by reacting a mixture of phenylacetic acid, dimethyl carbonate and K2C03, ina 1:20:2 molar ratio, in autoclave at a temperature of 225 C, for 15 hours.Example 9Ethyl a-phenylbutyrate[0029] A mixture of 2 g of ethyl phenylacetate, 30 ml of diethyl carbonate, 2.5 g ofK2C03, in the 1:20:1.5 molar ratio, is reacted in autoclave at 225 [deg.]C. After 14 hours,a 30% conversion is achieved, with formation of ethyl a-phenylbutyrate as the mono-C-ethylation product.Last updated: 14.03.2012  Worldwide Database  5.7.38; 92pEspacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...5 di 5 03/07/2012 16:36Claims: EP0525506  (A2) ― 1993-02-03A process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters andarylacetic acids.  Claims of EP0525506 (A2)The EPO does not accept any responsibility for the accuracy of data and informationoriginating from other authorities than the EPO; in particular, the EPO does notguarantee that they are complete, up-to-date or fit for specific purposes.1. A process for the a-monoalkylation of arylacetonitriles, arylacetoesters or arylaceticacids of formula (I) by means of treatment with dialkyl carbonates, to give a-aryl-a-alkylacetonitriles or a-aryl-a-al- kylacetoesters of formula (II), according to the schemewherein Ar is an aromatic or hetero-aromatic ring, for example a phenyl, naphthyl,thiophene ring and the like, optionally having one or more substituents, such as C1-C4alkyl, C1-C4 alkoxy, halogens, carboxy, C1-C4 alkoxycarbonyl, arylcarbonyl, nitrilegroups,X is a CN, COOR or COOH group,X' is a CN or COOR group,R is a C1-C4 alkyl group,characterized in that compound (I), a dialkyl carbonate and a base are reacted in liquidphase in molar ratios ranging from 1:1:0.005 to 1:50:5, at temperatures ranging fromabout 100[deg.]C to about 270 [deg.]C.2. A process according to claim 1, characterized in that dimethyl carbonate is used asthe dialkyl carbonate.3. A process according to claim 1, characterized in that diethyl carbonate is used as thedialkyl carbonate.4. A process according to claims 1-3, characterized in that alkali metal carbonates orbicarbonates are used as the bases.5. A process according to claims 1-4, characterized in that the reaction is carried out attemperatures ranging from about 120 [deg.] C to about 250 [deg.] C.6. A process according to claims 1-5, characterized in that a compound (I), selectedfrom the group consisting of (3-methoxycarbonyl-phenyl)acetonitrile,(3-benzoylphenyl)acetonitrile, the esters of (6-methoxy-2-naphthyl)acetic, (2-fluoro-4-biphenyl)acetic, (4-isobutylphenyl)acetic, (3-benzoylphenyl)acetic and phenylaceticacids and the acids themselves, is subjected to a-monomethylation.Last updated: 14.03.2012  Worldwide Database  5.7.38; 92pEspacenetEspacenet - Claims http://worldwide.espacenet.com/publicationDetails/claims?CC=EP&...1 di 2 03/07/2012 16:36Espacenet - Claims http://worldwide.espacenet.com/publicationDetails/claims?CC=EP&...2 di 2 03/07/2012 16:36


Description: EP0525506  (A2) ― 1993-02-03
A process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters and
arylacetic acids.  
Description of EP0525506 (A2)
The EPO does not accept any responsibility for the accuracy of data and information
originating from other authorities than the EPO; in particular, the EPO does not
guarantee that they are complete, up-to-date or fit for specific purposes.
[0001] The present invention relates to a process for the a-monoalkylation of
arylacetonitriles, arylacetoesters and arylacetic acids of formula (I), to obtain a-aryl-
a-alkyl-acetonitriles or a-aryl-a-alkyl-acetoesters of formula (II), using dialkyl carbonates
in liquid phase, according to the following scheme:
wherein Ar is an aromatic or hetero-aromatic ring, for example a phenyl, naphthyl,
thiophene ring and the like, optionally having one or more substituents, such as C1-C4
alkyl, C1-C4 alkoxy, halogens, carboxy, C1-C4 alkoxycarbonyl, arylcarbonyl, nitrile
groups,
X is a CN, COOR or COOH group,
X' is a CN or COOR group,
R is a C, -C4. alkyl group, preferably methyl or ethyl.
[0002] The resulting compounds of formula (II) are useful intermediates; in particular,
they are useful to prepare, by means of simple hydrolysis of the CN or COOR groups,
a-arylpropionic acids, some of which are important from the therapeutical point of view:
see, for instance, ibuprofen, naproxen, ketoprofen, fluorbiprofen and the like.
[0003] According to the prior art techniques, particularly, the main processes for the
preparation of arylpropionic acid comprise: (1) direct or indirect methylation of the
corresponding arylacetic acid derivatives; (2) in the case of ketoprofen, introduction of
the carbonyl function on the aromatic ring; (3) introduction of the propionic group as
such; (4) rearrangements of propiophenones (the relevant literature being extremely
wide: see, for instance, USP 3,641,127, DOS 2,646,792, DOS 2,744,832, USP
3,959,364, USP 3,720,708).
[0004] a-Arylpropionic acids (particularly those useful as antiinflammatory drugs), are
important from the economic point of view, therefore even complex preparation
processes can be industrially interesting, whenever they yield products which are pure
or can easily be purified.
[0005] The process which is apparently the simplest consists in the selective
introduction of a methyl group on the reactive methylene of an arylacetonitrile. Said
reaction was studied accurately also under phase-transfer catalysis conditions (M.
Mikolajczyk et al., Tetrahedron Lett. 3757 (1975), but it always gave reaction mixtures; in
fact, even in the presence of unconverted reagent, the formation of the dimethyl
derivative could not be avoided, which makes the separation of the monomethyl
derivative difficult and expensive.
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[0006] On the contrary, no alkylation reactions of arylacetoesters are disclosed: in fact,
in this case, the -CH2- group is not acidic enough, therefore the carbanion forms with
difficulty, and anyhow the ester will be hydrolyzed under phase-transfer conditions.
However, arylacetoesters are known to act as intermediates for the above mentioned
antiinflammatory drugs when they are transformed, by means of strong bases, such as
sodium hydride, into the corresponding anions which are then treated with methyl
iodide. Nevertheless, the monomethylation selectivity is never high: see, for example,
monomethylation of methyl (6-methoxy-2-naphthyl)acetate to methyl 2-(6-methoxy-
2-naphthyl)propionate (USP 3,896,157).
[0007] Recently, dialkyl carbonates have been reported to act as alkylation agents on
phenols, mercaptans, amines, arylacetonitriles and other CH-acid compounds
[0008] (P. Tundo et al., Ind. Eng. Chem. Res. 28, 881 (1989)).
[0009] The reaction is carried out continuously on a column containing catalytic amounts
of the base and the phase-transfer catalyst and it proceeds without base consumption
since the acidity is removed from the reaction mixture in form of C02, due to the
instability of the O-alkylcarbonic acids, which represent the leaving group of the dialkyl
carbonates during the methylation reaction.
[0010] The continuous alkylation of methyl-phenylacetate has also been described
(Italian patent appl. n 20159A/90), but this reaction proceeds markedly more slowly than
that to the corresponding nitriles. The reported conversions are of 60% only.
[0011] However, continuous reactions in vapour phase, such as those disclosed in EP
240,863 and USP 4,894,471, and in Italian Pat. appl. 20159A/90, cannot be used in case
of high-boiling products, since such products are difficult to vapourize: the high boiling
point of many arylacetonitriles and arylacetoesters can lead to the decomposition
thereof, due to the extended time at high temperature on the fix bed in which the
reaction takes place.
[0012] Now it has surprisingly been found that a-monoalkylation of arylacetonitriles,
arylacetoesters and arylacetic acids with dialkyl carbonates proceeds in a highly
satisfactory way from the point of view of both selectivity and yields also when such a
reaction is carried out in the liquid phase, in batch processes, which obviously do not
suffer from the problem of the vapourizing of the high-boiling substrates, which are
liable to heat-decomposition. The high selectivity with respect to monoalkyl derivatives
achieved by the invention is definitely unforeseeable, since said monoalkyl derivatives,
on the contrary to what happens in case of the vapour phase process disclosed in the
above cited EP 240,863, USP 4,894,471 and It. Pat. appl. 20159A/90, remain for a long
time in the reaction medium, in the presence of an alkylating agent and under
conditions which are foreseen to be suitable for the formation of the undesired dialkyl
derivatives: in fact, a very high selectivity (>99%, as evident from the following examples)
is achieved in the presence of a very high dialkyl carbonate excess (from 10 to 50 moles
for mole of compound I), which is actually used as the reaction solvent. When X, in
formula I, is COOH, the reaction according to the invention occurs with initial formation
of arylacetoester Ar-CH2-COOR (U. Romano, Chimica oggi, 1984, 37), which is
subsequently mono-alkylated at the a-position.
[0013] A further characteristic distinguishing the batch process of the present invention
from the one in vapour phase of the prior art resides in the fact that the reaction can be
carried out in absence of the phase-transfer catalyst which is essential in the vapour
phase. On the contrary, the presence of bases, such as alkali metal carbonates, for
example K2C03, is necessary. The base amount can range from catalytic to
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stoichiometric amounts, or even excess amounts to the stoichiometric ratio (related to
compound I). Since the temperatures required to obtain good results in "normal" times
from the industrial point of view are generally higher than 100[deg.]C, and since
dimethyl carbonate (DMC) boils under said temperature range, the monomethylation
reaction is carried out in apparatuses capable of bearing the required pressures, which,
on the other hand, are relatively mild, generally non exceeding 15-25 bars.
[0014] It should be noted that monoalkylation of compounds I batchwise, according to
the invention, is a much simpler process than that in vapour phase which, as it happens
with all the continuous processes, requires a precise optimisation, particularly as far as
the flow rate of the reagents is concerned. According to the present invention, on the
contrary, it is sufficient to place compound I, the dialkyl carbonate and the base (in a
molar ratio from 1:1:0.005 to 1:50:5) in the reactor and to heat the mixture to
temperatures ranging from about 100 [deg.] C to about 270 C, preferably from about
120 [deg.]C to about 250 C, for times varying from about 2 hours to about 40 hours.
After that, the reaction mixture can be worked up conventionally, by filtering the solid
residue (usually K2C03), recovering the dialkyl carbonate excess and isolating the
desired product by distillation or crystallization.
[0015] The following Examples further illustrate the invention.
Example 1
2-(3-Methoxycarbonyl-phenyl)propionitrile
[0016] The reaction for the selective methylation is carried out placing into a 250 ml (O =
45 mm) stainless steel autoclave a mixture of (3-methoxycarbonyl-phenyl)acetonitrile (10
g, 96% purity), dimethyl carbonate (86 ml) and K2C03 (12 g), in the 1:18:2 molar ratio.
Air is replaced by a N2 stream; then the mixture is heated at a temperature of
180[deg.]C, with stirring. During the reaction, which is completed within 6 hours, the
pressure raises from 7 bars, reached at the working temperature, to about 12 bars after
5 hours of isothermal heating. After cooling K2C03 is filtered off, DMC is recovered and
the residue is distilled (b.p. 0.08 = 109-110[deg.]C) to obtain 8.3 g of
2-(3-methoxycarbonyl-phenyl)propionitrile which is 99,5% pure (78% yield) (>99%
selectivity in monomethylation).
[0017] The same result is obtained, under the same conditions, by decreasing the
K2C03 amount to 1/1 Oth of that described above.
[0018] From the resulting product, the corresponding 3-(1-cyanoethyl)benzoic acid is
obtained by means of selective alkali hydrolysis, which is a known intermediate for the
preparation of ketoprofen.
Example 2
2-(3-Methoxycarbonyl-phenyl)butyronitrile
[0019] The procedure of example (1) is followed, using diethyl carbonate instead of
dimethyl carbonate. The reaction, which is completed within about 24 hours, takes place
at a pressure ranging from 3 bars, which is the value achieved at the working pressure,
to about 7 bars.
[0020] The title product is obtained in a 80% yield; the monomethylation selectivity being
>99%.
Example 3
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2-(3-Benzoyl-phenyl)propionitrile
[0021] A mixture of (3-benzoylphenyl)acetonitrile (1 g), dimethyl carbonate (15 ml) and
K2C03 (3 g) in the 1:40:5 molar ratio, is reacted in a steel autoclave at the temperature
of 140 [deg.]C for 10 hours and 30 minutes. After recovering DMC, 0.85 g of the title
product are obtained, with a monomethylation selectivity >99% (80% yield), which is
hydrolyzed to obtain ketoprofen by known methods.
Example 4
2-Phenylpropionitrile
[0022] The procedure of example (1) is followed, using phenylacetonitrile, dimethyl
carbonate and a catalytic amount of alkali carbonate in a 1:18:0.05 molar ratio. Li2C03,
Na2CO3, K2C03 and Cs2 C03 were used respectively, to obtain the following results:
Example 5
Naproxen
a) Monomethylation of methyl (6-methoxy-2-naphthyl)acetate
[0023] The reaction for the selective methylation is carried out placing a mixture of
methyl- (6-methoxy-2-naphthyl)acetate (USP 3,896,157; 2 g), dimethyl carbonate (10 ml)
and K2C03 (0.9 g), in the 1:15:1.5 molar ratio into a 250 ml (Oi = 45 mm) stainless steel
autoclave. Air is replaced by a N2 stream; then the mixture is heated to 210[deg.]C, with
stirring. During the reaction, which is completed within 6 hours, the pressure rises from
18 bars, which are achieved at the working temperature, to about 20 bars after 5 hours
of isothermal heating. K2C03 is filtered off and the residue is hydrolyzed directly.
[0024] Alternatively, the reaction for the selective methylation can be carried out by
reacting a mixture of (6-methoxy-2-naphthyl)acetic acid, dimethyl carbonate and K2C03,
in the 1:20:2 molar ratio, in autoclave at a temperature of 220 [deg.] C. The reaction is
completed within about 8 hours. (In this case DMC acts first as a methylating agent for
the carboxylic group, through an already known reaction; then the monomethylation
reaction takes place on the resulting ester).
b) Hydrolysis of methyl 2(methoxy-2-naphthyl)pro-pionate
[0025] The reaction product is refluxed in 100 ml of 5% NaOH for 1 hour and 30
minutes. The precipitate is neutralized and filtered, to obtain 1.8 g of Naproxen. Yield
(starting from the not methylated ester): 90%.
Example 6
Flurbiprofen
[0026] Following the procedure of example (5), a mixture of 2 g of methyl (2-fluoro-
4-biphenyl)acetate (USP 3,755,427), 14 ml of dimethyl carbonate and 1.7 g of K2C03, in
a 1:20:1.5 molar ratio, is reacted in autoclave at a temperature of 210[deg.]C; the
reaction is completed within 6 hours. The resulting product, methyl a-(2-fluoro-
4-biphenyl)propionate, is hydrolyzed with 100 ml of 5% NaOH, as in example 5, to give
a-(2-fluoro-4-biphenyl)propionic acid (Flurbiprofen) with 100 ml of 5% NaOH, as in
example 5. Yield (starting from the not methylated ester): 85%.
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Example 7
Ibuprofen
[0027] Following the procedure of example 1, a mixture of 2 g of methyl
(4-isobutylphenyl)acetate (EP 347,939), 16 ml of dimethyl carbonate and 2 g of K2C03,
in a 1:20:1.5 molar ratio, is reacted in autoclave at a temperature of 210[deg.]C. The
reaction is completed within about 8 hours. The product, methyl
a-(4-isobutylphenyl)propionate, is hydrolyzed to a-(4-isobutyl)propionic acid (Ibuprofen)
as in the examples above. Yield (starting from the not methylated ester): 90%.
Example 8
a-Phenylpropionic acid
[0028] Following the procedure of examples 5-7, a mixture of 2 g of methyl
phenylacetate, 23 ml of dimethyl carbonate, 2.8 g of K2 C03, in a 1:20:1.5 molar ratio, is
reacted in autoclave at a temperature of 210[deg.]C for 8 hours. The product, methyl
a-phenylpropionate, is hydrolyzed to a-phenylpropionic acid according to the procedure
of example 5. Yield 85%. a-Phenylmethylpropionate can be obtained under similar
conditions, by reacting a mixture of phenylacetic acid, dimethyl carbonate and K2C03, in
a 1:20:2 molar ratio, in autoclave at a temperature of 225 C, for 15 hours.
Example 9
Ethyl a-phenylbutyrate
[0029] A mixture of 2 g of ethyl phenylacetate, 30 ml of diethyl carbonate, 2.5 g of
K2C03, in the 1:20:1.5 molar ratio, is reacted in autoclave at 225 [deg.]C. After 14 hours,
a 30% conversion is achieved, with formation of ethyl a-phenylbutyrate as the mono-C-
ethylation product.
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Claims: EP0525506  (A2) ― 1993-02-03
A process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters and
arylacetic acids.  
Claims of EP0525506 (A2)
The EPO does not accept any responsibility for the accuracy of data and information
originating from other authorities than the EPO; in particular, the EPO does not
guarantee that they are complete, up-to-date or fit for specific purposes.
1. A process for the a-monoalkylation of arylacetonitriles, arylacetoesters or arylacetic
acids of formula (I) by means of treatment with dialkyl carbonates, to give a-aryl-
a-alkylacetonitriles or a-aryl-a-al- kylacetoesters of formula (II), according to the scheme
wherein Ar is an aromatic or hetero-aromatic ring, for example a phenyl, naphthyl,
thiophene ring and the like, optionally having one or more substituents, such as C1-C4
alkyl, C1-C4 alkoxy, halogens, carboxy, C1-C4 alkoxycarbonyl, arylcarbonyl, nitrile
groups,
X is a CN, COOR or COOH group,
X' is a CN or COOR group,
R is a C1-C4 alkyl group,
characterized in that compound (I), a dialkyl carbonate and a base are reacted in liquid
phase in molar ratios ranging from 1:1:0.005 to 1:50:5, at temperatures ranging from
about 100[deg.]C to about 270 [deg.]C.
2. A process according to claim 1, characterized in that dimethyl carbonate is used as
the dialkyl carbonate.
3. A process according to claim 1, characterized in that diethyl carbonate is used as the
dialkyl carbonate.
4. A process according to claims 1-3, characterized in that alkali metal carbonates or
bicarbonates are used as the bases.
5. A process according to claims 1-4, characterized in that the reaction is carried out at
temperatures ranging from about 120 [deg.] C to about 250 [deg.] C.
6. A process according to claims 1-5, characterized in that a compound (I), selected
from the group consisting of (3-methoxycarbonyl-phenyl)acetonitrile,
(3-benzoylphenyl)acetonitrile, the esters of (6-methoxy-2-naphthyl)acetic, (2-fluoro-
4-biphenyl)acetic, (4-isobutylphenyl)acetic, (3-benzoylphenyl)acetic and phenylacetic
acids and the acids themselves, is subjected to a-monomethylation.
Last updated: 14.03.2012  Worldwide Database  5.7.38; 92p
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Name not available

Claims: US5278333  (A) ― 1994-01-11Process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters andarylacetic acids  Claims of US5278333 (A)The EPO does not accept any responsibility for the accuracy of data and informationoriginating from other authorities than the EPO; in particular, the EPO does notguarantee that they are complete, up-to-date or fit for specific purposes.We claim:1. Process for the preparation of an .alpha.-substituted compound of the formula:##STR2## in which Ar is phenyl, naphthyl, or thienyl, each of which is unsubstituted forsubstituted with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo,carboxy, alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy group, arylcarbonyl, orcyano, X' is --CN or --COOR, and R is alkyl of 1 to 4 carbon atoms,which comprises heating a reaction mixture consisting essentially of (i) an acetic acidderivative of the formula:Ar--CH2 --Xin which Ar is as previously defined and X is --CN, --COOH, or --COOR, in which R is aspreviously defined, (ii) from 1 to 50 molar equivalents, per mole of acetic acid derivative,of a dialkyl carbonate of the formula ROCOOR, in which R is as previously defined, and(iii) from 0.005 to 5 molar equivalents, per mole of acetic acid derivative, of a base,in liquid phase at temperatures of from about 100 DEG C. to about 270 DEG C.2. The process according to claim 1 wherein the dialkyl carbonate is dimethyl carbonate.3. The process according to claim 1 wherein the dialkyl carbonate is diethyl carbonate.4. The process according to claim 1 wherein the base is an alkali earth metal carbonateor bicarbonate.5. The process according to claim 1 wherein the reaction mixture is heated attemperatures of from about 120 DEG C. to about 250 DEG C.6. The process according to claim 1 wherein Ar is phenyl, 3-methoxycarbonylphenyl,3-benzoylphenyl, or 6-methoxynaphth-2-yl.Last updated: 14.03.2012  Worldwide Database  5.7.38; 92pEspacenetEspacenet - Claims http://worldwide.espacenet.com/publicationDetails/claims?CC=US&...1 di 1 03/07/2012 17:00Description: US5278333  (A) ― 1994-01-11Process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters andarylacetic acids  Description of US5278333 (A)The EPO does not accept any responsibility for the accuracy of data and informationoriginating from other authorities than the EPO; in particular, the EPO does notguarantee that they are complete, up-to-date or fit for specific purposes.The present invention relates to a process for the .alpha.-monoalkylation ofarylacetonitriles, arylacetoesters and arylacetic acids of formula (I), to obtain.alpha.-aryl-.alpha.-alkyl-acetonitriles or .alpha.-aryl-.alpha.-alkyl-acetoesters of formula(II), using dialkyl carbonates in liquid phase, according to the following scheme:##STR1## wherein Ar is an aromatic or hetero-aromatic ring, for example a phenyl,naphthyl, thiophene ring and the like, optionally having one or more substituents, suchas C1 -C4 alkyl, C1 -C4 alkoxy, halogens, carboxy, C1 -C4 alkoxycarbonyl, arylcarbonyl,nitrile groups,X is a CN, COOR or COOH group,X' is a CN or COOR group,R is a C1 -C4 alkyl group, preferably methyl or ethyl.The resulting compounds of formula (II) are useful intermediates; in particular, they areuseful to prepare, by means of simple hydrolysis of the CN or COOR groups,.alpha.-arylpropionic acids, some of which are important from the therapeutical point ofview: see, for instance, ibuprofen, naproxen, ketoprofen, fluorbiprofen and the like.According to the prior art techniques, particularly, the main processes for the preparationof arylpropionic acid comprise: (1) direct or indirect methylation of the correspondingarylacetic acid derivatives; (2) in the case of ketoprofen, introduction of the carbonylfunction on the aromatic ring; (3) introduction of the propionic group as such; (4)rearrangements of propiophenones (the relevant literature being extremely wide: see, forinstance, U.S. Pat. No. 3,641,127, DOS 2,646,792, DOS 2,744,832, U.S. Pat. Nos.3,959,364, 3,720,708)..alpha.-Arylpropionic acids (particularly those useful as antiinflammatory drugs), areimportant from the economic point of view, therefore even complex preparationprocesses can be industrially interesting, whenever they yield products which are pureor can easily be purified.The process which is apparently the simplest consists in the selective introduction of amethyl group on the reactive methylene of an arylacetonitrile. Said reaction was studiedaccurately also under phase-transfer catalysis conditions (M. Mikolajczyk et al.,Tetrahedron Lett. 3757 (1975), but it always gave reaction mixtures; in fact, even in thepresence of unconverted reagent, the formation of the dimethyl derivative could not beavoided, which makes the separation of the monomethyl derivative difficult andexpensive.EspacenetEspacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...1 di 6 03/07/2012 16:59On the contrary, no alkylation reactions of arylacetoesters are disclosed: in fact, in thiscase, the --CH2 -- group is not acidic enough, therefore the carbanion forms withdifficulty, and anyhow the ester will be hydrolyzed under phase-transfer conditions.However, arylacetoesters are known to act as intermediates for the above mentionedantiinflammatory drugs when they are transformed, by means of strong bases, such assodium hydride, into the corresponding anions which are then treated with methyliodide. Nevertheless, the monomethylation selectivity is never high: see, for example,monomethylation of methyl (6-methoxy-2-naphthyl)acetate to methyl 2-(6-methoxy-2-naphthyl)propionate (U.S. Pat. No. 3,896,157).Recently, dialkyl carbonates have been reported to act as alkylation agents on phenols,mercaptans, amines, arylacetonitriles and other CH-acid compounds (P. Tundo et al.,Ind. Eng. Chem. Res. 28, 881 (1989)). The reaction is carried out continuously on acolumn containing catalytic amounts of the base and the phase-transfer catalyst and itproceeds without base consumption since the acidity is removed from the reactionmixture in form of CO2, due to the instability of the O-alkylcarbonic acids, whichrepresent the leaving group of the dialkyl carbonates during the methylation reaction.The continuous alkylation of methyl-phenylacetate has also been described (Italianpatent appl. n DEG 20159A/90), but this reaction proceeds markedly more slowly thanthat to the corresponding nitriles. The reported conversions are of 60% only.However, continuous reactions in vapour phase, such as those disclosed in EP 240,863and U.S. Pat. No. 4,894,471, and in Italian Pat. appl. 20159A/90, cannot be used in caseof high-boiling products, since such products are difficult to vapourize: the high boilingpoint of many arylacetonitriles and arylacetoesters can lead to the decompositionthereof, due to the extended time at high temperature on the fix bed in which thereaction takes place.Now it has surprisingly been found that .alpha.-monoalkylation of arylacetonitriles,arylacetoesters and arylacetic acids with dialkyl carbonates proceeds in a highlysatisfactory way from the point of view of both selectivity and yields also when such areaction is carried out in the liquid phase, in batch processes, which obviously do notsuffer from the problem of the vapourizing of the high-boiling substrates, which areliable to heat-decomposition. The high selectivity with respect to monoalkyl derivativesachieved by the invention is definitely unforeseeable, since said monoalkyl derivatives,on the contrary to what happens in case of the vapour phase process disclosed in theabove cited EP 240,863, U.S. Pat. No. 4,894,471 and It. Pat. appl. 20159A/90, remain fora long time in the reaction medium, in the presence of an alkylating agent and underconditions which are foreseen to be suitable for the formation of the undesired dialkylderivatives: in fact, a very high selectivity (>99%, as evident from the following examples)is achieved in the presence of a very high dialkyl carbonate excess (from 10 to 50 molesfor mole of compound I), which is actually used as the reaction solvent. When X, informula I, is COOH, the reaction according to the invention occurs with initial formationof arylacetoester Ar--CH2 --COOR (U. Romano, Chimica oggi, 1984, 37), which issubsequently mono-alkylated at the .alpha.-position.A further characteristic distinguishing the batch process of the present invention fromthe one in vapour phase of the prior art resides in the fact that the reaction can becarried out in absence of the phase-transfer catalyst which is essential in the vapourphase. On the contrary, the presence of bases, such as alkali metal carbonates, forexample K2 CO3, is necessary. The base amount can range from catalytic tostoichiometric amounts, or even excess amounts to the stoichiometric ratio (related tocompound I). Since the temperatures required to obtain good results in "normal" timesfrom the industrial point of view are generally higher than 100 DEG C., and sincedimethyl carbonate (DMC) boils under said temperature range, the monomethylationEspacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...2 di 6 03/07/2012 16:59reaction is carried out in apparatuses capable of bearing the required pressures, which,o the other hand, are relatively mild, generally not exceeding 15-25 bars.It should be noted that monoalkylation of compounds I batchwise, according to theinvention, is a much simpler process than that in vapour phase which, as it happenswith all the continuous processes, requires a precise optimisation, particularly as far asthe flow rate of the reagents is concerned. According to the present invention, on thecontrary, it is sufficient to place compound I, the dialkyl carbonate and the base (in amolar ratio from 1:1:0.005 to 1:50:5) in the reactor and to heat the mixture totemperatures ranging from about 100 DEG C. to about 270 DEG C., preferably fromabout 120 DEG C. to about 250 DEG C., for times varying from about 2 hours to about40 hours. After that, the reaction mixture can be worked up conventionally, by filteringthe solid residue (usually K2 CO3), recovering the dialkyl carbonate excess and isolatingthe desired product by distillation or crystallization.The following Examples further illustrate the invention.EXAMPLE 12-(3-Methoxycarbonyl-phenyl)propionitrileThe reaction for the selective methylation is carried out placing into a 250 ml (.phi.i =45mm) stainless steel autoclave a mixture of (3-methoxycarbonylphenyl)acetonitrile (10 g,96% purity), dimethyl carbonate (86 ml) and K2 CO3 (12 g), in the 1:18:2 molar ratio. Airis replaced by a N2 stream; then the mixture is heated at a temperature of 180 DEG C.,with stirring. During the reaction, which is completed within 6 hours, the pressure raisesfrom 7 bars, reached at the working temperature, to about 12 bars after 5 hours ofisothermal heating. After cooling K2 CO3 is filtered off, DMC is recovered and theresidue is distilled (b.p. 0.078=109 DEG-110 DEG C.) to obtain 8.3 g of2-(3-methoxycarbonyl-phenyl)propionitrile which is 99,5% pure (78% yield) (>99%selectivity in monomethylation).The same result is obtained, under the same conditions, by decreasing the K2 CO3amount to 1/10th of that described above.From the resulting product, the corresponding 3-(1-cyanoethyl)benzoic acid is obtainedby means of selective alkali hydrolysis, which is a known intermediate for thepreparation of ketoprofen.EXAMPLE 22-(3-Methoxycarbonyl-phenyl)butyronitrileThe procedure of example (1) is followed, using diethyl carbonate instead of dimethylcarbonate. The reaction, which is completed within about 24 hours, takes place at apressure ranging from 3 bars, which is the value achieved at the working pressure, toabout 7 bars.The title product is obtained in a 80% yield; the monomethylation selectivity being >99%.EXAMPLE 32-(3-Benzoyl-phenyl)propionitrileA mixture of (3-benzoylphenyl)acetonitrile (1 g), dimethyl carbonate (15 ml) and K2 CO3(3 g) in the 1:40:5 molar ratio, is reacted in a steel autoclave at the temperature of 140Espacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...3 di 6 03/07/2012 16:59DEG C. for 10 hours and 30 minutes. After recovering DMC, 0.85 g of the title productare obtained, with a monomethylation selectivity >99% (80% yield), which is hydrolyzedto obtain ketoprofen by known methods.EXAMPLE 42-PhenylpropionitrileThe procedure of example (1) is followed, using phenylacetonitrile, dimethyl carbonateand a catalytic amount of alkali carbonate in a 1:18:0.05 molar ratio. Li2 CO3, Na2 CO3,K2 CO3 and Cs2 CO3 were used respectively, to obtain the following results:______________________________________reactiontime conversionmonomethylationbase (h) (%) selectivity______________________________________Li2 CO37.5 5Na2 CO38.75 89 >99%K2 CO37.5 98 >99%Cs2 CO35.0 99 >99%______________________________________EXAMPLE 5a) Monomethylation of methyl (6-methoxy-2-naphthyl)acetateThe reaction for the selective methylation is carried out placing a mixture of methyl(6-methoxy-2-naphthyl)acetate (U.S. Pat. No. 3,896,157; 2 g), dimethyl carbonate (10ml) and K2 CO3 (0.9 g), in the 1:15:1.5 molar ratio into a 250 ml (.phi.i =45 mm)stainless steel autoclave. Air is replaced by a N2 stream; then the mixture is heated to210 DEG C., with stirring. During the reaction, which is completed within 6 hours, thepressure rises from 18 bars, which are achieved at the working temperature, to about 20bars after 5 hours of isothermal heating. K2 CO3 is filtered off and the residue ishydrolyzed directly.Alternatively, the reaction for the selective methylation can be carried out by reacting aEspacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...4 di 6 03/07/2012 16:59mixture of (6-methoxy-2-naphthyl)acetic acid, dimethyl carbonate and K2 CO3, in the1:20:2 molar ratio, in autoclave at a temperature of 220 DEG C. The reaction iscompleted within about 8 hours. (In this case DMC acts first as a methylating agent forthe carboxylic group, through an already known reaction; then the monomethylationreaction takes place on the resulting ester).b) Hydrolysis of methyl 2-(methoxy-2-naphthyl)propionateThe reaction product is refluxed in 100 ml of 5% NaOH for 1 hour and 30 minutes. Theprecipitate is neutralized and filtered, to obtain 1.8 g of Naproxen. Yield (starting fromthe not methylated ester): 90%.EXAMPLE 6FlurbiprofenFollowing the procedure of example (5), a mixture of 2 g of methyl (2-fluoro-4-biphenyl)acetate (U.S. Pat. No. 3,755,427), 14 ml of dimethyl carbonate and 1.7 g ofK2 CO3, in a 1:20:1.5 molar ratio, is reacted in autoclave at a temperature of 210 DEGC.; the reaction is completed within 6 hours. The resulting product, methyl .alpha.-(2-fluoro-4-biphenyl)propionate, is hydrolyzed with 100 ml of 5% NaOH, as in example 5, togive .alpha.-(2-fluoro-4-biphenyl)propionic acid (Flurbiprofen) with 100 ml of 5% NaOH,as in example 5. Yield (starting from the not methylated ester): 85%.EXAMPLE 7IbuprofenFollowing the procedure of example 1, a mixture of 2 g of methyl(4-isobutylphenyl)acetate (EP 347,939), 16 ml of dimethyl carbonate and 2 g of K2 CO3,in a 1:20:1.5 molar ratio, is reacted in autoclave at a temperature of 210 DEG C. Thereaction is completed within about 8 hours. The product, methyl .alpha.-(4-isobutylphenyl)propionate, is hydrolyzed to .alpha.-(4-isobutyl)propionic acid (Ibuprofen)as in the examples above. Yield (starting from the not methylated ester): 90%.EXAMPLE 8.alpha.-Phenylpropionic acidFollowing the procedure of examples 5-7, a mixture of 2 g of methyl phenylacetate, 23ml of dimethyl carbonate, 2.8 g of K2 CO3, in a 1:20:1.5 molar ratio, is reacted inautoclave at a temperature of 210 DEG C. for 8 hours. The product, methyl.alpha.-phenylpropionate, is hydrolyzed to .alpha.-phenylpropionic acid according to theprocedure of example 5. Yield 85%..alpha.-Phenylmethylpropionate can be obtained under similar conditions, by reacting amixture of phenylacetic acid, dimethyl carbonate and K2 CO3, in a 1:20:2 molar ratio, inautoclave at a temperature of 225 DEG C., for 15 hours.EXAMPLE 9Ethyl .alpha.-phenylbutyrateA mixture of 2 g of ethyl phenylacetate, 30 ml of diethyl carbonate, 2.5 g of K2 CO3, inthe 1:20:1.5 molar ratio, is reacted in autoclave at 225 DEG C. After 14 hours, a 30%conversion is achieved, with formation of ethyl .alpha.-phenylbutyrate as the mono-C-Espacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...5 di 6 03/07/2012 16:59ethylation product.Last updated: 14.03.2012  Worldwide Database  5.7.38; 92pEspacenet - Description http://worldwide.espacenet.com/publicationDetails/description?CC=...6 di 6 03/07/2012 16:59

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A process for the alpha-monoalkylation of arylacetonitriles, arylacetoesters and arylacetic acids.

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