MANUFACTURE OF 1-SUBSTITUTED METHYLIDENE COMPOUNDS
This application claims priority to European application
No. EP 12168163.9 filed on 16 May 2012, the whole content of this application
being incorporated herein by reference for all purposes.
The present invention concerns a method for the manufacture of
1-substituted methylidene compounds.
1-substituted pyrazoles, e.g. 1-alkylpyrazoles, as is described
in US 201 1/000962, are intermediates for fungicides.
Intermediates which can be used to provide such fungicides are compounds
having the formula
In which R1 and R2 are certain organic substituents and Y is an ester group,
a nitrile group or an amido group.
Compounds of formula (I) can be manufactured in a process which
comprises several steps. For example, a compound of formula R -C(0)-CH 2Y is
reacted with an orthoformate in the presence of a molar excess of an anhydride
of a carboxylic acid, e.g. in the presence of acetic acid anhydride, to provide an
intermediate alkoxymethylidene compound which in turn is reacted with a
monosubstituted hydrazine to form the compound of formula (I). This is
described on page 11 of WO 2012/010692. The use of an excess of an anhydride
of a carboxylic acid in the reaction between the compound of
formula R -C(0)CH 2Y and the orthoformate provides a lot of waste.
Object of the present invention is to provide an improved process to
provide methylidene compounds useful for the manufacture of pyrazoles.
The present invention provides a method for the manufacture of a
compound of formula (I)
by the reaction of a compound of formula (II), R -C(0)-CH 2Y, with an
orthoformate of formula (III), HC-(OR ) 3 in the presence of a base
wherein
R2 is selected from C1 to C4 alkyl groups are substituted by one, two or three
halogen atoms selected from the group consisting of F, CI and Br or a CF3
group ;
R3 is CI to C8 alkyl ; C3 to C8 cycloalkyl ; C2 to C8 alkenyl ; benzyl or phenyl ;
CI to C8 alkyl, C3 to C8 cycloalkyl, C2 to C8 alkenyl, benzyl or phenyl
substituted by one or more groups selected from the group consisting of R', X,
OR', SR', NR' 2, SiR'3, COOR', C(0)R', CN and CONR' 2 wherein R' is H or a
CI to C12 group, and X is fluorine, chlorine, bromine and iodine, preferably
fluorine or chlorine ;
Y is selected from the group consisting of C(0)OR 4, CN and C(0)NR 5R6
wherein R4, R5 and R6 are independently of each other are selected from the
group consisting of CI to C12 alkyl ; C3 to C8 cycloalkyl ; C2 to C12 alkenyl ;
C2 to C12 alkynyl ; C6 to C8 aryl ; C7 to C19 arylalkyl ; and C7 to C19
alkylaryl ; each of which may be substituted by one or more groups selected
from the group consisting of R X, OR', SR', NR' 2, SiR'3, COOR', C(0)R', CN
and CONR' 2 wherein R' is H or a CI to CI2 group ; and R5 and R6 together with
the nitrogen atom to which they are attached may form a 5-membered or
6-membered ring which may optionally contain one or more further heteroatoms
selected from the group consisting of O, S and an S0 2 group and which may be
substituted by one or more groups selected from the group consisting of R', X,
OR', SR', NR' 2, SiR' 3, COOR', C(0)R', CN and CONR' 2 wherein R' is H or a
CI to C12 group ; and X is fluorine, chlorine, bromine and iodine, preferably
fluorine or chlorine ;
A is OR3 wherein R3 has the meaning given above ;
Z is selected from the group consisting of O, S and N+R R8 wherein R7 and R8
independently from each other are selected from the group consisting of CI
to C12 alkyl ; C3 to C8 cycloalkyl ; C2 to C12 alkenyl ; C2 to C12 alkynyl ; C6
to C8 aryl ; C7 to C19 arylalkyl ; and C7 to C19 alkylaryl ; each of which may
be substituted by one or more groups selected from the group consisting of R',
X, OR', SR', NR' 2, SiR's, COOR', C(0)R', CN and CONR' 2 wherein R' is H or
a CI to CI group ; and R7 and R8 together with the nitrogen atom to which they
are attached may form a 5-membered or 6-membered ring which may optionally
contain one or more further heteroatoms selected from the group consisting of O,
S and an S0 2 group and which may be substituted by one or more groups
selected from the group consisting of R', X, OR', SR', NR' 2, SiR' 3, COOR',
C(0)R', CN and CONR' 2 wherein R' is H or a CI to C12 group ; and X is
fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine ;
and when Z is N R R8 the positive charge is balanced by an anion, e.g. by a
sulfate anion or CI .
R1 preferably is CI to C5 alkyl ; or CI to C5 alkyl, substituted by at least
one halogen atom, and more preferably, R1 is methyl, ethyl, n-propyl, i-propyl,
n-butyl, s-butyl, t-butyl or n-pentyl. Especially preferably, R is methyl or ethyl,
most preferab ly, methyl.
Preferably, in the context of the present invention, R2 is chloromethyl,
dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chlorobromomethyl, chlorofluoromethyl, chlorodifluoromethyl,
fluorodichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 1-chloroethyl, 2,2-dichloroethyl, 1,2-dichloroethyl,
2-chlorofluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,
2,2,2-trichloroethyl, pentafluoroethyl and l,l,l-trifluoro-prop-2-yl ; especially
preferably, R2 is CH2F, CHF2, CC1F2 or CF3. In many fungicidal pyrazoles, R2 is
CHF2. Thus, in the frame of the present invention, R2 is most preferably CC1F2
or CHF2. If R2 is CC1F2, it can be reduced to CHF2 as described
in WO 2012/010692 using hydrides, Zn/alcohol or H2/catalyst, e.g. Pd.
Preferably, Z is O.
Preferably, Y is C(0)OR 4 wherein R4 is a CI to C5 alkyl group.
More preferably, R1 is methyl or ethyl, R2 is CHF2, CC1F2 or CF3, and R3
is methyl or ethyl.
Preferably, R , R4, R5, R6, R7 and R8 are methyl, ethyl, propyl or butyl, and
especially, methyl or ethyl.
Especially preferably, R1 is methyl, R2 is CHF2, CC1F2 or CF3, and R3 and
R4 are methyl or ethyl.
The base may be any inorganic or organic Bronstedt base.
Inorganic bases can for instance be selected from alkali metal phosphates,
acetates, hydroxides, carbonates and hydrogen carbonates ; for example, K2CO3,
Cs2C0 3, Na2C0 3, NaHC0 3, K3P0 4, NaOAc, NaOH, LiOH or KOH are useful
inorganic bases.
Organic bases are preferred. Preferred organic bases comprise at least one
3-coordinated N atom.
For example, amines having the formula (IV), NR 1, are suitable.
According to one embodiment, R9, R 10 and R 11 are the same or different
and are H or CI to CIO alkyl with the proviso that at least one of R9, R 10 and R 11
is not H. Preferably, R9, R 10 and R 11 are CI to C3 alkyl ; especially preferably,
R9, R 10 and R 11 are ethyl.
According to another embodiment, at least R9 and R 10 form a saturated ring
with 3 to 8 members ; R 11 is H or CI to CIO alkyl. The saturated ring may
comprise one or more hetero atoms, selected from N, O and S. Examples are
aziridine, pyrrolidine, piperidine, N-methylpyrolidine, N-methylpiperidine and
piperazine, and morpholine. Examples for aromatic amines are, for example,
imidazole, pyridine, pyrimidine, dimethylaminopyridine ; but other aromatic
amines may also be used.
According to still another embodiment, R9 forms a saturated or unsaturated
ring with 5 to 8 members ; R 10 and R 11 are H or CI to CIO alkyl. Examples are
cyclohexylamine, aniline and methylaniline.
According to another embodiment, R9, R 10 and R 11 form a cyclic system.
Examples are l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and
l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
Trialkylamines wherein R9, R 10 and R 11 are CI to C4 alkyl, more
preferably, C1 to C3 alkyl, and most preferably are methyl or ethyl, are
especially preferred.
The base, especially the amine, is preferably applied in catalytically
amounts. Preferably, the molar ratio between the base, especially the amine, and
the compound of formula (II) is equal to or greater than 0.001 :1. Preferably, it is
equal to or lower than 0.1:1. A preferred range for the molar ratio of base and
the compound of formula (II) is from 0.00 1:1 to 0.1:1, and more preferably, it is
from 0.001:1 to 0.05:1.
The reaction between the compound of formula (II) and (III) is performed
at a temperature which allows for a reasonably fast reaction. Preferably, the
temperature is equal to or greater than 80°C. More preferably, it is equal to or
greater than 90°C. Especially preferably, it is equal to or greater than 100°C.
The upper limit of the reaction temperature is selected such that no
undesired amounts of side reactions take place. Often, the reaction is performed
at a temperature equal to or lower than 180°C, preferably, equal to or lower
than 160°C.
If desired, the reaction between compounds of formula (II) and (III) can be
performed in the presence of one or more high boiling solvents, for example, in
the presence of at least one solvent selected from the group consisting of aprotic
organic solvents. According to a preferred embodiment, an excess of the
compound of formula (III) is applied as solvent. Triethylortho formate is the
preferred compound of formula (III), and thus, it is the especially preferred
solvent.
In said reaction between the compounds of formulae (II) and (III), an
alcohol R OH is formed. The alcohol is generally removed from the reaction
equilibrium by distillation. The alcohol is often very pure and must not be
dumped, can be used as such, e.g. in chemical processes as reactant or solvent.
The reaction can be performed under ambient pressure, in a vacuum or at a
pressure higher than ambient pressure. Since, as mentioned above, an alcohol
R OH is removed from the reaction, the reaction preferably is performed at
ambient pressure or under applying a vacuum.
If desired, the reaction can be performed in the presence of an inert gas,
e.g. in the presence ofN2.
The reaction temperature generally is selected such that the reaction is
performed reasonably fast with low side reactions, if any. It may be dependent
from the starting materials and the base used. Preferably, the reaction
temperature is equal to or higher than 80°C. Preferably, it is equal to or lower
than 180°C. A preferred range for the reaction temperature is from 80 to 150°C.
The reaction time may be dependent from the reaction temperature, the
starting materials and the base used. It may range from 1 minute to 5 hours.
Often, it will be from 30 minutes to 3 hours.
If desired, the working up of the resulting reaction mixture can be
performed according to methods known in the art. For example, solvent can be
evaporated off, and the desired compound of formula (I) can be isolated and
purified by distillation under a vacuum. But due to the high purity of the product
after solvent removal, an additional step of purification is not necessary.
The compounds of formula (I) can be reacted, for example, as is described
in WO 2012/010692, with monosubstituted hydrazines under cyclization to form
the pyrazoles having the formula
Wherein R1, R2 and Y have the meaning given above. Such pyrazoles are
precursors of fungicidal active compounds ; see for example, US 201 1/0009642
and WO 03/070705. Often, in fungicides, the 3-halo group is CHF2. Thus, if a
pyrazole compound is produced having a CC1F2 group, this group can be reduced
to form a difluoromethyl group. The reduction can be performed as described
in WO 2012010692 using metal hydrides, H2/catalyst (e.g. H2/Pd) or
metal/hydrogen source, e.g. Zn/ethanol.
The advantages of the method of the invention are, i.a., a lower energy
consumption because the reaction between the ester and the orthoformate can be
performed at a lower temperature and with a faster reaction rate, no waste
production because no acetic acid anhydride (or any other anhydride) is
necessary, nearly one equivalent of triethylorto formate is consumed, and the
yield is near quantitative and the purity of the product is exceptional.
Should the disclosure of any patents, patent applications, and publications
which are incorporated herein by reference conflict with the description of the
present application to the extent that it may render a term unclear, the present
description shall take precedence.
The following examples are intended to explain the invention in further
detail without the intention to limit it.
General remarks :
Triethylortho formate (TEOF) is commercially available. Ethyl
difluorochloroacetate (ECDFAA) is commercially available from Solvay Fluor
GmbH, Hannover /Deutschland.
Example 1 : Manufacture of 4-chloro-2-[l -ethoxy-meth-(Z)-ylidene]-4,4-
difiuoro-3-oxo-butyric acid ethyl Ester ("EME-CDFAA")
Triethylorthoformate (37 g = 0.25 mol), ECDFAA (10 g = 50 mmol) and
triethylamine (15.6 mg = 0.15 mmol) were given into a flask equipped with a
Liebig condenser suitable for vacuum distillation. The resulting mixture was
heated to 110°C. The pressure was lowered to 300 mbar, and ethanol formed
was distilled off. After 3 hours, the ECDFAA was completely consumed and
converted to the desired EME-CDFAA, and any remaining ethanol was
evaporated off. The resulting mixture was then brought to 100°C, and the
pressure was lowered slowly from 300 mbar to 10 mbar to distill off any excess
of the triethyl orthoformate. 12.2g of an amber- yellow oil with a purity of 99 %
(determined by gas chromatography) remained in the flask. The raw product
could be used immediately without further purification for the next reaction step.
NMR (500 MHz, CHLOROFORM-;/), d ppm (the spectrum shows a
ratio of E to Z compound of 1:2) : 1.25 - 1.35 (4 t, 6 H) ; 4.20 - 4.38 (4 q, 4 H)
and 7.76 (bs, 1 H).
Example 2 (comparison example) : Manufacture of 4-chloro-2-[l-ethoxy-meth-
(Z)-ylidene]-4,4-difiuoro-3-oxo-butyric acid ethyl Ester ("EME-CDFAA") using
acetic acid anhydride
Triethylortho formate (415 g = 2.15 mol), ECDFAA (280 g = 1.4 mol) and
acetic acid anhydride (428 g = 4.2 mol) were given into a flask equipped with a
vacuum distillation cooler. The resulting mixture was heated to 135°C (outer
temperature. Slowly, formed light boilers were distilled off. After 9 hours, the
mixture was heated to 110°C under slowly lowering the pressure from ambient
pressure to a vacuum of 10 mbar ; all light boilers were distilled out of the
reaction mixture. A yellow-brown liquid with a purity of 87 % (determined by
gas chromatography) remained in the flask. The raw product could be used
immediately without further purification for the next reaction step.
NMR (500 MHz, CHLOROFORM-;/), d ppm (the spectrum shows a
ratio of E to Z compound of 1:2.5) : 1.25 - 1.35 (4 t, 6 H) ; 4.20 - 4.38 (4 q, 4 H)
and 7.76 (bs, 1 H).

C L A I M S
1. A method for the manufacture of a compound of formula (I)
by the reaction of a compound of formula (II), R -C(0)-CH 2Y, with an
orthoformate of formula (III), HC-(OR ) 3 in the presence of a base
wherein
R2 is selected from C1to C4 alkyl groups are substituted by one, two or three
halogen atoms selected from the group consisting of F, CI and Br or a CF3
group ;
R3 is CI to C8 alkyl ; C3 to C8 cycloalkyl ; C2 to C8 alkenyl ; benzyl or phenyl ;
CI to C8 alkyl, C3 to C8 cycloalkyl, C2 to C8 alkenyl, benzyl or phenyl
substituted by one or more groups selected from the group consisting of R', X,
OR', SR', NR' 2, SiR'3, COOR', C(0)R', CN and CONR'2 wherein R' is H or a
CI to C12 group, and X is fluorine, chlorine, bromine and iodine ;
Y is selected from the group consisting of C(0)OR 4, CN and C(0)NR 5R6
wherein R4, R5 and R6 are independently of each other are selected from the
group consisting of CI to C12 alkyl ; C3 to C8 cycloalkyl ; C2 to C12 alkenyl ;
C2 to C12 alkynyl ; C6 to C8 aryl ; C7 to C19 arylalkyl ; and C7 to C19
alkylaryl ; each of which may be substituted by one or more groups selected
from the group consisting of R X, OR', SR', NR' 2, SiR'3, COOR', C(0)R', CN
and CONR'2 wherein R' is H or a CI to CI2 group ; and R5 and R6 together with
the nitrogen atom to which they are attached may form a 5-membered or
6-membered ring which may optionally contain one or more further heteroatoms
selected from the group consisting of O, S and an S0 2 group and which may be
substituted by one or more groups selected from the group consisting of R', X,
OR', SR', NR' 2, SiR'3, COOR', C(0)R', CN and CONR' 2 wherein R' is H or a
CI to C12 group ; and X is fluorine, chlorine, bromine and iodine ;
A is OR3 wherein R has the meaning given above ;
Z is selected from the group consisting of O, S and N+R R8 wherein R7 and R8
independently from each other are selected from the group consisting of CI
to C12 alkyl ; C3 to C8 cycloalkyl ; C2 to C12 alkenyl ; C2 to C12 alkynyl ; C6
to C8 aryl ; C7 to C19 arylalkyl ; and C7 to C19 alkylaryl ; each of which may
be substituted by one or more groups selected from the group consisting of R',
X, OR', SR', NR' 2, SiR's, COOR', C(0)R', CN and CONR' 2 wherein R' is H or
a CI to C12 group ; and R7 and R8 together with the nitrogen atom to which they
are attached may form a 5-membered or 6-membered ring which may optionally
contain one or more further heteroatoms selected from the group consisting of O,
S and an S0 2 group and which may be substituted by one or more groups
selected from the group consisting of R', X, OR', SR', NR' 2, SiR' 3, COOR',
C(0)R', CN and CONR' 2 wherein R' is H or a CI to C12 group ; and X is
fluorine, chlorine, bromine and iodine ;
and when Z is N+R R8 the positive charge is balanced by an anion, e.g. by a
sulfate anion or CI .
2. The method of claim 1 wherein R1 is an organic substituent selected
from the group consisting of CI to C5 alkyl.
3. The method of claims 1 or 2 wherein Z is O.
4. The method of anyone of claims 1 to 3 wherein Y is C(0)OR 3 wherein
R3 is a CI to C5 alkyl group.
5. The method of anyone of claims 1 to 4 wherein R2 is selected from the
group consisting of chloromethyl, dichloromethyl, trichloromethyl,
fluoromethyl, difluoromethyl, trifluoromethyl, chlorobromomethyl,
chloro fluoromethyl, chlorodifluoromethyl, fluorodichloromethyl, 1-fluoroethyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-chloroethyl,
2,2-dichloroethyl, 1,2-dichloroethyl, 2-chlorofluoroethyl, 2-chloro-2,2-
difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl
and l,l,l-trifluoro-prop-2-yl.
6. The method of anyone of claims 1 to 5 wherein R2 is CC1F2.
7. The method of anyone of claims 1 to 3 wherein R3, R4, R5, R6, R7
and R8 are CI to C5 alkyl.
8. The method of anyone of claims 1 to 7 wherein the base is N¾ or an
organic base.
9. The method of anyone of claims 1 to 8 wherein the organic base is
selected from primary, secondary and tertiary amines.
10. The method of anyone of claims 1 to 9 wherein the base is selected
from amines having the formula (IV), NR R10R , wherein R9, R10 and R1 1 are
the same or different and are H or CI to CIO alkyl with the proviso that at least
one of R9, R10 and R1 1 is not H ; or wherein at least R9 and R10 form a saturated
ring with 3 to 8 members which optionally may contain one or more hetero
atoms selected from the group consisting of N, O and S, and R1 1 is H or CI
to CIO alkyl ; or wherein R9 forms a saturated or unsaturated ring with 5
to 8 members ; R10 and R1 1 are H or CI to CIO alkyl.
11. The method of claim 10 wherein R9, R10 and R11 are C1 to C3 alkyl.
12. The method of claim 11 wherein R9, R10 and R1 1 are ethyl.
13. The method of anyone of claims 1 to 12 wherein the molar ratio of
base and the compound of formula (II) is from 0.001 :1 to 0.1:1.
14. The method of anyone of claims 1 to 13 wherein the reaction
temperature is from 80 to 150°C.
15. The method of anyone of claims 1 to 14 wherein the reaction time is
from 1 minute to 5 hours.