Process for the Preparation of Enolate Salts of 4-Fluoro-2-hydroxymethylene-3-oxobuty
rates
Field of the Invention
The present invention relates to a process for the preparation of enolate salts of
4-fluoro-2-hydroxymethylene-3-oxobutyrates, as well a process for the preparation of
enol ethers and enol esters from said enolate salts, and to the enolate salts in solid
form. In particular, it relates to a process for the preparation of alkali or alkaline earth
enolates of formula
wherein R is Ci_io alkyl, R2 and R3 are independently hydrogen or fluorine, M is an
alkali or alkaline earth metal, and n s 1 or 2,
a process for the preparation of enol ethers and enol esters of formula
wherein R1, R2 and R3 are as defined above and R4 is C i - alkyl, aryl-Ci-4 alkyl,
C2-6 alkanoyl or aroyl,
as well as the enolate salts of formula I in solid form.
Background of the Invention
Derivatives of 4-fluoro-2-hydroxymethylene-3-oxobutyrates, in particular the enol
ethers of formula III above, wherein R4 is lower alkyl, are valuable intermediates in the
synthesis of heterocyclic compounds such as pyrazoles (see e. g. JP 01-1 13371 A,
US 5 093 347, WO 2005/123690 A1). A known synthesis (cf. WO 2005/123690 A1) of
said enol ethers is based on the reaction of the corresponding 3-oxobutyrates with
trialkyl orthoformates (HC(OR )3), which are relatively expensive, in the presence of
acetic anhydride. The orthoformate and acetic anhydride are both used in excess.
Moreover, the process suffers from poor atom economy because only one of the three
alkoxy groups of the trialkyi orthoformate remains in the product and the other two
combine with acetic anhydride to give acetic acid and the corresponding alkyl acetate
as byproducts.
Accordingly, it was an object of the present invention to provide an alternative method
for the production of the enolates and/or enol ethers or esters of formulae I and III
above, which has an improved atom economy and does not require expensive
reagents.
Summary of the Invention
The problem underlying the present invention has been solved by a process, wherein
an enolate salt of a 4-fluoro-3-oxobutyrate of formula
n+
wherein R is C1-10 alkyl, R2 and R3 are independently hydrogen or fluorine, M is an
alkali or alkaline earth metal, and n is 1 or 2, is reacted with carbon monoxide to obtain
an enolate salt of a 4-fluoro-2-hydroxymethylene-3-oxobutyrate of formula
wherein R , R2, R3, M and are as defined above.
Since carbon monoxide is a gas under the reaction conditions, unreacted carbon
monoxide can easily be recovered after completion of the reaction. Another advantage
of the process according to the invention is the fact that no catalyst is required and no
byproducts are formed.
In another embodiment, the enolate salt of formula I , which has been obtained as de¬
scribed above, is further reacted with an alkylating or acylating reagent of formula
X-R 4 (IV),
wherein R4 is selected from the group consisting of Ci-s alkyl, aryl-Ci--4 alkyl, C2-6 alkanoyl
and aroyl, and X is a leaving group, to give an enol ether or ester of a 4-fluoro-
2-hydroxymethylene-3-oxobutyrate of formula
wherein R1, R2, R3 and R4 are as defined above.
According to the invention, the enolate starting materials of formula I I may conveniently
be prepared from the corresponding 1,1-difluoroethyl methyl ethers of formula
wherein R2 and R3 are as defined above, following the steps of
(i) eliminating fluoromethane in the presence of antimony pentafluoride, to obtain an
acetyl fluoride of formula
wherein R2 and R3 are as defined above,
reacting said acetyl fluoride (VII) with an alkali or alkaline earth chloride to obtain
the corresponding acetyl chloride of formula
wherein R2 and R3 are as defined above,
(iii) reacting said acetyl chloride (VIII) with ketene (CH2=C=0) to obtain the
corresponding acetoacetyl chloride of formula
wherein R2 and R3 are as defined above, and
reacting said acetoacetyl chloride (IX) with an alcohol of formula
R -OH (X),
wherein R1 is as defined above, to obtain the 4-fluoro-3-oxobutyrate of formula
or a tautomer thereof,
wherein R1, R2 and R3 are as defined above,
treating said 4-fluoro-3-oxobutyrate of formula XI with a base of formula
Vn A- (XII),
wherein M and n are as defined above and A- is an anion, preferably selected
from the group consisting of HO- , R-O - , H- , and R , wherein R is Ci alkyl, to
obtain the enolate salt of formula II.
The above process for the preparation of the enolate salts of formula I I from the
corresponding 1,1-difluoroethyl methyl ethers of formula VI is also an object of the
present invention.
The enolate salts of formula I in solid form are likewise an object of the present
invention.
Detailed Description of the Invention
Here and hereinbelow, the expression " -, alkyl" comprises any linear or branched
alkyl groups having 1 to n carbon atoms. For example, "C1-10 alkyl" comprises groups
such as methyl, ethyl, 1-propyl, 1-methylethyl (isopropyl), 1-butyl, 1-methyl propyl (secbutyl),
2-methylpropyl (isobutyl), ,1-dimethylethyl ( -butyl), pentyl, 3-methylbutyl
(isopentyl), ,1-dimethylpropyl ( -pentyl), 2,2-dimethylpropyl (neopentyl), hexyl,
heptyl, octyl, nonyl and decyl. Accordingly, "C-i-e alkyl" comprises groups such as
methyl, ethyl, 1-propyl, 1-methylethyl, 1-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl,
pentyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl and hexyl,
while "Ci - 4 alkyl" comprises methyl, ethyl, 1-propyl, 1-methylethyl, 1-butyl, 1-methyl¬
propyl, 2-methylpropyl and 1,1-dimethylethyl.
Here and hereinbelow, the expression alkyl" comprises C 1- alkyl groups
substituted with one or more aryl groups while the expression "aryl" comprises hydrocarbyl
groups containing at least one aromatic ring, such as, for example, phenyl or
naphthyl. Non-limiting examples of aryl -Ci - alkyl groups are phenylmethyl (benzyl), diphenylmethyl
(benzhydryl), triphenylmethyl (trityl), 2-phenylethyl (phenethyl), 3-phenylpropyl
(hydrocinnamyl), 4-phenylbutyl and naphthylmethyl.
The expression "C2- 6 alkanoyl" comprises acyl group derived from alkanoic acids
having 2 to 6 carbon atoms. Examples of C2- 6 alkanoyl groups are acetyl, propanoyl
(propionyl), butanoyl (butyryl), 2-methylpropanoyl (isobutyryl), pentanoyl (valeryl),
2,2-dimethylpropanoyl (pivaloyl) and hexanoyl.
The expression "aroyl" comprises acyl groups derived from arenecarboxylic acids,
which may be monocyclic or bi- or polycyclic, and may have substituents such as
alkyl groups or halogens. Examples of aroyl groups are benzoyl, 4-methylbenzoyl
(p-toluoyl), 1-naphthoyl and 2-naphthoyl.
Leaving groups are groups which can easily be cleaved in nucleophilic substitution
reactions. Examples of suitable leaving groups are halogenides, in particular chloride,
bromide or iodide in alkyl, arylalkyl or acyl halogenides, or alkanoates in alkanoic
anhydrides, such as acetic anhydride, or sulfates, such as the methyl sulfate or ethyl
sulfate anion in dimethyl or diethyl sulfate, or sulfonates, such as the /o-toluenesulfonate
(tosylate) anion in alkyl />toluenesulfonates.
Alkali metals are those of the first group of the periodic table of the chemical elements,
in particular lithium, sodium, potassium, rubidium and cesium. Alkaline earth elements
are those of the second group of the periodic table, in particular magnesium, calcium,
strontium and barium. In formulae I and II, n is 1 when M is an alkali metal, and n is 2
when M is an alkaline earth metal.
The reaction of the 4-fluoro-3-oxobutyrate enolate salt (II) with carbon monoxide is ad¬
vantageously carried out at a temperature in the range of 2 0 to 8 0 °C.
The carbon monoxide pressure is suitably in the range of 1 to 100 bar ( 105 to 107 Pa),
preferably in the range of 2 to 5 0 bar (2* 105 to 5 * 106 Pa), and more preferably in the
range of 5 to 2 0 bar (5 05 to 2 06 Pa).
The reaction with carbon monoxide can be carried out without solvent or in a suitable
solvent. Suitable solvents are for example polar solvents such as alcohols, in particular
lower alcohols, or esters. Preferred alcohols are those having the formula R -OH,
wherein R has the same meaning as in formulae I and II, while preferred esters are
the esters derived from said alcohols.
In a preferred embodiment the enolate salt of the 4-fluoro-3-oxobutyrate (II) is pre¬
pared in situ from the corresponding 4-fluoro-3-oxobutyrate and a strong base of the
corresponding metal M. The strong base can be employed in a stoichiometric amount,
it is not necessary to use an excess of base. The strong base may be any strong base
that is able to deprotonate the 4-fluoro-3-oxobutyrate, the a-methylene group of which
is relatively acidic. Suitable strong bases are for example the hydroxides, hydrides or
alkoxides of the alkali and alkaline earth metals or alkali metal alkyls such as
methyllithium or butyllithium.
In a more preferred embodiment, the strong base is an alkoxide of formula
M^(OR ) (V)
wherein R , M and are as defined above.
Most preferably, the metal M is sodium and, consequently, n \s 1.
In another preferred embodiment, the substituent R1 in formulae I, II, III and V is C -
alkyl, most preferably methyl or ethyl.
ln still another preferred embodiment, the substituents R2 and R3 in formulae I, II and
III are fluorine and hydrogen, respectively.
In the most preferred embodiment, M is sodium, n is 1, R is methyl or ethyl, R2 is
fluorine, and R3 is hydrogen.
The enolate salt of the 4-fluoro-2-hydroxymethylene-3-oxobutyrate (I) may also exist in
other tautomeric forms such as the formyl form depicted below
The enolate salt of the 4-fluoro-2-hydroxymethylene-3-oxobutyrate (I) is preferably
obtained in solid form, either by conducting the reaction with carbon monoxide without
using a solvent or by isolating the enolate salt (I) from its solution in a conventional
way, for example by evaporating the solvent or precipitating the product by adding
another solvent wherein it is poorly soluble.
In the solid enolate salt of formula I, M is preferably sodium and, consequently, n \s 1.
Also preferably, R1 in the solid enolate salt of formula I is C 1- alkyl, more preferably
methyl or ethyl.
In another preferred embodiment the substituents R2 and R3 in the solid enolate salt of
formula I are fluorine and hydrogen, respectively.
ln the most preferred embodiment, M is sodium, n is 1, R is methyl or ethyl, R2 is
fluorine, and R3 is hydrogen.
The enol ethers or esters of formula III may exist in the depicted keto form or, if R3 is
hydrogen, in the tautomeric enol form of formula
wherein R , R2 and R4 are as defined above, or as a mixture of both forms.
Especially preferred enol ethers (III) are those where R4 is C1-4 alkyl, in particular
methyl. They can be prepared by reacting the enolate salt I with a suitable alkylating
agent such as a alkyl halide or tosylate, in particular a C1-4 alkyl bromide or iodide,
such as methyl iodide.
Especially preferred enol esters (III) are those where R4 is - alkanoyi, in particular
acetyl.
When the enolate starting materials of formula I I are prepared from the 1,1-difluoroethyl
methyl ethers of formula VI, the antimony pentafluoride in step (i) is advantageously
used in catalytic amounts, preferably in an amount of 1 to 5 mol%, based on
the amount of 1,1-difluoroethyl methyl ether (VI). The reaction of step (i) may be
carried without solvent (neat) or in an inert solvent, such as a haloalkane. The same
solvent may also be used in the subsequent steps. Suitable haloalkanes are fluoro- or
chloroalkanes, for example dichloromethane or 1,2-dichloroethane. The reaction
temperature of step (i) is advantageously in the range of about 0 °C to about 50 °C,
preferably at room temperature (about 20 °C to about 30 °C). Since the products of
step (i), in particular the fluoromethane formed as byproduct, are low-boiling com¬
pounds (CH3F: bp = -78 °C), step (i) is advantageously carried out in an autoclave.
The halogen exchange step (step (ii)) in the synthesis of the enolates of formula I I may
be carried out by simply adding a solid alkali or alkaline earth chloride, preferably
lithium chloride, to the acetyl fluoride of formula VII or, preferably, to the reaction
mixture obtained in step (i). The reaction temperature in step (ii) is conveniently in the
same range as in step (i), preferably at room temperature (about 20 °C to about 30 °C).
The amount of alkali or alkaline earth chloride is advantageously 1.0 to 1.2 molar
equivalents per mol of 1,1-difluoroethyl methyl ether (VI).
It has been found that the reaction rate can be substantially increased by using a
phase transfer catalyst, thus reducing the required reaction time from e.g. about 24 h
for lithium chloride without catalyst to about 10 h or less when a catalyst is used.
Suitable phase transfer catalysts are those known in the art, for example tetraalkylammonium
salts such as tetrabutylammonium chloride. Using a phase transfer catalyst
has the advantage that it is also possible to accomplish the halogen exchange with
less reactive chlorides such as calcium chloride within a reasonable period of time.
The metal fluoride formed in the halogen exchange step (ii) is advantageously filtered
off before isolating the acetyl chloride of formula VIII or, preferably, subjecting the
reaction mixture obtained in step (ii) to the reaction with ketene, i.e., step (iii). The
ketene is advantageously used in gaseous form, such as the crude (about 70% w/w)
ketene gas obtained by pyrolysis of acetic acid. The reaction with ketene may be
conducted in the presence of a Lewis acid such as boron trifluoride, but it is also
possible to conduct it without addition of a Lewis acid as catalyst. The reaction
temperature in step (iii) is advantageously in the range of -50 °C to 0 °C and
preferably in the range of -30 °C to -10 °C.
The acetoacetyl chloride (IX) obtained in step (iii) or, preferably, the reaction mixture
obtained in step (iii) is reacted (quenched) with an alcohol of formula X to obtain the 4-
fluoro-3-oxobutyrate of formula XI, which may also be present in the tautomeric enol
form depicted below
The alcohol is advantageously used in moderate excess, for example about 2 mol per
mol of 1,1-difluoroethyl methyl ether (VI) starting material, in order to ensure complete
reaction. The reaction with the alcohol is conveniently carried out at a temperature of
-30 °C to -10 °C, for example at about -15 °C.
In a preferred embodiment, the steps (i) to (iv) are conducted without isolating any of
the intermediates of formulae VII, VIII and IX.
The 4-fluoro-3-oxobutyrate of formula XI may be isolated and purified according to
methods known in the art, for example by evaporating the low-boiling components of
the reaction mixture obtained in step (iv), followed by distillation of the thus-obtained
crude product.
The enolate salt of formula II is obtained in the conventional way by reacting the
4-fluoro-3-oxobutyrate of formula XI with a strong base of the corresponding metal M,
said base having the formula
wherein M and are as defined above and A- is an anion, preferably selected from the
group consisting of HO- , R-O - , H- , and R- , wherein R is Ci-6 alkyl. Examples of
suitable bases are the hydroxides, Ci_6 alkoxides, hydrides or C - alkyls of the alkali
or alkaline earth metal M. Preferred alkoxides are those derived from the alcohol
R -OH used in step (iv) above. Suitable metal alkyls are those conventionally used in
organic synthesis, such as methyllithium or butyllithium.
The following examples, which however are not intended to limit the scope of the in¬
vention, will illustrate in more detail selected embodiments and preferred modes of
carrying out the invention.
Example 1
Ethyl 4,4-difluoro-2-hydroxymethylene-3-oxobutyrate, sodium salt (I; R = Et, R2 = F,
R3 = H, M = Na, n = 1)
Ethyl 4,4-difluoro-3-oxobutyrate (234.2 g, 1.41 mol) was dissolved in ethyl acetate
(260 g) in an autoclave. Sodium ethoxide (96.0 g, 1.41 mol) was added at 20 °C and
the reaction mixture was heated to 60 °C. At that temperature, the autoclave was
pressurized with carbon monoxide (10 bar). After 5 h the carbon monoxide uptake had
ceased and the pressure was released. The solvent was evaporated in vacuo obtain
the desired product as slightly yellow solid.
Yield: 256 g ( 1 .18 mol, 84%).
The product was characterized via H, 3C and 1 F NMR spectroscopy.
H NMR (DMSO- , 500 MHz): d 8.14 (s, 1H), 5.68 (t, = 58 Hz, 1H), 3.92 (q,
= 7 Hz, 2H), 1.13 (t, - = 7 Hz, 3H).
C {1H} NMR (DMSO-ofe, 125 MHz): d 175.1 (t, Jc-F = 20 Hz), 169.9 (s), 161 .8 (s),
113.1 (t, VC-F = 314 Hz), 78.5 (t, VC-F = 2.8 Hz), 59.8 (s), 14.0 (s).
9F NMR (DMSO- , 470 MHz): d -124.3 (d, 2 F- = 58 Hz).
Example 2
Ethyl 3-acetoxy-2-(2,2-difluoroacetyl)-acrylate (III; R = Et, R2 = F, R3 = H, R4 = acetyl)
(Mixture of the keto and enol forms)
Ethyl-4,4-difluoro-3-oxobutyrate ( 110.7 g, 0.67 mol) was dissolved in ethyl acetate
(1 15 g) in an autoclave. Sodium ethoxide (45.3 g, 0.67 mol) was added at 20 °C and
the reaction mixture was heated to 60 °C. The autoclave was then pressurized with
carbon monoxide (10 bar) for 5 h. After that time carbon monoxide uptake had ceased
and the pressure was released. The reaction mixture was cooled to 0 °C and acetyl
chloride (57.5 g, 0.73 mol) was added over 1 h. The reaction mixture was stirred for an
additional hour at 30 °C and then filtered to remove NaCI. The filtrate was evaporated
in vacuo to obtain the desired product as a colorless liquid. According to 1H NMR data
the product was a mixture of ca. 85% enol form (ethyl 3-acetoxy-2-(1-hydroxy-2,2-
difluorovinyl)-acrylate) and ca. 15% keto form.
Yield: 125 g (0.53 mol, 79%).
The product was characterized via 19F, H and 3C NMR spectroscopy.
H NMR (CDCI3 500 MHz): d 1.71 (s, 0.85H, enol), 6.55 (t, = 54 Hz, 0.1 5H,
keto), 5.41 (s, 1H), 4.21^.14 (m, 2H), 2.42 (s, 3 H), 1.26-1 .20 (m, 3H).
3C { H} NMR (CDCI3 125 MHz): d 192.1 (t, VC-F = 27 Hz, keto), 17 1.7 (s), 170.8
(s), 165.5 (s), 164.7 (t, VC-F = 25 Hz, enol), 109.4 (t, VC-F = 242 Hz, keto or enol),
109.3 (t, VC-F = 314 Hz, keto or enol), 9 1.4 (t, VC-F = 6.0 Hz), 6 1.1 (s), 2 1.0 (2 s , keto
and enol), 14.0 (2 s, keto and enol).
F NMR (CDC , 376 MHz): d - 28.0 (d, F h = 54 Hz, keto), - 127.9 (d,
- = 53.4 Hz, enol),-126.5 (d, -F = 53.4 Hz, enol).
Example 3
Ethyl 2-(2,2-difluoroacetyl)-3-methoxyacrylate (III; R = Et, R2 = F, R3 = H, R4 = OMe)
(Mixture of the keto and enol forms)
Ethyl-4,4-difluoro-3-oxobutyrate (150 g, 0.90 mol) was dissolved in ethyl acetate (160 g)
in an autoclave and treated with sodium ethoxide and carbon monoxide in the same
manner as described in Examples 1 and 2. After the CO uptake had ceased, the
pressure was released and the reaction mixture was cooled to 0 °C before methyl
iodide (128.2 g, 0.90 mol) was added slowly. After stirring for 3 h at 50 °C, the reaction
mixture was filtered and the filtrate was distilled to remove the ethyl acetate. The
product was obtained as a colorless liquid (141 g, 75%).
The product was characterized via 9F, H and 13C NMR spectroscopy. Due to rapid
proton exchange the keto-enol tautomery could not be observed in the H NMR
spectrum. According to the 9F NMR data the product was a tautomeric mixture of ca.
76% enol form and ca. 24% keto form.
H NMR (DMSO-ofe, 500 MHz): d 6.40 (t, J - = 53 Hz, 1H), 4.61 (s, 1H), 3.97 (q,
= 7.1 Hz, 2H), 3.90 (s, 3H), 1.10 (t, 3 -H = 7.1 Hz, 3H)
3C {1H} NMR (DMSO-ofe, 125 MHz): d 195.9 (t, VC-F = 24 Hz), 175.2 (t,
C- = 2 1 Hz), 170.6 (s), 168.3 (s), 14.0 (t, VC-F = 248 Hz), 109.8 (t, VC-F = 247 Hz),
92.0 (s), 58.2 (s) 56.6 (s), 15.6 (s).
9F NMR (DMSO- , 376 MHz): d - 13 1.4 (d, 2 - = 52.8 Hz, 0.38F), -131 .0 (d,
J - = 52.8 Hz, 0.38F), -125.0 (d, J - = 53 Hz, 0.24F).
Example 4
Ethyl 4,4-difluoro-3-oxobutyrate (XI; R = Et, R2 = F, R3 = H)
An autoclave equipped with stirrer, liquid metering pump system and solids-addition
device, was charged with 1,2-dichloroethane (187 g) and antimony pentafluoride (2.5 g,
11.4 mmol, 3 mol%) and sealed. The temperature in the autoclave was adjusted to
25 °C and methyl 1, 1 ,2,2-tetrafluoroethyl ether (50 g, 379 mmol) was metered into the
closed autoclave. After stirring the reaction mixture at 25 °C for 3 h, solid lithium
chloride (17.7 g, 416 mmol) was added. The reaction mixture was stirred for another
24 h and then cooled to 0 °C. The autoclave was opened and the reaction mixture was
filtrated under nitrogen pressure. The filtrate was transferred into a flask fitted with a
gas inlet tube, cooled to -15 °C and BF3-etherate ( 1.61 g, 11.4 mmol, 3 mol%) was
added. To the reaction mixture gaseous ketene (29.6 g, 70% w/w, 493 mmol) obtained
by pyrolysis of acetic acid was dosed via the inlet tube within 1 h, before the reaction
mixture was quenched with ethanol (34.9 g, 757 mmol) at -15 °C. The solvents were
removed in vacuo and the crude product was distilled to obtain a colorless liquid.
Yield: 44.0 g (70%)
bp = 62 °C
The product was characterized via NMR and GC. According to the 1H NMR data the
product was a tautomeric mixture of ca. 60% keto form and ca. 40% enol form (ethyl
4,4-difluoro-3-hydroxybut-2-enoate).
H NMR (CDCb, 400 MHz): d 11.76 (s, 0.4H, enol), 6.04 (t, 2J - = 54 Hz, 0.6H,
keto), 5.89 (t, - = 54 Hz, 0.4H, enol), 5.48 (s, 0.4H, enol), 4.28^1.20 (m, 2H), 2.28
(s, .2H, keto), 1.33-1 .26 (m, 3H).
9F NMR (CDCb, 376 MHz): d -127.6 (d, JF-H = 54 Hz, keto), -129.0 (d,
2^_ H = 54 Hz, enol).
Example 5
Methyl 4,4-difluoro-3-oxobutyrate (XI; R = Me, R2 = F, R3 = H)
The procedure of Example 4 was repeated using methanol instead of ethanol. After
distillation the methyl ester was obtained as a colorless liquid. According to the
1H NMR data the product was a tautomeric mixture of ca. 60% keto form and ca. 40%
enol form (methyl 4,4-difluoro-3-hydroxybut-2-enoate).
Yield: 72%
1H NMR (CDCb, 500 MHz): d 11.65 (s, 0.4H, enol), 6.01 (t, 2 - = 54 Hz, 0.6H,
keto), 5.88 (t, 2 J - = 54 Hz, 0.4H, enol), 5.48 (s, 0.4H, enol), 3.75-3.70 ( , 3H), 2.26
(s, 1.2H, keto).
9F NMR (CDCb, 376 MHz): d -127.6 (d, 2 F- = 54 Hz, keto), -129.0 (d,
= 54 Hz, enol).
Example 6
Ethyl 4,4-difluoro-3-oxobutyrate (XI; R = Et, R = F, R3 = H)
The procedure of Example 4 was repeated without addition of BF3-etherate. The crude
product obtained was analyzed using H NMR.
Yield: 34 g (54%), besides 6.6 g (14%) ethyl difluoroacetate.
Example 7
Ethyl 4,4-difluoro-3-oxobutyrate (XI; R = Et, R2 = F, R3 = H)
The procedure of Example 4 was repeated without addition of BF3-etherate, but the
lithium chloride was added together with tetrabutylammonium chloride (10.5 g,
37.9 mmol) as phase transfer catalyst and the reaction time for the halogen exchange
was 0 h instead of 24 h.
Yield: 44 g (70%).
Claims
A process for the production of an enolate salt of a 4-fluoro-2-hydroxymethyl
3-oxobutyrate of formula
or a tautomer thereof,
wherein R is Ci_io alkyl, R2 and R3 are independently hydrogen or fluorine, M is
an alkali or alkaline earth metal, and n is 1 or 2,
comprising the step of reacting a 4-fluoro-3-oxobutyrate enolate salt of formula
wherein R , R2, R3, M and are as defined above, and/or a tautomer thereof, with
carbon monoxide.
2. A process for the production of an enol ether or ester of a 4-fluoro-2-hydroxymethylene-
3-oxobutyrate of formula
or a tautomer thereof,
wherein R , R2 and R3 are as defined in claim 1 and R4 is selected from the group
consisting of Ci_6 alkyl, aryl-Ci-4 alkyl, C2-6 alkanoyl and aroyl,
comprising the steps of
(i) providing an enolate salt of formula I according to the process of claim 1,
and
reacting said enolate salt of formula I with an alkylating or acylating reagent
of formula
X-R 4 (IV),
wherein R4 is as defined above and X is a leaving group.
The process of claim 1 or 2, wherein the enolate salt of the 4-fluoro-3-oxobutyrate
(II) is prepared in s/ from the corresponding 4-fluoro-3-oxobutyrate and a strong
base of the corresponding metal M.
The process of claim 3, wherein the strong base is an alkoxide of formula
M^(OR^ (V),
wherein R , M and n re as defined in claim 1.
The process of any of claims 1 to 4 , wherein M is sodium and n is 1.
The process of any of claims 1 to 5, wherein R is C alkyl.
The process of any of claims 1 to 6, wherein R2 is fluorine and R3 is hydrogen.
8. The process of any of claims 1 to 7, wherein the enolate salt of the 4-fluoro-
2-hydroxymethylene-3-oxobutyrate (I) is obtained in solid form.
9. The process of any of claims 1 to 8, wherein the enolate salt of formula I I has
been synthesized by a process comprising the steps of
(i) eliminating fluoromethane from a 1,1-difluoroethyl methyl ether of formula
wherein R2 and R3 are as defined above,
reacting said acetyl fluoride (VII) with an alkali or alkaline earth chloride to
obtain the corresponding acetyl chloride of formula
wherein R2 and R3 are as defined above,
(iii) reacting said acetyl chloride (VIII) with ketene (CH2=C=0) to obtain the
corresponding acetoacetyl chloride of formula
wherein R2 and R3 are as defined above, and
reacting said acetoacetyl chloride (IX) with an alcohol of formula
R -OH (X).
wherein R1 is as defined above, to obtain the 4-fluoro-3-oxobutyrate of
formula
wherein R1, R2 and R3 are as defined above, or an enol tautomer thereof,
and
treating said 4-fluoro-3-oxobutyrate (XI) with a strong base of formula
n M - (XII),
wherein M and n are as defined above and A is an anion, preferably
selected from the group consisting of HO- , R-0 ~, H- , and R~, wherein R is
C-i-6 alkyl, to obtain the enoiate salt of formula II.
The process of claim 9, wherein steps (i) to (iv) in the synthesis of the enoiate salt
of formula II are conducted without isolating the intermediates of formulae VII, VIII
and IX.
11. The process of claim 9 or 10, wherein step (ii) in the synthesis of the enoiate salt
of formula II is conducted in the presence of a phase transfer catalyst.
A solid enoiate salt of a 4-fluoro-2-hydroxymethylene-3-oxobutyrate of formula
wherein R is C1-10 alkyl, R2 and R3 are independently hydrogen or fluorine, M is
an alkali or alkaline earth metal, and n is 1 or 2 .
13. The solid enoiate salt of claim 12, wherein M is sodium and n is 1.
14. The solid enoiate salt of claim 12 or 13, wherein R is C1-4 alkyl.
15. The solid enoiate salt of any of claims 2 to 14, wherein R2 is fluorine and R3 is
hydrogen.