FR2604189A1 - Process for the preparation of fluorinated benzyl derivatives - Google Patents

Abstract

Process for the preparation of mono- or difluorinated benzyl derivatives by electrochemical fluorination of benzyl derivatives. The fluorobenzyl derivatives are employed as biologically active agents.

Description

PROCESS FOR ELECTROCHEMICAL FLUORATION OF BENZYLIC DERIVATIVES
The present invention relates to a process for the preparation of fluorinated benzyl derivatives. It relates more specifically to a process for the electrochemical fluorination of benzyl groups.

 The preparation of fluorinated compounds on the methylene group of a benzylic link has long been sought by industry, especially for the future synthesis of fluorinated amino acids in alpha of the aromatic ring.

It is known from the Journal of Organic Chemistry, 1984, 49, (7), pp. 1163-1169, "three methods for obtaining 3-fluoro-phenylalanine from 3-phenyloxoic acid. 2 propanoic or one of its derivatives
- the first consists in carrying out a fluorodehydroxylation
medium of sulfur tetrafluoride in hydrofluoric acid,
- the second is to open an aziridine ring in the middle
hydrofluoric acid / pyridine,
- the third is to perform a reductive amination of
3-fluorophenylpyruvic acid obtained by direct fluorination
by the molecular fluorine of the methyl ester of the acid
phenylpyruvic in oenolic form.

 None of the three preceding methods can be used industrially. The use of sulfur tetrafluoride is to be banned in industry for toxicity problems. The use of a derivative bearing an aziridine ring is economically not conceivable from an industrial point of view. The use of molecular fluorine is also not an easy process to implement from the point of view of safety.

It is also known from "Middleton and Bingham (Journal of
Organic Chemistry 1980, 45, 2883-2887) to prepare difluoro-1,1 arylacetic derivatives by fluorination of the 2-oxo-arylacetic derivatives with diethylaminosulfur trifluoride (DAST), which latter derivative is particularly dangerous because it is very explosive. This process is therefore not industrial.

 The aromatic groups bearing a flucromethylene carbonyl group have been sought for some years for their biological pharmaceutical or agricultural activity.

 The present invention has made it possible to achieve a safe and non-hazardous means of manufacturing these products.

dans laquelle :
- n est égal àlou 2,
- A représente un groupe choisi parmi les radicaux
alkylcarbonyle, arylcarbonyle (dont le radical aryle est
éventuellement substitué par un groupe alkyle, alcoxy,
halogéno, nitro), perfluoroalkylcarbonyle, alcoxycarbonyle,
phényloxycarbonyle, carboxylique, fluorocarbonyle,
carboxamide, cyano, trifluorométhyle, alkylsulfonyle,
trifluorométhylsulfonyle, arylsulfonyle (dont le radical aryle
est éventuellement substitué par un groupe alkyle, alcoxy,
halogéno ou nitro), sulfonique, sulfonates alcalins,
alkyloxysulfonyle, phényloxysulfonyle, sulfonamides,
alcoxyoxalyle,
- R représente au moins un groupe situé en position 2, 4 ou 6
choisi parmi les radicaux alkyle, alcoxy, aryle, aryloxy,
hydrogéno, halogéno, par mise en contact dans une cellule électrolytique en présence éventuellement d'un solvant
- d'un composé de formule (II)

It relates to a process for the preparation of benzyl derivatives of general formula (I)

in which :
n is equal to 1 or 2,
- A represents a group chosen from the radicals
alkylcarbonyl, arylcarbonyl (the aryl radical of which is
optionally substituted by alkyl, alkoxy,
halogeno, nitro), perfluoroalkylcarbonyl, alkoxycarbonyl,
phenyloxycarbonyl, carboxylic, fluorocarbonyl,
carboxamide, cyano, trifluoromethyl, alkylsulfonyl,
trifluoromethylsulfonyl, arylsulfonyl (including the aryl radical
is optionally substituted with an alkyl, alkoxy group,
halogeno or nitro), sulphonic acid, alkaline sulphonates,
alkyloxysulfonyl, phenyloxysulfonyl, sulfonamides,
alkoxyoxalyl,
- R represents at least one group located in position 2, 4 or 6
chosen from alkyl, alkoxy, aryl and aryloxy radicals,
hydrogeno, halo, by contacting in an electrolytic cell in the presence, if appropriate, of a solvent
a compound of formula (II)

in which A and R have the preceding meaning, with a fluorination agent chosen from fluorides
alkaline, amine hydrofluorides and fluorides
quaternary ammonium compounds
R'1 R'2 R'3 R'4 N + IF, nHFI
in which R'1, R'2, R'3, R'4 identical or
different is an alkyl, hydrogen or alkenylene group and
is a whole or fractional number between 2 and 10.

 Among the derivatives of formula (II), it is possible to use all products bearing an electron-withdrawing substituent A, that is to say from compounds of formula (II), ketones, sulphones and carboxylic esters. or sulfonic, 2,2,2-trifluoroethyl benzines.

 Among the radicals R, it is possible to use all compounds bearing substituents located in the ortho or para position relative to the methylene group. The substituents are preferably activating groups either by induction or by mesomerism. When the aromatic derivative carries a plurality of substituents R, it is preferable that one of them is in the para position relative to the methylene group.

 The compounds of formula II in which R is alkyl, alkoxy, phenyl or phenoxy are preferably selected.

Among the compounds of formula (II)
4'-dimethoxy-4'-benzylphenylketone
- 4-methoxyphenylacetate ethyl
4-methoxyphenylacetonitrile
- 4-methoxyphenylacetone
4-methoxyethyl benzylsulphonate
methyl 4-methoxybenzylsulphonate
- 3,4-dimethoxyphenylacetate ethyl
The fluorinating agent is chosen from hydrofluoride of amines or ammonium fluorides solvated by hydrofluoric acid.

These agents include, but are not limited to, triethylamine / 3HF, tetraethylammonium fluoride / 3HF, ammonium fluoride / 2.2HF, pyridine / 10HF, better known as reactive Olah, methylpyridines / 10 HF.

 It is also possible to use inorganic fluorinating agents such as alkaline fluorides such as potassium fluoride, sodium fluoride and cesium fluoride. These alkaline fluorides are generally used in solution in acetic acid or trifluoroacetic acid.

The process can be carried out without a solvent when the derivative of formula (II) is soluble in the fluorinating agent. In the case where it is not soluble, the operation is preferably carried out in the presence of a dipolar aprotic solvent such as in particular:
- acetonitrile
- sulfolane
N-methylpyrrolidone (NMP)
dimethylsulfoxide (DMSO)
dimethylformamide (DMF)
- the glymas
It is preferred to use acetonitrile or sulfolane.

 From the electrochemical point of view, a glass cell or a material compatible with the solvent and the fluorinating agent is preferably used. Marmi resistant materials include polytetrafluoroethylene or polychlorotrifluoroethylene.

 The electrodes are preferably based on platinum or carbon such as graphite or vitreous carbon.

 The potential applied to the two electrodes is a function of the solvent used, the product to be fluorinated and the desired degree of fluorination (mono or difluorination).

 For a better implementation of the method, it is preferred to use a potential of less than 2.5 volts and preferably a potential of between 0.5 and 2.5 volts.

 The reaction temperature is limited by the solvent used.

It is preferably between 10 and 500C. These limits will be adapted by those skilled in the art to the desired product, the solvent used and the nature of the electrochemical cell.

 For an easy implementation of the invention it is preferred to use a molar ratio of the fluorinating agent or aryl derivative of between 1 and 5. It is obvious that a greater amount of fluorinating agent is not harmful to the method of the invention, one skilled in the art will adapt from an economic point of view the molar ratio to use.

Among the products of formula (I) derived from the present invention, mention may be made
dimethoxy-4 ', 4 "mono and difluoro-2 (2) benzylphenyl ketone,
- Methoxy-4'mono-fluorophenylacetate ethyl
methoxy-4'mono (and di) fluoro-2 (2) phenylacetonitrile,
methoxy-4'mono (and di) fluoro-3 (3) phenyl-3-prcpanone-2,
methoxy-4'mono (and di) fluoro-2 (2) beneylsulphonate
ethyl and methyl,
dimethoxy-3 ', 4'mOno (and di) fluor2 (2) phenylacetate
ethyl.

 These products are used, as mentioned above, as biological agents, especially pharmaceutical or agricultural.

 The invention will be more fully described with the aid of the following examples which should not be considered as limiting the invention.

EXAMPLES
Example 1 - Monofluorination
In a glass electrolysis cell of 100 cm3, thermostatted at about 13 C, provided with a magnetic stirring device and maintained under a deoxygenated dry nitrogen stream, 1.28 g (5 x 10 3 mol. ) 4,4'-dimethoxybenzylphenylketone,
3.50 years of dried acetonitrile on molecular sieves 3.1010 m and 10 cm3 (5 x 10-2 mol) of triethylamine trifluorhydrate; the substrate concentration is 0.1 mol./dm3 and that of the fluorinating reagent is 1 mol./dm3. The electrodes are not separated by a diaphragm. The anode, in platinum grid is a truncated cone (25 mm high, diameters: 40 inm at the base and 50 mm at the top). The cathode is made of 1.5 mm diameter platinum wire helically wound.The reference electrode is the Pleskov Ag / Ag N03 electrode 10-2 MM Electrolysis is carried out with controlled potential and discontinuous waves: + 1.2 V (3 s) and 0 V (2 s). The potential of the anode is controlled at + 1.2 V by a potentiostat (100 V - 1 A) controlled by a square wave generator.

After passing 1225 A. s. (2412.5A / mol - electrolysis time 45 min) the electrolysis solution is poured into 300 ml of iced water containing 10 cm3 of 28% ammonia.

 After removal of the acetonitrile under reduced pressure, the aqueous phase is extracted twice with 100 cm3 of methylene chloride. The organic phase, after washing with water until neutral pH, drying over magnesium sulfate and concentration under partial vacuum, provides 1.40 g of crude product. Purification of 0.155 g of this crude product by liquid chromatography under pressure (column PARrISIL 10 - mobile phase: 75% petroleum ether - 25% ethyl ether) makes it possible to isolate 0.108 g (4 × 10 -4 mol) of dimethoxy- 4 ', 4 "mono-fluoro-2-benzylphenylketone (mp 37 ° -38 ° C.) and 2 × 10 -3 g (7.8 × 10 -6 mol) of starting material The yield of monofluorocetone is 72% with 99% conversion rate.

Elemental Analysis for C16H1503F: Calculated: (% C) 70.06 (% H) 5.51 (% F) 6.93 Found: (% C) 70.28 (% H) 5.43 (% F) 6.92
EXAMPLE 2 (difluorination) 1.28 g (5 × 10 3 mol.) Of 4,4'-dimethoxybenzylphenylketone, 50 cm.sup.3 of acetonitrile dried over molecular sieve 3.10-10 μm and 10 cm.sup.3 are introduced into the electrolysis cell ( 5 x 10-2 mol.) Of triethylamine trifluorhydrate; the substrate concentration is 0.1 mol./dm3 and that of the fluorinating reagent is 1 mol./dm3.

 Discontinuous wave electrolysis is started at + 1.2 V and as the electrolysis current decreases, this value of the potential is progressively raised to 1.6 V. After passing 2895 A.s.

(5790 A.s./Mol.electrolysis time 6 h) the same treatment as for Example 1 leads to 1.48 g of crude product. Purification of this crude product by chromatography on a silica column makes it possible to isolate 0.73 g (2.5 × 10 -3 mol.) Of dimethoxy-4 ', 4 "difluoro-2,2-benzylphenylketone (mp = 56.degree. 57 C) The yield of difluorocetone is 50% for a conversion rate of 100%.

Elemental Analysis for C16H14O3F2 - Calculated: (% C) 65.75 (% H) 4.83 (% F) 13.00 - Found: (% C) 65.26 (% H) 4.83 (% F) 12 71
Examples 3 to 18 (see table below)

<tb> Voltage <SEP> Quantity <SEP> Yield
<tb> Ex. <SEP> A <SEP> I <SEP> R <SEP> I <SEP> (V) <SEP> Electrical <SEP> n <SEP> t (mn) <SEP> Rate <SEP> of <SEP> 1 <SEP> (2) <SEP> 1 <SEP>
<tb> (1) <SEP> quoted <SEP> conver- <SEP> (%)
<tb> I <SEP> I <SEP> I <SEP> I <SEP> I <SEP> (As <SEP> I <SEP><SEP> I
<tb> / mol)
<tb> -C-CH3
<tb> 3 <SEP> CH3-O-4 <SEP> 1.20 <SEP> 1930 <SEP> 1 <SEP> 40 <SEP> 80 <SEP> 69
<tb> lio <SEP> t <SEP><SEP> I <SEP> I <SEP> I <SEP> I <SEP> I <SEP> I <SEP> I <SEP>
<tb> -C-CH3
<tb> 4 <SEP> CH3-O-4 <SEP> 1.60 <SEP> 6079 <SEP> 2 <SEP> 120 <SEP> 100 <SEP> 61
<tb> O
<tb> -C-CH3
<tb> 5 <SEP> H <SEP> 2.15 <SEP> 2509 <SEP> 1 <SEP> 60 <SEP> 100 <SEP> 7
<tb> O
<tb> It <SEP> I <SEP> | <SEP> | <SEP> | <SEP> | <SEP> It <SEP> I <SEP> I <SEP> I
<tb> 6 <SEP> -CO2C2H5 <SEP> CH3-O-4 <SEP> 1.28 <SEP> 2219 <SEP> 1 <SEP> 45 <SEP> 100 <SEP> 69
<tb> He <SEP> | <SEP> | <SEP> I <SEP> I <SEP> It <SEP> I <SEP> I <SEP> I
<tb> 7 <SEP> -CO2C2H5 <SEP> CH3-O-4 <SEP> 1.45 <SEP> 5365 <SEP> 2 <SEP> 100 <SEP> 100 <SEP> 55
<tb> 8 <SEP> -CO2C2H5 <SEP> Cl-4 <SEP> 1.70 <SEP> 2509 <SEP> 1 <SEP> 50 <SEP> 75 <SEP> 36
<tb> 9 <SEP> -CO2C2H5 <SEP> (CH3-O) 2-3'-4 '<SEP> 0.80 <SEP> 2605 <SEP> 1 <SEP> 75 <SEP> 92 <SEP> 73
<Tb>

<tb> Voltage <SEP> Quantity <SEP> Yield
<tb> Ex. <SEP> A <SEP> R <SEP> (V) <SEP> Electrical <SEP> n <SEP> t (mn) <SEP><SEP> Rate <SEP> (2)
<tb> (1) <SEP> quoted <SEP> conver- <SEP> (%)
<tb> (As <SEP> sion
<tb> / mol)
<tb> 10 <SEP> -CO2C2H5 <SEP> (CH3-O) 2-3'-4 '<SEP> 0.92 <SEP> 5114 <SEP> 2 <SEP> 105 <SEP> 62 <SEP> 39
<tb> I <SEP> I <SEP> | <SEP> | <SEP> I <SEP> I <SEP> I <SEP> I <SEP> I <SEP> I
<tb> 11 <SEP> -SO3C2H5 <SEP> CH3-O-4 <SEP> 1.37 <SEP> 2316 <SEP> 1 <SEP> 45 <SEP> 96 <SEP> 71
<tb> | <SEP> | <SEP> I <SEP> I <SEP> I <SEP> | <SEP> | <SEP> | <SEP> I <SEP> I <SEP> I
<tb> 12 <SEP> -SO3C2H5 <SEP> CH3-O-4 <SEP> 1.50 <SEP> 4825 <SEP> 2 <SEP> 110 <SEP> 84 <SEP> 42 <SEP> (3)
<tb> 13 <SEP> -SO3CH3 <SEP> CH3-O-4 <SEP> 1.48 <SEP> 2895 <SEP> 1 <SEP> 35 <SEP> 100 <SEP> 40 <SEP> (4)
<tb> | <SEP> | <SEP> I <SEP> I <SEP> I <SEP> | <SEP> | <SEP> | <SEP> I <SEP> I <SEP> I
<tb> 14 <SEP> -SO3CH3 <SEP> CH3-O-4 <SEP> 1.46 <SEP> 5790 <SEP> 2 <SEP> 105 <SEP> 100 <SEP> 26 <SEP> (5)
<tb> 15 <SEP> -SO3C2H5 <SEP> CH3-4 <SEP> 1.85 <SEP> 2412 <SEP> 1 <SEP> 40 <SEP> 74 <SEP> 15
<tb> | <SEP> | <SEP> I <SEP> I <SEP> I <SEP> It <SEP> I <SEP> I <SEP> I
<tb> 16 <SEP> -C = N <SEP> CH3-O-4 <SEP> 1.37 <SEP> 2509 <SEP> 1 <SEP> 60 <SEP> 97 <SEP> 67
<tb> 17 <SEP> -C = N <SEP> CH3-O-4 <SEP> 1.60 <SEP> 5597 <SEP> 2 <SEP> 90 <SEP> 100 <SEP> 50
<tb> 18 <SEP> -C = N <SEP> CH3-4 <SEP> 1.74 <SEP> 2509 <SEP> 1 <SEP> 60 <SEP> 65 <SEP> 58
<tb> (1) Working potential expressed in volts relative to the electrode of
reference Ag / AgNO3 10-2M. (2) Yield of isolated product in relation to the starting material
transformed.

(3) We also observe the formation of

 detected by 19F NMR assay of the crude electrolysis product.

(4) Training of:

 according to the 19F NMR of the crude electrolysis product.

d'après la RMN19F du produit brut d'électrolyse. (5) Formation of

according to the 19F NMR of the crude electrolysis product.

Claims (8)

REVENDICAIIONS  1. Process for preparing benzyl derivatives of general formula (I)

 in which  n is 1 or 2,  - A represents a group chosen from the radicals  alkylcarbonyl, arylcarbonyl (the aryl radical of which is  optionally substituted by alkyl, alkoxy,  halogeno, nitro), perfluoroalkylcarbonyl, alkoxycarbonyl,  phenyloxycarbonyl, carboxylic, fluorocarbonyl,  carboxamide, cyano, trifluoromethyl, alkylsulfonyl,  trifluoromethylsulfonyl, arylsulfonyl (including the aryl radical  is optionally substituted with an alkyl, alkoxy group,  halogeno or nitro), sulphonic acid, alkaline sulphonates,  alkyloxysulfonyl, phenyloxysulfonyl, sulfonamides,  alkoxyoxalyl,  - R represents at least one group located in position 2, 4 or 6  chosen from alkyl, alkoxy, aryl and aryloxy radicals,  hydrogeno, halo, by contacting in an electrolytic cell in the presence, if appropriate, of a solvent  a compound of formula (II)

 in which A and R have the preceding meaning.  is a whole or fractional number between 2 and 10.  different is an alkyl, hydrogen or alkenylene group and  in which R'1, R'2, R'3, R'4 identical or  R'1 R'2 3 R4 N + IF, nHFI  quaternary ammonium compounds  alkaline, amine hydrofluorides and fluorides with a fluorinating agent chosen from fluorides  2. Method according to claim 1 characterized in that among the compounds of formula (II) are chosen compounds in which the substituent A represents alkylcarbonyl, arylcarbonyl, cyano, alkoxycarbonyl and alkylsulfonyl.  3. Method according to claim 1 characterized in that among the compounds of formula (II) are chosen compounds in which the substituent R represents an alkyl, alkoxy, phenyl, phenoxy and preferably a methoxy group.  4. Method according to claim 1 characterized in that the fluorinating agent is selected from (C2H5) 3N, 3HF (C2H5) 4NF, 3HF t NH4F, 2.2HF, C5H5N, HF.  5. Method according to claims 1 and 4 characterized in that the optional solvent is selected from acetonitrile, sulfolane, N-methylpyrrolidone, dimethylsulfoxide, dimethylformamide, glymes.  6. Method according to claim 5 characterized in that the solvent is selected from acetonitrile and sulfolane.  7. Method according to claim 1 characterized in that the fluorinating agent is potassium fluoride and the solvent is acetic acid or trifluoroacetic acid.  8. The method of claim 1 characterized in that the molar ratio of the fluorinating agent to the aryl derivative is between 1 and 5.