Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/10—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide
  • C07C51/12—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide on an oxygen-containing group in organic compounds, e.g. alcohols

Definitions

• the invention relates to organic synthesis, namely the synthesis of carboxylic acids by direct carbonylation of alcohols in a continuous process. It relates more particularly to the synthesis of phenylalkyl acids, which are synthesis intermediates useful in pharmaceutical chemistry, by direct carbonylation of phenylalkylalcohols.
• organic synthesis namely the synthesis of carboxylic acids by direct carbonylation of alcohols in a continuous process. It relates more particularly to the synthesis of phenylalkyl acids, which are synthesis intermediates useful in pharmaceutical chemistry, by direct carbonylation of phenylalkylalcohols.
• carboxylic acids and in particular phenylalkyl acids, can be obtained from phenylalkylalcohols by carbonylation using CO under pressure, optionally in the presence of a catalyst.
• R 2a and R 2b are, independently of one another, hydrogen, halogen, lower alkoxy, cyano,
• this process is used in batch mode for the synthesis of 2-3,5-bis-trifluoromethylphenyl-2-methyl-propionic acid by reaction of 2- (3,5-bis-trifluoromethyl) -phenyl) -propan-2-ol with CF 3 SO 3 H in CH 2 Cl 2 at a temperature of 20 ° C and a pressure of 30 bar CO for 170 minutes.
• the targeted molecules are of pharmaceutical interest.
• This process involves two steps:
• R1 and R2 are independently of one another a C1-C4 alkyl
• R3 is -C (O) - (CC 4 ) alkyl
• Z is hydrogen or C1-C10 alkyl.
• the process carried out in an autoclave, comprises the reaction of a compound of formula
• the object of the invention is a continuous process for the carbonylation of an alcohol known as "starting alcohol” in the so-called “target acid” acid, the starting alcohol being: (R 1 R 3 ) C - X
• R 1 , R 3 represent residues bonded to the carbon atom by a single covalent bond, or an aliphatic ring which integrates the central carbon atom and which is bonded thereto on each side by a single covalent bond;
• R represents (Z 1 Z 2 ) HC- or (Z 1 Z 2 ) C-, knowing that this radical (Z 1 Z 2 ) C - may be an unsaturated ring, substituted or unsubstituted, such as a benzene ring,
• At least one liquid phase comprising said starting alcohol, optionally in a suitable solvent, and a strong acid, is preferably continuously introduced into an end of said reactor,
• said at least one liquid phase is subjected to axial mechanical stirring, under the influence of a CO pressure of between 2 and 250 bar, and preferably between 5 and 100 bar, for a transit time t of between 10 seconds and 10 minutes, preferably between 10 seconds and 6 minutes, and more preferably between 45 seconds and 4 minutes,
• the temperature of said at least one liquid phase during the reaction is advantageously between 0 ° C and 150 ° C, preferably between 10 ° C and 100 ° C, and even more preferably between 20 ° C and 80 ° C ° C, and wherein the process of increasing the temperature ⁇ of the liquid between the inlet and the outlet of the reactor is controlled so that the ratio ⁇ / AT ad (where AT ad represents the adiabatic increase in temperature) is between 0.02 and 0.6 when the ratio between the characteristic heat transfer time t the rm and the characteristic material transfer time t mat is between 1 and 50.
• C - X can represent (R 1 R 3 ) (HZ 1 Z 2 C) C - OH.
• the target acid may correspond to the formula: R - (R 1 R 3 ) C - COOH or to the formula Z 1 Z 2 C - (R 1 R 3 ) C - COOH.
• R 1 and R 3 may be, simultaneously or independently of one another, selected from the group consisting of: H; F, Cl, Br, I; an alkyl radical, linear or branched, possibly partially or totally halogenated; an aryl residue, for example phenyl, substituted or not.
• R 1 and R 3 may also together represent a cycloalkyl of (CH 2 ) n type , substituted or unsubstituted, where n is preferably equal to 2, 3, 4, or 5.
• Z 1 and Z 2 may be, simultaneously or independently of one another, selected from the group consisting of: H; F, Cl, Br, I; an alkyl radical, linear or branched, possibly partially or totally halogenated; an aryl radical, for example phenyl, substituted or unsubstituted.
• (Z 1 Z 2 ) may also together represent a cycloalkyl of (CH 2 ) n type , substituted or unsubstituted, where n is preferably equal to 2, 3, 4, or 5.
• the structural element (Z 1 Z 2 ) C (represented by the symbol R) may be an unsaturated ring, substituted or unsubstituted, and preferably a benzene ring or a phenyl radical mono- or polysubstituted by one or more groups preferably selected. in the group consisting of:
• H H
• F, Cl, Br, I a linear or branched alkyl residue and optionally partially or completely substituted, preferably with one or more halogen atoms or one or more alkyl groups (preferably methyl, ethyl, propyl, butyl), and even more preferably by one or more radicals; CF 3 or C 2 F 5 .
• This acid is advantageously selected from:
• Lewis type acid preferably AICI 3 or SbF 5
• a complex between a Lewis acid and a protonic acid preferably the complex formed between fluorosulfonic acid HS0 3 F and SbF 5 ),
• the process according to the invention is carried out so that the ratio ⁇ / AT ad is between 0.02 and 0.2 when m / is between 1, 5 and 12, and preferably so that that ⁇ / AT ad is between 0.03 and 0.15 when m / t mat is between 2 and 8.
• the starting compound (here called “the starting alcohol”) is: with the structural formula or
• R 1 , R 3 represent moieties bonded to the carbon atom by a single covalent bond, or an aliphatic ring which integrates the central carbon atom and which is bonded thereto on each side by a single covalent bond;
• this radical (3a) may be a unsaturated, substituted ring such as a benzene ring,
• such a compound of type (2) is:
• the target compound (referred to herein as the "target acid”) produced from the carbonylation reaction according to the invention is: R - (R 1 R 3 ) C - COOH (5),
• the carbon atom C may be saturated and in this case carries a hydrogen atom, or may be unsaturated, for example in the case or said radical (3a) is an unsaturated ring, substituted or unsubstituted, such as a benzene ring.
• this method therefore comprises three mechanistic steps:
• the process according to the invention is a continuous process carried out in a tubular reactor of the horizontal stirring piston type. Consequently, these three mechanistic steps are not visible separately and do not correspond to identifiable sequences in the execution of the method.
• R 1 and R 3 may be, simultaneously or independently of one another:
• An aryl radical for example phenyl, substituted or otherwise.
• R 1 and R 3 may be part of a cycloalkyl of (CH 2 ) n type , substituted or unsubstituted, where n is preferably equal to 2, 3, 4 or 5.
• Z 1 and Z 2 can be, simultaneously or independently of one another:
• aryl radical for example phenyl, substituted or otherwise
• (Z 1 Z 2 ) may be a cycloalkyl of (CH 2 ) n type , substituted or unsubstituted, where n is preferably equal to 2, 3, 4, or 5;
• the structural element (Z 1 Z 2 ) C may also be an unsaturated, substituted or unsubstituted ring, such as a benzene ring; for example, R may be a mono- or polysubstituted phenyl radical, in particular by one or more halogen atoms or one or more linear or branched alkyl groups (especially methyl, ethyl, propyl, butyl) and optionally partially or totally substituted (by halogenated example), for example by one or more radicals CF 3 or C 2 F 5 .
• the process according to the invention is carried out in the presence of a strong acid.
• sulfuric acid may be used, but a superacid is preferred, ie an acid having a higher H 0 acidity than concentrated sulfuric acid on the Hammett scale, which is well known in the art. skilled person; an acid with an acidity H 0 of at least 12.0 is preferred.
• perchloric acid trifluoroacetic acid, fluoroantimonic acid HSb 6 , chlorosulphonic acid, fluorosulphonic acid, or preferably trifluoromethanesulfonic acid HS0 3 CF 3 (often called "acid triflic ").
• Lewis-type acids AlCl 3 , SbF 5 for example
• complexes between a Lewis acid and a protonic acid for example the complex formed between fluorosulfonic acid HS0 3 F and SbF 5 which is known as "magic acid”
• the process according to the invention can take place in the presence of a solvent, which contributes to the heat dissipation of the reaction enthalpy.
• This solvent must be inert in relation to the strong acid and the carbonylation, and it must be able to dissolve the starting alcohol in a sufficient manner.
• a halogenated alkane such as CH 2 Cl 2
• a chlorobenzene such as toluene
• an alkylbenzene such as toluene
• the process according to the invention is carried out in a continuous reactor of the piston-reactor type (also called piston-flow reactor), of length L and of volume V, in which the chemical species (in particular the starting alcohol optionally in its solvent, strong acid, gaseous CO) enter at one end and move throughout the reactor gradually transforming.
• the reactor preferably has a cylindrical shape. It must be provided with an axial stirring means, and preferably a mechanical axial stirring means.
• axial stirring means here means any device which ensures a stirring of the reaction mixture over the entire length, or a significant part of it, by a means having an axis parallel to the axis of the reactor. This means of axial stirring facilitates, on the one hand, the course of the reaction, by mixing the chemical species entering with the catalyst, which is in dispersed form in a liquid phase, and also facilitates the heat transfer.
• At least one liquid phase comprising said starting alcohol, optionally in a suitable solvent, and a strong acid, is preferably continuously introduced into an end of said reactor,
• said at least one liquid phase is subjected to axial mechanical stirring, under the influence of a CO pressure of between 2 and 250 bar, and preferably between 5 and 100 bar, for a transit time t of between 10 seconds and 10 seconds. minutes, preferably between 10 seconds and 6 minutes, and more preferably between 45 seconds and 4 minutes, leaving the liquid phase of said reactor.
• the temperature of said at least one liquid phase during the reaction is advantageously between 0 ° C. and 150 ° C., preferably between 10 ° C. and 100 ° C., and even more preferably between 20 ° C. and 80 ° C.
• An essential characteristic of the process according to the invention is the careful control of the temperature increase ⁇ of the liquid between the inlet and the outlet of the reactor, which must be such that the ratio ⁇ / AT ad (where AT ad represents the adiabatic temperature increase) is between 0.02 and 0.6 when the ratio between the characteristic heat transfer time t the rm and the characteristic material transfer time t mat is between 1 and 50.
• the piston reactor has a temperature and concentration profile that can vary along its axis.
• Such a reactor can be modeled as a series of elementary reactors arranged in series along an axis and each having a length AL and a volume AV. Under the operating conditions of this reactor, the composition of the feed and the total volume flow rate F are uniform and constant, and the residence time
• T V / F (Equation 1) is constant for all molecules entering the reactor.
• This type of reactor is known, and one skilled in the art also knows that if a very exothermic reaction is carried out in a piston reactor, the radial heat transfer can become limiting. This is the case of carbonylation reactions,
• the process according to the invention involves a chemical reaction of the type
• Equation 2 A (liquid) + v B (gas) -> v p Product (Equation 2) where v is the stoichiometric coefficient of the gas and v p is the stoichiometric coefficient of the product.
• the gas B is CO
• the starting alcohol to be carbonylated is in the form of a liquid which is pure or diluted in a liquid solvent, or in the form of a solid diluted in a liquid solvent. , and this liquid phase comprises a strong acid.
• the overall transfer coefficient K (also called global exchange coefficient) is defined by the equation
• ATmi ⁇ [(T (coolant) leaves ie - T (process) input] - [(T (coolant) input - T (process) output] ⁇ /
• a continuous piston-type reactor having the following characteristics is used:
• the characteristic time ratio is therefore:
• the temperature increase of the liquid ⁇ between the inlet and the outlet of the reactor is such that:
• T ad is the adiabatic increase in temperature
• ⁇ ⁇ ⁇ is the enthalpy of the reaction
• X A is the stoichiometric coefficient of compound A.
• C A o means the concentration of the liquid at the reactor inlet.
• the reaction is conducted in such a way that the increase in temperature ⁇ of the liquid between the inlet and the outlet of the reactor is such that the ratio ⁇ / AJ ad (where AJ ad represents the adiabatic temperature increase) is between 0.02 and 0.6 when the ratio between the characteristic heat transfer time t the rm and the characteristic material transfer time t mat is between 1, 5 and 50.
• This process can be used without solvent, ie the mixture between said starting alcohol and the strong acid is the liquid that enters the reactor. But it is better to use a suitable solvent.
• the liquid entering the reactor comprises two liquid phases: the organic phase which comprises the starting alcohol and its solvent, and the strong acid phase.
• the reaction proceeds in this case in three-phase medium, the CO gas representing the third phase.
• the control of mass transfer is therefore critical; for this purpose, the reactor must have an axial stirring means, which will be described below.
• the ratio ⁇ / AJ ad is between 0.02 and 0.2 when t tom / t mat is between 1, 5 and 12. In an even more preferred embodiment, ⁇ / AJ ad is between 0.03 and 0.15 when t tom / t mat is between 2 and 8.
• the process according to the invention is implemented in a tubular cylindrical piston reactor having an internal diameter of between 20 mm and 100 mm. Above 100 mm, the productivity of the reactor decreases because for the exchange surface remains large, the flow must be reduced. Below 20 mm, the area / volume ratio is very important, but the flow rate is insufficient for industrial production.
• the internal diameter of the piston reactor is between 30 mm and 75 mm, and even more preferably between 40 mm and 60 mm.
• the length of the reaction chamber of the reactor is between 10 cm and 100 cm. Below 10 cm, the residence time is too short. Above 100 cm, machining of the tubular reactor becomes difficult, and stirring of the reaction mixture is difficult to accomplish. A preferred length is between 20 cm and 80 cm.
• the reactor must be provided with axial stirring means, which is preferably a mechanical means of axial stirring.
• axial stirring means here means any device which ensures a stirring of the reaction mixture over the entire length, or a significant part of it, by a means having an axis parallel to the axis of the reactor. Different means can be used for this purpose, such as a series of kneaders, a worm, a propeller, but this mechanical means of axial stirring must not disturb the "piston" nature of the reactor, as defined by the equation (1).
• Said axial stirring means facilitates, on the one hand, the progress of the reaction by mixing the chemical species entering the reactor, and facilitates the other hand heat transfer.
• the continuous process can be described as having several steps.
• At least one liquid phase comprising said starting alcohol and the strong acid is introduced continuously, preferably at an end of said reactor. Then said at least one liquid phase is subjected to a temperature of between 0 ° C. and 150 ° C. and with axial mechanical stirring, under the influence of a carbon monoxide pressure of between 1 and 200 bar (preferred: between 2 and 50 bar) during a passage time t of between 1 second and 10 minutes (preferred: 10 seconds and 6 minutes, and even more preferably 40 seconds to 3 minutes).
• a carbon monoxide pressure of between 1 and 200 bar (preferred: between 2 and 50 bar)
• a passage time t of between 1 second and 10 minutes (preferred: 10 seconds and 6 minutes, and even more preferably 40 seconds to 3 minutes).
• the process according to the invention makes it possible to produce industrial quantities of carboxylic acid, for example of the order of 2 to 20 kg / h in the case of phenylalkyl acids. This gives access to an annual production of about 20 to 100 tonnes with a single reactor. For a continuous reactor, this represents a productivity quite interesting on the industrial level, even in the case of simple molecules.
• the investment cost of a reactor capable of implementing the process according to the invention is lower than that for a batch reactor, and the need for manpower is reduced.
• the "scaling up" of the process is greatly simplified since the process according to the invention can be implemented in a small industrial continuous reactor, which does not differ much from an experimental laboratory reactor.
• the reactor diameter can be increased, but this possibility is limited by heat transfer, as explained above.
• using a plurality of reactors given their simplicity, the continuous nature of the process and the fact that this continuous process does not require the intervention of a lot of manpower
• the starting alcohol (1) is a molecule in which C - X represents C (R) - OH (2) where R represents a phenyl mono- or polysubstituted radical, in particular by a halogen or an alkyl group, for example 2,3,4-trifluorophenyl-, 2,3,4-trichlorophenyl-, 2,3 (or 3,4 or 4,5 or 2,5 or 3,5 or 2,4-bischlorophenyl-, 2 (or 3 or 4 or 5) -chlorophenyl-, 2 (or 3 or 4 or 5) -fluorophenyl-, 2 (or 3 or 4 or 5) -methylphenyl, 2,3 (or 3,4 or 4,5 or 2,5 or 3,5 or 2,4) bimethylphenyl-, and the process proceeds as follows:
• the axial stirring in the reactor is in the order of 1400 rpm, the residence time is about 3 minutes, the temperature ("target temperature") of the reaction is maintained at 40 ° C - 50 ° C (for example about 45 ° C), the pressure of CO is constant and about 5 to 50 bar (for example 40 to 50 bar);
• the solution is subjected to separation and recovery steps known per se.
• the aqueous phase containing the triflic acid is separated from the organic phase which contains the target acid, the triflic acid is recovered by distillation and recycled in the reaction, the organic phase is treated with sodium hydroxide for obtain a salt of the acid targeted in the water and this solution is acidified to regenerate the acid which is extracted; it can be crystallized in a suitable solvent.
• formic acid is used in addition to the CO under pressure, which in certain cases makes it possible to reduce the CO pressure and to better solubilize it. This mechanism probably involves a dehydration reaction
• This reaction is carried out in the liquid phase without a solvent, the gas phase consisting of pure hydrogen at an initial pressure of 2 bar.
• the catalyst consists of pulverulent carbon (equivalent particle diameter of the order of 50 ⁇ ) charged to 5% by weight of palladium.
• the mass concentration of the catalyst is 2.5 g / l and the hydrogenation is carried out at room temperature.
• a quartz pressure sensor is used to measure the hydrogen pressure as a function of time.
• the reactor has a double envelope; a thermostatically circulated water circulation inside the double jacket makes it possible to keep the temperature of the reactor constant. Initially, the unstirred reactor is maintained under nitrogen pressure; it is then purged with hydrogen. At a hydrogen pressure of 2 bar, agitation is started and the drop is recorded. hydrogen pressure.
• ⁇ ⁇ 2 is the specific flow of disappearance of hydrogen. This flow can be expressed showing either the reaction rate or the transfer flux: knowing that r v is the volume reaction rate of the hydrogenation, the retention of solid in the reactor and (K H 2a) g i 0 bai the overall conductance of hydrogen transfer from the gas phase to the surface of the catalyst.
• the reaction rate can be expressed as resulting from a first order kinetics with respect to the hydrogen concentration, ie:
• the overall transfer conductance can be expressed as a function of the partial gas-liquid and liquid-solid transfer conductances by:
• the starting alcohol can be synthesized by treating the corresponding Grignard reagent with a ketone; this reaction must respect precise conditions to avoid a risk of explosion.
• the acid which was used to carry out the process according to the invention was triflic acid, at 2.5 parts relative to the pure alcohol.
• the tubular reactor used is Hastelloy C22 alloy. It has two inputs for liquids and one for gases.
• a solution of the starting alcohol (at 40% by weight) in CH 2 Cl 2 is prepared ; this solution is preheated to the reactor temperature (45 ° C.).
• This solution is injected into the reactor with a constant flow rate of 65 g / min (ie 26 g of pure alcohol), at the same time as triflic acid at a rate of 65 g / min (ie 2.5 parts).
• the CO pressure is regulated by a pressure reducer at 45 ⁇ 2 bar at the outlet of the bottle and kept constant during the reaction; the consumption was of the order of 7 to 9 g / min.
• the temperature of the reactor is kept constant at 45 ⁇ 2 ° C., the residence time of the reaction mixture in the reactor is of the order of 3 minutes. Horizontal agitation during the reaction is set at 1400 rpm. All flow rates are controlled using mass flow meters.
• the solution is cooled in line to about 20-25 ° C, then relaxed at atmospheric pressure and collected in a first tank for 7 minutes (about 2 times the residence time in the reactor). Finally, it is collected in a tank containing water at about 5 ° C for hydrolysis. Separating the aqueous phase containing triflic acid for upgrading (distillation), the organic phase (solvent CH 2 CI 2 containing the target carboxylic acid) is treated with sodium hydroxide to form the sodium salt in water. Finally, it is acidified to obtain the target acid which is extracted and crystallized in toluene.
• This acid has a high purity. It can be used as such as a starting point or intermediate for the synthesis of other more complex molecules, especially molecules of pharmaceutical interest.
• Example 3
• corresponding alcohol here denotes the alcohol according to the formula (1) which leads to the acid of the formula (5).
• one or more of said methyl groups (CH 3 ) can be replaced by an ethyl or n-propyl group, and in the molecule (c) one or more of said ethyl groups by a methyl or n-propyl group.

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