Process for producing an atropoisomeric chemical compound

Abstract

The invention relates to a continuous process for producing a chemical compound A comprising: providing a mixture comprising the chemical compound A and a chemical compound B which is an atropoisomer of the chemical compound A; chromatographic separation of the mixture, so as to collect a fraction rich in chemical compound A and a fraction rich in chemical compound B; racemization treatment of the fraction rich in chemical compound B, in which the chemical compound B is partially converted into chemical compound A, so as to obtain a racemized fraction; recycling the racemized fraction to the step of chromatographic separation of the mixture. The invention also relates to an installation for implementing this process. Figure 1.

Description

Title of the invention: Process for producing an atropoisomeric chemical compound Field of the invention

[0001] The present invention relates to a continuous process for producing an atropoisomeric chemical compound, in the form of an enantiomerically enriched fraction, as well as an installation suitable for carrying out this process. This process combines a purification of a racemic mixture in order to isolate a desired compound (in the form of an enantiomerically enriched fraction) and a racemization in order to recycle the unwanted compound. Technical background

[0002] Atropoisomeric compounds are compounds that are stereoisomeric due to the blocking of a rotation about one or more single bonds. Obtaining various enantiomerically enriched atropoisomeric compounds is useful especially in pharmaceutical research and production.

[0003] The article Synthesis, Chiroptical Properties and Density Functional Theory Calculations of 3,3'-Biphenyl-2,2'-BiTropone, by Cavazza et al., in Chirality 25:648-655 (2013), describes the synthesis and separation by chiral HPLC chromatography of atropoisomers of 3,3'-bisphenyl-2,2'-bitropone.

[0004] Document WO 2022 / 076623 describes a process for the racemization and purification of atropoisomers. The purification is carried out by chiral resolution by crystallization. The process described is a batch process. The purification of atropoisomer by crystallization only allows a theoretical yield of this step of 50%. The undesired enantiomer is isolated and then racemized in a second step. A third purification step can then be carried out on this racemate allowing an additional theoretical maximum yield of 25% (i.e. 75% in total) to be achieved.

[0005] The article Enantioenriched Axially Chiral beta-diketimines: Determination of the IAN-amine Barrier to Atropisomerization, by Cortright et al., in Heterocycles 62:223-227 (2004) focuses on the thermal racemization of compounds derived from isoquinoline and 2-amino-napthalene.

[0006] The article Conversion of Racemic Alkyl Aryl Tallow oxides into Pure Enantiomers Using a Recycle Photoreactor: Tandem Use of Chromatography on Chiral Support and Pho-toracemization on Solid Support, by Tozawa et al., in J. Org. Chem. 88, 11, 6955-6961 (2023), describes a process for converting a racemic mixture of alkyl aryl sulfoxides into pure enantiomers by separation on a chiral chromatography column, in tandem with racemization in a photoreactor. Only the se Preparation and racemization by photoactivation is described in this article. It does not address the separation of atropoisomers and / or racemization by heat treatment.

[0007] There is a need to provide an efficient and easy-to-implement process and plant for the production of atropoisomeric chemical compounds in a purified form. Summary of the invention

[0008] The invention relates firstly to a continuous process for producing a chemical compound A comprising: • the supply of a mixture comprising chemical compound A and a chemical compound B which is an atropoisomer of chemical compound A; • a chromatographic separation of the mixture, so as to collect a fraction rich in chemical compound A and a fraction rich in chemical compound B; • a racemization treatment of the fraction rich in chemical compound B, in which chemical compound B is partially converted into chemical compound A, so as to obtain a racemized fraction; • recycling of the racemized fraction to the chromatographic separation step of the mixture.

[0009] In embodiments, the chromatographic separation of the mixture is a multi-column separation, preferably with a non-static bed, and more preferably chosen from AMB, SMB, VARICOL, POWERFEED, MODICON, iSMB, SSMB, DCC or MCSGP separations.

[0010] In embodiments, the racemization treatment is a thermal racemization treatment.

[0011] In embodiments, the method comprises a step of concentrating the fraction rich in chemical compound B before the racemization treatment step; or comprises a step of concentrating the racemized fraction before the step of recycling it to the step of chromatographic separation of the mixture.

[0012] In embodiments, the fraction rich in chemical compound B comprises a solvent, and the method does not comprise modifying the solvent between collecting the fraction rich in chemical compound B and the racemization treatment thereof.

[0013] The invention also relates to a continuous production plant for a chemical compound A, comprising: • a chromatographic separation unit; • a supply line for a mixture comprising chemical compound A and a chemical compound B which is an atropoisomer of chemical compound A, feeding the chromatographic separation unit; • a collection line for a fraction rich in chemical compound A and a collection line for a fraction rich in chemical compound B at the outlet of the chromatographic separation unit; • a racemization treatment unit for the fraction rich in chemical compound B, configured to partially convert chemical compound B into chemical compound A, supplied by the collection line for the fraction rich in chemical compound B; • a racemized fraction collection line, at the outlet of the racemization treatment unit, and feeding the chromatographic separation unit.

[0014] In embodiments, the chromatographic separation unit is a multi-column separation unit, preferably with a non-static bed, and preferably chosen from AMB, SMB, VARICOL, POWERFEED, MODICON, iSMB, SSMB, DCC and MCSGP separation units.

[0015] In embodiments, the racemization processing unit is a thermal racemization processing unit.

[0016] In embodiments, the installation comprises a concentration unit on the collection line of fraction rich in chemical compound B; or comprising a concentration unit on the collection line of racemized fraction.

[0017] The present invention makes it possible to meet the need expressed in the state of the art. More particularly, it provides an efficient and easy-to-implement process and installation for the production of atropoisomeric chemical compounds in a purified form.

[0018] In particular, in the state of the art, the purification of a racemic mixture is carried out with a maximum yield of 50%. The invention makes it possible to isolate the compound of interest with a yield greater than 50%. Brief description of the figures

[0019] [Fig.l]. [Fig.l] schematically represents an installation according to the invention. Detailed description

[0020] The invention is now described in more detail and in a non-limiting manner in the following description. Atropoisomers

[0021] The invention aims at the production of a chemical compound A, from a (starting) mixture comprising at least the desired chemical compound A and a chemical compound B, A and B being atropoisomers of each other.

[0022] As mentioned above, atropoisomeric compounds are compounds that are stereoisomeric due to restricted rotation about one or more single bonds. Energy differences due to steric constraint or other contributors create a barrier to rotation high enough to allow isolation of individual conformers.

[0023] The chemical compounds A and B may in particular be chosen from biaryls, such as substituted diphenic acids and biphenyl derivatives having substituents on all the ortho positions; they may also be dimers of naphthalene derivatives; they may also be cyclic aliphatic compounds, comprising for example at least one aromatic ring and one aliphatic ring linked by a single bond; they may also be compounds with heteroaryl groups, alkenes, amides, benzamides or anilides.

[0024] In embodiments, compounds A and B may have one of the following general formulas:

[0025] [Chem.l] al) "y"' r2 r3 r4 ■: Ar2 i

[0026] [Chem.2] : Ar, ] Ri" "TX ...y^ ...- ¾ ON

[0027] [Chem. 3]

[0028] [Chem. 4]

[0029] in which: Arl represents: • An aryl group, in particular phenyl or naphthyl. This aryl group may be substituted by one or more alkyl (C1-C4), ether (C1-C4) or alkylamino (C1-C4) groups. • Or a heteroaryl group, for example (without limitation) a pyridinyl, pyrimidyl, pyrazyl, pyrazolo, pyrrolidic group. This heteroaryl group may be substituted by one or more alkyl (C1-C4), ether (C1-C4) or alkylamino (C1-C4) groups. Ar2 represents: • An aryl group, in particular phenyl or naphthyl. This aryl group may be substituted by one or more alkyl (C1-C4), ether (C1-C4) or alkylamino (C1-C4) groups. • Or a heteroaryl group, for example (without limitation) a pyridinyl, pyrimidyl, pyrazyl, pyrazolo, pyrrolidic group. This heteroaryl group may be substituted by one or more alkyl (C1-C4), ether (C1-C4) or alkylamino (C1-C4) groups. RI, R2, R3, R4 each independently represent an alkyl group (C1-C4), ether (C1-C4), alcohol (OH), secondary (C1-C4) or tertiary (C1-C4) alkylamino or primary amino (NH2), nitrile, hydrogen, alkylthio (C1-C4), alkyl sulfone (C1-C4) or halogen (F, Cl, Br, I). - R5, R6 each independently represent an alkyl group (C1-C4) or tertiary (C1-C4) ... C1-C4), acyl (C1-C4), amide (mono or dialkylated C1-C4 or phenyl) or acrylate. - X represents an oxygen atom, a sulfur atom, a sulfinyl group -S(=O)- or a sulfonyl group -S(=O)2-.

[0030] Atropisomers may be denoted by the respective notations M (or Ra) or P (or Sa). Starting with the substituent having the highest priority on the nearest ring, and defining the shortest path to the substituent having the highest priority on the other ring, the configuration is denoted P if it involves a clockwise rotation, and M if it involves a counterclockwise rotation.

[0031] Chemical compound A may be of M (or Ra) conformation while chemical compound B may be of P (or Sa) conformation.

[0032] Conversely, chemical compound B may be of M (or Ra) conformation while chemical compound A may be of P (or Sa) conformation.

[0033] The initial mixture may be a racemic mixture. It may be obtained by a synthesis process, in particular an achiral synthesis process.

[0034] In this mixture, preferably, the molar proportion of compound A relative to the sum of compounds A and B may be from 30 to 70%, more preferably from 40 to 60%, more preferably from 45 to 55%. It may be, for example, approximately 50%. The starting mixture may also contain a solvent or mixture of solvents, which are preferably suitable for carrying out the chromatography and racemization steps. The contents of the atropisomers in the starting mixture are variable and adjusted according to the solubility of the atropoisomers. For example, the total concentration of A and B in the initial mixture may be from 1 to 200 g / L, preferably from 2 to 100 g / L, in particular from 5 to 50 g / L, or from 10 to 30 g / L, or from 15 to 25 g / L.

[0035] The initial mixture may contain impurities, for example reagents, synthesis intermediates or secondary products of the synthesis. Preferably, the content of impurities (compounds other than compounds A, B and the solvent(s)) is less than 5 g / L, more preferably less than 1 g / L, more preferably less than 0.5 g / L. Too high a content of impurities is likely to disrupt the chromatographic separation and lead to accumulation effects.

[0036] General presentation of the installation and the process

[0037] Referring to [Fig.l], the installation according to the invention comprises at least a chromatographic separation unit 2 and a racemization treatment unit 4.

[0038] A mixture supply line (comprising compound A and compound B) 11 feeds the chromatographic separation unit 2, from a mixture source 1.

[0039] This mixture source 1 may be, for example, a reservoir containing the mixture. The mixture source 1 may be supplied from a synthesis installation. Alternatively, the mixture source 1 may be a unit of a mixture synthesis installation, when the method of the invention is implemented directly at the end of this synthesis.

[0040] A collection line for a fraction rich in compound A 12 and a collection line for a fraction rich in compound B 13a, 13b are connected to the outlet of the chromatographic separation unit 2.

[0041] The collection line for the fraction rich in compound A 12 can feed a downstream unit 6. The downstream unit 6 can represent a simple storage unit, or an additional treatment unit, for example a concentration unit or a synthesis unit necessary for the subsequent stages of the process.

[0042] The collection line for the fraction rich in compound B 13a, 13b feeds the racemization treatment unit 4, which is configured to partially convert compound B into compound A. This unit may be a reactor, in particular a photochemical reactor or, preferably, a synthesis reactor allowing, if necessary, the temperature and pressure regulations of the reaction medium.

[0043] The photochemical reactor may be a continuous reactor. The reactor is configured to maintain the reaction medium at a given temperature and pressure subjected to a light source which may be a light source emitting in the ultraviolet (wavelength from 100 to 380 nm), the visible (wavelength from 380 to 700 nm) or the infrared (wavelength greater than 700 nm) for a certain duration. For example, a tubular reactor or a micro / meso fluidic reactor (micro-structured reactor) may be used through which the reaction medium (fraction rich in compound B at the inlet, racemized fraction at the outlet) is passed in the presence of a catalyst or not. The temperature may be maintained by a heat transfer fluid circulating inside one or more exchangers, or by one or more electrical resistors for example. The residence time varies depending on the compounds and the kinetics of the isomerization reaction.For example, the residence time can be 2 seconds to 2 hours, preferably 10 seconds to 1 hour.

[0044] In the case of racemization by thermal effect, a continuous type reactor (tubular or continuous stirred tank reactor) can be used. The reactor is configured to maintain the reaction medium at a temperature and pressure (if necessary) data for a certain period of time. For example, a "tubular" type reactor can be used, or a micro-structured reactor through which the reaction medium is passed (fraction rich in compound B at the inlet, racemized fraction at the outlet). Heating can be provided by a heat transfer fluid circulating inside one or more heat exchangers, or by one or more electrical resistors for example. When temperatures higher than the boiling points of the solvents used in the reaction mixture are required, a back pressure of up to several tens of bar can be applied so as not to vaporize the solvents. The pressure is maintained by back pressure regulating devices installed at the reactor outlet.

[0045] The temperature applied in the reactor, during racemization, may be greater than 100°C, for example greater than 150°C, for example greater than 175°C. Preferred ranges may be from 100 to 400°C, in particular from 150 to 350°C, in particular from 175 to 300°C, in particular from 190 to 260°C.

[0046] The duration during which this temperature is applied may be at least 10 seconds, and in particular: from 10 seconds to 1 hour, in particular from 1 minute to 30 minutes, in particular from 2 minutes to 20 minutes, in particular from 5 minutes to 15 minutes.

[0047] At the outlet of the racemization treatment unit 4 is connected a racemized fraction collection line 14a, 14b, in order to allow recycling of the racemized fraction to the chromatographic separation unit 2.

[0048] In a preferred embodiment, and as illustrated, the racemized fraction is combined with the initial mixture before entering the chromatographic separation unit 2. Alternatively, it is possible to feed the chromatographic separation unit 2 separately with the initial mixture and with the racemized fraction, for example via two dedicated supply lines, or even by alternating the feeding of this unit with the initial mixture and with the racemized fraction, via the same supply line 11.

[0049] In the process of the invention, the initial mixture (optionally combined with the racemized fraction) enters the chromatographic separation unit 2, where it undergoes separation between a fraction rich in compound A and a fraction rich in compound B, which are recovered via the respective collection lines described above.

[0050] By "fraction rich in compound A" is meant a flow in which the molar proportion of compound A relative to the sum of compounds A and B is greater than the molar proportion of compound A relative to the sum of compounds A and B in the initial mixture (where appropriate combined with the racemized fraction). Conversely, by "fraction rich in compound B" is meant a flow in which the molar proportion of compound B relative to the sum of compounds A and B is greater than the molar proportion of compound B relative to the sum of compounds A and B in the mixture initial (if applicable combined with the racemized fraction).

[0051] In embodiments, in the fraction rich in compound A, the molar proportion of compound A relative to the sum of compounds A and B is greater than or equal to 80%, for example 90%, or 95%, or 98% or 99%. This proportion may in particular be within ranges of 80 to 100%, in particular 90 to 99.99%, or 95 to 99.95%, or 98 to 99.9%, or 99 to 99.5%.

[0052] In embodiments, in the fraction rich in compound B, the molar proportion of compound B relative to the sum of compounds A and B is greater than or equal to 80%, for example 90%, or 95%, or 98% or 99%. This proportion may in particular be within ranges of 80 to 100%, in particular 90 to 99.99%, or 95 to 99.95%, or 98 to 99.9%, or 99 to 99.5%.

[0053] The fraction rich in compound B undergoes the racemization treatment in the racemization treatment unit 4. Compound B is partially converted there into compound A, so as to convert the fraction rich in compound B into a racemized fraction. In this racemized fraction, the molar proportion of compound A relative to the sum of compounds A and B may be 30 to 70%, more preferably 40 to 60%, more preferably 45 to 55%, or 47 to 53%. It may be, for example, approximately 50%.

[0054] The racemized fraction is collected by the racemized fraction collection line 14a, 14b and recycled to the chromatographic separation unit 2.

[0055] The initial mixture, the fraction rich in compound A, the fraction rich in compound B and the racemized fraction may be compositions comprising compounds A and / or B and one or more solvents.

[0056] The solvent(s) may be aqueous, organic, or hydro-organic. They may comprise one or more organic compounds. The organic compounds may be chosen, for example, from alcohols (in particular methanol, ethanol, propanol, isopropanol), alkanes (in particular pentane, hexane, heptane and octane), ketones (in particular acetone and methyl ethyl ketone), nitriles (in particular acetonitrile), esters (in particular methyl acetate and ethyl acetate), acyclic ethers (in particular diethyl ether and methyl ethyl ether) or cyclic ethers (in particular tetrahydrofuran or 2-methyltetrahydrofuran, dioxane, etc.), and combinations thereof.

[0057] The term “solvent” also refers below to mixtures of solvents.

[0058] A preferred solvent is a mixture of alkane and alcohol (in particular heptane and ethanol), in particular in an alkane:alcohol mass ratio of 50:50 to 97:3, for example of 60:40 to 95:5.

[0059] Another preferred solvent mixture is a mixture of acetonitrile and alcohol (in particular acetonitrile and methanol), in particular in an acetonitrile:alcohol mass ratio of 10:90 to 80:20, for example of 15:85 to 50:50.

[0060] Preferably, there is no modification of the composition of the solvent between the chromatographic separation unit 2 and the racemization treatment unit 4. Thus, the fraction rich in compound B at the outlet of the chromatographic separation unit 2 and the racemized fraction have the same solvent. This variant makes it possible to simplify the process. In this case, the composition of the solvent can be optimized so as to obtain a performance and in particular a satisfactory yield for both the chromatographic separation and the racemization.

[0061] Alternatively, it is possible to provide for a modification of the composition of the solvent between the chromatographic separation unit 2 and the racemization treatment unit 4.

[0062] The installation may comprise a concentration unit.

[0063] For example, a concentration unit 3 may be arranged between the chromatographic separation unit 2 and the racemization treatment unit 4, on the compound B-rich fraction collection line 13a, 13b. In this case, this line comprises an upstream portion 13a connecting the chromatographic separation unit 2 to the concentration unit 3 and a downstream portion 13b connecting the concentration unit 3 to the racemization treatment unit 4.

[0064] Alternatively, a concentration unit 5 may be arranged between the racemization treatment unit 4 and the chromatographic separation unit 2 (or the mixing source 1), on the racemized fraction collection line 14a, 14b. In this case, this line comprises an upstream portion 14a connecting the racemization treatment unit 4 to the concentration unit 5 and a downstream portion 14b connecting the concentration unit 5 to the chromatographic separation unit 2 (or to the mixing source 1).

[0065] Both concentration units may be present, but preferably only one of these two units is present - in other words, with respect to the schematic illustration of [Fig.l], the installation comprises either the concentration unit 3 between the chromatographic separation unit 2 and the racemization treatment unit 4, or the concentration unit 5 between the racemization treatment unit 4 and the chromatographic separation unit 2 (or the mixing source 1) - but not both.

[0066] Each concentration unit 3, 5 may be (or may comprise) an evaporator, for example a plate or tubular evaporator, single effect or multiple effects, single pass or recirculation, steam or mechanical steam recompression, with or without thermocompressor, falling film or scraped film. Each concentration unit 3, 5 may be (or may comprise) a synthesis reactor equipped with one or more distillation columns. Alternatively, each concentration unit 3, 5 may be (or may comprise) a membrane separation device.

[0067] Each concentration unit has the purpose of concentrating the composition which passes through the unit, that is to say to increase the rate of dry matter, and in particular to increase the concentration of compounds A and / or B.

[0068] The total concentration of compounds A and B in the fraction rich in compound B is generally lower than that of the initial mixture. It may in particular be from 0.5 to 30 g / L, preferably from 1 to 10 g / L, more preferably from 2 to 5 g / L.

[0069] After concentration (whether on the fraction rich in compound B or on the racemized fraction), the total concentration of compounds A and B can be increased in particular up to a range of 1 to 200 g / L, in particular 2 to 100 g / L, or 5 to 50 g / L, or 10 to 30 g / L, or 15 to 25 g / L. In one embodiment, the total concentration of compounds A and B after concentration is substantially equal to the total concentration of compounds A and B in the initial mixture.

[0070] Depending on the concentration technology used, a change in the composition of the solvent can be obtained, when the latter is a mixture. For example, the use of a solvent distillation unit of the falling or scraped film evaporator type or a synthesis reactor equipped with a distillation column leads to a preferential evaporation of a solvent can be observed, resulting in a modification of the solvent composition at the outlet of the concentration unit. The same applies to a membrane concentration unit for example. In such cases, it may be useful to provide for a readjustment by adding solvent(s) after the concentration, making it possible to substantially restore the initial solvent composition.In such cases, preferably the total concentration of compounds A and B after concentration is substantially equal to the total concentration of compounds A and B after concentration and readjustment by addition of solvent(s) may be 1 to 200 g / L, in particular 2 to 100 g / L, or 5 to 50 g / L, or 10 to 30 g / L, or 15 to 25 g / L. Preferably, the total concentration of compounds A and B after concentration and readjustment by addition of solvent(s) is substantially equal to the total concentration of compounds A and B in the initial mixture.

[0071] Increasing the total concentration of compounds A and B upstream of the racemization treatment unit 4 promotes the productivity of the racemization and, where appropriate, makes it possible to reduce the duration of the racemization treatment.

[0072] The process of the invention is of the continuous type, in the sense that the unwanted atropoisomer is recycled and combined with fresh initial mixture. The unwanted atropoisomer is not isolated and collected. Thus, the process makes it possible to achieve a yield greater than 50%, preferably greater than 80%, more preferably greater than 90% (proportion of the desired isomer recovered from the initial mixture) after one or more cycles of recycling by racemization and purification by chromatography.

[0073] In preferred embodiments, the method does not include a step of crystallization of compound A and / or compound B.

[0074] In embodiments, the material flows between successive units described above are continuous (without interruption). In particular, a continuous flow feeds the racemization treatment unit 4 (from the chromatographic separation unit 2) without interruption and / or a continuous flow feeds the chromatographic separation unit 2 (from the racemization treatment unit 4) without interruption.

[0075] Alternatively, one or more units may have a sequential operation. For example, a separation unit may have distinct phases of loading, elution and possibly washing. Storage units may be provided between successive units as described above, in order to serve as buffers and to allow the continuous process to be carried out in this case. Chromatographic separation

[0076] The chromatographic separation unit comprises one or more enclosures or columns, generally cylindrical, containing a stationary phase.

[0077] The stationary phase may be a polar stationary phase of silica type, or an apolar stationary phase of Cl8, C8, cyano, phenyl type for example, and preferably a chiral stationary phase. The chiral stationary phase may be based on cyclodextrin or proteins, or macrocyclic antibiotics or preferably of Pirkle type, or preferably based on polysaccharides (immobilized or impregnated stationary phases). Mixtures of the above stationary phases may also be used. These stationary phases may have a particle size (Dv50) of between 5 and 600 pm, preferably between 10 and 50 pm.

[0078] Compounds A and B have a different interaction with the stationary phase, so that one of the two is more retained than the other on this stationary phase. This principle makes it possible to carry out the desired separation. Compound A can be the most retained or the least retained of the two.

[0079] The chromatographic unit may be a static bed system. In this case, it may comprise several columns in series or in parallel, but generally a chromatographic separation in a static bed system is implemented with a single column.

[0080] Examples of such static bed chromatographic systems are HPLC (high performance liquid chromatography) and CYCLOJET (i.e. stationary state recycling) systems.

[0081] The CYCLOJET system is as described in US 6,063,284, to which express reference is made. It is a single-column discontinuous chromatographic separation system, in which the (i) most retained and then (ii) least retained species are collected separately at the outlet of the column, an unseparated portion of the chromatogram being recycled by a main pump. The mixture to be separated is periodically injected by means of an injection loop into the recycled portion of the chromatogram. The injection loop is preferably connected between the main pump and the column. After several chromatographic cycles, the process reaches a periodic steady state in which the quantity of injected products is equal to the quantity of products collected separately at the outlet of the column.

[0082] According to one embodiment, the chromatographic separation in a single-column static bed system with steady-state recycling is cyclical and comprises the following steps: • establishment and maintenance of a chromatographic profile circulating in the column by means of an eluent pump; • injection into said circulating chromatographic profile of a sample comprising the at least two compounds to be separated, discontinuously and at each cycle, the injection being carried out by means of an injection loop controlled in an injection position by an injection valve, in order to inject the sample present in the loop into the circulating chromatographic profile, the injection valve remaining in the injection position from the start of the injection until the moment when the entire profile is eluted from the column, then switching the injection valve into a loading position, to load the injection loop when the entire profile is in the column, and • collection of at least two fractions from the circulating profile, discontinuously and periodically.

[0083] This separation may also include the following step: • passage of eluent into the column as a mobile phase, essentially continuously during the cycle, by means of the eluent pump.

[0084] This separation may also include the following steps: • recording of events occurring from the start of the collection of a first fraction until the next start of the collection of the first fraction; • interruption of the eluent pump when collecting a third fraction, this interruption continuing until the end of the cycle, so that the cycles are temporally reproducible.

[0085] According to one embodiment, there is no loss of circulating profile during injection into the maintained circulating profile.

[0086] A detailed embodiment of this system is shown in col. 5 1.36-col. 10 1.41 of the aforementioned document US 6,063,284.

[0087] The chromatographic separation unit may also be a non-static bed chromatographic system. A non-static bed system is a multi-column system, in which the relative positions of the stationary phase bed and the points injection and / or collection flows move over time.

[0088] In such a system, the chromatographic separation is carried out in a set of several columns, with successively, cyclically, in a given part of the system: • a step of collecting a raffinate, a step of injecting the mixture to be separated, a step of collecting an extract and a step of injecting eluent.

[0089] The above various steps follow one another in time in a part of the system. The part in question of the system is preferably located between the output of a column and the input of the next column. Alternatively, the part in question of the system may include a column or part of a column.

[0090] At any given time, one or more of the above steps may be simultaneously implemented in one or more parts of the system. For example, all of these steps may be simultaneously implemented in respective parts of the system.

[0091] By "raffinate" is meant the fraction obtained by elution which contains the species relatively least retained by the stationary phase, and therefore whose elution is the fastest.

[0092] By “extract” is meant the fraction obtained by elution which contains the species relatively most retained by the stationary phase, and therefore whose elution is the slowest.

[0093] In embodiments, the raffinate is the fraction enriched in compound A and the extract is the fraction enriched in compound B.

[0094] In other embodiments, the raffinate is the fraction enriched in compound B and the extract is the fraction enriched in compound A.

[0095] The eluent is a fluid injected to displace the species retained by the stationary phase. The eluent used is preferably a solvent as described above in relation to the different fractions.

[0096] By "mobile phase" is meant the fluid that moves in the columns of the system. Depending on its position, each column is crossed by a volume of mobile phase depending on the zone in which the column is located, this volume being able to be different from the volume of eluent which is injected into one or other of the columns. In the case of a multi-column process with zones identified between the inlet and outlet lines (as described in more detail below), the term "mobile phase volume" designates the volume of fluid which enters a zone. This fluid may be different from the eluent in the strict sense, but it contributes to the movement of the products in each column of the zone. We thus speak of the volume of mobile phase associated with each zone. The preferred configuration of the zones in the chromatographic system is described in more detail below.

[0097] In certain advantageous embodiments, the chromatographic system comprises members for sequencing the injection and collection lines. In particular, the sequencing of these injection and collection lines takes place over an operating cycle of the system. An “operating cycle” or “cycle” designates the duration at the end of which the injection and collection lines have been sequenced until they return to their initial position in the system. At the end of a cycle, the system is again in its initial configuration. A cycle generally comprises as many “periods” as there are columns. Thus, the cycle of a method implemented on a system with 8 columns is composed of 8 successive periods.

[0098] Preferably, the chromatographic system comprises from 4 to 10 columns.

[0099] Preferably, the chromatographic separation is carried out continuously.

[0100] Preferably, the chromatographic separation is a periodic accumulation chromatographic process.

[0101] By "accumulation process" is meant a chromatographic process in which the injection of the mixture to be separated (starting flow) is intercalated or added to a non-zero concentration profile passing from the outlet to the inlet of a column.

[0102] Examples of such non-static bed chromatographic systems operating with accumulation processes are the SMB, iSMB, SSMB, AMB, VARICOL, MODICON, POWERFEED, DCC or MCSGP systems.

[0103] The simulated moving bed (or SMB) process is a continuous multi-column process, the injection of the mixture to be separated being carried out over the entire cycle.

[0104] The SMB process may in particular be a four-zone SMB process. In this case, the system comprises a set of columns connected in series and in a closed loop, the outlet of a column being connected to an inlet of the next column. The system comprises at least one injection line for the mixture to be separated, a raffinate collection line, an eluent injection line and an extract collection line. The injection lines (of the starting flow and eluent) and the fraction collection lines move periodically and synchronously (synchronous sequencing) within the loop in the direction of the flow of the fluid circulating through the loop. The duration between two shifts of all the injection and collection lines of a column corresponds to a period; at the end of a cycle all the points have returned to their initial position, the system having a cyclic operation. A cycle comprises as many periods as there are columns.

[0105] An AMB (actual moving bed) system operates similarly to an SMB system. However, instead of moving the injection points of the mixture to be separated and the eluent, as well as the collection points, by means of a valve system, a set of columns are physically moved. relative to the feed and collection points. Again, the operation simulates a continuous counter-current moving bed.

[0106] A VARICOL chromatography system is as described in US 6,136,198, US 6,375,839, US 6,413,419 and US 6,712,973, to which express reference is made. A VARICOL system comprises a plurality of individual columns connected in series. An eluent is passed through the columns in a first direction. Unlike the SMB system, the injection points for the mixture to be separated and for the eluent and the collection points for the separated compounds in the system are moved periodically but asynchronously, by means of a set of valves. The overall effect is to create separation zones of variable length over time, thus allocating the stationary phase dynamically to the areas where it is most useful, and allowing similar separation power with fewer columns and increased productivity.

[0107] The chromatographic separation of the invention may be a process with continuous injection of the mixture to be separated (i.e. a process in which the injection of the mixture to be separated is a continuous flow). The injection of the mixture to be separated is then carried out throughout the duration of the cycle. The chromatographic separation of the invention may also be a process with quasi-continuous injection of the mixture to be separated.

[0108] Alternatively, the chromatographic separation of the invention may be a process in which the injection of the mixture to be separated is discontinuous. In such a process, the injection of the mixture to be separated is not carried out over the entire cycle but for a total duration of less than one cycle. As a process with discontinuous injection of the mixture to be separated, mention may be made of the iSMB process ("improved simulated moving bed" or improved SMB in French), described in documents EP 0342629 and US 5,064,539, to which express reference is made. In this process, in one step the system operates in a closed loop, without injection or collection of product.

[0109] Other variants of the SMB systems are: the time-varying SMB system and the POWERFEED system, as described in US 5,102,553 and in the article PowerFeed operation of simulated moving bed units: changing flow-rates during the switching interval, by Zhang et al. in Journal of Chromatography A, 1006:87-99 (2003), to which express reference is made; the MODICON system, as described in US 7,479,228, to which express reference is made; and the SMB system with internal recirculation, as described in US 8,282,831, to which express reference is made.

[0110] A DCC chromatography system is as described in document FR 2889077, to which express reference is made. A DCC system is a sequential method with periodic movement of the mobile phase injection points and mixture to be separated, having the characteristic of being constantly in an open loop. It uses two or more columns.

[0111] The sequential SMB method, or SSMB ("sequential simulated moving bed") is another preferred example. An SSMB system divides the introductions and collections of the flows into sub-sequences applied periodically. An SSMB system is for example described in document WO 2015 / 104464.

[0112] An SSMB chromatographic system preferably comprises zones 1, 2, 3 and 4: zone 1 is located between an eluent injection line and an extract collection line; zone 2 is located between the extract collection line and an injection line of the mixture to be separated; zone 3 is located between the injection line of the mixture to be separated and a raffinate collection line; and zone 4 is located between said raffinate collection line and the eluent injection line.

[0113] In one example, six cells or columns are used. This system can be operated according to a four-phase cyclic operation: • Phase 1: Loop phase, during which a continuous circulation in a closed loop is maintained on all cells placed in series, to move the interstitial volume from one cell to the next, without injecting eluent. The volume of mobile phase moved in this phase contributes to zones 1, 2, 3 and 4. • Phase 2: charge / charge injection. The charge (mixture to be separated) is injected at the top of the fourth cell. At the same time, a substantially identical volume of raffinate is collected at the outlet of the fifth cell. Cells 4 and 5 here constitute zone 3. Cells 2 and 3 constitute the separation zone between extract and charge injection. Here, they constitute zone 2. The volume of mobile phase displaced in this phase contributes to zone 3. • Phase 3: elution of the extract. The eluent is injected into the first cell to elute the extract, which is collected in a volume roughly identical to the bottom of the first cell. Cell 1 here constitutes zone 1. The volume of mobile phase displaced in this phase contributes to zone 1. • Phases 2 and 3 are preferably carried out simultaneously to increase the productivity of the system. • Phase 4: elution of the raffinate. The eluent is injected at the top of the first cell, and the raffinate is collected in a substantially identical volume at the outlet of the fifth. Cell 6 is here a buffer cell ensuring the separation between the bottom of the extract and the top of the raffinate. It constitutes zone 4. This zone can be omitted in the case where the degree of purity and / or the desired yield is relatively limited. The volume of mobile phase displaced in this phase contributes to zones 1, 2 and 3.

[0114] These phases are operated in order in a preferred embodiment, from 1 to 4. Their sequence constitutes a complete sequence (also called a period).

[0115] Each sequence (phases n°1 to 4) is repeated six times by shifting the cell inputs and outputs by incrementing the cell number, from the left to the right of the system: the charge is thus injected at the top of cell n°1 in sequence n°1, then at the top of cell n°2 in sequence n°2, etc.

[0116] A complete production cycle is carried out after completion of the six successive sequences, when the charge injection point, initially at the input of cell no. 1, returns again to the input of cell no. 1.

[0117] In the above, a description of the SSMB system has been given with reference to the case where the cells correspond to columns. This is not limiting, and the invention also applies to systems in which the cells, or compartments, are parts of a column.

[0118] Furthermore, the number of columns present in zones 1, 2, 3 and 4 can vary depending on the desired separation quality. It is therefore possible to design systems of the same type with one cell, two cells, three cells, four cells, five cells, six cells, and up to twelve cells or more.

[0119] The fluid flow rates in the different columns of the chromatographic separation unit can be adjusted so as to obtain the optimized operating parameters.

[0120] The chromatographic separation is preferably carried out at a temperature (called operating temperature) of 0 to 100°C, preferably 20 to 50°C, and more preferably 25 to 40°C. The above operating temperature corresponds to the average temperature at which the mobile phase is located in the chromatographic system. Examples

[0121] The following examples illustrate the invention without limiting it. Example 1 - racemization

[0122] Racemization experiments were carried out in a thermoregulated heated tubular reactor. The enantio-enriched substrate in solution was continuously added to the reactor using an HPLC pump. The addition rate was controlled to control the exposure time of the compound to the thermal conditions of the reaction. After a predetermined equilibration time to ensure stable operating conditions, a sample was taken and analyzed by HPLC to measure the residual enantiomeric excess of the medium.

[0123] Depending on the experiments, a compound X or Y was supplied at the reactor inlet.

[0124] Compound X has the following formula:

[0125] [Chem.5]

[0126] Compound Y has the following formula:

[0127] [Chem.6]

[0128] We designate by XI and X2, respectively Y1 and Y2, the two atropoisomers of each compound X and Y.

[0129] Each isomer XI, X2, Y1 or Y2 was supplied to the reactor dissolved in a solvent, with a chiral purity greater than or equal to 98% a / a.

[0130] Depending on the case, the solvent used was a heptane / ethanol mixture (denoted H / W) or an acetonitrile / methanol mixture (denoted A / M). These solvents are suitable for implementing a chromatographic separation.

[0131] The detailed experimental conditions and results are shown in the table below:

[0132] [Tables 1] Comp. SRC vR Q Vj T t P 47.2 XI A / M 20 / 80 50 2 0.4 0.1 200 5 50.3 90 / 10 17.5 10 0.5 1 200 20 48.1 Y1 A / M 40 / 60 50 2 0.2 0.1 200 20 49.9 Y1 A / M 20 / 80 50 2 0.1 0.1 200 20 49.6 Y2 A / M 40 / 60 50 2 0.1 0.1 200 20 48.9 Y2 A / M 20 / 80 50 2 0.1 0.1 200 20 50.0

[0133] In this table, the columns have the following meaning: • Comp.: nature of the compound supplied at the reactor inlet; • S: nature of the solvent; • R: mass ratio of the two components of the solvent (heptane / ethanol or acetonitrile / methanol); • C: concentration of the solution supplied at the reactor inlet, in g / L; • VR: reactor volume, in mL; • Q: flow rate, in mL / min; • V!: volume of solution injected into the reactor, in mL; • T: temperature, in °C; • t: residence time, in min; • P: concentration of the other isomer, at the reactor outlet, in % a / a. Example 2 - chromatographic separation

[0134] Chromatographic separation screening experiments of racemic mixtures of compound X and compound Y of Example 1. These experiments were carried out on Agilent 1100 series HPLC columns operated with Chemstation software (C.01.05

[35] ), equipped with a quaternary gradient pump, an automatic sampler, a column oven and a UV detector.

[0135] Several solvents were screened and several chiral stationary phases from the CHIRALPAK® range, with an average particle size of 20 pm.

[0136] The screening made it possible to identify several operating conditions allowing efficient separation of the isomers to be obtained.

[0137] Based on the screening data, a numerical simulation of an SMB separation system was carried out. The simulation was carried out on the Help-Chrom chromatographic process modeling and simulation software developed by Novasep (Axplora). This simulation makes it possible to optimize the operating parameters of the different chromatographic processes in batch or continuous mode (SMB / Varicol / Cyclojet). The following table gives a summary of the estimated productivity of the SMB separation for either racemate X or racemate Y, with an acetonitrile / methanol mixture as solvent in mass ratios of 20 / 80 or 40 / 60.

[0138] In this simulation, the column length is 10 cm, the concentration of the injected mixture is 50 g / L, and the total maximum pressure is 15 bar.

[0139] The results are shown in the table below:

[0140] [Tables2] Specification Racemate Y Solvent 20 / 80 Racemate Y Solvent 40 / 60 Racemate X Solvent 20 / 80 Racemate X Solvent 40 / 60 Extract S1 3.43 3.05 2.53 2.74 Reffinate S1 3.70 3.42 2.56 3.12 Extract S2 3.31 2.93 2.40 2.61 Reffinate S2 3.67 3.51 2.51 3.09

[0141] In this table, the productivity is expressed in KKD (kg of mixture injected per kg of stationary phase and per day).

[0142] The specifications imposed are as follows: • SI: 99% purity and 95% yield. • S2: 99.5% purity and 95% yield.

Claims

Claims

1. A continuous process for producing a chemical compound A comprising: • providing a mixture comprising the chemical compound A and a chemical compound B which is an atropoisomer of the chemical compound A; • chromatographic separation of the mixture, so as to collect a fraction rich in chemical compound A and a fraction rich in chemical compound B; • racemization treatment of the fraction rich in chemical compound B, in which the chemical compound B is partially converted into chemical compound A, so as to obtain a racemized fraction; • recycling the racemized fraction to the step of chromatographic separation of the mixture.

2. Method according to claim 1, in which the chromatographic separation of the mixture is a multi-column separation, preferably with a non-static bed, and more preferably chosen from AMB, SMB, VARICOL, POWERFEED, MODICON, iSMB, SSMB, DCC or MCSGP separations.

3. A method according to one of claims 1 to 2, wherein the racemization treatment is a thermal racemization treatment.

4. Method according to one of claims 1 to 3, comprising a step of concentrating the fraction rich in chemical compound B before the racemization treatment step; or comprising a step of concentrating the racemized fraction before the step of recycling the latter to the step of chromatographic separation of the mixture.

5. A method according to any one of claims 1 to 4, wherein the fraction rich in chemical compound B comprises a solvent, and the method does not comprise any modification of the solvent between the collection of the fraction rich in chemical compound B and the racemization treatment thereof.

6. Cl. Installation for the continuous production of a chemical compound A, comprising: • a chromatographic separation unit (2); • a supply line (11) for a mixture comprising the compound chemical compound A and a chemical compound B which is an atropoisomer of the chemical compound A, feeding the chromatographic separation unit (2); • a collection line for a fraction rich in chemical compound A (12) and a collection line for a fraction rich in chemical compound B (13a, 13b) at the outlet of the chromatographic separation unit (2); • a racemization treatment unit for the fraction rich in chemical compound B (4), configured to partially convert the chemical compound B into chemical compound A, fed by the collection line for a fraction rich in chemical compound B (13a, 13b); • a collection line for a racemized fraction (14a, 14b), at the outlet of the racemization treatment unit (4), and feeding the chromatographic separation unit (2).

7. Installation according to claim 6, in which the chromatographic separation unit (2) is a multi-column separation unit, preferably with a non-static bed, and preferably chosen from the separation units AMB, SMB, VARICOL, POWERFEED, MODICON, iSMB, SSMB, DCC and MCSGP.

8. Installation according to one of claims 6 to 7, in which the racemization treatment unit (4) is a thermal racemization treatment unit.

9. Installation according to one of claims 6 to 8, comprising a concentration unit (3) on the collection line for the fraction rich in chemical compound B (13a, 13b); or comprising a concentration unit (5) on the collection line for the racemized fraction (14a, 14b).

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