FR2810978A1 - Chromatographic process for resolving two enantiomers of tetralone intermediate of antidepressant sertraline, using enantioselective stationary phase and eluting with carbon dioxide - Google Patents

Abstract

Chromatographic process for resolving a mixture of the two enantiomers of the tetralone intermediate (II) formed during the synthesis of sertraline (I), eluting with a mixture containing carbon dioxide in the supercritical, critical, or subcritical state, the system percolating through an enantioselective stationary phase containing macrocyclic heterotopic coreceptors (MHCR). Chromatographic process for resolving a mixture of the two enantiomers of the tetralone intermediate of formula (II) formed during the synthesis of sertraline of formula (I), eluting with a mixture containing carbon dioxide in the supercritical, critical, or subcritical state, the system percolating through an enantioselective stationary phase containing macrocyclic heterotopic coreceptors (MHCR).

Description

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PROCESS FOR DEDOUPLING THE TETRALONE INTERMEDIATE OF
SERTRALINE
The invention relates to a method for producing the tetralone intermediate, used for the synthesis of sertraline, enantiomerically pure or enantiomerically enriched (S), using batch or continuous chromatography with an eluent containing carbon dioxide, supercritical, critical or subcritical state, which is drilled through an enantioselective stationary phase based on macrocyclic heterotopic coreceptors.

 The sertraline-tetralone compound, hereinafter referred to as tetralone, is the key intermediate for the synthesis of the antidepressant Zoloft or Sertraline hydrochloride. Zoloft is a drug used in the treatment of depression as claimed in US Patent Nos. 4,536,518; 5,196,607; 5,442,116 and 4,777,288. The processes for the preparation of sertraline are described therein and specify that the separation of the 4 stereoisomers formed during the synthesis is carried out in the last step. On the other hand, and as indicated in PCT / US 99/09307, there is a substantial benefit in overall synthetic yield from using enantiomerically pure or enantiomerically enriched tetralone.

The formulas of sertraline (formula (1)) and tetralone (formula (2) are as follows:

Patent Application PCT / US 99/09307 also claims the chromatographic resolution of tetralone by continuous chromatography, or by moving bed

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 simulated or cyclojet process, with an eluent, or mobile phase comprising at least one polar solvent.

 Critical phase, supercritical or subcritical chromatography is a complementary technique to gas chromatography and liquid chromatography, which has recently undergone important developments in the analytical and preparative fields. The fundamental principles of this technique and their applications have been described by R.

 Rosset, M. Caude and A. Jardy in the book "Chromatographies in liquid and supercritical phase", published by Masson, Paris 1991, in chapter XXVII, pages 815 to 911. The eluent system drilled through the stationary phase contains a gas in the super or subcritical state, carbon dioxide in most cases because of its low cost, its high volatility and its environmental safety. There are industrial continuous chromatography systems in supercritical or subcritical mode using the simulated moving bed principle, developed in particular by Novasep (Nancy, France).

 The use of the supercritical mode in preparative chromatography is particularly effective in terms of productivity as shown by Duval R. in Enantioselective Chromatography, a mature and strategy chirotechnology, An International Symposium on Chirality, September 7, 1999, Cambridge, U.K. The author has disclosed the separation of guaifenesin in a mixture of carbon dioxide / chloroform / diethylamine 60/40 / 0.1 at 28 C with a productivity of 940 kg of racemic guaifenesin chromatographically resolved by Kg of enantioselective carrier marketed by the Company. Chiralsep under the denomination CHIROSE C1-NCB, per year (365 x 24 hours) in continuous operation. The advantage of the use of carbon dioxide in a chromatographic process is important in terms of cost (low cost of buying carbon dioxide), also related to the productivity of the separation and "easy evaporation of the collected eluent ( facility for evaporation of carbon dioxide) to collect the desired products after separation In an industrial process where the quantities of mixture eluting to percolate through the stationary phase are important and may present a danger to the safety of persons (explosiveness) and the environment (air and soil pollution), carbon dioxide has certain advantages over liquid chromatography.

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The concept of macrocyclic heterotopic coreceptors was exposed by Nobel Prize winner JM Lehn in the book "Supramolecular Chemistry", published by
Boek University, Paris, France, 1997, chapter 4. 3, pp. 43-51.

 One of the examples mentioned by J. M. Lehn on these particular coreceptors relates to cyclic oligosaccharides or cyclodextrins, which in no way limits said coreceptors to this single family of compounds. FR97 / 03.076 patent applications; FR 97 / 10,817; 98 / 11,376; 98/11. 377 relate to the synthesis of macrocyclic heterotopic coreceptors, in particular by crosslinking of polyfunctional chiral compounds, chosen in particular from linear or cyclic oligosaccharides, or oligosaccharide residues of a polysaccharide chain, using bifunctional compounds, said synthesis making it possible to create chiral macrocavities in a three-dimensional cross-linked polymer network. The new compounds thus obtained, used as an enantioselective stationary phase, are capable of separating chiral molecules and in particular sertraline / tetralone.

 The very particular properties of said chiral stationary phases based on synthetic macrocyclic heterotopic coreceptors were exposed by Duval R. (thesis of Doctor in Science - Orléans, France 2000).

 The macrocyclic cavities obtained by synthesis, or chiral cages, have the property of inflating more or less according to the nature of the eluent and the temperature allowing or not the phenomenon of chiral discrimination.

 There are supports based on polysaccharide derivatives marketed by Daicel ("Chiral discrimination polysaccharides derivatives", Yashima and Okamido, Bull Chem Soc Jpn, 68, 329-3307, 1995), which however have the drawback of deteriorate when used with an eluent system consisting for example of 100% tetrahydrofuran.

 The supports described in patent applications FR97 / 03,076; FR97 / 10,817; FR98 / 11,376; FR98 / 11.377 have excellent stability to polar solvents and temperature, they are therefore able to work with any type of protic or polar aprotic solvent (tetrahydrofuran, acetone, methylene chloride, dimethylsulfoxide .....) to temperatures well above 100 C.

 The polarity of a solvent can be defined by the polarity parameter P '(see the book "Liquid and Supercritical Phase Chromatography").

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Rosset, Caude and Jardy, published by Masson, Paris, Fr. in 1991, pages 47 to 51, chapter 1). For the continuation and understanding of the text, so-called polar solvents are those whose polarity P 'is greater than 1.2 (corresponding to the polarity of squalane). For example, carbon tetrachloride has a polarity P 'of 1.6 and proves to be a very good solvent for the chiral selectors contained in the supports marketed by the Daicel Company, and makes it possible to destroy these supports irremediably if one drills tetrachloride. of carbon through a column containing them. Media such as those disclosed in FR97 / 03,076; FR 97 / 10,817; 98 / 11,376; 98/11. 377, on the other hand, retain their enantioselectivity performance with respect to tetralone-sertraline in 100% carbon tetrachloride and in all the other polar solvents commonly used in chromatography.

 The present invention relates to a chromatographic method for resolving the tetralone intermediate, obtained during the synthesis of sertraline, from a mixture of the two enantiomers of said tetralone, characterized in that in the eluent system used. at least one of the solvents is carbon dioxide which is used under physical conditions (temperature and pressure) where it is in the supercritical, critical or subcritical state, said eluent system being pierced through an enantioselective stationary phase containing macrocyclic heterotopic coreceptors.

The method according to the invention uses, as chromatographic method, especially batch chromatography, simulated moving bed continuous chromatography (USP 4,402,832, 5,434,298, 5,434,299, 5,498,752), which can be applied to both liquid chromatography and supercritical), or single column continuous chromatography by the so-called SSR method or "Steady State Recycling" (Grill CD, J. of Chromatog, A, 829, 359-371, 1998 and ibid, 796, 101-113, 1998).

 In the process according to the invention, the chemical nature of the eluant system which is pierced through the enantioselective stationary chromatographic phase is of course decisive.

 Indeed, the eluent system used is characterized in that at least one of its components is carbon dioxide, used under conditions of temperature and pressure such that it is in a supercritical state, or critical or subcritical. The carbon dioxide composition of the eluent system can

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 vary from 1 to 99%. The complement to 100% is made with a solvent or a binary mixture, ternary or quaternary solvents, said solvent or solvents being selected from solvents whose polarity P 'is greater than 1.2.

 In the process according to the invention, the enantioselective chromatographic stationary phase used consists of macrocyclic heterotopic coreceptors based on alkylethers, arylethers, alkylarylethers, arylalkylethers, alkyl esters, aryl esters, alkylaryl esters, arylalkyl esters, alkylcarbamates, arylcarbamates, alkylarylcarbamates, arylalkylcarbamates of cyclodextrins. or oligosaccharides or polysaccharides, or mixed derivatives of the above compounds, crosslinked using bifunctional compounds, and constituting, after crosslinking, three-dimensional chiral cavities or macrocyclic cages of heterotopic coreceptors.

 The concept of coreceptor molecules, and in particular macrocyclic heterotopic coreceptors, has been explained by the Nobel Prize winner JM Lehn in the book "Supramolecular Chemistry" published by De Boeck University, Paris, France 1997, in chapter 4. 3. pp. 43-51. In this regard, Lehn cited natural cyclodextrins as macrocyclic heterotopic coreceptor molecules while observing other synthetic macrocyclic receptor families (cyclophanes and cryptophans, for example).

 According to a particularly advantageous embodiment of the process according to the invention, the enantioselective stationary phase used is chosen from those described in the patent applications FR 97/03076, FR97 / 10817, FR 98/11776 and FR 98 / 11.377, which are enantioselective stationary phases for chromatography, based on synthetic macrocyclic heterotopic coreceptors.

 The chemical definition of macrocyls, or three-dimensional chiral molecular cages of these synthetic macrocyclic heterotopic coreceptors, is given in the following general formulas I to IV:

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where: - X represents an oxygen atom or the group -NH, - m is the non-zero integer at most equal to 5, - N1, N2, N3 and N4 in the general formulas I, II, III and IV are identical or different and can take values between 0 and 10,000, - R represents a hydrogen atom or a substituted or unsubstituted alkyl radical, linear or branched, having from 1 to 8 carbon atoms, - Y represents a single bond or a group -NH-C (O) -, or a group -C (O) -, - A represents an alkylene, or arylene, or aminoarylene, or oxyarylene radical having 6 to 18 carbon atoms or an aralkylene radical or an arylaminoalkylene or aryloxyalkylene radical having 7 to 40 carbon atoms, "Support" represents a conventional chromatographic support which may be an inorganic or organic compound, - L represents a bis-thioether radical, of general formula V bis-sulfoxide, of general formula VI or bis-sulfone, of general formula VII or a bis-silane, of general formula VIII-A or VIII-B below:

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Où R5 représente l'hydrogène, un halogène, un hydroxyle, un alkoxy, un radical alkyle linéaire ou ramifié ayant 1 à 5 atomes de carbone ou W représente une simple liaison ou le groupement

-C Hz--C HZ--C H2-S, W1 et W3 identiques ou différents, représentent chacun un radical alkylène linéaire ou ramifié ayant de 1 à 21 atomes de carbone, un radical arylène ayant de 6 à 18 atomes de carbone, ou un radical aralkylène ayant de 7 à 40 atomes de carbone ; W2 représente une simple liaison, Wi, un atome d'oxygène, un atome de soufre ou un diester symétrique de formule

et R4 représente le radical

Where R 5 represents hydrogen, a halogen, a hydroxyl, an alkoxy, a linear or branched alkyl radical having 1 to 5 carbon atoms or W represents a single bond or the grouping

Each of the same or different radicals represents a linear or branched alkylene radical having from 1 to 21 carbon atoms, an arylene radical having from 6 to 18 carbon atoms, or an aralkylene radical having 7 to 40 carbon atoms; W2 represents a single bond, Wi, an oxygen atom, a sulfur atom or a symmetrical diester of formula

and R4 represents the radical

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où X est un halogène, un hydroxyle ou un alkoxy, 0 est l'oxygène et W une simple liaison ou le groupement--CHr- CH2- CH2-S- * soit un radical L - unité chirale désignée ci-dessous par la formule générale XI

représente l'unité chirale osidique d'un enchaînement linéaire, ramifié ou cyclique d'un dérivé de polysaccharide présentant la formule Xlla à Xllk cidessous, étant entendu que chaîne i et chaîne j symbolisent le fait que les unités chirales sont situées sur des chaînes distinctes, ou des enchaînements distincts d'unités osidiques, au sein du polysaccharide ou de l'oligosaccharide. where R6 is (CH2) n2 or oxygen and where n1 varies from 0 to 3000 and n2 from 0 to
10, - U represents either

where X is halogen, hydroxyl or alkoxy, O is oxygen and W is a single bond or the group -CHr-CH2-CH2-S- * is a chiral L-unit designated below by the formula General XI

represents the chiral unit of a linear, branched or cyclic chain of a polysaccharide derivative having the formula Xlla to Xllk below, it being understood that chain i and chain j symbolize the fact that the chiral units are located on separate chains , or separate sequences of saccharide units, within the polysaccharide or oligosaccharide.

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((R5b)3Si-WH2--CH2]m A-Y- (XIII) dans laquelle m est un nombre entier non nul au plus égal à 5, Y représente une simple liaison ou un groupement -NH-C(O)- ou un groupement -C(O)--, A est tel que défini ci-dessus, W représente une simple liaison ou le groupement

---CH2--CH2--CH-S- et R5b représente un halogène, un hydroxyle ou un alkoxy, - ou un radical de formule générale [CH(R) = CH]m1 A-Y (XIV) où R, A, et Y ont la même signification que dans les formules (I) à (IV) et mi la même signification que dans la formule XIII. in which: a) the symbols X 1, X 2 and X 3, which are identical or different, each represent an oxygen atom or the group --NH; b) Each of the symbols R1, R2, R3 independently represent: a chlorosilane, hydroxysilane or alkoxysilane radical having the general formula:

((R5b) 3Si-WH2-CH2] m AY- (XIII) wherein m is a non-zero integer at most equal to 5, Y is a single bond or a group -NH-C (O) - or a -C (O) - group, A is as defined above, W represents a single bond or grouping

CH 2 -CH 2 -CH-S- and R 5b represents a halogen, a hydroxyl or an alkoxy, or a radical of general formula [CH (R) = CH] m 1 AY (XIV) where R, A, and Y have the same meaning as in formulas (I) to (IV) and have the same meaning as in formula XIII.

 or a radical having the formula A2-A1-CXa (XV) in which Xa represents an oxygen atom, A1 represents a single bond or an -NH- group and A2 represents a radical having from 6 to 24 carbon atoms, an aralkyl radical having from 7 to 36 carbon atoms - or a hydrogen atom n being a number of between 5 and 20,000, it being understood that in each chiral osidic unit (Xlla) to (Xllk), at least one symbols Xi; X 2 and X 3 represent an oxygen atom, and in at least part of the structural units constituting the polysaccharide, at least one of the symbols R 1, R 2, R 3 represents a precursor radical of the compounds (1), (II), (III) or (IV) and at least one of the symbols R1, R2, R3 represents a radical of general formula (XV).

 Carriers capable of forming covalent bonds to form the compounds of general formula 1 and II may be of inorganic or organic nature. A mineral support may be for example silica gels, alumina, zirconia previously modified with the aid of siloxane derivatives. An organic support may consist of a synthetic polymer such as polystyrenes, polystyrenes

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 divinylbenzenes, polyamides, polyacrylamides, polyureas, polyurethanes, polyvinyl alcohols ... suitably modified to include ethylenic or thiol bonds for example.

 According to an advantageous embodiment of the process according to the invention, the arylene radicals contained respectively in the radicals of general formulas I, II, III and IV may be substituted by one or more atoms or radicals, which may be identical or different, chosen from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms and nitro groups; the arylenes, oxyarylenes or aryloxyalkylenes contained in the radicals of general formula I, II, III and IV being preferably phenyl or phenyloxy or phenyloxyalkylene radicals or naphthylenes, naphthyloxy or naphthyloxyalkylene radicals optionally substituted with one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy radicals containing from 1 to 4 carbon atoms and nitro groups.

 An enantioselective chromatographic stationary phase consisting of the compounds of general formulas III or IV can consist essentially of said compounds, that is to say with 100% of crosslinked polymer, or constituted by a composite with a support. In this case, the supports used may be inorganic or organic as those indicated above and also comprising silicates (magnesium silicate), ceramics or phosphates such as hydroxyapatite, they may be chemically modified or not, this modification not being mandatory. Indeed, the chemical and thermal stability is ensured by the crosslinking and it is not necessary to bind the support by a covalent bond with the compounds of general formulas III and IV.

 The enantioselective stationary phases according to the invention make it possible to separate the tetralone / sertraline with selectivity factors greater than 1.2 and are therefore suitable for use in the industrial production of tetralone (S). Said supports are stable in all common organic solvents, including those of polarity P 'greater than 1.2. They are also stable in these same solvents at operating temperatures above 80 C. It is conceivable to use them at temperatures up to 200 C, the glass transition temperature of said crosslinked polymers being around 250 C on average.

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EXAMPLES Example 1. CHM-GS55 Preparation of the stationary phase
1.27 grams of di-2-o-pentenyl-p-cyclodextrin (di-2-o-pentenyl-p-CD) obtained according to the technique described in USP Patent 6,042,723 are dissolved in 150 ml of pyridine. 50 ml of the pyridine / water azeotrope are distilled at ordinary pressure. 0.1 g of ethane dithiol are added and the solution is maintained for 5 days at 70 ° C. with the addition of azobis-isobutyronitrile every 8 hours (a few grains). The dipentenyl-p-CD and ethane dithiol copolymer obtained is dried in the presence of 5 g of 5 m spherical silica gel and 300 porosity.

The solid obtained is washed with heptane and dried at 70 ° C. under vacuum to constant weight. The dry solid is taken up in 100 ml of heptane and 0.3 g of 4allyloxyphenyl isocyanate are added. The suspension is kept for 24 hours at ambient temperature and is then dried again at 70 ° C. under vacuum. 0.1 g of ethane dithiol are added in solution in 100 ml of a mixture of ethanol / water 50/50 and the suspension is heated for 72 hours at 70 C mass. Some grains of azobis-isobutyronitrile are added every 8 hours. The suspension is filtered on sintered n 4 and then washed with ethanol. The precipitate is dried at 70 ° C. under vacuum. It is then taken up with stirring in 100 ml of pyridine. 20 ml are distilled at ordinary pressure. 5 g of 3,5-dimethylphenyl isocyanate are added and the suspension is heated for 48 hours at reflux. The mass is cooled, filtered and washed with 50 ml of ethanol, water and acetone and then dried at 70 ° C. under vacuum (weight = 6.2 g).

 An HPLC column of 250 x 4.6 mm (length x inside diameter) is filled with the support by the so-called wet method (suspending solvent: ethanol) at 600 bar pressure.

 The CHM-GS55 column is conditioned in pure carbon dioxide under 150 bars of pressure.

Chromatography of tetralone / sertraline
The enantioselectivity test is performed on tetralone / sertraline.

The chromatographic conditions are as follows: CHM-GS55 column, 5 m, 250 × 4. 6 mm

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 - eluent system: carbon dioxide / polar modifier as indicated in the table below, - flow rate: 3 ml / min. 150 bar pressure, 40 C temperature, 280 nm UV detection. The results of the chromatography are summarized in the following table.

 With each eluent, two peaks of chromatography were obtained. The second peak corresponds to the S enantiomer of tetralone / sertraline.

For each test the retention time for the second peak Rt2 was measured, and the capacity factor K'2, the selectivity factor a and the resolution Rs were determined.

These various parameters are conventional and their definition is given below with reference to FIG. 1: capacity factor K'2: tR1-tR0 / tR0 the selectivity factor [alpha]: K'2 / K'1 the resolution Rs: 2 (tR2-tR1)
W2 + W1
The values obtained with each of the chosen eluents are given in Table 1 below.

<Tb>
<Tb>

Table <SEP> 1
<tb> CO2 / modifier <SEP> polar <SEP>% <SEP> modifying <SEP> Rt2 <SEP>K'2<SEP> a <SEP> Rs
<tb> polar <SEP> in <SEP> min
<tb> Methanol <SEP> 5 <SEP> 11.2 <SEP> 8.1 <SEP> 1.26 <SEP> 2.4
<tb> Chlorobutane <SEP> 20 <SEP> 14.1 <SEP> 11.2 <SEP> 1.20 <SEP> 4.2
<tb> Chloroform <SEP> 10 <SEP> 17.7 <SEP> 12.8 <SEP> 1.21 <SEP> 2,3
<tb> Methyltertiobutylether <SEP> 20 <SEP> 15.6 <SEP> 9.5 <SEP> 1.30 <SEP> 5.7
<Tb>
Example 2. CHM-LC 73 Preparation of the stationary phase
5 g of ss-cyclodextrin are refluxed in 200 ml of pyridine. 50 ml of the pyridine / water azeotrope are distilled at ordinary pressure. The reaction mass is cooled to 80 ° C. and 4 g of 4-octenyloxyphenylisocyanate are added. The medium is stirred for 24 hours at 80 ° C. The disappearance of p-cyclodextrin is monitored by TLC (30% aqueous ammonia / 2/1/1 ethanol / isopropanol). 16.3 g of 3,4-dimethylphenyl isocyanate are added and the reaction mass is maintained

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 48 hours at 80 ° C. The medium is then poured with stirring on 1.5 d'of heptane. The precipitate is filtered on sintered n ° 4, washed with 200 ml of heptane and dried at 80 ° C. under vacuum until constant weight. 0.83 g of the preceding derivative are dissolved in 12 ml of chloroform. 4.1 g of polyamide beads (25 m diameter of particle) are added. The suspension is stirred for 1 hour at 20-30 ° C. and then dried at 30 ° C. under vacuum. The residue is taken up in 50 ml of heptane and 0.3 g of trithio-cyanuric acid are added in 20 ml of methanol. The suspension is heated for 48 hours at 80 ° C. with the addition of a few milligrams of benzoyl peroxide every 8 hours. The medium is filtered and washed with 50 ml of ethanol, water and acetone. The solid is dried at 80 ° C. under vacuum to constant weight (weight: 4.5 g).

 An HPLC column is filled with the support under conditions identical to those described in Example 1.

Chromatography of tetralone / sertraline
The chromatography tests were carried out using the stationary phase prepared as above, under the same conditions as in Example 1.

The results are expressed as in Example 1 and are summarized in Table 2 below:

<Tb>
<tb> Table <SEP> 2
<tb> CO2 / modifier <SEP> polar <SEP>% <SEP> modifying <SEP> Rtz <SEP>K'z<SEP> a <SEP> Rs
<tb> polar <SEP> in <SEP> min
<tb> Methanol <SEP> 5 <SEP> 13.9 <SEP> 9.7 <SEP> 1.38 <SEP> 5.9
<tb> Chlorobutane <SEP> 20 <SEP> 15.6 <SEP> 13.2 <SEP> 1.20 <SEP> 4.2
<tb> Chloroform <SEP> 10 <SEP> 17.3 <SEP> 14.8 <SEP> 1.11 <SEP> 2.4
<tb> Methyltertiobutylether <SEP> 20 <SEP> 16.5 <SEP> 11.7 <SEP> 1.40 <SEP>] <SEP> 6.5
<Tb>

With the aid of the stationary phase described in this example, various separations were also carried out under the following conditions: 1 / tetralone in methanol: Solute: () tetralone / sertraline in solution at 0.2 mg / ml in methanol System eluent: C02 / Methyltertiobutyl ether (MTBE) 80/20 Flow rate: 3 ml / min

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Inlet pressure = 250 bars; AP = 150 bar; C02 in supercritical condition
UV detection at 254 nm-OD = 0.1- temperature: 22 C.

 The chromatogram obtained is shown in FIG. 2, in which the abscissa axis represents the time in mn and the ordinate axis the volume in l of eluted solution.

2 / tetralone in MTBE: Solute: () tetralone / sertraline in solution at 8 mg / ml (test a), 18 mg / ml (test b), 70 mg / ml (test c) and 243 mg / ml (test d) ) in MTBE.

Injection quantity: 50 l Eluting system: CO2 / Methyltertiobutyl ether (MTBE) 80/20 Flow rate: 3 ml / min. Inlet pressure = 250 bar; AP = 150 bar; C02 in supercritical condition.

UV detection at 254 nm-temperature: 40 C.

 The chromatograms (a) to (d) obtained are shown in FIG. 3, in which the abscissa axis represents the time in mn and the ordinate axis the volume in elution solution (a). in test a, the chromatogram (b) corresponds to test b, the chromatogram (c) corresponds to test c and the chromatogram (d) corresponds to test d.

At the end of the various tests the following amounts of enantiomers S of tetralone / sertraline were recovered: Test a: 76 g Test b: 180 g Test c: 697 g Test d: 2430 g
Under the above conditions, it was possible to treat 250 g of racemic tetralone per kg of stationary phase (CSP CHM-LC 73) per 24 hours.

EXAMPLE 3 CHM - 99130 Preparation of the stationary phase
1.62 g of cellulose are suspended in 150 ml of pyridine. 50 ml of pyridine / water azeotrope are removed at ordinary pressure reflux. 1.47 g of 4vinylphenyl isocyanate are added and the reaction mass is refluxed.

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The medium is cooled and then poured onto 1 liter of heptane. The precipitate is filtered on sintered n 4 and then dried at 80 C under vacuum to constant weight (dry weight: 3.8 g). The solid is then taken up in 50 ml of tetrahydrofuran and 2.6 ml of ymercaptopropyltrimethoxysilane are added after total dissolution. The medium is refluxed for 24 hours with addition of 0.1 ml of benzoyl peroxide every 8 hours.

 The reaction mass is cooled to 40 ° C. and 10 g of polystyrene divinylbenzene (5 m beads) are added. The solution is evaporated to dryness. The support is dried at 60 ° C. under vacuum until constant weight. It is taken up in 50 ml of water and 50 ml of methanol. 1 ml of 12N hydrochloric acid is added and the mixture is stirred for 4 hours at room temperature and then filtered. The solid is washed with water until neutral pH and then with acetone. An HPLC column is filled with the support.

Chromatography of tetralone / sertraline
The chromatographic tests are carried out on the stationary phase prepared above, under conditions identical to those described in Example 1, however using a greater number of eluent systems as indicated in Table 3 below, in which the results obtained are also mentioned.

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<Tb>
<Tb>

Table <SEP> 3
<tb> Modifying <SEP> polar <SEP>% <SEP> Modifying <SEP> Rt2 <SEP>K'2<SEP> a <SEP> Rs
<tb> polar
<tb> Methanol <SEP> 25 <SEP> 12 <SEP> 04 <SEP> 8 <SEP> 26 <SEP> 1 <SEP> 18 <SEP> 1 <SEP> 48 <SEP>
<tb> Methanol / Diethylamine <SEP> 2.5 / 01 <SEP> 10. <SEP> 88 <SEP> 7.37 <SEP> 1.19 <SEP> 1.47
<tb> MTBE <SEP> 10 <SEQ> 1739 <SEP> 1238 <SEP> 1 <SEP> 24 <SEP> 1.63
<tb> Diisopropylether <SEP> 15 <SEP> 15. <SEP> 60 <SEP> 11. <SEP> 00 <SEP> 1.24 <SEP> 2.83
<tb> Acetonitrile <SEP> 5 <SEP> 10.52 <SEP> 7 <SEP> 10 <SEP> 1.19 <SEP> 0 <SEP> 94
<tb> Acetate <SEP> ethyl <SEP> 10 <SEP> 9.89 <SEP> 6 <SEP> 61 <SEP> 1 <SEP> 21 <SEP> 1.69
<tb> Acetate <SEP> ethyl <SEP> 7.5 <SEP> 12. <SEP> 75 <SEP> 8 <SEP> 81 <SEP> 1 <SEP> 21 <SEP> 2.10
<tb> Acetate <SEP> of ethyl <SEP> 2 <SEP> 29. <SEP> 70 <SEP> 21.85 <SE> 1.23 <SEP> 3.34
<Tb>

Chlorobutane I 5 26.01 19 01 1 24 2.97

Chlorobutane I 5 26.01 19 01 1 24 2.97

<Tb>
<tb> Chlorobutane <SEP> 10 <SEP> 1544 <SEP> 10. <SEP> 88 <SEP> 1.24 <SEP> 2 <SEP> 14
<tb> Dichloromethane <SEP> 5 <SEP> 18. <SEP> 38 <SEP> 13. <SEP> 13 <SEP> 1.22 <SEP> 1.84
<tb> Chloroform <SEP> 5 <SEP> 18. <SEP> 95 <SEP> 13 <SEP> 58 <SE> 1.23 <SEP> 2.59
<tb> Dichloroethane <SEP> 5 <SEP> 17. <SEP> 14 <SEP> 12. <SEP> 19 <SEP> 1.22 <SEP> 2.33
<tb> Isopropyl Chloride <SEP><SEP> 10 <SEP> 19.98 <SEP> 14. <SEP> 37 <SEP> 1. <SEP> 24 <SEP> 2. <SEP> 38
<tb> Tnchlorethylene <SEP> 4 <SEP> 19.16 <SEP> 1374 <SEP> 1.22 <SEP> 2 <SEP> 60 <SEP>
<tb> Chlorobenzene <SEP> 5 <SEP> 17. <SEP> 53 <SEP> 12. <SEP> 49 <SEP> 1.23 <SEP> 2.06
<tb> Dichlorobenzene <SEP> 10 <SEP> 8 <SEP> 43 <SEP> 5.48 <SEP> 1 <SEP> 18 <SEP> 1.30
<tb> Dichlorobenzene <SEP> 5 <SEP> 16. <SEP> 73 <SEP> 11. <SEP> 87 <SEP> 1.19 <SEP> 1.69
<Tb>

Claims (11)

Chromatographic method for the resolution of the tetralone intermediate, obtained during the synthesis of sertraline, from a mixture of the two enantiomers of said tetralone, characterized in that in the eluent system used one at least one solvent is carbon dioxide which is used under physical conditions in which it is in the supercritical, critical or subcritical state, said eluting system being perforated through an enantioselective stationary phase containing macrocyclic heterotopic coreceptors.  2- Method according to claim 1, characterized in that it is conducted continuously or in batches.  3- A method according to claim 1 or claim 2, characterized in that it is conducted in a simulated moving bed or by the technique called Steady State Recycling (SSR).  4- Process according to any one of claims 1 to 3, characterized in that the eluent system contains between 1 and 99% of carbon dioxide, the complement to 100% being constituted by a solvent or a mixture of solvents, binary, ternary or quaternary, each of the solvents being chosen from solvents whose polarity P 'is greater than 1.2.  5. Process according to any one of claims 1 to 4, characterized in that the macrocyclic heterotopic coreceptors contained in the chiral stationary phase consist of alkyl ether, arylether, alkylarylethers, arylalkylethers, aryl esters, alkyl esters, arylalkyl esters, alkylaryl esters, alkylcarbamates derivatives. , arylcarbamates, alkylarylcarbamates, arylalkylcarbamates, cyclodextrins or oligosaccharides or polysaccharides, crosslinked with bifunctional compounds, and constituting three-dimensional chiral cavities or macrocyclic cages.  6. Process according to claim 5, characterized in that the macrocyclic cages have one of the following formulas: <Desc / Clms Page number 22>

<Desc / Clms Page number 23>

<Desc / Clms Page number 24>

 where: - X represents an oxygen atom or the group -NH, - m is the non-zero integer at most equal to 5, - N1, N2, N3 and N4 in the general formulas I, II, III and IV are identical or different and can take values between 0 and 10,000, - R represents a hydrogen atom or a substituted or unsubstituted alkyl radical, linear or branched, having from 1 to 8 carbon atoms, - Y represents a single bond or a group -NH-C (O) -, or a group -C (O) -, - A represents an alkylene, or arylene, or aminoarylene, or oxyarylene radical having 6 to 18 carbon atoms or an aralkylene radical or an arylaminoalkylene or aryloxyalkylene radical having 7 to 40 carbon atoms, "Support" represents a conventional chromatographic support which may be an inorganic or organic compound, - L represents a bis-thioether radical, of general formula V bis-sulfoxide, of general formula VI or bis-sulfone, of general formula VII or a bis-silane, of general formula VIII-A or VIII-B below: <Desc / Clms Page number 25>

 The same or different W 1 and W 3 are each a linear or branched alkylene radical having from 1 to 21 carbon atoms, an arylene radical having from 6 to 18 carbon atoms or an aralkylene radical having 7 to 40 carbon atoms; W 2 represents a single bond, W 1, an oxygen atom, a sulfur atom or a symmetrical diester of formula

 R5 represents hydrogen, a halogen, a hydroxyl, an alkoxy or a linear or branched alkyl radical having from 1 to 5 carbon atoms; W represents a single bond or grouping

<Desc / Clms Page number 26>  represents the chiral unit of a linear, branched or cyclic chain of a polysaccharide derivative having the formula Xlla to Xllk below, it being understood that chain i and chain j symbolize the fact that the chiral units are located on separate chains , or separate sequences of saccharide units, within the polysaccharide or oligosaccharide.

 single bond or the group -CH2 --- CH2 # CH2 # S # * is a radical L chiral unit designated below by the general formula XI

 where X is halogen, hydroxyl or alkoxy, 0 is oxygen and W is

10, - U represents either  where R6 is (CH2) n2 or oxygen and where n1 varies from 0 to 3000 and n2 from 0 to <Desc / Clms Page number 27>

<Desc / Clms Page number 28>  in which: c) the symbols X 1, X 2 and X 3, which are identical or different, each represent an oxygen atom or the -NH group;

<Desc / Clms Page number 29>  Where m is a non-zero integer at most equal to 5, Y is a single bond or a group -NH-C (O) - or a group -C (O) -, A is as defined above, W represents a single bond or the group -CH2-CH2-CH2-S- and R5b represents a halogen, a hydroxyl or an alkoxy, - or a radical of general formula [CH (R) = CH] m1 AY (XIV) where R, A, and Y have the same meaning as in formulas (I) to (IV) and m1 have the same meaning as in formula XIII.

 d) Each of the symbols R 1, R 2, R 3 represent independently: a chlorosilane, hydroxysilane or alkoxysilane radical having the general formula:  or a radical having the formula A2-A1-CXa (XV) in which Xa represents an oxygen atom, A1 represents a single bond or an -NH- group and A2 represents a radical having from 6 to 24 carbon atoms, an aralkyl radical having from 7 to 36 carbon atoms - or a hydrogen atom n being a number of between 5 and 20,000, it being understood that in each chiral osidic unit (Xlla) to (Xllk), at least one symbols X1; X 2 and X 3 represent an oxygen atom, and in at least part of the structural units constituting the polysaccharide, at least one of the symbols R 1, R 2, R 3 represents a precursor radical of the compounds (1), (II), (III) or (IV) and at least one of the symbols R1, R2, R3 represents a radical of general formula (XV).  7- Process according to any one of claims 1 to 6, characterized in that the chiral stationary phase consists of a support essentially containing macrocyclic heterotopic coreceptors of general formulas I to IV or a composite support consisting of said heterotopic coreceptors and an organic or inorganic chromatographic material.  8- Process according to claim 7, characterized in that the organic or inorganic chromatographic material consists of an organic polymer such as polystyrenes, polystyrenes divinyl benzenes, polyamides, <Desc / Clms Page number 30>  polyacrylamides, polyureas, polyurethanes, or any other type of polymeric material, or a mineral compound such as silica gels, zirconia, alumina or silicates such as magnesium silicate or ceramics or phosphates such as hydroxyapatite.  9- Method according to any one of claims 6 to 8, characterized in that the sequence of the chiral units constituting the macrocyclic cages according to claim 5, may be linear or cyclic, and that in the case where the sequence is cyclic it is preferably constituted by an a, or p or y-cyclodextrin.  10- Process according to any one of claims 1 to 9, characterized in that the chiral stationary phase has a chemical stability at temperature, in the presence of solvents of polarity P 'according to Rohrschneider greater than 1.2, greater than 80 C.  11- Method according to any one of claims 1 to 10 characterized in that the temperature of the eluent system is between -50 C and +200 C.