WO2010064212A1 - Procédé d'obtention d'un dérivé de 1,2,3,4-tétrahydro-isoquinoléine optiquement pur - Google Patents

Procédé d'obtention d'un dérivé de 1,2,3,4-tétrahydro-isoquinoléine optiquement pur Download PDF

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WO2010064212A1
WO2010064212A1 PCT/IB2009/055504 IB2009055504W WO2010064212A1 WO 2010064212 A1 WO2010064212 A1 WO 2010064212A1 IB 2009055504 W IB2009055504 W IB 2009055504W WO 2010064212 A1 WO2010064212 A1 WO 2010064212A1
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organic solvent
water
phenyl
ethyl
mixture
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PCT/IB2009/055504
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English (en)
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Silke Erbeck
Ralf Koberstein
Antonio Soi
Andrea Zistler
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Actelion Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals

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  • the present invention relates to a method for obtaining enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline from a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)- ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline.
  • (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline is an important synthetic intermediate in the preparation of almorexant, a 1,2,3,4-tetrahydro-isoquinoline derivative with orexin antagonist properties which is currently in clinical development for the treatment of sleep disorders.
  • 1,2,3,4-tetrahydro-isoquinoline derivatives with orexin antagonist properties and their preparation are described in WO 01/68609.
  • optical resolution of 6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l, 2,3, 4-tetrahydro-isoquino line is achieved with a high enantiomeric excess and a good yield.
  • the invention relates to a process for obtaining enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline from a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1, 2,3, 4-tetrahydro-isoquino line and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)- ethyl]-l,2,3,4-tetrahydro-isoquinoline, which process comprises the following sequential steps: either a) bringing to a given temperature T which may be up to the boiling temperature of the organic solvent(s) and optionally present water, a mixture of (7?)-6,7-dimethoxy- l-[
  • the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” or “around” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 1O 0 C to Y plus 1O 0 C, and preferably to an interval extending from Y minus 5 0 C to Y plus 5 0 C.
  • room temperature refers to a temperature of about 25°C.
  • enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl- phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline refers to a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline containing at least 70%, preferably at least 80% or 90% and more preferably at least 95% or 98% of (S)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-te
  • the process of embodiment i) above will be such that it comprises steps a) to c).
  • the process of embodiment i) above will be such that it comprises steps d) to f).
  • the process according to one of embodiments i) to iii) above will be such that R is methyl.
  • the process according to one of embodiments i) to iv) above will be such that the method used for collecting the crystallised salt at step b) or removing the crystallised salt at step e) will consist in a filtration.
  • the process according to one of embodiments i), ii) and iv) above will be such that the method used for collecting the crystallised salt at step b) will consist in a decantation.
  • the process according to one of embodiments i), ii) and iv) above will be such that the method used for collecting the crystallised salt at step b) will consist in a centrifugation followed by a decantation.
  • the process according to one of embodiments i), iii) and iv) above will be such that the method used for removing the crystallised salt at step e) will consist in a decantation.
  • the process according to one of embodiments i), iii) and iv) above will be such that the method used for removing the crystallised salt at step e) will consist in a centrifugation followed by a decantation.
  • the process of embodiment x) above will be such that the organic solvent or organic solvent mixture optionally mixed with water is selected from ethyl acetate, tetrahydrofurane, methyl ethyl ketone, acetone and a mixture of acetone with ethanol, whereby the organic solvent or organic solvent mixture is mixed with water in a proportion of a least 7 volumes of organic solvent per volume of water.
  • the organic solvent or organic solvent mixture optionally mixed with water is selected from the following mixtures:
  • - a mixture of acetone and water, which contains from 8 to 20 (and preferably from 10 to 15) volumes of acetone per volume of water; and - a mixture of acetone, ethanol and water, which contains from 7 to 11 (and preferably from 8 to 10) volumes of acetone per volume of water and from 0.5 to 1.5 volumes of ethanol per volume of water.
  • the process of embodiment x) above will be such that the organic solvent or organic solvent mixture optionally mixed with water is selected from the following mixtures:
  • the process according to one of embodiments i) to ix) above will be such that the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline and the compound of formula I or the compound of formula F will be in solution or in suspension in different organic solvents each optionally mixed with water.
  • the process of embodiment xiv) above will be such that: 1) the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of enantiomers is selected from tetrahydrofurane and acetone, whereby said tetrahydrofurane or acetone is mixed with water in a proportion of a least 10 volumes of tetrahydrofurane or acetone per volume of water; and 2) the organic solvent or organic solvent mixture optionally mixed with water containing the compound of formula I or the compound of formula F is tetrahydrofurane, whereby said tetrahydrofurane is mixed with water in a proportion of a least 3 volumes of tetrahydrofurane per volume of water (and preferably in a proportion of 3 to 20 volumes of tetrahydrofurane per volume of water), it being understood that if for both the mixture of enantiomers and the compound of formula I or the compound of formula F the organic solvent is tetrahydrofurane and ace
  • the process according to one of embodiments i) to ix) above will be such that the compound of formula I or the compound of formula F will be added as a solid.
  • the process of embodiment xvi) above will be such that: - either the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)- ethyl]-l,2,3,4-tetrahydro-isoquinoline will be a mixture of 4-methyl-2-pentanone and water, whereby 4-methyl-2-pentanone is mixed with water in a proportion of a least 10 volumes of 4-methyl-2
  • the process of embodiment xvi) above will be such that the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline will be a mixture of acetone, ethanol and water, whereby acetone, ethanol and water are mixed in a proportion of at least 9 volumes of acetone per volume of water and per volume of ethanol (and preferably such that said organic solvent or organic solvent mixture optionally mixed with water will be a mixture of acetone, ethanol and water which contains about 9 volumes of acetone and about 1 volume of ethanol per
  • the organic solvent or organic solvent mixture(s) used in the process according to one of embodiments i) to xviii) above will have a boiling temperature T B of at least 40 0 C (and in particular of at least 50 0 C).
  • the temperature T used in step a) or step d) of the process according to one of embodiments i) to xix) above will be close to the boiling temperature T B of the organic solvent or organic solvent mixture(s) optionally mixed with water used in said step, that is, between 0 and 10 0 C below T B .
  • step b) and step e) of the process according to one of embodiments i) to xx) above will be such that the time until the mixture obtained at step a) or d) reaches the cooling down temperature is not more than 24 hours, preferably not more than 16 hours, more preferably not more than 5 hours and in particular not more than 3 hours.
  • the cooling down temperature used at step b) or step e) of the process according to one of embodiments i) to xxi) above will be a temperature that is at least 20 0 C or 25°C lower, and in particular at least 30 0 C or 40 0 C lower, than the temperature T of step a) or step d) (and especially such a temperature that would be around room temperature).
  • the base used in step c) or f) of the process according to one of embodiments i) to xxii) above will be selected from NaOH, KOH, LiOH, Ca(OH) 2 , NaOMe, NaOEt, Na 2 CO 3 and K 2 CO 3 .
  • the base used in step c) or f) of the process according to one of embodiments i) to xxii) above will be selected from NaOH, KOH, LiOH and Ca(OH) 2 (and in particular from NaOH and KOH).
  • the removal of possibly remaining compound of formula I or compound of formula F at step c) or at step f) of the process according to one of embodiments i) to xxiv) above is performed by an acid/base extraction procedure.
  • the quantity of compound of formula I or of compound of formula F used in step a) or in step d) of the process according to one of embodiments i) to xxv) above will preferably be from 0.9 to 1.6 equivalents (and in particular be from 1 to 1.4 equivalents) of compound of formula I or of compound of formula F per equivalent of (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline present in the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)- ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline and (5)-6
  • 1,2,3,4-tetrahydro-isoquinoline contained in the filtrate collected after step b) or in the crystalline salt collected after step e) are converted into 6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline before being reduced into a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1,2,3, 4-tetrahydro- isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-
  • the process according to embodiment xxvii) or xxviii) above will be such that the reduction step is carried out either by reaction with NaBH 4 or by catalytic hydrogenation (the catalyst used for this catalytic hydrogenation reaction being notably Pd/C).
  • the catalyst used for this catalytic hydrogenation reaction being notably Pd/C.
  • xxx) According to a particular embodiment of this invention, if the enantiomeric excess obtained for the product of the process according to one of embodiments i) to xxix) above is found to be insufficient, said process may be repeated once or twice to improve the enantiomeric excess.
  • the compounds of formula I and the compounds of formula F used in the invention process can be manufactured by standard methods well known to one skilled in the art.
  • Ar is a phenyl group substituted, in addition to the NH 2 group, with the R group as defined in formula I.
  • the reaction of the substituted aniline with acetic acid (J5',45)-4-acetoxy-2,5-dioxo- tetrahydro-furan-3-yl ester (obtained for example by reaction of D-(-)-tartaric acid with acetyl chloride or acetic anhydride in heated toluene) can notably be carried out in a solvent like DCM at a temperature preferably above RT (e.g. about 40 0 C).
  • Subsequent cleavage of the ester groups can be performed by reacting the obtained intermediate with a base like KOH in a solvent like water.
  • Ar is a phenyl group substituted, in addition to the NH 2 group, with the R group as defined in formula F.
  • a process for obtaining enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline from a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1, 2,3, 4-tetrahydro-isoquino line and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)- ethyl]-l,2,3,4-tetrahydro-isoquinoline can be carried out, which process comprises the following sequential steps: either a) bringing to a given temperature T which may be up to the boiling temperature of the organic solvent(s) and optionally present water, a mixture of (7?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-pheny
  • organic solvent or organic solvent mixture optionally mixed with water may in particular be EA, THF, MEK, acetone or a mixture of acetone with EtOH, each of these organic solvents or organic solvent mixtures being preferably mixed with water in a proportion of a least 10 volumes of organic solvent per volume of water.
  • the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of enantiomers can be selected from THF and acetone, whereby said THF or acetone is mixed with water in a proportion of a least 10 volumes of THF or acetone per volume of water; and 2) the organic solvent or organic solvent mixture optionally mixed with water containing the compound of formula I can be THF, whereby said THF is mixed with water in a proportion of a least 3 volumes of THF per volume of water, it being understood that if for both the mixture of enantiomers and the compound of formula I or the compound of formula F the organic solvent is tetrahydrofurane, then the proportion of water optionally added is different.
  • step a) or step d) of the process above the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (7?)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro-isoquino line and
  • (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline can be a mixture of 4-methyl-2-pentanone and water, whereby 4-methyl-2-pentanone can be mixed with water in a proportion of a least 10 volumes of 4-methyl-2-pentanone per volume of water.
  • the quantity of compound of formula I or of compound of formula F used in step a) or in step d) of the process above will be from 0.9 to 1.5 equivalents of compound of formula I or of compound of formula F per equivalent of (5)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l, 2,3, 4-tetrahydro-isoquino line present in the mixture of (7?)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-
  • the quantity of (5)-enantiomer present in the mixture can be determined by one skilled in the art using standard methods (e.g. measurement of rotatory power of the mixture and comparison with a known reference).
  • the organic solvent or organic solvent mixture(s) used in the process above will have a boiling temperature of at least 40 0 C (and in particular of at least 50 0 C).
  • the mixture obtained at step a) or at step d) is heated at or close to the reflux temperature of the organic solvent or organic solvent mixture optionally mixed with water.
  • T B is the boiling temperature of the organic solvent or organic solvent mixture(s) optionally mixed with water used in said step
  • the temperature used in step a) or step d) of the process will preferably be between 0 and 10 0 C below T B .
  • the time until the mixture obtained at step a) or at step d) reaches the cooling down temperature should preferably not be more than 24 hours.
  • the cooling down temperature used at step b) or step e) of the process above will preferably be a temperature that is at least 20 0 C or 25°C lower, and in particular at least 30 0 C or 40 0 C lower, than the temperature of step a) or the temperature of step d). Preferred embodiments will be such that the cooling down temperature used at step b) or step e) of the process above will be around RT.
  • the enantiomeric excess obtained for the product of the resolution process according to the invention is found to be insufficient, said process may be repeated one or twice.
  • the base used in step c) or step f) will be a stong base, for example NaOH, KOH, LiOH, Ca(OH) 2 , NaOMe, NaOEt, Na 2 CO 3 or K 2 CO 3 (and in particular NaOH or KOH).
  • a stong base for example NaOH, KOH, LiOH, Ca(OH) 2 , NaOMe, NaOEt, Na 2 CO 3 or K 2 CO 3 (and in particular NaOH or KOH).
  • the compounds synthesised were characterised by 1 H-NMR or by chiral HPLC.
  • 1 H-NMR 300 MHz: Varian Oxford or 400 MHz: Bruker Avance
  • Method . 1 A suspension of intermediate D. ii (40O g, 1.24 mol) in water (2.8 L) was treated portionwise with KOH (270 g, 4.8 mol). The obtained clear solution was stirred for 2 h and made acidic by addition of cone. HCl (32%, 640 mL). EA (2.4 L) was added, the layers were separated and the aq. layer was extracted 4 times with EA (4 x 2.4 L). The combined org. layers were concentrated to a final volume of 2.6 L and diluted with toluene (3.0 L). Additional solvents (3.0 L) were distilled off and further toluene (2.0 L) was added to the residual mixture. The suspension was filtered and the residue was dried in vacuo to give the desired product (267 g, 88% yield).
  • EA 100 L was added, the mixture was intensively stirred for 5 min, the layers were separated and the aq. layer was extracted additional nine times with EA (9 x 100 L).
  • Method . 2 To a solution of intermediate Li in MeOH (as obtained in Preparation I, step Li, method 3) was added 5 mol% sulfuric acid and heated. The formed water was distilled off together with MeOH until the esterification was complete. MeOH was then completely removed to yield the desired product.
  • a 640 L enamelled reaction vessel was charged with a solution of intermediate I.iii (68.5 kg, 180 mol) in DCM (475 L, from Preparation I, step I.iii, method 2).
  • the suspension turned into a clear solution and the mixture was stirred for 4 h at 88°C.
  • the solution was cooled to 50 0 C in 2 h and stirred for 1 h at 50 0 C.
  • the solution was cooled to 20 0 C within 2 h whereby a turbid grey solution occurred which was further cooled to 0 0 C within 4 h.
  • Method 3 Intermediate I.iii was suspended in toluene and heated to 80-100 0 C. After addition of 1.5 eq. phosphorus oxychloride the mixture was heated for 6 h to 80-100 0 C and then cooled within 3 h to 20 0 C. The obtained suspension (hydrochloride salt) was added to water while maintaining the pH of the aq. layer during addition and subsequent stirring between 7 and 8 by addition of a NaOH solution. The mixture was stirred until all precipitate was dissolved. After phase separation, residual water was removed by azeotropic distillation to give a solution of the desired product (free base) in toluene. Then 1.0 eq.
  • a pre-heated solution (70 0 C) of the respective tartranilic acid (0.274 mmol, 1.0 eq.) in the given solvent / solvent mixture was added to a pre-heated solution (70 0 C) of r ⁇ c-6,7-dimethoxy-l-[2-(4-trifluoro-methyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline (100 mg, 0.274 mmol) in EtOH (2.0 mL).
  • EtOH 2.0 mL
  • the mixture was slowly cooled to RT and kept at this temperature until precipitation occurred.
  • the precipitate was filtered off, washed with small volume of EtOH, dried in vacuo and analyzed by 1 H NMR.
  • - eluent A / eluent B 10 / 90 (isocratic); - flow rate: 0.8 mL/min; temperature: RT t R ((iS)-isomer): 12.9 min; t R ((i?)-isomer): 18.6 min.
  • the precipitate was filtered off and dried to give the respective 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1,2,3,4-tetrahydro-isoquinoline in the given enantiomeric ratio (e.r.) which was determined after transfer to the free base by chiral HPLC.
  • the yield (Y) is calculated based on the quantity of racemic starting material (maximum theoretical yield: 50%).
  • the tartranilic acid was added as a solid and solvent B was used to rinse the funnel.
  • the tartranilic acid was added as a solid.
  • a 640 L enamelled reaction vessel was charged with r ⁇ c-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline (27.9 kg, 76.4 mol, determined by LOD) as solution in EtOH (400.8 kg; 500 L, as obtained following a protocol similar to that of Preparation I, step Lv, method 2).
  • the solution was concentrated by distilling off EtOH (400 L) at an external temperature of 60 0 C and reduced pressure (170-120 mbar).
  • Acetone (230 L) was added and the solution was concentrated by distilling off solvent (230 L) at an external temperature of 60 0 C and under reduced pressure (400-500 mbar).
  • the mixture was heated to 80 0 C and a clear yellow solution was obtained.
  • Example 21 A solution of NCS (1.47 g, l l.O mmol) in ether (3O mL) was treated with r ⁇ c-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline (2.O g, 5.50 mmol) under exclusion from light and stirred for 30 min at RT. A NaOH solution (1.0 M, 20 mL) was added and the mixture was vigorously stirred for further 30 min. The layers were separated and the aq. layer was extracted with DCM. The combined org. layers were washed with brine, dried over Na 2 SO 4 and concentrated partially in vacuo.
  • a solution of NaOCl in water (12.6%, 30.2 kg) was diluted with water (60 kg) and treated within 20 min with a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1,2,3,4-tetrahydro-isoquinoline (enriched in (i?)-enantiomer; 14.4 kg, 39.3 mol) in DCM (170 L) by keeping IT below 30 0 C.

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Abstract

La présente invention concerne un procédé d'obtention de 6,7-diméthoxy-1-[2-(4-trifluorométhylphényl)éthyl]-1,2,3,4-tétrahydro-isoquinoléine énantiomériquement enrichie à partir d'un mélange de (R)-6,7-diméthoxy-1-[2-(4-trifluorométhylphényl)éthyl]-1,2,3,4-tétrahydro-isoquinoléine et de (S)-6,7-diméthoxy-1-[2-(4-trifluorométhylphényl)éthyl]-1,2,3,4-tétrahydro-isoquinoléine.
PCT/IB2009/055504 2008-12-05 2009-12-04 Procédé d'obtention d'un dérivé de 1,2,3,4-tétrahydro-isoquinoléine optiquement pur WO2010064212A1 (fr)

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ELVERS B ET AL (EDITOR): "ULLMANN'S ENCYCLOPEDIA OF INDUSTRIAL CHEMISTRY", vol. A18, 1991, VCH, WEINHEIM, article "OCCURRENCE AND PRODUCTION OF OPTICALLY ACTIVE COMPOUNDS", pages: 182 - 183, XP001167124 *
JACQUES J ET AL: "Enantiomers, Racemates, and Resolutions", 1981, JOHN WILEY & SONS, NEW YORK, XP002292433 *
K.C. RICE; A. BROSSI, J ORG. CHEM., vol. 45, no. 4, 1980, pages 592 - 601
MONTZKA, T.A. ET AL., J. ORG. CHEM., vol. 33, no. 10, October 1968 (1968-10-01), pages 3993 - 3995, XP002576424 *
T.A. MONTZKA ET AL., J. ORG. CHEM., vol. 33, no. 10, 1968, pages 3993 - 3995

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WO2016161996A1 (fr) * 2015-04-09 2016-10-13 Zentiva, K.S. Procédé de résolution chirale de l'intermédiaire clé de la synthèse d'aprémilast et son utilisation pour la préparation d'aprémilast pur

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