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    Lieu1

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    6 views9 pages

    Hanh OkOkUS2011263896A1

    Uploaded by

    hongnhung6p
    Lieu1

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
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    (19) United States US 201102638961 c2) Patent Application Publication —(o) Pub. No.: US 2011/0263896 Al Lorenz et al. (43) Pub, Date: Oct. 27, 2011 os) 76) en @ (86) (0) Sep. 5, 2008, PROCESS FOR ENANTIOSEPARATION OF ‘CHIRAL SYSTEMS WITH COMPOUND FORMATION USING TWO SUBSEQUENT (CRYSTALLIZATION STEPS Inventors: Heike Lorenz, Magdeburg (DB) Henning Kaemmerer, Magdeburz (DE); Daniel Polenske, Egeln (DE); Andreas Seidel-Morgenstern, Mogdeburg (DE) Appl. No. 13/062,470 PCT Filed: Jun. 18, 2009 PCTNo. PCTIRP2009/087562 $371 (0), (2), 4) Date: Jun, 23,2011 Foreign Application Priority Data ey 081637332 Publication Classification G1) Inc cure 227236 (2006.01) (2) US.CL 02/884 on ABSTRACT “Method for enantioseparation ofa chiral system with com pound formation comprising a pair of enantiomers. The ‘nethowl comprises thesteps of pacing the chiral system to be processed, which s optically enriched by a argt enantiomer, in the phase region ofthe temary phase diagram of chiral compouad forming systems to achieve the establishment of the soldiguid phase equilibria; phase-separating the liquid ‘and slid phase formed by the placing step: sifting the cute: tie composition of the remaining liquid towards @ lower eutectic composition (x) until the overall composition is located in the 2-phaso region ofthe teary phase diagram of chiral compound forming systems; and performing crystal sation in the 2-phase region of the ternary phase diagram for obiaining the target enantiomer inthe solid phase, In some cases the shifting step can be skipped Patent Application Publication Oct. 27, 2011 Sheet 1 of 3 US 2011/0263896 Al SOLVENT PURITY AT EUTECTIC COMPOSITION (Xe) FIG.1 Patent Application Publication Oct. 27, 2011 Sheet 2 of 3 US 2011/0263896 Al SOLVENT PURITY AT EUTECTIC COMPOSITION (Xe) OBTAINED PURITY (Xa) FIG.2 Patent Application Publication Oct. 27, 2011 Sheet 3 of 3 US 2011/0263896 Al SOLVENT (+) (-) REQUIRED PUIRTY (X gcqurep) OBTAINED PUIRTY AT EUTECTIC COMPOSITION (X¢) FIG.3 US 2011/0263896 Al PROCESS FOR ENANTIOSEPARATION OF CHIRAL SYSTEMS WITH COMPOUND FORMATION USING TWO SUBSEQUENT ‘CRYSTALLIZATION STEPS FIELD OF INVENTION 10001] The preset invention relates to a method fr sepe- ration of rcemstes and in patio a iethod foe enati- ‘separation of a chiral system with compound formation. {002} racemate isan equimolae mixture of tea nant ‘mers, Enantiomers are isomers. substances which differ from each other only inthe arangement of the atoms but not inthesum formula, Enantiomers show chirality the have the properies of image and mimor image or hand and oppo site hand. Usaly, the two enantiomers are refered 10 as -enantiomerand D-enantiomeror(S)-and (R)-enantomes {0003} "More than al of pharmaceutical eve substances are chal. However, often only one ofthe two enantiomers, ‘an be used as aetve substance, since both dierent ena ‘mers usually have a different physiological effet on the human organism. Besides this, obtining pure enantiomers is very important in the agricultural ebemisty and the food industry. The marke for substances of pure enantiomers (or example in phamaceatial agets, plant protecting agents, Ayes and fragrances) has substantially risen inthe last yeas 10004} 4 separation of such ocemates is usualy dil, since the chemical and physical properties excep for the beviourt linear polarize ight an oter chiral substances identical. Herein, only 5 10 10% of al chiral systems are ‘coaglonserate forming systems which ean be separate by prelereatal crystallization without prior enrichment by the target enantiomer de to thermodynamic reasons. However, the majority (euore than 9096) of all chil substances, are ‘compound forming systems whieh cannot beseparated. Thus, ‘lotoeffort has been mode to provide elicit methods for separation of raceme forming systems. Sucha method ofthe state ofthe at known fom DE 10 2005 039 S01 AL and W02007023129 A2, for example. [0005] However, such methods usualy segue an initial ‘enantiomeric enrichment of the racemic solution in the order ‘ofthe eutetic composition ofthe casidered chiral system to Yield further method step the target enantiomer andor the racemae fom enriched faton(s) e.the prefeenialeys- tlizaton. Therefore, a comparsly lange amount of enemy ‘and time is nocessry to provide such an enschod solution, 10006] itis thoobjct of the present invention to provide an ‘enhanced method eapable of delivery of optically pure enan- tiomers and which acdesses the above mentioned problems 0007] This object i achieved by a method according to ‘aim 1, which method is for enantoseparation ofa chiral system with compound formation compesing a pair ofenan- tomers, wlerin the chiral system hs an eutectic omposi- tion that exeeds already the ryuired purity a the prodctto be achieved by the cleime method. The method comprises ihe steps of: placing the eutectic composition inthe 3-phase region ofthe temary phase diagram of chiral compound frm- ing systomstoachieve he establishment ofthe corresponding solidligid phase equilibria: and subsequently phase-sepa- rating the liquid and the solid phase formed by the placing step for obizining the target enantiomer inthe guid phase. 008] This objects further achieved by a method accord ing wo chim 2, which method is for enantioseparation ofa chia system with compound formation comprising a pairof ‘enantiomers. The method comprises the steps of: placing the Oct. 27, 2011 chiral system to be processed, which is optically enriched by ‘target enantiomer inthe 3-phase region of the terry phase iagram of chiral compound forasing systems to aehieve the establishment of the solidliquid phase equilibria: phase separating the liquid and solid phase formed by the placing step: shifling the eutectic composition ofthe remaining liquid towards a lower eutectic composition, placing the overall composition ia the outer 2-phase region; and performing jallsaton inthe outer 2-phase region ofthe temary phase siagram for obtaining the target enantiomer in the solid phase. [0009] An adjustment of the concentration of the soltion by e.panial evaporzation leads to an overall composition, ‘which is located in the outer 2-phase region (FIG. 2, 15). Selective erystallzation can be performed in this -phase region ofthe temary phase diggram in order to obtain the pure target enantiomer in the soli phase, [0010] Advantageous developments are set out in the ‘dependent claims. [0011] The optically enriched chiral system to which the above-described method is applied can be an optically carichod gud solution, In his ease, the placing. step can be performed by atleast ane of partial evaporation ofthe opti- cally enriched solution, solvent change of the optically enriched solution, and addition ofan antisolvent tothe opt- cally enriched solution [0012] In addition, the optically ensiched chiral system to ‘which the ove-deseribed method is applied can bean opti- cally enriched solid mixture. In this ase, the placing step can be performed by partial dissolution of the optically enriched sold mixture ina solvent [0013] Preferably, inorder to start with « minimum of ini- tial enrichment and to gan the highest yield, the placing step places the optically enriched chiral system onto the inner phase boundary of the 2-and 3-pliase region of the ternary phase diagram of chiral compound forming systems 10 achieve theestablishmentof the solidTiquid phase equilibria, [0014] Iispossibleto perform he phase-separating step by decanting the enriched liquid phase or by removing the solid phaseby filtration orany ater technique of solidTiquid phase separation, [0015] The hilting step can bepecformed by temperature ‘change until the overall composition is located inthe 2-phase region ofthe corresponding ternary phase diagram. Prefer- ably, an additional evaporization stp is therefore required, [0016] The sifting step ean also be performed by a (par- tial) exchange of the solveat until the overall composition is located in the 2-phase region of the eoresponding ternary phase diagram. Preferably an addtional evaporization step is therefore required. [0017] The shifting step ean also be performed by a com bination of a temperature change and a (pantial) solvent exchange until the solution composition is located in the 2-phase region, Preferably, an adltional evaporization step is therefore roquited. [0018] Preferably, the sifting step shifts the remaining liquid oat the outer phase boundary between the 2- and the S-phase region of the temary phase diagram of the chiral compound forming systom in onder to obtain the highest yield. [0019] Preferably, the crystallization is performed in the ‘outer 2-phase region to gain pare target enantiomer in the cxystalline phase, [0020] The removed solid phase can be dried to dryness. US 2011/0263896 Al [0021] The previously described methods for enantosepa- ration of chiral systems with compound formation have the following advantages: 4) The inital enantiomeric enrichment canbe very small. e.g. 1hexcess is sulicient ») Stable, thermodynamically dominated proces ie. method (caulibrium conditions apply) +) Symmetric approach, each ofthe two enantiomers can be the target «d) Method can be operated in a continuous manner [0022] Hereinafter, the preseat invention will be further

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