CA2258032A1 - Enantiomer separation from chromane acid esters - Google Patents

Enantiomer separation from chromane acid esters Download PDF

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Publication number
CA2258032A1
CA2258032A1 CA002258032A CA2258032A CA2258032A1 CA 2258032 A1 CA2258032 A1 CA 2258032A1 CA 002258032 A CA002258032 A CA 002258032A CA 2258032 A CA2258032 A CA 2258032A CA 2258032 A1 CA2258032 A1 CA 2258032A1
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atoms
substituted
process according
resolution
enantiomers
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French (fr)
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Ralf M. Devant
Helmut Reubold
Michael Schulte
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Merck Patent GmbH
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D311/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/66Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Treatment Of Liquids With Adsorbents In General (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Pyrane Compounds (AREA)

Abstract

The invention relates to processes for the chromatographic separation of enantiomeric esters from 2-alkanoyl-chromane derivatives of the formula (I) in which Z is -(CH2)n1-(CHA)n2-(CH2)n3, where n1 = 0, 1, 2 or 3, n2 = 0 or 1, n3 = 0, 1, 2 or 3, with the proviso that n1 + n2 + n3 < 4, R6, R7, R8 and R9 are mutually independently H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl with 3 to 7 atoms, -CH2NH2, -CH2NHA, -CH2NA2, CH2NHAc or -CH2NHSO2CH3, where two neighbouring radicals may also be an alkylene chain with 3 or 4 C atoms, A is alkyl with 1 to 6 C atoms, Ac is alkanoyl with 1 to 10 C atoms or aroyl with 7 to 11 C atoms, Ph is unsubstituted or R5, 2, 3 or 4-pyridyl or phenoxy-substituted phenyl, R5 is unsubstituted or 1-5 F, CF3 or wholly or partially fluorine-substituted A, A and/or OA-substituted phenyl, by means of chromatography on sorbents containing aromatic carbamate-substituted polysaccharides, e.g. cellulose, especially cellulose-tris(3,5 dimethyl phenyl carbamate), using eluents containing C1 to C5 alcohols. Suitable eluents are C1 to C5 alcohols, especially methanol and ethanol or their mixtures. Preferred eluents are C1 to C5 alcohols and C1 to C10 hydrocarbons, especially mixtures of hexane or heptane with 2-propanol.

Description

13 NOV '98 10:Zl ~1ERCK PRTENT G~1BH 49 6151 727191 S.Z/9 FIL ~
Resolution o~ ~ s of chr~an acid eQtors The invention relates to the chromatogr~phic resoluti~n of ~n~ntiomers of esters o~ 2-alkanoyl-S chroman de~i~tives o~ ~he ~onmul~ I, i~ p~rti~ular ~y~eans of conti~uous processes.
R~

R~ZJ~O--A
Rg , Tn ~ormula I:
1~ . .
Z is - (CH2)",,- (CEIA)~~2- ~CH2)"3, where nl = O, 1, 2 or 3;
~2 = O or l;
n3 a 0, 1, ~ OX 3 w~ th the proviso that nl + n2 + n3 ~ 4, .

R6,R7,R~ and RYindependentl~ o~ ~ne another are H, A, OA, phenoxy, OH, F, ~1, Br, I, ~N, C~" NOl, NH2, NHA, N~, ~c, Ph, cycloalkyl ha~ing 3-7 C atoms, -CH~
~0 -~H2NHA, -CH~N~, -C~NHA~ or -CH2NHSU~C~" where two adj dcent radica~s oan also be an alkylene chain '~ having 3 or 4 C ato~s, ~ is alkyl having 1-6 ~ atoms, Ac is alkanoyl having 1 1~ ~ atoms or aroyl havin~ 7-11 C~ atoms, Ph is phenyl which is unsuhstituted or substituted ~y R5, 2-, 3- or 4-pyrïdyl o~ phenoxy.

R5 is phenyl which is unsubstituted or substituted by 1-5 F, or by CF3, or by comple~ely or partially ~luorine-substituted A, A, and~or OA.

Esters of the 2-alkanoylchroman derivatives according to Formula I, in particular those in which the sum nl + n2 + n3 has the value 0 or 1 (in the latter case Z is preferably -CH2-), are important intermediates, in particular in the production of pharmaceutically active amino(thio)ether derivatives, such as are disclosed, for example, in EP-A-0 707 007.
If these chroman derivatives are optically active, the resolution of the enantiomers is necessary or desirable.
For certain chroman derivatives, synthesis routes for enantiomerically pure chroman derivatives are described in J. Heterocyclic Chem. 29, 431 ff (1992). These syntheses, however, cannot easily be transferred to other similar compounds. In J. Med.
Chem. 38, pages 858 - 868 (1995), it is proposed in connection with leukotriene B4 receptor antagonists to resolve enantiomers of certain benzopyrancarboxylic acid derivatives by batch chromatography on chiral phases. For the resolution of enantiomers of chroman-2-carboxylates, it is furthermore proposed in EP-A-0 448 254 to hydrolyse one of the enantiomeric esters by means of microbial lipase. This process is only applicable if the proposed chroman ester is cleavable by the lipase.
It is thus the object to resolve enantiomers of derivatized chroman esters without being restricted by the limited substrate specificity.
In principle, enantiomers can be resolved on chiral sorbents. A large number of chiral sorbents are known to the person skilled in the art, for example those based on cellulose derivatives, cyclodextrins, or poly(meth)acrylamide derivatives having an optically active side chain. Such chiral sorbents and their use are disclosed, for example, in EP-A-0 147 804, EP-A-0 155 637, DE 36 19 303, DE 40 05 868 or DE 40 06 923.
It was found that the resolution of enantiomers of chroman-2-carboxylic acid esters, in particular of ethyl chroman-2-carboxylate, was not possible on a CA 022~8032 1998-12-11 13 NOV '98 10: Z1 rlERCK PRTENT G~1~H 49 6151 7Z7191 S. 3/9 number of customar~ chiral sorbent~;: polymethac~ylarnide de~ivatives bonded to sili~a ~el (DE 3 b . 19 3 03;
Chi raSpher~~ ; Merck , DE ), cyc l ode~rirl der i va tives }~onded to silica gel ~DE 40 0~ g23; t~hiraDex~D; Merc~c, U~), dlni~robenzoylphenylg~lycine ~aker) p~o~ed to be un~it~bl~ . ~esolution was a~so not possible using two sorbents based on ~ellulos~: the enanti~me~s could not be resolved eithe~ o~ cel~ulose t~iacetate ~Merck, D~) or on c~llulose tris(3,5-dime~hyl~enzoa~e) (~dsorbed on si}ica gel; CH~AL~'EL~ OJi ~aicel, JP). 5~rprisingly, however, it wa~ found that a ~esolution is pos~i~le on a sorbent b~sed on c~llulo~, which resembles CHI~ALCEL~ OJ, and in which the same aroma~ic su~stituent ~3,5-dimethylphenyl) is present bonded yia 15 a carbamate bond ins~ead of an ester ~ond. resolution on cellulose tris(~,S-dimethylphe~ylcarbamate tadsorbed on silica yeli CHIRALCE~ OD; Daicel, ~P) was possiblè
with good ~esolution ~actor~ using alcohols or alcohol-hydro~arhon mixtures as eluents and by ~éans of calumn 20 chromatography ~hatch process~ anc~ also by means of continuous "simulated moving bed" chxomatography ~SMB.
chromato~raphy). ~imilarly, r~solution on a sor-~ent in which ~he 3,S-di~ethylphenylcarba~a~ radicals ~rè
bonded to amyl~se ~CHIRA~PAR~ AD; Daicel, JP) was al~o 2S possibie. Good sorbents otherwise also pro~ed to be porous eellulose es~ers prepared a~cordin~ to ~P 0 3 .~ 270, e.g cellulose ~ribenzoate.
Partieularly suitable eluents proved to be ~ to ¢5-alcohols, i~ particula~ methanol and ethanol, or mixtures thereof, a~ w~ll as ~ixtures of ~ ~o Cs~
alcohols and C~ to Cl~-hydrocarbons, in partic~lar mixtures of hexane or h~ptane with 2-propanol The cou~tercurren~ chromatography proce~s, which is the basis of ~sim~lated movin~ bed~
chrom~tog~a~hy (SM~ chromatography), is sh.own schem~tically in Figure 1 I~ this f igure, ~l) deno~es the flow of the sorben~. In the SM~ process,'the ~low of the so~ben~, ~hich ~n be realized physically only with dif~ioulty, is simulated ~y cyclic s~itching o~
, 13 . ' 98 10: 21 MERCK PRTENT G~18H 49 6151 727191 ~ C ~9 r ~ 4 --multi-w~y valves, ~hich link several columns ~o~nec~ed to ~ive a circuit.
The e~peri~ental realization of ~he resolution was carried out in an SMB.unit which op~ates according to the four-zone model explai~ed below Accordlng to the invent~on, SMB units can al~o be u~ed which operate according to other models, e.g. ~he ~hree-zo~e model.
Sui~able process varian~s are known fro~ the li~era~re to the person.skilled in the art.
lOThe i~ve~io~ relates ~o processes for the resolution of enantiomers of dertvatized chroma~ esters of the formul I, in particulax o~ chroman-2.-carbo~ylic acid esters, i'n ~a~ticular in turn o~ et~yl ch~oman-2-carboxylates, :by means of chromatography on sorhe~ts which cont~in polysa~ch~rides, for example cellulose, substituted with aro~atic carbamates, in p~rti~u1ar cellulose tris~3,5-dimethylphenylcarbamA te), uslng eluents ~on~ainlng C, to C~-al~ohols. Sui~a~le eluents are C, to Cs-alcohols, in particular meth~nol and e~nol, or mixt~res thereof. Preferred eluents are mixtures o~ ~, to ~5-alcohols and ~5 to ClO-~ydxocax~ons, in partlcul~r ~ixtures of hexane or hepta~e with 2-propanol.
Derivatized chroman esters of the ~or~ula I, ~s well as the preferred meanings of the radi~als mentioned in formula I, are dis~losed in E~-A-O ~07 ~_007. Preferred compo~nds o~ ~he ~or~ula I are chroman-2-~rbo~ylic acid esters, in particular ethyl chroman-. 2-carboxylate. ~or the preferred derivatized ch~o~an .
esters, the r~dicals of for~ula I have the ~ollowing meanings: R, R, ~ and R~ are H; in Z nl, n2 and n3 are equal ~o 0; the ethyl ester ~A is e~ual to ethyl) is p~rt icularly preferred.
The Cl to C5-alcohols mentioned as elue~ts are, according to .the inventlon, methanol, ethanol, n-propanol, i-p~opanol, n-butanol, i-bu~anol, methanol or ethanol is preferred Mixtuxes of these alcohols can also be u~ed according to the in~ention. ~articularly prefe~red eluents are mix~ures aecordin~ to ~he invention of the already mentioned C1 to Cs-alcohols and linear, branched or cyclic Cs to ClO-hydrocarbons, where the mixtures can consist of more than one of the alcohols mentioned and more than one of these hydrocarbons. The following may be mentioned by way of example of the linear, branched or cyclic C5 to Cl0-hydrocarbons: n-pentane, isopentane, n-hexane, isohexane, cyclohexane, n-heptane, isoheptane, n-octane, isooctane. In the mixtures of alcohol and hydrocarbon, the amount of hydrocarbon is preferentially between 70 and 99% by volume, particularly preferentially between 85 and 95% by volume.
The resolution according to the invention can be carried out in the conventional batch process. The resolution is preferably carried out by means of the continuously operating SMB process, as is explained in greater detail in the following referring to Figure 1.
The prerequisite for resolution of enantiomers on a preparative scale is a resolution which is as good as possible (base line resolution, high selectivity factor a). Moreover, since in customary batchwise chromatography at a specific time in the resolution only the region of the separating column is used in which the material to be resolved is just on its path through the column, very efficient separating columns are needed (high number of theoretical plates). On the whole, in conventional column resolution, the time-volume capacity, in particular, is not very high;
processes of this type are accordingly cost-intensive.
When using continuous processes, for example SMB
chromatography, a considerably improved time-volume capacity is achieved. SMB chromatography is a continuous countercurrent process in which the mobile phase and the stationary phase are led in opposite directions (Chirality 5, 267 ff. (1993)). As a result, differently than in the batchwise procedure, the entire stationary phase is used at any time in a resolution, which markedly increases the selectivity of the CA 022~8032 1998-12-11 resolution system. Compared with batch chromatography, a considerably lower number of theoretical plates are thus needed in the SMB.
As a result of the countercurrent principle, the SMB is ideally suitable for the resolution of two-substance mixtures (e.g. the two enantiomers of a racemate).
The continuous procedure of the SMB process, as is shown schematically in Figure 1 by way of example, allows the establishment of a temporary stationary state in which eluent (3) and also a solution of the two-substance mixture to be resolved (feed; (4)) can be supplied continuously to the system and the two resolved components (raffinate (6) and extract (5)) can likewise be continuously removed from the system. The supply and removal of the substance streams mentioned is carried out with the aid of four pumps (not shown).
The main stream of the eluent (2) is recycled using a further pump (recycling pump; not shown). Since only a relatively small amount of fresh eluent therefore has to be supplied to the system (feed + eluent,n,~, =
raffinate + extract), the solvent consumption per product unit in the SMB is markedly lower than in the case of batch chromatography. In the SMB, the column bed of a stationary phase is subdivided into four zones (one adsorption and desorption zone each for the two components to be resolved), which are defined relative to the supply and outlet points:

Zone I - between eluent and extract line Zone II - between extract and feed line Zone III - between feed and raffinate line Zone IV - between raffinate and eluent line In the case of the resolution of two-substance mixtures, conditions, i.e. flow rates in zones I-IV, are now found in which the more weakly retained component moves with the mobile phase and the more strongly retained component moves with the stationary CA 022~8032 1998-12-11 phase. The resolved components can then be removed in pure form with the extract or raffinate stream respectively.
Industrially, it is only possible with great difficulty to realize an actual movement of a stationary phase (1). This movement of the stationary phase is therefore simulated. To do this, the entire column bed is subdivided into individual columns connected cyclically one after the other. The total number of the columns is a multiple of the number 4, since the system, as mentioned above, has four chromatographic zones. Between the individual columns are found four two-way valves each, which constitute a connection to the four supply and outlet lines. On account of these valves, it is thus possible for each point between the columns to take on each function (eluent, feed supply or raffinate or extract outlet respectively). At a given point in time, the position of the four supply and outlet lines defines the four chromatographic zones. If the position of the four lines after a defined time is now reconnected by one column unit in the direction of the eluent movement, this corresponds to a movement of the column bed in the opposite direction. By means of reconnection of the feed points at defined time intervals, each individual column thus passes successively through all four zones until the supply and outlet lines again assume their original positions and a cycle is thus completed.
After a number of cycles have been passed through, a stationary state is established which makes it possible, with a suitable choice of the flow rates in the system and a suitable interval for switching the valves, to withdraw the resolved products in pure form as extract and raffinate streams.
Without further details, it is also assumed from this that a person skilled in the art can utilize the above description to the widest possible extent.
The preferred embodiments are therefore only to be CA 022~8032 1998-12-11 interpreted as descriptive and in no way as limiting disclosure in any manner.
The complete disclosure of all applications, patents and publications mentioned above and below, as well as the corresponding Application DE 196 23 755.6, filed on 14.06.96, is incorporated by means of reference in this application.

Exam~les:
The following examples are intended to illustrate the inventioni they are not a restriction of the inventive idea. Various variants of the resolution of enantiomers according to the invention using ethyl chroman-2-carboxylate are described by way of example.
If mixtures are given as eluents, the details are given in ratios by volume (v:v).

ExamPle 1: Resolution of enantiomers of ethyl chroman-2-carboxylate on ~ TRI~r-rT'T-~19 OD
(methanol as eluent) Experimental conditions:

25 Column: CHIRALCEL~ OD (Daicel; column dimensions: 250 x 4 mm) Eluent: Methanol Flow rate: 0.8 ml/min Detection: W at 220 nm Results: The first enantiomer is eluted after 5.35 minutes, the second after 6.73 minutes ( a = 1.95).

35 Example 2: Resolution of enantiomers of ethyl chroman-2-carboxylate on r~TR~r-CT~'T-~ OD
(h~ne/2-propanol (90:10; ~:~) as eluent) CA 022~8032 1998-12-11 Experimental conditions as Example l; but hexane/2-propanol (90:10; v:v) as eluent.

Result: The first enantiomer is eluted after 8.19 minutes, the second after 43.63 minutes ( a = 9 . 26).

ExamPle 3: Resolution of enantiomers of ethyl chroman-2-carboxylate on r~TP~T.~T.~.T.~ OD
(further eluents) Experimental conditions as Example l; but a) ethanol and b) heptane/2-propanol (90:10; v:v) as eluents.

Results:

Eluent: Retention time Retention time a (lst enantiomer) (2nd enantiomer) (a) Ethanol 5.17 min 7.27 min 2.65 (b) Heptane/2- 9.27 min 44.32 min 7.53 propanol (90:10) Example 4: Resolution of enantiomers of ethyl chroman-2-carboxylate on c~TR~rpAK~ AD
(ethanol as eluent) Experimental conditions:

Column: CHIRALPAK~ AD (Daicel; column dimensions: 250 x 4 mm) Eluent: Ethanol Flow rate: 0.8 ml/min Detection: W at 220 nm 30 Result: The first enantiomer is eluted after 5.19 minutes, the second after 6.29 minutes ( a = 2.01).

CA 022~8032 1998-12-11 -- 10 --~xample 5: Resolution of enantiomers of ethyl chroman-2-carboxylate on r~TP~TPAK AD
(methanol as eluent) Experimental conditions as Example 4; but methanol as eluent.

Result: The first enantiomer is eluted after 5.27 minutes, the second after 7.08 minutes ( a = 2.55).

Example 6: Resolution of enantiomers of ethyl chroman-2-carboxylate on porous cellulose tribenzoate Experimental conditions:

Column: Porous cellulose tribenzoate in bead form (column dimensions: 3 columns each 125 x 4 mm) Eluent: Methanol Flow rate: 0.5 ml/min Detection: W at 220 nm Result: The first enantiomer is eluted after 17.50 minutes, the second after 23.10 minutes (a = 1.53).

Example 7: Resolution of the enantiomers of ethyl chroman-2-carboxylate on C~TT~T-CT~'T~ OD
(preparative column resolution in the batch process) Stationary phase: Chiralcel~ OD (particle size: 20 ~m) Column dimensions: 250 x 50 mm Flow rate: 45 ml/min Eluent: Heptane/2-propanol (90:10; v:v) CA 022~8032 1998-12-11 At an application rate of 1 ml of chroman-2-carboxylic acid ester (racemic pure substance), a base line resolution still results; i.e. the purity of the resolved enantiomers is > 99.5%.

Exam~le 8: Resolution of enantiomers of ethyl chroman-2-carboxylate on ~TR~T-CEL~ OD
(preparative resolution in the continuous SMB process) SMB system: LICOSEP~ 12-26 (Separex), equipped with 8 Superformance~ columns (Merck; 26 mm internal diameter) Stationary 15 phase: CHIRALCEL OD (particle size: 20 ~m length of the column bed: 100 mm) Eluent: Heptane/2-propanol (90:10) Temperature: 25~C
Feed concentration: 10 g/l Feed flow rate: 5 ml/min Recycling flow rate: 50 ml/min Using these parameters, a throughput of 200 g of racemate per 24 h is achieved. The purities of raffinate and extract are 99%.

ComDarison Exam~le A: Resolution of enantiomers of ethyl chroman-2-carboxylate on cellulose triacetate Experimental conditions:
Column: Cellulose triacetate (Merck; column dimensions: 250 x 10 mm) Eluent: Methanol Flow rate: 1.8 ml/min CA 022~8032 1998-12-11 , .. .. .

Detection: W at 220 nm Result: The two enantiomers elute unresolved after 15.6 minutes (a = O . oo ) .

Com~ison ~Y~E~le B: Resolution of enantiomers of ethyl chroman-2-carboxylate on cellulose-tris(3,5-dimethyl-benzoate) (methanol as eluent) Experimental conditions:

Column: Cellulose tris(3,5-dimethylbenzoate), adsorbed on silica gel (CHIRALCEL~ OJ:
Daicel; column dimensions: 250 x 4 mm) Eluent: Methanol Flow rate: 0.8 ml/min Detection: W at 220 nm 20 Result: Both enantiomers elute unresolved after 11.50 minutes (a = O . 00 ) .

Çç~A~ison Exam~le C: Resolution of enantiomers of ethyl chroman-2-carboxylate on cellulose tris(3,5-dimethyl-benzoate) (ethanol as eluent) Experimental conditions as Comparison Example B; but ethanol as eluent.
Result: The enantiomers elute after 10.8 or 11.1 minutes respectively (a = 1. 04), however the elution peaks overlap almost completely.

CA 022~8032 1998-12-11

Claims (9)

Claims
1. Process for the chromatographic resolution of enantiomeric esters of 2-alkanoylchroman derivatives of the formula I, in which z is -(CH2)n1 -(CHA)n2 -(CH2)n3, where n1 = 0, 1, 2 or 3;
n2 = 0 or 1;
n3 = 0, 1, 2 or 3 with the proviso that n1 + n2 + n3 < 4, R6,R7,R8 and R9 independently of one another are H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl having 3-7 C atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2NHAc or -CH2NHSO2CH3, where two adjacent radicals can also be an alkylene chain having 3 or 4 C atoms, A is alkyl having 1-6 C atoms, Ac is alkanoyl having 1-10 C atoms or aroyl having 7-11 C atoms, Ph is phenyl which is unsubstituted or substituted by R5, 2-, 3- or 4-pyridyl or phenoxy, R5 is phenyl which is unsubstituted or substituted by 1-5 F, or by CF3, or by completely or partially fluorine-substituted A, A and/or OA, characterized in that the resolution is carried out on a sorbent which contains polysaccharides substituted by aromatic carbamates, and in that an eluent containing C1 to C5-alcohols is used.
2. Process according to Claim 1, characterized in that the substituted polysaccharide contained in the sorbent is a cellulose derivative.
3. Process according to Claim 1 or 2, characterized in that enantiomers are resolved in which the radicals mentioned in formula I have the following meaning: R6, R7, R8 and R9 are H; in Z n1, n2 and n3 are equal to 0.
4. Process according to Claim 3, characterized in that enantiomers are resolved in which the radical A in formula I is ethyl.
5. Process according to one of Claims 1 - 4, characterized in that the sorbent contains cellulose tris(3,5-dimethylphenylcarbamate).
6. Process according to one of Claims 1 - 5, characterized in that the eluent used is a C1 to C5-alcohol.
7. Process according to one of Claims 1 - 5, characterized in that the eluent used is a mixture comprising a C1 to C5-alcohol and a C5 to C10-hydrocarbon.
8. Process according to one of Claims 1 - 7, characterized in that the process is carried out in the batch process.
9. Process according to one of Claims 1 - 7, characterized in that the process is carried out continuously according to the SMB process.
CA002258032A 1996-06-14 1997-05-07 Enantiomer separation from chromane acid esters Abandoned CA2258032A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19623755 1996-06-14
DE19623755.6 1996-06-14

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EP (1) EP0906302B1 (en)
JP (1) JP2000512283A (en)
KR (1) KR20000016726A (en)
CN (1) CN1221413A (en)
AT (1) ATE203988T1 (en)
AU (1) AU2892497A (en)
BR (1) BR9709716A (en)
CA (1) CA2258032A1 (en)
DE (1) DE59704253D1 (en)
DK (1) DK0906302T3 (en)
ES (1) ES2162290T3 (en)
GR (1) GR3037032T3 (en)
NO (1) NO985810D0 (en)
PL (1) PL330422A1 (en)
PT (1) PT906302E (en)
SK (1) SK168298A3 (en)
WO (1) WO1997047617A1 (en)

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CN101328161B (en) * 2007-06-20 2011-09-14 北京德众万全药物技术开发有限公司 Method for separating and detecting nebivolol hydrochloride impurity by liquid phase chromatography
CN105218502B (en) * 2015-10-26 2017-12-15 浙江工业大学 A kind of method of asymmetric synthesis of chiral benzodihydropyran compound

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GR3037032T3 (en) 2002-01-31
BR9709716A (en) 1999-08-10
EP0906302B1 (en) 2001-08-08
KR20000016726A (en) 2000-03-25
NO985810D0 (en) 1998-12-11
PT906302E (en) 2002-01-30
JP2000512283A (en) 2000-09-19
CN1221413A (en) 1999-06-30
SK168298A3 (en) 1999-05-07
DE59704253D1 (en) 2001-09-13
ES2162290T3 (en) 2001-12-16
ATE203988T1 (en) 2001-08-15
WO1997047617A1 (en) 1997-12-18
AU2892497A (en) 1998-01-07
EP0906302A1 (en) 1999-04-07

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