WO2002068391A1 - Process for resolving racemic mixtures of piperidine derivatives - Google Patents
Process for resolving racemic mixtures of piperidine derivatives Download PDFInfo
- Publication number
- WO2002068391A1 WO2002068391A1 PCT/US2001/042934 US0142934W WO02068391A1 WO 2002068391 A1 WO2002068391 A1 WO 2002068391A1 US 0142934 W US0142934 W US 0142934W WO 02068391 A1 WO02068391 A1 WO 02068391A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- enantiomer
- mixture
- benzoyl
- acid
- salt
- Prior art date
Links
- NQRYJNQNLNOLGT-UHFFFAOYSA-N C1CCNCC1 Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or 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 to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the present invention relates to a process for resolving racemic mixtures.
- the invention is a process to separate the enantiomers in a racemic mixture so that the resolved stereoisomers can be used in preparing chiral compbunds.
- Chiral compounds such as ethyl nipecotate, are often useful as precursors in the synthesis of intermediates and useful compounds in the pharmaceutical industry.
- the racemic mixture is often utilized with favorable results in the formation of intermediates and compounds, in some instances it is desirable to utilize only the more active (R) or (S) enantiomer in order to synthesize substantially pure optically active pharmaceutical compounds.
- known resolution schemes for these compounds are often time consuming and require multiple operations.
- the present invention provides a process for resolving a racemic mixture of compounds of Structural Formula I
- R1 is C ⁇
- the present invention further, provides a process for resolving racemic ethyl nipecotate.
- a racemic mixture comprising the (R) and (S) enantiomers of ethyl nipecotate is reacted in a solvent with a resolving agent selected from the group consisting of di-benzoyl-L-tartaric acid and (S)-mandelic acid.
- the reaction is carried out at a temperature sufficient to form soluble diastereomeric salts comprising the (R) enantiomer and the resolving agent, and the (S) enantiomer and the resolving agent, respectively.
- the reaction mixture is cooled to a temperature such that the diastereomeric salt comprising the (S) enantiomer precipitates from the mixture, wherein the diastereomeric salt comprising the (R) enantiomer remains in solution.
- the precipitated salt comprising the (S) enantiomer is then isolated from the mixture.
- N refers to normal or normality
- mmol refers to millimole or millimoles
- g refers to gram or grams
- d refers to density
- min refers to minutes
- L refers to liters
- mL refers to milliliter or milliliters
- M refers to mole or moles
- 1 H-NMR refers to proton Nuclear Magnetic resonance
- 13 C-NMR refers to carbon-13 Nuclear Magnetic Resonance
- TLC refers to thin layer chromatography
- HPLC refers to high performance liquid chromatography
- GC refers to gas chromatography.
- enantiomer is used to describe one of a pair of isomers that are mirror-images of each other and are non-superimposable.
- diastereomer is used to describe a salt of an enantiomer.
- racemic mixture is used to describe mixtures of a compound comprising (R) and (S) enantiomers.
- enantiomeric excess is used to describe the relative amount of an enantiomer in a racemic mixture.
- diastereomeric excess is used to describe the relative amount of a particular salt of an enantiomer (diastereomer) in a mixture of diastereomers.
- the diastereomeric excess of a particular diasteromer may be determined by calculating the amount of an individual diastereomer as a percentage of the diasteromeric mixture by the equation noted for enantomeric excess.
- de is used to describe diastereomeric excess.
- substantially pure is used to describe enantiomeric or diastereomeric purity of a single enantiomer or diastereomer which is greater than or equal to 90%, preferably greater than 95%.
- lower alkyl is used to describe a C1-C4 straight or branched chain alkyl group.
- Examples of lower alkyl include methyl, ethyl, isopropyl, n- propyl, n-butyl, iso-butyl and tert-butyl.
- the present invention describes a process for resolving a racemic mixture.
- the invention further describes novel diastereomer compounds.
- the invention also describes a process for preparing certain chiral compounds.
- Suitable solvents for use in the resolution reaction include solvents in which the racemic compound and the resolving agent are substantially soluble at the reaction temperature.
- Non-limiting examples of suitable solvents are conventional organic solvents such ethyl acetate, isopropyl acetate, butyl acetate, acetone, acetonitrile, methyl tert-butyl ether (MTBE), tetrahydrofuran, 1 ,4- dioxane, diethyl ether and C 1 to C alcohols, toluene, as well as water and mixtures of the foregoing.
- a particularly preferred solvent for resolving racemic ethyl nipecotate is ethanol.
- the ethanol can be absolute (99.5% or higher ethanol), or 95% denatured with toluene methanol isopropanol or mixtures of said denaturing agents.
- Use of an ethanol-based solvent hinders a transesterification reaction that might otherwise occur with the ethyl functional group of the ethyl nipecotate ester.
- an anti-solvent refers to a solvent in which the salt is significantly less soluble when compared to the solvent.
- an anti-solvent when used it is miscible with the selected solvent.
- Suitable anti-solvents include alkanes, such as pentane, hexane, heptane, cyclohexane, and the like.
- Suitable resolving agents for use in the resolution reaction include agents capable of forming diastereomeric salts with each of the (R) and (S) enantiomers of the racemic mixture.
- Preferred resolving agents for use in resolving racemic ethyl nipecotate are di-benzoyl-L-tartaric acid, di-benzoyl-D- tartaric acid, (S)-mandelic acid and (R)-mandelic acid, respectively.
- Particularly preferred are di-benzoyl-L-tartaric acid and (S)-mandelic acid, and most preferred is di-benzoyl-L-tartaric acid.
- the stoichiometry of the resolving agent in relation to the lower alkyl nipecotate ranges from about 0.1 to 1 equivalent, preferably from about 0.25 to 1 equivalent.
- the inventive process may be carried out at temperatures ranging from about -20 °C to reflux.
- the reaction temperature for forming the diastereomeric salts should be high enough to enable the racemic mixture and the resolving agent to be substantially dissolved in the solvent, and to allow the reaction to proceed to equilibrium in a reasonable amount of time.
- the reaction is carried out at an elevated temperature from of about 40 °C to about reflux.
- the reaction mixture is allowed to slowly cool to a temperature of from about ambient (room) temperature to about -20 °C. As the solution cools, one of the diastereomeric salts precipitates from the mixture, while the other diastereomeric salt remains in solution.
- the precipitate comprising a diastereomeric salt including one of the enantiomers, is then removed by conventional means, such as filtration, centrifugation, decanting, evaporation, drying and the like.
- reaction may be carried out at room temperature.
- one of the diastereomeric salts forms a slurry in the solution, rather than a precipitate as before, while the remaining salt remains in solution.
- the slurry may be separated from the solution by conventional means.
- Nipecotate esters and amides such as ethyl nipecotate, are precursors in the formation of intermediates for useful pharmaceutical compounds.
- Racemic nipecotate esters and amides are represented by Structural Formula I:
- R1 is methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl or tert- butyl; or -N(R2)2 where R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
- the nipecotate ester is ethyl nipecotate represented by Structural Formula II
- the resolving agent di-benzoyl-L-tartaric acid is reacted with ethyl nipecotate in a 91% aqueous 2B-ethanol solvent.
- the mixture is slowly heated until the ingredients are completely dissolved.
- the reaction is carried to completion, resulting in a mixture comprising diastereomeric di-benzoyl-L-tartrate salts.
- the reaction mixture is then allowed to slowly cool, preferably with seeding. As the mixture cools, the (S)-enantiomer-enriched tartrate salt precipitates from the reaction solution, while the (R)-enantiomer- enriched salt remains in solution.
- the diastereomeric (S) ethyl nipecotate salt of Scheme 1 may be recovered in high quality and at a high yield after a single crystallization or slurry operation.
- the (S) precipitate is shown by 1 H NMR to be a 2:1 nipecotate:tartrate complex as shown. Subsequent conversion of this tartrate precipitate to the corresponding free base and free acid, followed by Mosher amide formation and analysis, indicates the enantiomeric excess of the free amine to be > 98%.
- the yield of the desired enantiomer may be further increased by recycling the mother liquor remaining after the removal of the precipitate or slurry.
- the mother liquor consists substantially of the dissolved (R)-enriched diastereomeric salt in the solvent.
- the (R)-enriched mother liquor is concentrated in vacuo, and the diastereomeric salt is converted to the (R)-enantiomer free base by conventional means, such as by reacting the salt with aqueous sodium carbonate.
- the enantiomer is separated from the concentrate by one or more extractions with a suitable aqueous organic solvent, such as methyl tert-butyl ether, and then concentrated.
- the concentrate is epimerized into the respective (R) and (S) enantiomers by dissolving it in a suitable solvent, such as 91% aqueous 2B-ethanol, and treating it with a suitable epimerization agent, such as catalytic sodium ethoxide.
- a suitable solvent such as 91% aqueous 2B-ethanol
- a suitable epimerization agent such as catalytic sodium ethoxide.
- the racemic mixture is neutralized with an acid, such as concentrated hydrochloric acid, and filtered.
- the racemic mixture is thereafter resolved with an appropriate resolving agent as before, and the resulting precipitate is added to the precipitate from the initial resolution.
- Sodium ethoxide is the preferred epimerization agent, although other known epimerization agents, such as sodium hydride, sodium methoxide, sodium or potassium tert-butoxide, potassium ethoxide and methoxide, various lithium salts and sodium amide, may also be utilized, provided that the epimerization agent does not promote competing reactions.
- strong mineral acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid are used in the neutralization reaction, although the reaction may be carried out utilizing weaker acids.
- neutralization with weak acids may lead to inferior quality and/or tacky products in low yield. In the case of some weak acids, low yields may be caused by interferences from salts of such weak acids.
- the recycling step may be repeated as many times as desired, owever, as will be appreciated by those skilled in the art, the benefits to be obtained by the recycling operation diminish with each successive repetition.
- the resolution of racemic ethyl nipecotate by the process described above represents a straightforward, efficient and reproducible method for generating substantially pure resolved diastereomeric salts with high yield (35% or more, based upon 100% theory).
- the preferred embodiment of the resolution described above utilizes di-benzoyl-L-tartaric acid as the resolving agent, other resolving agents, such as (S)-mandelic acid, may also be utilized.
- the degree of initial resolution obtained utilizing (S)-mandelic acid as the resolving agent is not as favorable as that obtained utilizing di-benzoyl-L-tartaric acid. Accordingly, when (S)-mandelic acid is utilized, it is preferred to utilize an extra crystallization step to obtain a substantially pure diastereomeric salt at high yield. Further details of this process are provided in Example 5.
- optically active acids were tried as potential resolving agents. These acids include di-p-tolyl-L-tartaric acid, di-p-tolyl-D-tartaric acid, (R)- camphorsulfonic acid and (S)-camphorsulfonic acid. These acids either failed to form a crystalline salt, or in those cases in which a crystalline salt did form, recrystallization failed to provide an efficient optical purification. Thus, di- benzoyl-L-and D-tartaric acid and (S)- and (R)-mandelic acid are believed to be unique as readily available, efficient resolving agents for the compounds of Formula I.
- a feature of the present invention is that the resolved diastereomeric tartrate or mandelate salts may be neutralized to afford the corresponding free base in situ, and thereafter directly reacted with other compounds to synthesize useful chiral compounds. There is no need to generate a free base (S)- enantiomer in a separate reaction step prior to formation of the chiral compound.
- the coupling reaction utilizes the acid chloride, 2-thiopheneacetyl chloride, under Schotten-Bauman conditions.
- the base used to neutralize the salts in situ also serves as the base for the Schotten-Bauman reaction.
- the amide linkage fashioned by these procedures provides excellent yields of high quality product. Further details of an exemplary process . for preparing the 3-piperidinecarboxylate product of Scheme III are provided in Example 3.
- the resolution processes described above utilize either di- benzoyl-L-tartaric acid or (S)-mandelic acid as the resolving agent, thereby resulting in the formation of the respective (S)-enriched diastereomeric tartrate and mandelate salts
- the reaction may alternatively be carried out utilizing either di-benzoyl-D-tartaric acid or (R)-mandelic acid as the resolving agent.
- the opposite diastereomeric salt is precipitated, namely the (R)-enriched tartrate or mandelate diastereomer.
- the process described above is particularly useful for resolving a racemic mixture of ethyl nipecotate.
- related nipecotate esters such as methyl, isopropyl, n-propyl, n-butyl, iso-butyl and tert-butyl nipecotate may also be resolved.
- a reaction scheme for forming the (S)-enriched diastereomeric tartrate salt of racemic N,N-dimethyl-3-carboxamide when di-benzoyl-L-tartaric acid is utilized as the resolving agent is illustrated below:
- Example 6 describes details of the preparation of the (S)-N,N-dimethyl-3-piperidinecarboxamide-L-(dibenzoyl) tartrate salt shown above. This compound may be used as an intermediate in the preparation of the compound (S) N,N-dimethyl 1-benzyl-3-piperidinecarboxylate 1-methiodide, which is useful as an immunopotentiating agent.
- Examples 7-9 Details of the preparation of (S) N,N-dimethyl 1-benzyl-3-piperidinecarboxamide 1-methiodide) from the tartrate salt are provided in Examples 7-9.
- Appropriate starting materials and reagents can be used to prepare the desired intermediates and compounds using the techniques described herein.
- the reagents are either commercially available, or may be prepared utilizing accepted chemical methods.
- the reaction time, reaction temperature and conditions described in the Examples below relate to the starting materials utilized in those Examples.
- the optimum time, temperature and conditions for any particular process are, as known in the chemical arts, frequently a compromise that is determined by considering the competing goals of throughput, which is generally favored by one set of reaction conditions, and maximum yield, which is generally favored by another set of conditions.
- the mixture was then heated to dissolution, with complete dissolution observed at 76 °C. The heat was turned off and the solution was allowed to gradually cool unaided. The solution was seeded at 71 °C, and allowed to cool (precipitate observed at 63 °C) unaided to room temperature. The reaction mixture was allowed to stir a total of 18 hours after seeding. The white precipitate was collected and washed with 91% aqueous 2B- ethanol (2 x 200 mL) followed by vacuum drying at 45-50 °C for 6 hours to provide 346 g (32%) of the di-benzoyl-al-tartrate salt as a white solid: m.p.
- the free base was dissolved in 220 ⁇ L of CH 2 CI 2 and treated sequentially with (R)-(+)- ⁇ -methoxy ⁇ - (trifluoromethyl)phenylacetic acid ((R)-Mosher acid, 66 mg, 2 equivalents), 4- dimethylamino pyridine (2 mg, 0.1 equivalents), and 1 ,3-dicyclohexylcarbodiimide (58 mg, 2 equivalents) as a solution in 60 ⁇ L of CH 2 CI 2 . After stirring for 30 minutes, the cloudy white reaction product was analyzed by GC and HPLC.
- Absolute configuration of resolved ethyl nipecotate was determined through Mosher amide formation and comparison of retention times (GC and HPLC) with Mosher amides derived from commercially-obtained samples of (S)-ethyi nipecotate obtained from Chemie S.p.A., and samples of (R)-ethyl nipecotate prepared according to the procedure described in Zheng, X.; Day, C; Gollamudi, R., Chirality, 1995, 7, 90.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/415,758 US20040039206A1 (en) | 2001-11-13 | 2001-11-13 | Process for resolving racemic mixtures of piperidine derivatives |
AU2001297647A AU2001297647A1 (en) | 2000-11-20 | 2001-11-13 | Process for resolving racemic mixtures of piperidine derivatives |
EP01273837A EP1341762A1 (en) | 2000-11-20 | 2001-11-13 | Process for resolving racemic mixtures of piperidine derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24997100P | 2000-11-20 | 2000-11-20 | |
US60/249,971 | 2000-11-20 |
Publications (2)
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WO2002068391A1 true WO2002068391A1 (en) | 2002-09-06 |
WO2002068391A8 WO2002068391A8 (en) | 2003-12-11 |
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PCT/US2001/042934 WO2002068391A1 (en) | 2000-11-20 | 2001-11-13 | Process for resolving racemic mixtures of piperidine derivatives |
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EP (1) | EP1341762A1 (en) |
AU (1) | AU2001297647A1 (en) |
WO (1) | WO2002068391A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6664271B1 (en) * | 1999-05-21 | 2003-12-16 | Eli Lilly And Company | Immunopotentiator agents |
WO2005054168A3 (en) * | 2003-11-28 | 2005-10-27 | Astrazeneca Ab | A process for resolving, optionally substituted, mandelic acids by salt formation with a chiral base cyclic amide |
WO2014128139A1 (en) | 2013-02-20 | 2014-08-28 | Reuter Chemische Apparatebau Kg | Process for the preparation of enantiomerically enriched 3-aminopiperidine |
WO2014173855A1 (en) | 2013-04-22 | 2014-10-30 | Reuter Chemische Apparatebau Kg | Process for preparing enantiomerically enriched 3-hydroxymethylpiperidine |
CN109761886A (en) * | 2019-02-21 | 2019-05-17 | 北京悦康科创医药科技股份有限公司 | A kind of method for splitting of argatroban starting material isomer impurities |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000071519A2 (en) * | 1999-05-21 | 2000-11-30 | Eli Lilly And Company | Immunopotentiator agents |
-
2001
- 2001-11-13 WO PCT/US2001/042934 patent/WO2002068391A1/en not_active Application Discontinuation
- 2001-11-13 EP EP01273837A patent/EP1341762A1/en not_active Withdrawn
- 2001-11-13 AU AU2001297647A patent/AU2001297647A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000071519A2 (en) * | 1999-05-21 | 2000-11-30 | Eli Lilly And Company | Immunopotentiator agents |
Non-Patent Citations (2)
Title |
---|
ELIEL, ERNEST L.; WILEN, SAMUEL H.: "Stereochemistry of organic compounds", 1994, JOHN WILEY & SONS,INC., USA, XP002204678 * |
ZHENG X ET AL: "Synthesis of Stereoisomers of Antithrombotic Nipecotamides", CHIRALITY, WILEY-LISS, NEW YORK, US, no. 7, 1995, pages 90 - 95, XP000926538, ISSN: 0899-0042 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6664271B1 (en) * | 1999-05-21 | 2003-12-16 | Eli Lilly And Company | Immunopotentiator agents |
JP4906511B2 (en) * | 2003-11-28 | 2012-03-28 | アストラゼネカ アクチボラグ | Method for resolution of optionally substituted mandelic acid by salt formation with a chiral base cyclic amide |
JP2007513885A (en) * | 2003-11-28 | 2007-05-31 | アストラゼネカ アクチボラグ | Method for resolution of optionally substituted mandelic acid by salt formation with a chiral base cyclic amide |
CN100448834C (en) * | 2003-11-28 | 2009-01-07 | 阿斯利康(瑞典)有限公司 | A process for resolving, optionally substituted, mandelic acids by salt formation with a chiral base cyclic amide |
AU2004295152B2 (en) * | 2003-11-28 | 2009-07-02 | Astrazeneca Ab | A process for resolving, optionally substituted, mandelic acids by salt formation with a chiral base cyclic amide |
US7960582B2 (en) | 2003-11-28 | 2011-06-14 | Astrazeneca Ab | Process for the preparation and resolution of mandelic acid derivatives |
WO2005054168A3 (en) * | 2003-11-28 | 2005-10-27 | Astrazeneca Ab | A process for resolving, optionally substituted, mandelic acids by salt formation with a chiral base cyclic amide |
WO2014128139A1 (en) | 2013-02-20 | 2014-08-28 | Reuter Chemische Apparatebau Kg | Process for the preparation of enantiomerically enriched 3-aminopiperidine |
EP3653607A2 (en) | 2013-02-20 | 2020-05-20 | Reuter Chemische Apparatenbau e.K. | Process for the preparation of enantiomerically enriched 3-aminopiperidine |
EP4289819A2 (en) | 2013-02-20 | 2023-12-13 | Reuter Chemische Apparatebau e.K. | Process for the preparation of enantiomerically enriched 3-aminopiperidine |
WO2014173855A1 (en) | 2013-04-22 | 2014-10-30 | Reuter Chemische Apparatebau Kg | Process for preparing enantiomerically enriched 3-hydroxymethylpiperidine |
CN109761886A (en) * | 2019-02-21 | 2019-05-17 | 北京悦康科创医药科技股份有限公司 | A kind of method for splitting of argatroban starting material isomer impurities |
CN109761886B (en) * | 2019-02-21 | 2020-09-11 | 北京悦康科创医药科技股份有限公司 | Resolution method of argatroban starting material isomer impurities |
Also Published As
Publication number | Publication date |
---|---|
AU2001297647A1 (en) | 2002-09-12 |
WO2002068391A8 (en) | 2003-12-11 |
EP1341762A1 (en) | 2003-09-10 |
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