EP1745137A1 - Preparation enzymatique d'un aminoacide beta-2 enrichi de maniere enantiomere - Google Patents

Preparation enzymatique d'un aminoacide beta-2 enrichi de maniere enantiomere

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Publication number
EP1745137A1
EP1745137A1 EP05715607A EP05715607A EP1745137A1 EP 1745137 A1 EP1745137 A1 EP 1745137A1 EP 05715607 A EP05715607 A EP 05715607A EP 05715607 A EP05715607 A EP 05715607A EP 1745137 A1 EP1745137 A1 EP 1745137A1
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EP
European Patent Office
Prior art keywords
formula
amino acid
defined above
optionally substituted
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05715607A
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German (de)
English (en)
Inventor
Bernardus Kaptein
Quirinus Bernardus Broxterman
Joannes Gerardus Theodorus Kierkels
Thierry Milcent
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DSM IP Assets BV
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DSM IP Assets BV
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Priority to EP05715607A priority Critical patent/EP1745137A1/fr
Publication of EP1745137A1 publication Critical patent/EP1745137A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C12P13/08—Lysine; Diaminopimelic acid; Threonine; Valine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C12P13/22—Tryptophan; Tyrosine; Phenylalanine; 3,4-Dihydroxyphenylalanine
    • C12P13/222—Phenylalanine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture

Definitions

  • the invention relates to an enzymatic process for the preparation of an enantiomerically enriched ⁇ 2 -amino acid (ester).
  • An enzymatic process for the preparation of an enantiomerically enriched ⁇ 2 -amino acid (ester) is unknown.
  • Rossi D. et al. (1977) vol. 33, no. 12, pp 1557-1559, P 009030088 Basel ISSN 0014-4754 it is disclosed that N-phenylacetyl derivates of amino acids can be hydrolysed to produce optically active ⁇ -amino acids.
  • EP-A-1 367 129 discloses a process for the preparation of enantiomerically enriched N-unprotected ⁇ -amino acids by enzymatic hydrolysis of a mixture of enantiomers of N-unprotected ⁇ -amino acid esters using a hydrolase, wherein the hydrolysis occurs in a two-phase system of water and an organic solvent that, under the given reaction conditions, forms a two-phase system with water.
  • 61, 6893-6900 discloses a slightly related enzymatic process to a different compound in which an enantiomerically enriched 3-amino-2-methyl-propionic acid is prepared by reacting racemic N-protected 3-amino-2-methyl-propionic acid methyl ester with immobilized
  • Candida Antarctica lipase relates to N-protected ⁇ 2 -amino acids and N-protected ⁇ 2 -amino acid esters. Furthermore, a disadvantage of this process is that it is necessary to use a multistep kinetic resolution in order to get an acceptable enantiomeric excess of 3-amino-2-methyl-propionic acid. It is the object of the invention to provide a simple enzymatic process for the preparation of an enantiomerically enriched ⁇ 2 -amino acid (ester), i.e. a process without the need of multistep kinetic resolutions and/or N-protection of the ⁇ 2 -amino acid (ester). This object is achieved according to the invention by reacting a stereoselective hydrolytic enzyme with a mixture of enantiomers of a ⁇ 2 -amino acid ester represented by formula 2
  • R 1 stands for an optionally substituted alkyl and wherein R 2 , R 3 and R 4 each independently stand for H, an optionally substituted (hetero)aryl, an optionally substituted alkyl, OR 5 , CO 2 R 6 , C(O)R 7 , SR 8 , NR 9 R 10 , OC(O)R 11 wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently stand for H, an optionally substituted alkyl or for an optionally substituted (hetero)aryl and wherein R 2 and R 3 , R 2 and R 4 or R 3 and R 4 may form a ring together with the carbon atom to which they are attached and by either collecting the resulting enantiomerically enriched ⁇ 2 -amino acid of formula 1
  • esters which process leads to ⁇ 2 -amino acid (ester)s with an acceptable enantiomeric excess. Furthermore, the process of the invention is well scalable and can be applied at an industrial scale. With ⁇ -amino acid (ester) is meant a ⁇ -amino acid(ester) substituted on the 2-position ( ⁇ -position). For a definition of ⁇ 2 -amino acid(ester) see also Sewald,
  • the ⁇ 2 -amino acid (ester) of formula 2 has a chiral center on at least the ⁇ -position; the ⁇ 2 -amino acid (ester) of formula 2 may however also have other chiral centers, for example the carbon atom to which R 2 , R 3 and R 4 are attached may be chiral; this carbon atom is chiral when R 2 , R 3 and R 4 are not the same.
  • 'mixture of enantiomers' is meant a random mixture of (R) and (S)-enantiomers.
  • R 1 stands for an optionally substituted alkyl of 1-20 C- atoms, more preferably of 1-12 C-atoms (C-atoms of the substituents included).
  • R 1 may stand for a C C alkyl, e.g. methyl, ethyl, n-butyl; substituted methyl, e.g.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently stand for H, an optionally substituted alkyl of 1-12 C-atoms, more preferably of 1-8 C-atoms (C-atoms of the substituents included) or for a (hetero)aryl of 5 2-10 C-atoms (C-atoms of the substituents included).
  • the heteroatom(s) is/are chosen from the group of N, O and S.
  • R 2 and R 3 , R 2 and R 4 or R 3 and R 4 may form a ring of preferably 3-6 C-atoms.
  • the ring they form may for example be a (hetero)cycloalkyl or a (hetero)aryl, each of which rings may optionally be substituted.
  • substituents include alkyl, (hetero)aryl, sulfonyl, alkoxycarbonyl, amidocarbonyl, nitrile, hydroxy, alkoxy, aryloxy, thioalkyl, mercapto, amino and fluorine.
  • enantiomerically enriched' having an enantiomeric excess (e.e.) of either the (R)- or (S) - 15 enantiomer of a compound'.
  • the enantiomeric excess is > 80%, more preferably > 85%, even more preferably > 90%, in particular >95%, more in particular > 97%, even more in particular > 98%, most in particular > 99%.
  • Collecting includes for example isolation by means of conventional methods, for example ultrafiltration, concentration, column chromatography, extraction 0 or crystallization and further reaction of the obtained product (enantiomerically enriched ⁇ 2 -amino acid or enantiomerically enriched ⁇ 2 -amino acid ester).
  • Hydrolytic enzymes are also known as hydrolases. Hydrolases are enzymes that catalyze a hydrolysis reaction. Thus, hydrolases act to break down a compound (i.e. the substrate) by cleaving a covalent bond in the compound and 5 inserting a water molecule across the bond.
  • hydrolases include those enzymes that act on ester bonds, on carbon-nitrogen bonds, on peptide bonds, and on acid anhydrides, amongst others.
  • 'hydrolytic enzyme' is meant an enzyme with the ability to hydrolyze a carboxylic ester group to form the corresponding carboxylic acid group.
  • 'stereoselectivity' of the hydrolytic enzyme is meant that the hydrolytic enzyme preferably catalyzes the hydrolysis of one of the enantiomers of the ⁇ 2 -amino acid ester.
  • the stereoselectivity of an enzyme may be expressed in terms of E-ratio, the ratio of the specificity constants V max /K m of the two enantiomers as described in C-S.
  • the hydrolytic enzyme has an E-ratio > 5, more preferably an E-ratio > 10, even more preferably an E-ratio > 50, most preferably an E-ratio > 100.
  • a stereoselective hydrolytic enzyme suitable for use in the present invention may for example be found in one of the general classes of hydrolytic enzymes, for instance in the group of esterases, lipases, proteases, peptidases or acylases, preferably in the group of esterases or lipases.
  • the hydrolytic enzyme may be derived from both eukaryotic and prokaryotic cells, including but not limited to those from the following mammalian sources: porcine liver, porcine pancreas, for example commercially available porcine pancreatic lipase type II (L-3126, Sigma); porcine kidney and bovine pancreas; those from the plant source wheat germ; those from the following mold genera: Absidia; Aspergillus; Fusarium; Gibberella; Mucor, Neurospora; Trichoderma; Rhizopus; Rhizomucor, for example Rhizomucor miehei; Thermomyces, for example Thermomyces lanugenousus; those from the following bacterial genera: Achromobacter, Alcaligenes; Bacillus; for example Bacillus licheniformis; Brevibacterium; Corynebacterium; Providencia; Pseudomonas, for example Pseudomonas fluorescens, Pseudomonas cepas
  • the stereoselective hydrolytic enzyme is found in the group of enzymes classified as carboxylic ester hydrolases (EC 3.1.1) or in the group of enzymes classified as peptidases, for example EC 3.4.1, EC 3.4.11, EC 3.4.21, more preferably EC 3.4.21.62, EC 3.4.22 or EC 3.4.23.
  • a stereoselective hydrolytic enzyme may also be found in the group of commercially available hydrolytic enzymes.
  • hydrolytic enzymes examples include enzymes supplied by Fluka: Candida cylindracea lipase, lipase Hog pancreas, lipase Pseudomonas fluorescens, lipase Aspergillus oryzae, lipase Rhizopus niveus, lipase Rhizomucor miehei, lipase Candida antarctica, lipase Mucor javanicus, lipase Rhizopus arrhizus, lipase Penicillium roqueforti, lipase Candida lipolytica, lipoprotein lipase Pseudomonas sp., type B, lipoprotein lipase Pseudomonas cepacia, lipoprotein lipase Chromobacterium viscosum, esterase Bacillus stearothermophilus, esterase Bacillus thermoglucosidasius, esterase Mucor miehei,
  • stereoselective hydrolytic enzymes are: subtilisin, alcalase 2.5L, Bacillus licheniformis protease, Candida Antarctica lipase A, porcine pancreatic lipase type II.
  • the stereoselective hydrolytic enzyme may be used in any form.
  • the hydrolytic enzyme may be used - for example in the form of a dispersion, a solution or in immobilized form - as crude enzyme, as a commercially available enzyme, as an enzyme further purified from a commercially available preparation, as an enzyme obtained from its source by a combination of known purification methods, in whole (optionally permeabilized and/or immobilized) cells that naturally or through genetic modification possess the required stereoselective hydrolytic enzyme activity, or in a lysate of cells with such activity. It will be clear to the average person skilled in the art that use can also be made of mutants of naturally occurring (wild type) enzymes with hydrolytic activity in the process according to the invention.
  • Mutants of wild-type enzymes can for example be made by modifying the DNA encoding the wild type enzymes using mutagenesis techniques known to the person skilled in the art (random mutagenesis, site-directed mutagenesis, directed evolution, gene shuffling, etc.) so that the DNA encodes an enzyme that differs by at least one amino acid from the wild type enzyme and by effecting the expression of the thus modified DNA in a suitable (host) cell.
  • Mutants of the stereoselective hydrolytic enzyme may have improved properties with respect to (stereo)selectivity and/or activity and/or stability and/or solvent resistance and/or pH prophile and/or temperature prophile.
  • a stereoselective hydrolytic enzyme may for example be selected for the process of the invention by screening several enzymes or host cells expressing genes encoding enzymes for the presence of stereoselective hydrolytic enzyme activity.
  • the person skilled in the art knows how to screen for enzymes with a desired activity.
  • conditions under which the substrate (such as the compound of formula 2) and the enzyme are brought into contact are chosen such that it is a good compromise between on the one hand the stability of the enzyme, the substrate and the reaction product and on the other hand the reaction velocity (which usually increases at higher temperatures). Screening for enzymes may be performed at any scale. For practical reasons, if large numbers of enzymes are screened, a reaction volume between 0.15ml and 10ml is used.
  • stereoselective hydrolytic enzymes suitable for the stereoselective hydrolysis of a compound of formula 2 by monitoring the progress of the hydrolysis of the compound of formula 2 in an aqueous solution in the presence of an enzyme using an analytical method, for example TLC, HPLC or GC.
  • aqueous solutions are water and water with co-solvent, for example a water-miscible organic solvent or a water-immiscible solvent.
  • water-miscible organic solvents include methanol, ethanol, aceton, dioxane, acetonitrile, tetrahydrofuran, dimethylsulfoxide and dimethylformamide.
  • water-immiscible organic solvents examples include methyl-t-butyl ether, methyl-isobutyl ketone.toluene, hexane, xylene and iso-octane.
  • the amount of co-solvent is in principle not critical and is usually chosen between 5 and 25 % v/v. In case the substrate is liquid it may be present in water as such. In case the substrate is solid, it may be advantageous that a co-solvent is also present.
  • the enzyme/substrate ratio in the 'hydrolysis screening' is in principle not critical and may be chosen between 1/20 and 2/1.
  • the amount of substrate used is in principle also not critical and may for example be between 5mM and 1.5 M.
  • the pH of the 'hydrolysis screening' is in principle not critical and may for example be chosen between 5 and 10, preferably between 6 and 8 and may be kept constant by using a buffered aqueous solution using a buffer concentration of for example between 10mM and 500mM. Alternatively, the pH of the screening reaction may be kept constant by using an automated pH-stat system.
  • the temperature of the 'hydrolysis screening' is in principle not critical and may be chosen between 20 and 40°C. Alternatively, if an enzyme is sought, which should operate at high temperature, the temperature may be chosen higher. The choice of the reaction conditions of the process of the invention depends on the choice of hydrolytic enzyme.
  • the temperature of the process is chosen between 0 and 90°C, in particular between 10 and 40°C; usually the pH of the process is chosen between 4 and 10 and as a solvent usually water, an aqueous solvent, for example water/_-butanol or water/dioxane, or a two-phase system of water and a water immiscible solvent, for example toluene, hexane, heptane, methyl .-butyl ether, methyl iso-butyl ketone is used.
  • a solvent usually water, an aqueous solvent, for example water/_-butanol or water/dioxane, or a two-phase system of water and a water immiscible solvent, for example toluene, hexane, heptane, methyl .-butyl ether, methyl iso-butyl ketone.
  • the resulting enantiomerically enriched ⁇ 2 -amino acid of formula 1 obtained in the process of the invention may be isolated by using a known method for the isolation of an acid from water or from an aqueous layer.
  • the remaining enantiomerically enriched ⁇ 2 -amino acid ester of formula 2 obtained in the process of the invention may also be isolated in a manner known per se, for example by extraction with an organic solvent, crystallization or (ion exchange) chromatography.
  • the collected remaining enantiomerically enriched ⁇ 2 - amino acid ester of formula 2 is further hydrolysed to form the corresponding enantiomerically enriched ⁇ 2 -amino acid.
  • esters may be hydrolysed by acid hydrolysis using an aqueous solution of a mineral acid solution, for example HCI or H 2 SO 4 , by saponification using an aqueous solution of sodium hydroxide, or by enzymatic hydrolysis.
  • a mixture of enantiomers of ⁇ 2 -amino acid esters of formula 2, wherein R 1 , R 2 , R 3 and R 4 are as defined above may be prepared using methods known in the art.
  • a ⁇ 2 -amino acid ester of formula 2 may be prepared by reduction of the corresponding nitrile of formula 3
  • R 1 , R 2 , R 3 and R 4 are as defined above with a suitable reducing agent and optionally in the presence of a suitable catalyst.
  • the nitrile of formula 3, wherein R 1 , R 2 and R 3 are as defined above and wherein R 4 stands for H may be prepared by reduction of the double bond of the corresponding nitrile of formula 4,
  • the mixture of enantiomers of ⁇ 2 - amino acid esters of formula 2, wherein R 1 , R 2 and R 3 are as defined above and R 4 stands for H may be prepared by a one-pot reduction (this is: without isolation of the intermediate nitrile of formula 3) of the corresponding nitrile of formula 4 with a suitable reducing agent and optionally in the presence of a suitable catalyst. In this reduction both the double bond and the nitrile group of the compound of formula 3 are reduced.
  • Suitable reducing agents (and catalyst combinations) are known to the person skilled in the art and include for.
  • R 1 , R 2 and R 3 are as defined above in a manner known per se by introducing R 4 via nucleophilic 1 ,4-addition using a suitable nucleophile.
  • the person skilled in the art knows which nucleophiles to use to introduce the desired R 4 .
  • nucleophiles examples include alkyl lithium, for example methyl lithium; Grignard reagents; alkoxides, for example a salt of benzylalcohol, for instance the potassium salt; thiols, for example thioacetic acid or benzylmercaptan, both of which may be in the form of a salt; nitrogen nucleophiles, for example amines, for example hydroxylamine; azides; or imides, for example potassium phtalimide or potassium bisformimide.
  • a nitrile of formula 4 wherein R 1 , R 2 and R 3 are as defined above may also be prepared by condensation of a ketone or aldehyde of formula 6
  • Suitable bases and dehydrating reagents are well known in the art. Suitable bases, include for example piperidine, triethylamine, OH " , diazabicycloundecene (DBU) and diazabicyclononene (DBN). An example of a dehydrating reagent is ammoniumacetate.
  • a mixture of enantiomers of ⁇ 2 -amino acid esters of formula 2, wherein R 1 , R 2 , R 3 and R 4 are as defined above may, for example, also be prepared by reacting NH 3 or an NH 3 -analogue with the 2-substituted acrylic acid ester of formula 5
  • NH 3 -analogue a compound which will give the free amine in the compound of formula 2 (optionally after removal of a protecting group).
  • examples of NH 3 -analogues include benzylamine, dibenzylamine, azide, hydroxylamine, potassium phtalimide and potassium bisformimide.
  • Enantiomerically enriched ⁇ 2 -amino acids and enantiomerically enriched ⁇ 2 -amino acid esters may be used as building blocks in the preparation of pharmaceuticals and agrochemicals.
  • ⁇ 2 -homo-threonine can be used in the preparation of the pharmaceutically active ingredient of ⁇ -lactam antibiotics (EP290385, EP742223, EP371875, EP774463, C Fuganti et al. Org. Bio-Org.Chem (1993), 2247-2249).
  • ⁇ 2 -amino acids may for example also be used in the preparation of the pharmaceutically active ingredient of platelet aggregation inhibitors (US 5,344,957, WO93/07867) or in the preparation of the pharmaceutically active ingredient of enkephalinase inhibitors (to replace morphine, treatment of diarrhea, hypertension, cardiac insufficiency and as analgesics; EP 634396).
  • ⁇ 2 -amino acids/esters may also be used to prepare pharmaceutically active ingredients useful as an antibiotic (WO02/41886) or as a medicine against constipation (Drugs Fut. (2000), 25(12), p1308).
  • the invention therefore, also relates to a process wherein the enantiomerically enriched ⁇ 2 -amino acid (ester) prepared according to the invention is further converted into a pharmaceutically active ingredient in a manner known per se.
  • the invention also relates to a process wherein the pharmaceutically active ingredient as obtained above is formulated into a pharmaceutical composition comprising the pharmaceutically active ingredient and an excipient.
  • stereoselective hydrolytic enzyme suitable for use in the present invention may also be used in the preparation of an enantiomerically enriched ⁇ 2 -amino acid ester of formula (2), wherein R 1 , R 2 , R 3 and R 4 are as defined above from an enantiomerically enriched ⁇ 2 -amino acid ester of formula (8)
  • R 12 stands for an optionally substituted alkyl, but is not the same as R 1 , and an alcohol R 1 OH, wherein R 1 is as defined above.
  • R 1' stands for an optionally substituted alkyl of 1-20 C- atoms, more preferably of 1-12 C-atoms (C-atoms of the substituents included).
  • R 1' may stand for a C r C 4 alkyl, e.g. methyl, ethyl, /.-butyl; substituted methyl, e.g. benzyl; or substituted ethyl, e.g. trichloroethyl, methoxy-ethyl ortrifluoroethyl.
  • the molar amount of alcohol R 1 OH relative to the amount of amino acid ester of formula 8 is >5, more preferably > 10.

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Abstract

L'invention concerne un procédé pour préparer un aminoacide ß2 enrichi de manière énantiomère comprenant la mise en réaction d'une enzyme hydrolytique stéréosélective et d'un mélange d'énantiomères d'un ester d'aminoacide ß2 ; et la collecte dudit aminoacide ß2 enrichi de manière énantiomère ainsi obtenu. L'invention concerne également un procédé pour préparer un ester d'aminoacide ß2 comprenant la mise en réaction d'une enzyme hydrolytique stéréosélective et d'un mélange d'énantiomères d'un ester d'aminoacide ß2 et la collecte de l'ester d'aminoacide ß2 enrichi de manière énantiomère restant.
EP05715607A 2004-02-27 2005-02-24 Preparation enzymatique d'un aminoacide beta-2 enrichi de maniere enantiomere Withdrawn EP1745137A1 (fr)

Priority Applications (1)

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EP05715607A EP1745137A1 (fr) 2004-02-27 2005-02-24 Preparation enzymatique d'un aminoacide beta-2 enrichi de maniere enantiomere

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EP04075597 2004-02-27
PCT/EP2005/002103 WO2005085462A1 (fr) 2004-02-27 2005-02-24 Preparation enzymatique d'un aminoacide beta-2 enrichi de maniere enantiomere
EP05715607A EP1745137A1 (fr) 2004-02-27 2005-02-24 Preparation enzymatique d'un aminoacide beta-2 enrichi de maniere enantiomere

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EP1745137A1 true EP1745137A1 (fr) 2007-01-24

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CN103998618A (zh) * 2011-12-19 2014-08-20 住友化学株式会社 光学活性的α-取代-β-氨基酸的制造方法
RS58384B1 (sr) 2014-03-07 2019-04-30 Hoffmann La Roche Novi 6-fuzionisani heteroarildihidropirimidini za lečenje i profilaksu infekcije virusom hepatitisa b
CR20170424A (es) 2015-03-16 2018-01-26 Hoffmann La Roche Tratamiento combinado con un agonista de tlr7 y un inhibidor del ensamblaje de la cápsula del vhb
CN106316871B (zh) * 2016-08-25 2018-04-03 苏州山青竹生物医药有限公司 一种手性β2‑氨基酸衍生物及其制备方法
BR112019004560A2 (pt) 2016-09-13 2019-07-02 Hoffmann La Roche tratamento combinado com agonista de tlr7 e um inibidor de formação de capsídeo de hbv
EP3947383A1 (fr) 2019-03-25 2022-02-09 F. Hoffmann-La Roche AG Formes solides d'un composé du modificateur allostérique de la protéine capsidique du vhb

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