EP1373190A2 - Procede pour la production d'amides d'acide carboxylique - Google Patents

Procede pour la production d'amides d'acide carboxylique

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Publication number
EP1373190A2
EP1373190A2 EP02735153A EP02735153A EP1373190A2 EP 1373190 A2 EP1373190 A2 EP 1373190A2 EP 02735153 A EP02735153 A EP 02735153A EP 02735153 A EP02735153 A EP 02735153A EP 1373190 A2 EP1373190 A2 EP 1373190A2
Authority
EP
European Patent Office
Prior art keywords
coupling
resin
amine component
acid component
group
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Withdrawn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
EP02735153A
Other languages
German (de)
English (en)
Inventor
Joachim Rudolph
Günther Jung
Bernd Thern
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lanxess Deutschland GmbH
Original Assignee
Bayer Chemicals AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE10157882A external-priority patent/DE10157882A1/de
Application filed by Bayer Chemicals AG filed Critical Bayer Chemicals AG
Publication of EP1373190A2 publication Critical patent/EP1373190A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups

Definitions

  • the invention relates to a process for the preparation of carboxamides, in particular peptides.
  • Carboxamides are usually made by forming an amide bond CO-N between the carbonyl group of an acid component, e.g. a carboxylic acid and the nitrogen atom of an amine component, e.g. a primary or secondary amine. This bond formation is also referred to as condensation, but is referred to below as coupling.
  • an acid component e.g. a carboxylic acid
  • an amine component e.g. a primary or secondary amine
  • Coupling is of particular importance for peptide synthesis.
  • the aim of peptide synthesis is to build peptides from amino acids in such a way that the desired order of the amino acid building blocks is adhered to, the highest possible yield (efficiency) is achieved and epimerization - or racemization in the case of only one asymmetric carbon atom present - Avoid largely or completely during the reaction in favor of higher product purity.
  • the first step of the peptide synthesis is accordingly the synthesis of the partially protected amino acids 1, PG "-N (R") - CH (R ") - COOH, and 2, FfN (R) -CH (R) -CO-PG ' , These are reacted with one another in the second step, the coupling step, but this requires activation of the carboxy group.
  • the third step in peptide synthesis is deprotection, for which specific reagents have been introduced, e.g. treatment with
  • the PG 'protecting groups of the carboxy group e.g. Methyl, ethyl, benzyl, 4-nitrobenzyl and tert-butyl esters are split off similarly and by alkaline saponification.
  • the dipeptide which can be isolated after removal of one or both protective groups can be used in analogous reaction steps as the basis for the synthesis of higher (longer) peptides.
  • segment couplings e.g. to produce a dodecapeptide - instead of consecutively in 11 coupling steps - by linking three tetrapeptides, or even be required to develop special synthesis strategies.
  • Solid-phase synthesis or solid-phase technology means working methods, at which have at least one reactant - in the case of peptide synthesis, the acid or amine component, for example an amino acid or a peptide - in solid-phase-bound form. This is done by immobilizing the reaction partner on suitable carriers such as synthetic resins of various compositions. Either the carboxy group of the amino acid or the carboxy
  • Terminus (short: C-terminus / -terminal) of the peptide or the amino group of the amino acid or amino-terminus (short: N-terminus / -terminal) of the peptide on the support.
  • the dosing, reprocessing and separation of reaction products is made considerably easier.
  • the best-known solid-phase peptide synthesis is the Merrifield technology introduced by Merrifield and now largely automated.
  • the C-terminal amino acid unit of the peptide to be synthesized is usually linked to the insoluble support via its carboxy group. All functional groups of the amino acid side chains must be provided with permanent protective groups which are stable to the reaction conditions of the subsequent couplings.
  • the temporary protective group which initially masks the ⁇ -amino group during loading of the carrier, is then removed. An excess of a second amino acid is introduced, the carboxy group of this amino acid being activated with an activating reagent for the formation of the amide bond. After the coupling, the excess of reagents is removed by a washing process and the protective group of the N-terminus of the dipeptide is removed before the third amino acid is added. This process is repeated until the desired peptide sequence is assembled.
  • the peptide is cleaved from the carrier and the side chain protecting groups are removed.
  • the nature of the side chains and the immobilization are coordinated so that the deprotection and the release of the peptide from the solid phase can be carried out in one step.
  • the immobilization and transition via heterogeneous mixtures such as dispersions, in particular suspensions, to the homogeneous phase or the combination of solid and liquid phase technique is increasing.
  • DCC N, N'-dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDC N-ethyl-N '- (3-d
  • a coupling yield of 95% per coupling for the production of a pentapeptide, starting from a first amino acid means a yield of 81%, based on the first amino acid, after 4 couplings.
  • N-alkylamino acids are part of a variety of biologically active peptides (J.M. Humphrey, A.R. Chamberlin, Chem. Rev. 1997, 97, 2243-2266).
  • highly active activation reagents such as the iminium or uronium salts derived from HOBt or HOAt, e.g. BOP-Cl or the expensive HATU are known, so far has not achieved a breakthrough for the problem of the solid-phase coupling of sterically hindered N-alkylamino acids. For this reason, it has previously been necessary to circumvent this problem by using segment couplings and selective methylation on the resin, e.g.
  • Li et al described the activation reagents BEMT and BEP and their use in the total synthesis of cyclosporin O ((a) P. Li, J. Cheng Xu,
  • the object of the present invention was to provide a process for the preparation of carboxamides which enables the coupling of sterically hindered amino acids in high yields.
  • the task is solved by a special activation reagent in combination with the use of certain bases both together with the acid component in the activation step and together with the amine component for the coupling step.
  • the invention relates to a process for the preparation of carboxamides, in particular peptides, from an acid component in the form of a compound having at least one carboxy group and an amine component in the form of a compound having at least one primary or secondary amino group, in which
  • the amine component is initially introduced together with a coupling base in the form of an organic base with at least one nitrogen atom in a solvent,
  • an activation base in the form of an organic base with at least one nitrogen atom is added to a solvent
  • the process according to the invention is highly efficient and enables couplings which only took place in very low yields with the processes known hitherto and were therefore unsuitable, in particular, for the solid-phase synthesis of peptides.
  • an efficient solid and liquid phase synthesis of the naturally occurring peptides with N-alkylated and sterically hindered amino acids is possible.
  • the process is simple to carry out, the reaction proceeds very quickly and is completely epimerization-free even with high steric hindrance. Harmful heating when carrying out the reaction can also be dispensed with. It also allows the use of cheap coupling reagents such as
  • the present method is also suitable for the production of numerous N-methylated cyclopeptidic biologically active natural products, for example cyclosporins, tentoxins, dolastatins, jasamides, didemnides, nodularins and a number of other representatives (JM Humphrey, AR Chamberlin, Chem. Rev. 1997, 97 , 2243-2266). Furthermore, it can be used for a functionality screening of peptides by - instead of normal non-N-alkyl-substituted amino acids - N-methyl amino acids instead of normal non-N-alkyl substituted amino acids. N-methyl peptides are also more hydrophobic and stable towards proteolytic enzymes, which can improve their bioavailability and therapeutic potential.
  • the acid component and / or the amine component is preferably an amino acid or a peptide, the remaining carboxy and / or amino groups of which are protected.
  • the acid component and the amine component are usually used in a ratio, based on the amount of substance, of at least 1 to 1, preferably from 1 to 1 to 10 to 1, in particular from 1 to 1 to 5 to 1.
  • either the acid component and the amine component are identical or different amino acids or the acid component is an amino acid and the amine component is a peptide or the amine component is an amino acid and the acid component is Peptide, wherein further carboxy or primary or secondary amino groups present in addition to the at least one carboxy group and the at least one primary or secondary amino group are protected.
  • the amino group of the amine component is a secondary amino group and / or that on the ⁇ -C atom of the acid component bonded amino group is a secondary amino group
  • the amino group of the amine component and the protected or peptide-linked amino group of the acid component are both N-alkylated, preferably independently of one another N-alkylated with a methyl, ethyl or propyl -, Iso-propyl, cyclolhexyl or benzyl group or with one of these groups which is substituted with one or more amino and / or carboxy groups, these amino or carboxy groups in turn being protected by appropriate protective groups.
  • the unit (-OX) 2 represents two separate groups in the case of separate electron-withdrawing groups X.
  • a carbonate of the formula I is usually used as the activation reagent, in which one or both groups X independently of one another represent a group CH -n Y n , where n is one of the numbers 1, 2 or 3 and Y n is one, two or three the same or different halogen atoms, or a halogenated 1,3-dioxolan-2-one derivative whose four hydrogen atoms in the 4- and 5-positions are wholly or partly by one, two, three or four identical or different halogen atoms are substituted, or a monohalide of the formula II in which X represents a group CH 3 .
  • n is Y n , where n is one of the numbers 1, 2 or 3 and Y n is one, two or three identical or different halogen atoms, or a dihalide of the formula III.
  • halogen atoms are fluorine, chlorine and bromine, in particular chlorine, and in the case of two or three halogen atoms bonded to a carbon atom, these are preferably the same.
  • the acid component and the activation reagent are usually used in a ratio, based on the amount of substance, of at least 1 to 1, preferably from 1 to 1 to 4 to 1, in particular from 2 to 1 to 3 to 1.
  • a ratio of 3: 1 for diphosgene of 2: 1 and for phosgene and halogenated dioxolanones of 1: 1 is particularly preferred.
  • the coupling base and the activation base are usually selected independently of one another from the group comprising pyridine and the mono- or polysubstituted pyridine derivatives, preferably from the collidines, 2,4,6-tritert-butylpyridine, 2,6-ditert-butylpyridine, 2.6 -Ditert-butyl-4-methylpyridine, 2,6-
  • DIEA diisopropylethylamine
  • the collidines are the various trimethylpyridines and ethylmethylpyridines, for example 2,3,5-collidine and in particular 2,4,6-collidine. Mixtures of two or more bases can also be used.
  • the coupling efficiency can be increased by the targeted selection of the coupling and / or activation base.
  • the coupling base used together with the amine component is
  • 2,4,6-collidine pyridine, triethylamine or a sterically hindered trialkylamine, preferably a sterically hindered trialkylamine, in particular diisopropylethylamine or triisopropylamine, particularly preferably diisopropylethylamine.
  • the activation base used together with the acid component is a sterically hindered one- or multiple-alkyl-substituted pyridine derivative, preferably 2,4,6-collidine, 2,4,6-titer.
  • butylpyridine 2,6-ditert-butylpyridine, 2,6-ditert-butyl-4-methylpyridine, 2,6-dimethylpyridine or 2,3,5,6-tetramethylpyridine, particularly preferably 2,4,6-collidine.
  • the coupling efficiency increases particularly high when a steric with the sterically hindered pyridine derivative, preferably 2,4,6-collidine or 2,4,6-tri-tert-butylpyridine, in particular 2,4,6-collidine, is used as the activation base hindered trialkylamine, especially DIEA, is combined as a coupling base.
  • 2,4,6-tritert-butylpyridine generally increases the coupling efficiency less than 2,4,6-
  • the coupling base and / or the activation base are usually particularly preferred in a ratio to the amine component, based on the amount of substance, of at least 2 to 1, preferably 4 to 1 to 30 to 1, in particular 8 to 1 to 20 to 1 from 12 to 1 to 16 to 1.
  • the solvents according to (i) and (ii) are selected independently of one another from the organic and inorganic solvents which are liquid under the process conditions, usually from tetrahydrofuran, 1,4-dioxane, tetrahydropyran,
  • the solvents according to (i) and (ii) are particularly preferably identical.
  • DIEA as the coupling base
  • triphosgene as the activation reagent
  • 2,4,6- as the activation base
  • Collidine and tetrahydrofuran (THF) are used as solvents, in particular special, based on the amine component, 8 eq. DIEA, 1.15 eq. Triphosgene and 10 eq. 2,4,6-collidine.
  • the acid component is preferably used in a ratio of 3 to 1, based on the amount of triphosgene, ie, based on the amine component, about 3.5 eq. the acid component.
  • the process is usually carried out at a temperature of from 15 to 30 ° C., preferably from 18 to 25 ° C., in particular from 20 to 22 ° C.
  • 3 min is sufficient, preferably 10 s to 2 min, in particular 30 s to 1 min.
  • the reaction is preferably allowed to take place for a period of 5 minutes to 4 hours. It is usually shaken or stirred.
  • the amine component or the acid component is reversibly bound to a solid phase, preferably to a resin, in particular to a trityl resin, Wang polystyrene resin or Rink amide MBHA resin and particularly preferably to TCP resin:
  • the Wang resins and Sasrin resins based on a benzyl alcohol carrier are less suitable for the coupling of sterically hindered amino acids because of the
  • the TCP (trityl chloride polystyrene) resin a trityl resin available from RepChem Goldammer & Clausen (D-72076 Tübingen), is particularly suitable for the sequential construction of N-methyl peptides.
  • the TCP resin is an excellently balanced resin in terms of stability and cleavage, and prevents the formation of diketopiperazine on the dipeptide level due to the bulky trityl linker.
  • the TCP resin like the commercial product available from RepChem Goldammer & Clausen, is preferably hardly or not at all contaminated with Friedel-Crafts by-products, which can be problematic in solid-phase syntheses.
  • the method according to the invention is ideally suited for the attachment of an N-methylated Fmoc-protected amino acid to an N-methylated or non-methylated amino group of a peptidyl resin.
  • Activation is preferably used at least twice the amount of N-protected amino acid, based on the amount of substance of the activation reagent, in order to prevent that unreacted activation reagent can possibly have a decomposing influence on the coupling reaction.
  • liquid phase synthesis based on the amount of amine component,
  • Acid component in particular Fmoc-protected amino acid
  • an activation reagent in particular triphosgene
  • an activation base in particular 2,4,6-collidine
  • the coupling base and the activation base are used in an amount of at least 2 eq., preferably from 4 to 30 eq., in particular from 8 to 20 eq., particularly preferably from 12 to 16 eq., for example from 14 eq.
  • Liquid phase synthesis also proceeds in sterically hindered cases, e.g. the coupling of MeVal with MeVal, extremely fast, in high yields and free of epimerization.
  • the present method is suitable for automation, for example in a peptide synthesizer.
  • triphosgene was prepared as a stock solution in anhydrous tetrahydrofuran (THF (abs)) by adding 13.7 mg triphosgene per 1 ml
  • the Fmoc-amino acid (5 eq.) was in a polypropylene tube with a lid in the triphosgene / THF stock solution (1.65 eq. Triphosgene / 7.14 ml per mmol Amino acid) dissolved while swirling. As soon as the amino acid was completely dissolved, 2,4,6-collidine (14 eq. 371 ⁇ l per mmol amino acid) or 2,4,6-tri-tert-butylpyridine (14 eq.) was added, in the case of collidine a colorless precipitate was formed. The mixture was swirled for about 30 to 60 s to mix all the reagents and to activate the amino acid.
  • the suspension was then added to the pre-swollen resin using a Pasteur pipette.
  • the syringe was sealed and shaken on a shaker for 5 to 30 minutes at 20 ° C.
  • the resin was then washed successively 3 times with THF, methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane (DCM), MeOH.
  • the dipeptide was then cleaved from the resin with 1% trifluoroacetic acid (TFA) in dichloromethane (DCM).
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • Diastereomer mixture recorded (Fig. 2).
  • the HPLC chromatograms (UV detection) of the isolated DLLL isomer (FIG. 3) and the product of the coupling of pure L-FmocMeVal (FIG. 4) were also recorded under the same RP-HPLC conditions. In the latter case, only the LLLL diastereomer signal was found (Fig. 4), i.e. no epimerization occurred.
  • Fig. 3 RP-HPLC chromatogram of the DLLL isomer.
  • Fig. 4 RP-HPLC chromatogram of the LLLL isomer.
  • the protected N-methyl-L-amino acids FmocMeVal-OH and MeVal-OBn were coupled to the dipeptide FmocMeVal-MeVal-Obn.
  • TCP resin 150 mg were coated with 55 mg of Fmoc-MeLeu-OH (3 eq) in
  • the tetrapeptide Fmoc-MeLeu-MeLeu-MeVal-MeLeu-OH was obtained in a purity of over 99% exclusively via couplings according to the invention with triphosgene, which were carried out as described in Example 1. Only the first one The coupling had to be repeated once.
  • the HPLC spectrum of the tetrapeptide is shown in FIG. 5.
  • the tenth coupling shows that the coupling according to the invention with triphosgene of a non-N-methylated amino acid to an N-methylated can also proceed almost quantitatively.
  • Hexafluoroisopropanol was used to cleave the linear peptide from the resin. After freeze-drying, the crude peptide was obtained directly and without further
  • the occupancy of the resin with the first amino acid was 0.4 mmol / g resin.
  • Fig. 7 HPLC chromatogram of the crude product of the cyclization reaction to
  • Fig. 8 Mass spectrum of the purified cyclosporin O.
  • Example 6 Synthesis of Omphalotin A
  • Omphalotin A is a cyclododecapeptide with a high nematicidal activity, especially against the important phytopathogenic agents
  • Nematodes Meloidogyne incognita A. Mayer, H. Anke, O. Stemer, Nat. Prod. Lett. 1997, 10, 25-32; O. Sterner, W. Etzel, A. Mayer, H. Anke, Nat. Prod. Lett. 1997, 10, 33-38; WO 97/20857).
  • the dodecapeptide was then constructed with eleven couplings. After each coupling, the chloranil test or the Kaiser test was carried out (Fmoc Solid Phase Synthesis, W.C. Chan, P.D. White (ed.), Oxford University Press, 2000, pp. 61 ff). In the event of a negative test result, the clutch was coupled again. In
  • the occupancy of the resin with the first amino acid was 0.56 mmol / g resin.
  • a total of 2.0 g of resin were used, which corresponds to an amount of 1.12 mmol of peptide
  • ⁇ -NMR spectroscopy confirmed the identity of synthetic omphalotin A with the natural product (Fig. 13) (NMR data published in: O. Sterner, W. Etzel, A. Mayer, H. Anke, Nat. Prod. Lett. 1997, 10, 33-38).
  • the mass spectrum of the purified omphalotin A is shown in Fig. 14.
  • Fig. 11 HPLC chromatogram of the crude product of the cyclization reaction (Example 6).
  • Fig. 12 HPLC chromatogram of the purified end product, omphalotin A.
  • Fig. 13 ⁇ -NMR spectrum (700 MHz, CD 3 OD) of the purified end product, omphalotin A (Example 6).
  • Fig. 14 ESI mass spectrum of the purified end product, omphalotin A (Example 6).
  • the optically inactive amino acid Fmoc-sarcosine was coupled as the first amino acid onto the carrier polymer.
  • a solution of 1 eq Fmoc-SarOH and 3 eq DIEA in DCM (abs) was added to 200 mg TCP resin (substitution 1.04 mmol / g) and the suspension was shaken for 3 h.
  • Triphosgene was prepared as a stock solution with a concentration of 61.5 mmol / 1 (corresponding to 18.27 mg BTC per milliliter THF (abs)), of which per mmol
  • the HOAt coupling was used, which was carried out as in Example 6.
  • the HATU coupling was also used in some cases.
  • the procedure was as follows: The Fmoc-amino acid to be coupled (3.5 eq) was weighed out together with HATU (3.5 eq) and in the smallest possible amount of DCM (abs) / DMF (abs) (1: 1) solved. DIEA (7 eq) was added to the solution and left for 15 min for preactivation. This solution was then added directly to the deprotected peptidyl resin which had been pre-swollen in DMF (abs) and shaken for the time indicated in each case. The reaction solution was suctioned off and the resin was washed with DMF, DCM, DMF, DCM, MeOH (3 times each).
  • Fig. 15 HPLC chromatogram of the Fmoc-deprotected, linear dodecapeptide (Example 7).
  • Fig. 16 HPLC chromatogram of the crude product of the cyclization reaction
  • Fig. 17 HPLC chromatogram of the purified, optically pure omphalotin A (Example 7).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé pour la production d'amides d'acide carboxylique, notamment de peptides, à partir d'un constituant acide sous forme d'un composé comprenant au moins un groupe carboxy et d'un constituant amine sous forme d'un composé comprenant au moins un groupe amino primaire ou secondaire. L'invention concerne également l'utilisation de ces amides d'acide carboxylique.
EP02735153A 2001-03-28 2002-03-21 Procede pour la production d'amides d'acide carboxylique Withdrawn EP1373190A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DE10115213 2001-03-28
DE10115213 2001-03-28
DE10126431 2001-05-31
DE10126431 2001-05-31
DE10157882 2001-11-26
DE10157882A DE10157882A1 (de) 2001-03-28 2001-11-26 Verfahren zur Herstellung von Carbonsäureamiden
PCT/EP2002/003153 WO2002076927A2 (fr) 2001-03-28 2002-03-21 Procede pour la production d'amides d'acide carboxylique

Publications (1)

Publication Number Publication Date
EP1373190A2 true EP1373190A2 (fr) 2004-01-02

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EP02735153A Withdrawn EP1373190A2 (fr) 2001-03-28 2002-03-21 Procede pour la production d'amides d'acide carboxylique

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US (1) US6982315B2 (fr)
EP (1) EP1373190A2 (fr)
WO (1) WO2002076927A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080200648A1 (en) * 2004-07-16 2008-08-21 Lonza Ag Method of Peptide Synthesis
US7696165B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne analogues for preventing or treating viral-induced disorders
US7696166B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders
GB2472563B (en) * 2009-04-28 2013-02-27 Univ Leicester Method of preparing hairpin and cyclic polyamides
CN104744570A (zh) * 2013-12-31 2015-07-01 深圳先进技术研究院 一种环孢菌素的合成方法
CN107188816B (zh) * 2017-06-14 2023-06-06 上海欧睿生物科技有限公司 一种改进的脂肪酸单乙醇酰胺的合成方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS55145665A (en) * 1979-05-02 1980-11-13 Haruo Ogura Agent for forming active ester of amino acid
US5948693A (en) * 1994-09-01 1999-09-07 Wisconsin Alumni Research Foundation Solid phase synthesis of immunosuppressive agents
DE19545463A1 (de) * 1995-12-06 1997-06-12 Bayer Ag Organisch-chemische Verbindung und Verfahren zu ihrer Herstellung
IL125314A (en) * 1998-07-12 2004-07-25 Peptor Ltd Processes for attaching amino acids using a bite - (trichloromethyl) carbonate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02076927A2 *

Also Published As

Publication number Publication date
US20020193594A1 (en) 2002-12-19
WO2002076927A3 (fr) 2003-01-03
US6982315B2 (en) 2006-01-03
WO2002076927A2 (fr) 2002-10-03

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