WO2001027095A1 - Procede de preparation d'acide 2-(n-boc-aminomethyl)-thiazol-4-carboxylique - Google Patents

Procede de preparation d'acide 2-(n-boc-aminomethyl)-thiazol-4-carboxylique Download PDF

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Publication number
WO2001027095A1
WO2001027095A1 PCT/EP2000/010120 EP0010120W WO0127095A1 WO 2001027095 A1 WO2001027095 A1 WO 2001027095A1 EP 0010120 W EP0010120 W EP 0010120W WO 0127095 A1 WO0127095 A1 WO 0127095A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxylic acid
amino group
oxo
aminomethyl
glycinthioamide
Prior art date
Application number
PCT/EP2000/010120
Other languages
German (de)
English (en)
Inventor
Ernst Buschmann
Thomas Pfeiffer
Original Assignee
Basf Aktiengesellschaft
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
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to AU79196/00A priority Critical patent/AU7919600A/en
Publication of WO2001027095A1 publication Critical patent/WO2001027095A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a process for the preparation of a 2-aminomethylthiazole-4-carboxylic acid protected on the amino group.
  • 2-aminomethyl-thiazole-4-carboxylic acid is required as a building block for the synthesis of dolastatin 3, a cyclic peptide which has been isolated from the marine gastropod Dolabella auricularia (G. R. Pettit, J. Am. Chem. Soc. 1982 104 905). This peptide inhibits cell growth and is therefore of interest as a potential active ingredient in the treatment of cancer.
  • the synthesis of dolastatin 3 requires 2-aminomethyl-thiazole-4-carboxylic acid in the form of a nitrogen-protected derivative.
  • 2- (Nt-Butyloxycarbonyl-aminomethyl) thiazole-4-carboxylic acid can be prepared by reacting N-BOC-glycinthioamide with 3-bromo-2-oxo-propionic acid in the presence of CaCO in anhydrous ethanol.
  • the reaction is not reproducible and does not lead to satisfactory yields.
  • the CaCO 3 used is difficult to filter off after the reaction.
  • that of G. Jung et al. proposed process two extraction steps and a subsequent drying of the product solution. Such process steps require a large amount of time when carried out on an industrial scale.
  • the object of the invention is therefore to provide a process for the preparation of 2-aminomethyl-thiazole-4-carboxylic acids protected on the amino groups, the reaction being reproducible and leading to high yields. Finally, it should also be possible to carry out the reaction on an industrial scale.
  • This object is achieved with a process for the preparation of a 2-aminomethyl-thiazole-4-carboxylic acid protected on the amino group, a glycinthioamide carrying a protective group on the amino group with a 2-oxo-propionic acid carrying a leaving group in the 3-position in the presence at least one tertiary amine is reacted.
  • the synthesis is not restricted to a specific protected glycinthioamide.
  • protective groups which can be used are alkoxycarbonyl groups, such as tert-amyloxycarbonyl, isopropoxycarbonyl, methoxycarbonyl or benzyloxycarbonyl, the latter being able to substitute the benzyl group with halogen, alkyl, nitro or methoxy groups.
  • Acyl radicals such as acetyl, pivoloyl, propionyl, butyryl, trifluoroacetyl, phthaloyl, benzyl, are also suitable.
  • These protecting groups are common in the field of peptide synthesis.
  • trialkylamines are suitable as tertiary amines, e.g. Trimethylamine, triethylamine, tri-n-butylamine, diisopropylethylamine, dicyclohexylethylamine and dibenzylethylamine or also heterocyclic derivatives such as N-methyl-pyrrolidine, N-methyl-piperidine, N-methyl-morpholine, pyridine, 4-dimethylaminopyridine and 4-pyrrolidinopyridine. Triethylamine, diisopropylethylamine and N-methylmo holin are particularly suitable.
  • leaving groups for the 2-oxo-propionic acid bearing a leaving group in the 3-position customary leaving groups can be used for nucleophilic substitution. Examples are chloride, bromide, iodide, tosylate, triflate, nonaflate, etc.
  • Bromine is particularly preferred as a leaving group.
  • the synthesis is then carried out with 3-bromo-2-oxo-propionecarboxylic acid.
  • the reaction is advantageously carried out in a solvent.
  • Alcohols are preferably used, e.g. Methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol or n-pentanol.
  • Chlorinated hydrocarbons are also suitable, e.g. Methylene chloride, 1,2-dichloroethane or chlorobenzene. Dichloromethane is particularly suitable. Mixtures of chlorinated hydrocarbons and alcohols can also be used.
  • the reaction is preferably carried out at temperatures from -20 ° C to 70 ° C, in particular 5 ° C to 25 ° C.
  • the 3-bromo-2-oxo-propionic acid (bromopyruvic acid) can be used anhydrous or in the form of a hydrate.
  • 3-Bromo-2-oxo-propionic acid can be used in excess with respect to BOC-glycinthioamide. A suitable excess is between 20 to 100% by weight, preferably between 30 and 50% by weight.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

La synthèse de dolastatine 3, un inhibiteur de la croissance cellulaire, nécessite l'utilisation d'acide 2-aminométhyl-thiazol-4-carboxylique protégé au niveau du groupe amino en tant qu'élément constitutif. La présente invention concerne une synthèse qui permet d'obtenir ce composé à une pureté et un rendement élevés, si bien que ladite synthèse peut être utilisée à l'échelle industrielle. A cet effet, un thioamide de glycine portant un groupe protecteur au niveau du groupe amino est mis en réaction de préférence avec de l'acide 3-brom-2-oxo-propionique, en présence d'au moins une amine tertiaire.
PCT/EP2000/010120 1999-10-14 2000-10-13 Procede de preparation d'acide 2-(n-boc-aminomethyl)-thiazol-4-carboxylique WO2001027095A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU79196/00A AU7919600A (en) 1999-10-14 2000-10-13 Method for producing 2-(n-boc-aminomethyl)-thiazol-4-carboxylic acid

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19949569A DE19949569A1 (de) 1999-10-14 1999-10-14 Verfahren zur Herstellung von 2-(N-BOC-Aminomethyl)-thiazol-4-carbonsäure
DE19949569.6 1999-10-14

Publications (1)

Publication Number Publication Date
WO2001027095A1 true WO2001027095A1 (fr) 2001-04-19

Family

ID=7925653

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/010120 WO2001027095A1 (fr) 1999-10-14 2000-10-13 Procede de preparation d'acide 2-(n-boc-aminomethyl)-thiazol-4-carboxylique

Country Status (3)

Country Link
AU (1) AU7919600A (fr)
DE (1) DE19949569A1 (fr)
WO (1) WO2001027095A1 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BAILLY C ET AL: "Depsipeptide analogs of the antitumor drug distamycin containg thiazole amino acids residues", TETRAHEDRON, vol. 44, no. 18, 1988, pages 5833 - 5843, XP002149647, ISSN: 0040-4020 *

Also Published As

Publication number Publication date
AU7919600A (en) 2001-04-23
DE19949569A1 (de) 2001-04-19

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