EP4247826A1 - Catalyse à l'or assistée par l'argent pour la préparation de pentasaccharide de fondaparinux et d'intermédiaires - Google Patents

Catalyse à l'or assistée par l'argent pour la préparation de pentasaccharide de fondaparinux et d'intermédiaires

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Publication number
EP4247826A1
EP4247826A1 EP21894152.4A EP21894152A EP4247826A1 EP 4247826 A1 EP4247826 A1 EP 4247826A1 EP 21894152 A EP21894152 A EP 21894152A EP 4247826 A1 EP4247826 A1 EP 4247826A1
Authority
EP
European Patent Office
Prior art keywords
compound
resulting
pentasaccharide
fondaparinux
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Withdrawn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
EP21894152.4A
Other languages
German (de)
English (en)
Inventor
Srinivas HOTHA
Gulab WALKE
Niteshlal KASDEKAR
Yogesh SUTAR
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.)
Indian Institute of Science Education and Research
Original Assignee
Indian Institute of Science Education and Research
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 Indian Institute of Science Education and Research filed Critical Indian Institute of Science Education and Research
Publication of EP4247826A1 publication Critical patent/EP4247826A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Definitions

  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates. Specifically, the present invention relates to a novel catalytic process for the synthesis of Fondaparinux pentasaccharide and its intermediates. The present invention further relates to a silver assisted gold catalysis for glycosylation reactions in the synthesis of Fondaparinux pentasaccharide and its intermediates.
  • Sulfated linear polysaccharides consisting of alternating di saccharide units of a- 1,4-linked glucosamine and either glucuronic acid or iduronic acid such as heparin (H) and heparin sulfate (HS) are present on the surface of most animal cells, membranes and extracellular matrices. They play pivotal role in diverse biological pathways including tumor metastasis, cell growth, cell adhesion, wound healing, inflammation, diseases of central nervous system etc.
  • H and HS are heavily O- and N-sulfated, they belong to glycosaminoglycan polysaccharides and are extracted and isolated from natural animal sources (porcine intestine or bovine lung or some-times from turkeys, mice, camel, whales, lobsters, etc.). H and HS are routinely used as anti -coagulant drugs during major surgeries such as cardiopulmonary bypass, knee replacement, hip replacement in order to prevent occurrence of venous thrombosis.
  • Enoxaparin is isolated from UFH after P-eliminative cleavage employ-ing alkali through peeling off reaction whereas Nadroparin is obtained by deaminative cleavage employing nitrous acid.
  • Mechanistic investigations revealed that the H binds to antithrombin with high affinity, brings in a conformational change thereby converting it to a rapid (lOOOx) in-hibitor of thrombin (Flla).
  • antithrombin interacts with coagulation factor Xa (FXa).
  • LMWHs derived by chemical and/or enzymatic depolymerization procedures from UFH vary in both their relative abilities to enhance the inhibition of FXa and Flla (anti-FIIa) and in their physicochemical properties. It has been noticed that specific FXa inhibitory activity increases as the mean molecular weight decreases.
  • UFH (MWavg -15000) has Anti-FXa/ Anti-FIIa activity ratio of 1.0 whereas the same ratio for Enoxaparin (MWavg -4200) is 3.9 and Bemiparin (MWavg -3600) was 8.0.12
  • chemically and enzymatically extracted H and HS from animal sources suffer from microheterogeneity, presence of viral or prion contaminants; and hence, strongly influence their purity and quality from batch to batch. The problem manifested into a pinnacle due to the worldwide distribution of contaminated animal-sourced heparin about a decade ago.
  • Fondaparinux is a synthetic pentasaccharide based on the antithrombin-binding domain of Heparin sulfate and contains glucosamine, glucuronic acid and iduronic acid in its sequence.
  • Clinically approved anti-coagulant Fondaparinux is safe since it has zero contamination problems often associated with animal based heparins. Extensive structure-property relationship studies proved that essential sulfate and carboxylic acid groups shall be located at opposite sides of the pentasaccharide.
  • An object of the present invention is to provide a novel process for the synthesis of Fondaparinux, which can overcome deficiencies associated with the known arts.
  • Another object of the present invention is to provide a facile process for the synthesis of Fondaparinux that enables creation of diverse molecular entities differing in sulfation pattern.
  • Another object of the present invention is to provide a process for the synthesis of Fondaparinux that is scalable.
  • Another object of the present invention is to provide a process for the synthesis of Fondaparinux that provides a scalable route for the synthesis of unnatural and expensive intermediate, Iduronic acid.
  • Yet another object of the present invention is to provide a process for the synthesis of Fondaparinux wherein all glycosidations reactions are carried out in catalytic fashion.
  • Still another object of the present invention is to provide a process for the synthesis of Fondaparinux that has minimal number of steps and facile purifications.
  • Yet another object of the present invention is to provide a process for the synthesis of Fondaparinux with excellent process efficiency.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates. Specifically, the present invention relates to a novel catalytic process for the synthesis of Fondaparinux pentasaccharide and its intermediates.
  • the present invention further relates to a silver assisted gold catalyzed glycosylations for the synthesis of Fondaparinux pentasaccharide and its intermediates.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein all glycosidation steps are carried out in a catalytic fashion using silver assisted gold catalysis utilizing alkynylcyclohexyl carbonate donor chemistry.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein all glycosidation steps for linking monosachharide building blocks are carried out using silver assisted gold catalysis using Au-phosphite in the presence of AgOTf.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein silver assisted gold catalysed glycosidations are carried out for assembling the pentasaccharide in a highly convergent
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein silver assisted gold catalysed glycosidations are carried out for assembling the pentasaccharide by coupling trisaccharide fragment either with a disaccharide via 3+2 glycosylation or coupling trisaccharide with iduronate monosaccharide followed by coupling another monomer monosaccharide via 3+1+1 glycosylation.
  • the present invention relates to the process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the process comprises the steps of: a) Reacting trisaccharide DEF3 with either 3+2 glycosylation using disaccharide GH2 or by reacting trisaccharide DEF3 via 3+1+1 elongation by coupling iduronate GIO and azido-derivative H3, resulting in the formation of regioselectively protected pentasaccharide; and or
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein all the monosaccharide units are synthesized avoiding harsh reaction conditions or reagents.
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.”
  • the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment.
  • the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
  • the numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • inventive subject matter provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates. Specifically, the present invention relates to a novel catalytic process for the synthesis of Fondaparinux pentasaccharide and its intermediates.
  • the present invention further relates to a silver assisted gold catalyzed glycosylations for the synthesis of Fondaparinux pentasaccharide and its intermediates.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein all glycosidation steps are carried out in a catalytic fashion using silver assisted gold catalysis utilizing alkynylcyclohexyl carbonate donor chemistry.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein all glycosidation steps for linking sachharide building blocks are carried out using silver assisted gold catalysis using Au-phosphite in the presence of AgOT futilizing alkynylcyclohexyl carbonate donor chemistry.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein silver assisted gold catalysed glycosidations are carried out for assembling the pentasaccharide in a highly convergent [3+2] or [3+1+1] manner.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein silver assisted gold catalysed glycosidations are carried out for assembling the pentasaccharide by coupling trisaccharide fragment either with a disaccharide via 3+2 glycosylation or coupling trisaccharide with iduronate monosaccharide followed by coupling another monomer monosaccharide via 3+1+1 glycosylation.
  • the present invention relates to the process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the process comprises the steps of: a) Reacting trisaccharide DEF3 with either 3+2 glycosylation using disaccharide GH2 or by reacting trisaccharide DEF3 via 3+1+1 elongation by coupling iduronate G10 and azido-derivative H3, resulting in the formation of regioselectively protected pentasaccharide; and b) Deprotecting the regioselectively protected pentasaccharide, converting the azide to amine followed by regioselective sulfation, resulting in Fondaparinux.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein all the monosaccharide units are synthesized avoiding harsh reaction conditions or reagents.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein glycosylation reactions are carried out in stereoselective manner.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein silver assisted gold catalysed glycosylation are carried out in stereoselective manner resulting in 1,2-cis- selectivity in excellent yield.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein silver assisted gold catalyzed glycosylation reactions afford 1,2-czs-selectivity in excellent yield thereby facilitating easy purification of the desired compounds.
  • the 1,2-czs-selectivity reaction at room temperature avoids the use of cumbersome cryogenic reaction conditions.
  • An azide at the C-2 position strongly influences the stereochemical outcome of glycosidation in favor of desired 1,2-cis or a-glucoside.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the trisaccharides DEF3 can be synthesized by stepwise glycosylation using alkynylglycosyl carbonates and silver assisted gold catalysed glycosidations.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the trisaccharides DEF3 can be synthesized by coupling the fragments E10, F8 and D4, comprising the steps of: a) Coupling compound E10 with compound F8 using silver assisted gold catalysed glycosidation using Au-phosphite in the presence of AgOTf, resulting in the formation of compound EFl; b) Deprotecting the TBS group from EFl to obtain compound EF2; c) Coupling compound EF2 with compound D4 using silver assisted gold catalysed glycosidation using Au-phosphite in the presence of AgOTf, resulting in compound DEFI; d) Deprotecting the allyl group from DEFI resulting in compound DEF2; and e) Converting the secondary hydroxyl group of DEF2 into carbonate moiety resulting in tri saccharide compound DEF3.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein all the monosaccharide units can be synthesized starting from D-Glucose or D-Glucosamine.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein iduronic acid monosaccharide compound G13 is synthesized starting from D-Glucose by following the synthetic route as depicted in Scheme 2.
  • the present invention relates to a novel scalable route for the synthesis of unnatural and expensive iduronic acid compound.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the compound G10 can be prepared from aldehyde G4, comprising the steps of: a) Adding thiophenylmagnesium bromide to aldehyde G4 resulting in ztfo-compound G5; b) Acetylation of compound G5 resulting in compound G6; c) Oxidation of thiophene moiety of compound G6, followed by esterification resulting in iduronate compoundG7; d) Deacetylation of compound G7 resulting in compound G8; e) Conversion of furanose of iduronate G8 under acidic conditions to pyranose compound G9; and f) Conversion of compound G9 to isopropylidene derivative GIO.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the compound G13 is prepared from compound G10, comprising the steps of: a) Protecting the hydroxyl group of compound G10 with silyl protecting group resulting in compound Gil; b) Cleaving the isopropylidene group of compound Gil resulting in compound G12; and c) Coupling compound G12 with l-ethylnylcyclohexyl-(4-nitrophenyl) carbonate resulting in compound G13.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein monosaccharide unit F8 is synthesized starting from Glucosamine, comprising the steps of: a) Protecting amine functionality of glucosamine with Troc protecting group resulting in compound Fl; b) Selective allyl protection of compound Fl resulting in compound F2; c) Reacting compound F2 with benzylidene-dimethyl acetal resulting in compound F3; d) Unmasking the Troc protecting group to obtain compound F4; e) Converting the amine of compound F4 to azide in compound F5; f) Protecting the lone hydroxyl group resulting in compound F6; g) Hydrolysing the benzylideneacetal of compound F6 to obtain compound F7; and h) Regioselective protection of C6-hydroxyl group of F7 to obtain compound F8.
  • the intermediate Fl can also be synthesized as per the literature procedure reported by Hou et al. in Eur. J. Med. Chem. 2017, 132, 1-10 and by Craftet al. in
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein monosaccharide unitH3 is synthesized starting from Glucosamine, using the advanced intermediate F5 synthesized during the synthesis of F8, following the synthetic route as described in Scheme
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein monosaccharide unit D4 is synthesized starting from Glucosamine, using the advanced intermediate H2, synthesized during the synthesis of H3, wherein the compound D4 is prepared from compound H2, comprising the steps of: a) Regioselective silyl protection of compound H2 resulting in compound DI; b) Benzyl protection of lone hydroxyl group of compound DI resulting in compound D2; c) Deprotecting the allyl group of compound D2 to obtain compound D3; and d) Coupling compound D3 with l-ethylnylcyclohexyl-(4-nitrophenyl) carbonate resulting in compound D4.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the compound E10 is prepared from compound G2 comprising the steps of: a) Hydrolysis of isopropylidene group of benzyl protected diacetoneglucofuranoseGl resulting in compound El; b) Allyl protection of compound El under acidic conditions resulting in compound E2; c) Locking the C4 and C6 of compound E2 as benzylidene to obtain compound E3; d) Protecting the C2 hydroxyl of compound E3 as benzyl group to obtain compound E4; e) Hydrolysing the benzylidene group of compound E4 resulting in compound E5; f) Oxidation of primary hydroxyl group of compound E5 resulting in compound E6 which was then esterified to obtain compound E7; g) Silyl protection of compound E7 to obtain compound E8 followed by deallylation resulting in compound
  • the intermediate El can also be synthesized as per the literature procedure reported by Prentice et al. in J. Amer. Chem. Soc. 1956, 78, 4439-4440; Orgueira et al. in Chem. Eur. J. 2003, 9, 140-169 and by Zou et al. in Tetrahedron 2018, 74, 2376-2382.
  • the intermediate E3 can also be synthesized as per the literature procedure reported by Patricia, et al. in Carbohydrate Research 1976, 49, 325-333.
  • the present invention provides shared use of functionalized building blocks for the synthesis of Fondaparinux pentasaccharide and its intermediates.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the disaccharide compound GH2, required for coupling with the trisaccharide, is prepared by the process comprising the steps of : a) coupling compound G13 with compound H3, using silver assisted gold catalysed glycosidation using Au-phosphite in the presence of AgOTf, resulting in the formation of compound GH1; and b) deprotecting the TBS group from GH1 resulting in the formation of compound GH2.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the pentasaccharide
  • DEFGH1 is prepared via 3+2 glycosidation, by coupling the trisaccharide DEF3 with the disaccharide GH2 using silver assisted gold catalysed glycosidation using Au-phosphite in the presence of AgOTf.
  • the route of synthesis is described in Scheme 8.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the pentasaccharide DEFGH2 is prepared via 3+1+1 glycosidation, by the process comprising the steps of : a) Coupling the trisaccharide DEF3 with monosaccharide G10 using silver assisted gold catalysed glycosidation using Au-phosphite in the presence of AgOTf, resulting in the formation of tetrasaccharide compound DEFG1; b) Deprotecting the acetonide and PMB protecting groups of compound DEFG1 to obtain compound DEFG2; c) Conversion of the compound DEFG2 to DEFG3 by reaction with carbonate 36; and d) Coupling compound H3 with DEFG3 to obtain the pentasaccharide DEFGH2.
  • the route of synthesis of pentasaccharide DEFGH2 is prepared via 3+1+1 glycosidation is described in Scheme 9.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and its intermediates, wherein the pentasaccharide DEFGH1 is converted to a regioselectively protected pentasaccharide DEFGH5 by deprotecting the silyl and PMB protecting groups.
  • the silyl and PMB protecting groups of pentasaccharide DEFGH1 can be removed in any sequence, either removing silyl group followed by the removal of PMB group or by first removing PMB group followed by deprotection of silyl group, resulting in pentasaccharide DEFGH5.
  • the route has been described in Scheme 10.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and novel intermediates, wherein certain steps in the synthesis may not require purification of the product obtained, but can be used as such in the next step.
  • the products obtained at each step may or may not be always purified before proceeding further in the next step.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and novel intermediates, wherein the synthetic route is useful for the synthesis of other glycosamino-glycans selected from but not limited to Hyaluronic acid, Keratan Sulfate, Chondroitin sulfate, Idraparinux, Idrabiotaparinux and the like.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and novel intermediates, wherein the regioselectively protected pentasachharide, DEFGH2 or DEFGH1 or DEFGH3 or DEFGH4 or DEFGH5 can be deprotected by using standard deprotection conditions, well known to a person skilled in the art.
  • the different protecting groups like benzyl, benzoyl, acetate, allyl and ester can be deprotecting using synthetic methods as described in Greene’s Protective Groups In Organic Synthesis; 4 th Edition, Wiley Science; Chem. Sci. 2018, DOI: 10.1039/C8SC01743Cand in Angew.
  • the present invention relates to a process for the synthesis of Fondaparinux pentasaccharide and novel intermediates selected from the group consisting of but not limited to: [0083] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof.
  • Diacetonide compound G2 (38 g, 108.4 mmol) was dissolved in 380 mL of the 66.6% aqueous acetic acid and the mixture was stirred at 50 °C for 8 h. After removal of the solvent under reduced pressure, the remaining residue was co-evaporated twice with water and twice with toluene and the crude residue was purified by silica gel column chromatography to afford 30 g (89%) of the diol compound G3 as a white solid.
  • Example 45 Preparation of Compound GH2 [00178] To a solution of the compound GH1 (230 mg, 0.283 mmol) in anhydrous pyridine (2 mL) was added dropwise 2 mL of the 70% HF»py solution at 0 °C and the reaction mixture was allowed to stir at 25 °C for 5 h. After completion, ice-cold water (20 ml) was added and extracted with EtOAc (2 x 10 mL). The organic layer was washed with aqueous 1A HC1 (25 mL), saturated aq.
  • Example 47 Preparation of Compound DEFG1 [00182] To a solution of glycosyl donor DEF3 (340 mg, 0.217 mmol) and acceptor G10 (61 mg, 0.18 mmol) in anhydrous CH2C12 (2.0 mL) was added freshly activated 4A MS powder at 25 °C under argon atmosphere.
  • Example 48 Preparation of Compound DEFG2 [00184] To the compound DEFG1 (275 mg, 0.158 mmol) in a 25 mL flask was added 75% aq. dichloroacetic acid (5 mL) at 0 °C and the solution was stirred for 1 h. The reaction mixture was diluted with ice-cold water (25 mL), neutralized by portion-wise addition of the solid NaHCO3 and extracted with CH2C12 (3 x 15 mL).

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Abstract

La présente invention concerne un procédé de synthèse de pentasaccharide de fondaparinux et de ses intermédiaires. Plus précisément, la présente invention concerne un nouveau procédé catalytique pour la synthèse de pentasaccharide de fondaparinux et de ses intermédiaires. La présente invention concerne en outre une catalyse à l'or assistée par l'argent pour des réactions de glycosylation dans la synthèse de pentasaccharide de fondaparinux et de ses intermédiaires. (I)
EP21894152.4A 2020-11-19 2021-11-17 Catalyse à l'or assistée par l'argent pour la préparation de pentasaccharide de fondaparinux et d'intermédiaires Withdrawn EP4247826A1 (fr)

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PCT/IB2021/060650 WO2022107013A1 (fr) 2020-11-19 2021-11-17 Catalyse à l'or assistée par l'argent pour la préparation de pentasaccharide de fondaparinux et d'intermédiaires

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PT1440077E (pt) * 2001-09-07 2013-06-04 Alchemia Ltd Pentassacáridos de heparina sintéticos
KR101529061B1 (ko) * 2008-05-30 2015-06-16 모멘타 파머슈티컬스 인코포레이티드 당류 구조물, 그리고 이러한 구조물의 제조 및 사용 방법
US8420790B2 (en) * 2009-10-30 2013-04-16 Reliable Biopharmaceutical Corporation Efficient and scalable process for the manufacture of Fondaparinux sodium

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