WO2026010901A1 - Procédé de préparation d'un peptide lipidé et composés intermédiaires associés - Google Patents

Procédé de préparation d'un peptide lipidé et composés intermédiaires associés

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Publication number
WO2026010901A1
WO2026010901A1 PCT/US2025/036006 US2025036006W WO2026010901A1 WO 2026010901 A1 WO2026010901 A1 WO 2026010901A1 US 2025036006 W US2025036006 W US 2025036006W WO 2026010901 A1 WO2026010901 A1 WO 2026010901A1
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Prior art keywords
compound
acid
formula
solution
ray powder
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Pending
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PCT/US2025/036006
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English (en)
Inventor
Ellen Y. AGUILERA
Marc R. BECKER
Jr. Donald R. Gauthier
Jacob W. GREENWOOD
Clara HARTMANSHENN
Jeffrey T. Kuethe
Joshua Lee
Peter E. Maligres
Tiffany PIOU
David A. Thaisrivongs
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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Publication of WO2026010901A1 publication Critical patent/WO2026010901A1/fr
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Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides

Definitions

  • the present disclosure relates to a process for preparing a cry stalline lipidated peptide, such as a compound of Formula I,
  • the instant disclosure is directed to an efficient and scalable process for synthesizing a crystalline form of a compound of Formula I,
  • -A represents an anion thereof, which contains a lipid sidechain.
  • This compound is a lipidated dipeptide derivative containing 2,3-Diamino-propionic acid (DAP) and L-alanine (DAP-Ala).
  • DAP 2,3-Diamino-propionic acid
  • DAP-Ala L-alanine
  • the disclosure also provides salts and zwitterions of compounds of Formula I, such as the compound of Formula la.
  • the disclosure further provides crystalline solid forms of these compounds.
  • the present disclosure also relates to intermediate compounds useful in the preparation of the compound of Formula I, and salts and zwitterions thereof, and to processes for preparing such intermediates and salts and zwitterions thereof.
  • the disclosure further provides crystalline solid forms of these intermediate compounds.
  • the process of the instant invention prepares a compound of Formula I utilizing only two protecting groups. This process focuses on making chemically defined quaternary ammonium salts that are crystalline and allow the isolation of pure compounds.
  • the present disclosure solves the shortcomings of prior art processes via judicious choice of coupling conditions and protecting groups which enables the highly selective coupling of the three building blocks without the need for additional isolation, maximizing process efficiency.
  • the judicious selection of protecting groups and reagents minimizes the isolation of intermediates and enables the chemical control of the counter-anion in the lipid chain. This strategy can be expanded to various derivatives and bioactive molecules.
  • the present disclosure introduces a method for preparing a compound of Formula I to produce short peptide derivatives, removing the necessity for systematic isolation of intermediates and propelling the field of peptide synthesis forward.
  • the disclosed approach provides a more efficient, cost-effective, and versatile solution for the industrial-scale manufacturing of these biologically important molecules.
  • FIG. 1 is an X-ray powder diffraction pattern of crystalline Form I of Formula IA.
  • FIG. 2 is an X-ray powder diffraction pattern of crystalline Form II of Compound 4A.
  • FIG. 3 is an X-ray powder diffraction pattern of cry stalline Form III of Compound 4A.
  • FIG. 4 is an X-ray powder diffraction pattern of crystalline Form IV of Compound 4A.
  • FIG. 5 is an X-ray powder diffraction pattern of crystalline Form V of Compound 5.
  • FIG. 6 is an X-ray powder diffraction pattern of crystalline Form VI of Compound 5.
  • the present disclosure pertains to novel, scalable synthesis for preparing crystalline form of a compound of Formula I:
  • This compound is a lipidated DAP -Ala dipeptide derivative.
  • the process for preparing a compound of Formula I comprises the steps of: a) combining Compound 5: with isopropyl alcohol (IP A) and Acid A2 to obtain Compound 6: b) combining succinic anhydride and a first amine base with Compound 6 to obtain a solution containing a compound of Formula I; and c) isolating a compound of Formula I.
  • step b) the first amine base is combined with Compound 6 before the succinic anhydride is added to this combination.
  • Acid A2 is methanesulfonic acid (MsOH, or MSA), and A2‘ is mesylate or MsO".
  • the first amine base is triethylamine (TEA).
  • the process further comprises adding Acid A3 to the solution containing a compound of Formula I from step b) above, wherein Acid A3 is selected from 1,2- Ethanedisulfonic acid (EDSA), hydrochloric acid (HC1), and MsOH.
  • EDSA 1,2- Ethanedisulfonic acid
  • HC1 hydrochloric acid
  • MsOH MsOH.
  • A3 is EDSA.
  • A3 is EDSA dihydrate.
  • the disclosure is directed to a process for preparing a compound of Formula I A: comprising the steps of: a) combining Compound 5 with IPA and Acid A2, wherein Acid A2 is MsOH; b) adding succinic anhydride and a first amine base; c) adding Acid A3, wherein Acid A3 is EDSA; and d) isolating a crystalline compound of Formula IA.
  • the disclosure is directed to a process for preparing a crystalline Compound 5 comprising the steps of: a) combining Compound 2
  • step c) a mixture of Compound 4B and a corresponding compound having 2 anions, Compound 4B*, is generated. In various embodiments. Compound 4B predominates in said mixture.
  • the second amine base is N,N- Diisopropylethylamine (DIPEA).
  • Acid Al is trifluoroacetic acid (TFA) and the water-soluble solvent is acetonitrile (MeCN).
  • the coupling reagent is 1,1'- Carbonyldiimidazole (CDI).
  • the polar aprotic solvent is MeCN and the antisolvent is IP Ac.
  • the tri-alkyl amine base is TEA. In a further embodiment, the tri-alkyl amine base is DIPEA. In some embodiments, an MeCN polar aprotic solvent, IP Ac antisolvent, and DIPEA tri-alkyl amine base is used.
  • the processes of the disclosure may be conducted in a single vessel, as a “one-pot” process. Alternatively, the steps may be conducted sequentially. For clarity, it should be noted that any of the steps and reactions of the instant invention may occur simultaneously, or sequentially, unless otherwise specifically designated. In embodiments, the intermediate products may optionally be isolated.
  • the invention is directed to a compound of Formula I: wherein “-A” represents an anion.
  • the invention is directed to a cry stalline form of a compound of Formula I.
  • the disclosure also provides salts and zwitterions of a compound of Formula IA.
  • a compound of Formula IA can be depicted as:
  • the invention is directed to a crystalline form of a compound of Formula TA.
  • the crystalline form of a compound of Formula IA described herein is a hemi- EDSA salt.
  • the hemi-EDSA salt anhydrate of a compound of Formula IA is a crystalline material and is designated Form I (anhydrate).
  • Form I may be obtained by preparing EDSA slurry’, followed by filtering and washing with 2: 1 IPA/THF and dried under vacuum.
  • Form I is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 7.96, about 13.36, and about 18.79° 20.
  • the PXRD spectrum of Form I is illustrated in Figure 1.
  • Form I (anhydrate) is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 7.96, about 10.66, about 13.36, about 17.97, about 18.79 , and about 19.54° 20.
  • Form I (anhydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 2.22.
  • the invention is directed to Compound 2. , or a salt or zwitterion thereof.
  • the invention is directed to Compound 3, or a salt or zwiterion thereof.
  • the invention is directed to a crystalline form of Compound 4A that is one of Form II, Form III or Form IV, each being a hydrate.
  • Form II of Compound 4A is provided.
  • crystalline forms of Compound 4A are provided having an X-ray powder diffraction patern substantially similar to that set forth in Figure 2.
  • Form II (hydrate) is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 5.93, about 11.91 and about 24.55° 20. In certain embodiments, Form II is characterized by an X-ray powder diffraction containing at least 3 29 values measured using CuKa radiation selected from the group consisting of about 5.93, about 11.91, about 12.92, about 19.65, about 24.55 and about 26.54° 20.
  • Form II is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 5.93, about 6.02, about 8.11, about 9.00, about 11.10, about 11.91. about 12.92, about 15.73, about 16.38. about 17.25. about 18.00, about 18.55, about 19.05.
  • Form III (hydrate) is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 8.84, about 23.21, and about 23.56° 20. In certain embodiments, Form III (hydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 8.84, about 16.34, about 20.43, about 22.51, about 23.21, and about 23.56° 20. In certain embodiments, Form III (hydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 6.02. about 8. 17. about 8.84.
  • Form IV (hydrate) is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 6.03, about 12.02, and about 19.71° 20. In certain embodiments, Form IV (hydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 6.03. about 12.02, about 17.93, about 19.45, about 19.71 and about 20.51° 20.
  • Compound 4B is provided: wherein “-A1” represents an anion.
  • salts and zwitterions of Compound 4B are provided.
  • Compound 4B* is provided: wherein “-A1” represents an anion.
  • salts and/or zwitterions of Compound 4B* are provided.
  • Compounds 4C and 4C* represents the embodiments of 4B and 4B*, respectively, wherein AC is trifluoroacetate (TFA).
  • salts and/or zwitterions of Compound 5 are provided.
  • the invention is directed to a crystalline form of Compound 5 selected from Form V or Form VI.
  • Form V of Compound 5 is provided.
  • crystalline forms of Compound 5 are provided having an X-ray powder diffraction pattern substantially similar to that set forth in Figure 5.
  • Form VI is characterized by an X- ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 7.90, about 8.86 and about 9.48, about 13.16, about 15.88, and about 20.70° 20. In certain embodiments.
  • A2‘ represents an anion.
  • salts and/or zwitterions of Compound 6 are provided.
  • Compound 6* is provided.
  • Compound 6* represents the embodiment wherein A2‘ is MsO’.
  • salts and/or zwitterions of Compound 6* are provided.
  • a compound selected from Compound 6*, 4C, and 4C* is provided.
  • salts and/or zwitterions of Compounds 6*, 4C, and 4C* are provided.
  • the crystalline forms provided herein are identifiable on the basis of characteristic peaks in an X-ray powder diffraction analysis.
  • X-ray powder diffraction is a scientific technique using X-ray diffraction on powder, microcrystalline, or other solid materials for structural characterization of solid materials.
  • X-ray powder diffraction studies are widely used to characterize molecular structures, crystallinity, and polymorphism.
  • the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.
  • the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise.
  • the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.
  • the temperature, or the length of time for a reaction, as described herein means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter; where appropriate, the stated parameter may be rounded to the nearest whole number. For example, a temperature of about 30°C may vary between 25°C and 35°C.
  • the term “or,” as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term “or” includes each listed alternative separately.
  • the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.”
  • the terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps.
  • such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds.
  • the compounds of the present disclosure may be depicted with negative or positive formal charges. In various embodiments, these compounds exist in a charged state in a solution. In solution, any of the disclosed charged compounds may exist in a different protonation, anionic and/or zwitterionic state than that depicted. As such, zwitterions of any of the disclosed compounds are provided.
  • the compounds of the present disclosure may contain one or more asymmetric centers and can thus occur as “stereoisomers” including racemates and racemic mixtures, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this disclosure. The present disclosure is meant to comprehend all such isomeric forms of these compounds.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • the compounds of the present disclosure which contain olefinic double bounds, unless specified otherwise, are meant to include both E and Z geometric isomers.
  • Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed by the compounds of the present disclosure.
  • Some of the compounds described herein may exist as atropisomers when the rotational energy barrier around a single bond is sufficiently high to prevent free rotation at a given temperature, thus allowing isolation of individual conformers with distinct properties.
  • the individual atropisomers as well as mixtures thereof are encompassed by the compounds of the present disclosure.
  • individual atropisomers can be designated by established conventions such as those specified by the International Union of Pure Applied Chemistry (IUPAC) 2013 Recommendations.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of the present disclosure and embodiments thereof.
  • different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H, also denoted herein as D).
  • Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • salts refers to salts prepared from acceptable bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, JV.A'-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, A-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as arginine
  • Such acids include aryl sulfonic acids, such as but not limited to /?-toluenesulfomc acid, 3-methyl-toluenesulfonic acid, 2-methyl- toluenesulfonic acid, benzenesulfonic acid, 2-naphthalene sulfonic acid, 2,6-naphtalene sulfonic acid, as well as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, hippuric acid, adipic acid, phenyl acetic acid, trimethylacetic acid, tetrafluoroboric acid, tetraphenylboric acid, trifluoroacetic acid (TFA), maleic acid, fumaric acid, oxalic acid, or camphorsulfonic acid.
  • aryl sulfonic acids such as but not limited to /?-toluenesulfomc acid, 3-methyl-toluenesul
  • Particular embodiments include EDSA, MSA. TFA, TEA, terephthalic, hippuric. adipic and hydrochloric.
  • the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of the present disclosure by customary methods which are known to the person skilled in the art, for example, by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts.
  • the present disclosure also includes all salts of the compounds which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • Acid Al is selected from TFA, MsOH, and HC1.
  • Acid A2 is independently selected MsOH, HC1, sulfuric acid, TFA, and EDSA.
  • a water-soluble solvent is selected from MeCN, DMF, DMAc, NMP, THF, acetone and the like.
  • the coupling reagent is CDI, HATU, EDC, and DCC
  • an antisolvent is selected from IP Ac. MTBE, toluene, hexane, EtOAc, Me-THF and the like.
  • a molar equivalent of about 0.85, 0.95, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 of Acid Al is added to Compound 4A.
  • a mixture of Compounds 4B and 4B* is generated.
  • 4B and 4B :i! are present in the mixture.
  • 4B predominates.
  • 4B and 4B* are present in approximate ratios of 10: 1, 8: 1, 6: 1, 5: 1, 4: 1, 7:2, 3: 1, 5:2, 2: 1, 3:2 or 1 : 1 (w/w).
  • 6-Chlorohexanol 1 In a cylindrical vessel under nitrogen, 6-chlorohexanol (100 g. 0.73 mol, 1 eq) was charged to a stirring solution of sodium dihydrogen phosphate dihydrate (285 g, 1.83 mol, 2.5 eq) in 600 mL (6 vol) water at 20 °C. 800 mL (8 vol) IP Ac, TEMPO (5.7 g, 0.07 mol, 0.05 eq) and 10% sodium hypochlorite solution (52.1 g, 0.04 mol, 0.1 eq) was sequentially charged to the vessel. The resulting biphasic mixture was stirred at 20 °C for 30 min.
  • Aqueous sodium chlorite solution (449 g, containing 99 g sodium chlorite, 1.10 mol, 1.5 eq) was charged slowly to maintain batch temperature below 25 °C. The resulting mixture was agitated for 10 h. 20 wt% sodium sulfite solution (100 g, 1 vol) was charged slowly to quench the reaction. After phase separation, the organic layer was collected and extracted with 1.2 M sodium bicarbonate solution twice (9 + 3 vol). The resulting aqueous layers were combined, and the pH was adjusted to 3-5 by addition of 2 M HC1 (750 g). The resulting aqueous solution was extracted with 500 mL IP Ac twice (2x 5 vol). The combined organic layers were washed with 300 mL (3 vol) pure water. The resulting organic solution was concentrated under vacuum to afford Compound 1 (6- chlorohexanoic acid) as a solution (35 wt% in IPAc).
  • Form II (hydrate) of Compound 4A was obtained by preparing a slurry of crude Compound 4A in any one of the following solvents: ethyl acetate, isopropanol, acetone, di chloromethane, MeCN, THF, 1 -propanol, DMAc, ethanol, 2-methyl THF, cyclopen tylmethyl ether (CPME), toluene, methanol, and DMSO/H2O; followed by air drying to afford a crystalline solid.
  • a slurry is formed at 50 °C.
  • a slurry is formed at 25 °C.
  • a slurry is formed at 6 °C.
  • Form II was characterized by PXRD. The PXRD spectrum is illustrated in Figure 2.
  • Form III (hydrate) of Compound 4A was obtained by preparing a slurry of crude Compound 4A in acelonilrile/FbO 9: 1 ratio (v/v), followed by air drying to afford a crystalline solid.
  • Form III was characterized by PXRD, and the PXRD spectrum is illustrated in Figure 3.
  • Form IV (hydrate) of compound 4A may be obtained by heating Form III to 160 °C at a rate of 10 °C per minute.
  • the PXRD spectrum of Form IV is illustrated in Figure 4.
  • Form V (hydrate) of Compound 5 was obtained by preparing a slurry of crude Compound 5 in any one of the following solvents: ethyl acetate, isopropanol, acetone, dichloromethane, MeCN, THF, ethanol, 2-methyl THF, CPME, toluene, MTBE, IPAc, and DMSO/H2O; followed by air drying to afford a crystalline solid.
  • the solvent IPAc and/or MeCN is used in the slurry.
  • a slurry is formed at 50 °C.
  • a slurry is formed at 25 °C.
  • a slurry is formed at 6 °C.
  • Form V was characterized by PXRD. The PXRD spectrum is illustrated in Figure 5.
  • Form VI (hydrate) of Compound 5 was obtained by preparing a slurry of crude Compound 5 in methanol, followed by air drying to afford a cry stalline solid.
  • Form VI was characterized by PXRD. The PXRD spectrum is illustrated in Figure 6.
  • Step A To a solution of Compound 5 (1.0 kg. 2.32 mol) in IPA (10 L). MSA (0.75 L, 11.6 mol) was added at 25 °C. The reaction mixture was aged at 55 °C for 24 h and the resulting crude solution of Compound 6 was cooled to 0 °C. To the reaction mixture, TEA (1.75 L, 12.5 mol) was added slowly to maintain contents at 0 °C followed by addition of Succinic Anhydride (0.30 kg. 3.02 mol) . The slurry was then warmed to 25 °C and aged for at least 1 h to afford a solution containing a compound of Formula I.
  • Step B In a separate vessel, a solution of EDSA was prepared by dissolving EDSA (0.37 kg, 1.62 mol) in IPA (3.7 L) at 25 °C for at least 1 h.
  • Step C The resulting crude solution containing a compound of Formula I, was heated to
  • Step A To a solution of Compound 5 (1.0 kg. 2.32 mol) in IPA (10 L). MSA (0.75 L,
  • Step B In a separate vessel, a solution of EDSA was prepared by dissolving EDSA (0.37 kg, 1.62 mol) in IPA (3.7 L) at 25 °C for at least 1 h.
  • Step C The resulting crude solution containing a compound of Formula I, was heated to 52.5 °C. To the batch. 0.275 eq EDSA solution (0.638 mol) and aged overnight until a slurry is formed. Seeds of compound IA were added, and aged for at least 30 minutes. To the resulting slurry', 0.275 eq EDSA solution was charged slowly over 5 h The batch was then increased to 62.5 °C and aged for 2 h followed by cooling down the batch to 52.5 °C over 3 h. THF (5.5 L) was charged over 5 h to maintaining batch temperature at 52.5 °C. The batch was then cooled to 20 °C over 4 h.
  • Example 7 Method for Obtaining X-Ray Powder Diffraction Paterns
  • Powder X-ray Diffraction data were acquired on a Panalytical X-pert Pro PW3040 System configured in the Bragg-Brentano configuration and equipped with a Cu radiation source with monochromatization to Ka achieved using a Nickel filter. A fixed slit optical configuration was employed for data acquisition. Data were acquired between 2 and 40° 20. Samples were prepared by gently pressing powdered sample onto a shallow cavity zero background silicon holder.
  • Tables 1-6 provide the major 29 peak positions (“Pos.”) and d-spacings for each of the isolated cry stalline forms described herein. “Rel. Int.’' refers to relative intensities.

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Abstract

La présente invention se rapporte à un procédé efficace et évolutif de synthèse d'un peptide lipidé cristallin, tel qu'un composé représenté par la formule I, dans laquelle A représente un anion correspondant, et à un procédé de préparation de composés intermédiaires utiles pour générer un composé représenté par la formule I. L'invention se rapporte également à des composés représentés par la formule I ainsi qu'à des sels et à des zwitterions correspondants. L'invention se réfère en outre à des composés intermédiaires utiles dans la préparation de composés représentés par la formule I, à des sels et à des zwitterions correspondants ainsi qu'à des formes solides cristallines de ces composés.
PCT/US2025/036006 2024-07-03 2025-07-01 Procédé de préparation d'un peptide lipidé et composés intermédiaires associés Pending WO2026010901A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5312831A (en) * 1993-05-12 1994-05-17 American Cyanamid Company Urethanes and ureas that induce cytokine production
US20060019900A1 (en) * 2004-05-27 2006-01-26 The Regents Of The University Of California Alpha-4 beta-1 integrin ligands for imaging and therapy
US20090075936A1 (en) * 2005-02-11 2009-03-19 Cephalon, Inc. Proteasome inhibitors and methods of using the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5312831A (en) * 1993-05-12 1994-05-17 American Cyanamid Company Urethanes and ureas that induce cytokine production
US20060019900A1 (en) * 2004-05-27 2006-01-26 The Regents Of The University Of California Alpha-4 beta-1 integrin ligands for imaging and therapy
US20090075936A1 (en) * 2005-02-11 2009-03-19 Cephalon, Inc. Proteasome inhibitors and methods of using the same

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