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WO2025128106A1 - Intermédiaires pharmaceutiques et leurs procédés de préparation dans la synthèse de muscimol et de congénères et leurs dérivés - Google Patents

Intermédiaires pharmaceutiques et leurs procédés de préparation dans la synthèse de muscimol et de congénères et leurs dérivés Download PDF

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Publication number
WO2025128106A1
WO2025128106A1 PCT/US2023/083997 US2023083997W WO2025128106A1 WO 2025128106 A1 WO2025128106 A1 WO 2025128106A1 US 2023083997 W US2023083997 W US 2023083997W WO 2025128106 A1 WO2025128106 A1 WO 2025128106A1
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Prior art keywords
muscimol
compound
mixture
synthesis
derivatives
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PCT/US2023/083997
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English (en)
Inventor
William Allen BOULANGER
Zongbo Tong
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Priority to PCT/US2023/083997 priority Critical patent/WO2025128106A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D261/12—Oxygen atoms

Definitions

  • the present invention relates in general to novel pharmaceutical intermediates, including, but not limited to, muscimol mono-BOC (Le., tert-butyl ((3- hydroxyisoxazol-5-yl)methyl)carbamate) and to methods for efficiently preparing the same in the synthesis of muscimol (Le.. agarin, pantherine, 5-(aminomethyl)isoxazol-3- ol) and congeners and derivatives thereof.
  • muscimol mono-BOC Le., tert-butyl ((3- hydroxyisoxazol-5-yl)methyl)carbamate
  • Muscimol is a component of the mushroom Amanita Muscaria, and is one of the active principle compounds it contains. It is considered a hallucinogen with possible therapeutic applications. Syntheses of muscimol have appeared from the late 1960's, but to date, none have been practical for either large scale manufacture or for manufacture under GMP conditions for pharmaceutical use. See, for example, Synthesis of pantherine and related compounds By: Bowden, Kenneth; et al. Journal of the Chemical Society [Section] C: Organic (1968), (2), 172- 85., A convenient synthesis of muscimol by a 1 ,3-dipolar cycloaddition reaction By: Chiarino, D.; et al.
  • muscimol as a free base is a very delicate compound that is freely soluble in water, making it very difficult to free it from the associated salts in its production. This can only be achieved by ion exchange chromatography.
  • Some of the syntheses are very short, but depend upon the use of fulminate intermediates, which have a reputation for explosivity in the presence of certain metals. Other preparations require material not available in significant quantities.
  • muscimol is extremely stable at low pH, but above pH 7, it rapidly decomposes, apparently via a polymerization. This means that if a hydrohalide form is produced initially, a base as weak as sodium bicarbonate to create the free base is sufficient to significantly reduce the yield on small scale, and to destroy the product completely on larger scale, where manipulation times are longer. Bench scale preparations use ion exchange chromatography, but this comes at a price of yield. The simple solution to this is to keep the product in the hydrohalide form, preferably hydrochloride, which is much more stable. This creates a new issue of how to purify the crude muscimol hydrochloride. This process addresses the issue both prior to the creation of muscimol proper, and at the final step.
  • the starting material is readily available commercially, and the first step goes nearly quantitatively to form the stable dimethoxylketal.
  • the ketal serves the double function of not only protecting the ketone, but also kinetically de-activating the neighboring chloride as a leaving group due to steric interference.
  • the hydroxylamine reaction proved to give poor yields and purity; residual hydroxyl amine carried through to later steps and proved problematic.
  • the final two steps are also very problematic, and likely the reason for the reported irreproducibility.
  • the authors provide scant detail for the ring closure reaction, and even in their hands, this reaction gave poor yields.
  • the desired reaction pathway requires protonation of one of the ketal methoxy's, ring closure by displacement by the hydroxyl on the amide nitrogen, then protonation and elimination of the remaining methoxy to form the ring double bond. Competing with this mechanism is simple acid- catalyzed hydrolysis of the amide bond, leading to product loss.
  • muscimol mono-BOC i.e. , tert-butyl ((3-hydroxyisoxazol-5-yl)methyl
  • the present invention is directed to a compound/pharmaceutical intermediate, comprising, consisting essentially of, and/or consisting of the structure: wherein Ri-R 3 are the same or different and selected from the group consisting of H; OH; and an alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl, alkenyl, and/or alkynyl group containing approximately 1 to approximately 25 carbon atom(s), wherein the carbon atom(s) may be a linking group to, or part of, a halogen, a N, O, and/or S containing moiety, and/or one or more functional groups comprising alcohols, esters, ammonium salts, phosphonium salts, and combinations thereof.
  • Ri-R 3 are the same or different and selected from the group consisting of H; OH; and an alkyl, cycloalkyl, poly
  • the present invention is further directed to a compound/pharmaceutical intermediate, comprising, consisting essentially of, and/or consisting of the structure:
  • the present invention is directed to a compound/pharmaceutical intermediate, comprising, consisting essentially of, and/or wherein Ri-R 3 are the same or different and selected from the group consisting of H; OH; and an alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl, alkenyl, and/or alkynyl group containing approximately 1 to approximately 25 carbon atom(s), with the proviso that at least two of RI-R 3 comprise methyl groups.
  • Ri-R 3 are the same or different and selected from the group consisting of H; OH; and an alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkanoyl, aroyl, alkenyl, and/or alkynyl group containing approximately 1 to
  • the present invention is further directed to a compound/pharmaceutical intermediate, comprising, consisting essentially of, and/or consisting of the structure: tert-butyl ((3-hydroxyisoxazol-5-yl)methyl)carbamate
  • the first tautomer of the compound generally comprises the 1 H-NMR spectrogram of Figure 3 and/or the 13 C-NMR spectrogram of Figure 4.
  • Muscimol is prepared using the above-identified intermediate.
  • the exposure to concentrated HCI is preferably brief, and at an elevated temperature. What is more, if the concentrated HCI is removed by typical evaporation, even at low temperature, the required time at elevated temperature favors hydrolysis.
  • the product can be extracted from subsequently diluted HCI by use of a solvent, such as ethyl acetate or isopropyl acetate, and any carried-over HCI can be washed away with brine from the extracts.
  • a flow reactor is used. The reaction naturally off-gasses both HCI and methyl chloride as it proceeds, so some arrangement must be created where gas can be removed, but not be allowed to push the liquid prematurely through the reactor.
  • reaction fluid passes through a series of vented cells in a heated bath.
  • Two basically different designs of such cells were used. Each cell was configured such that the liquid enters on the bottom of the cell, slowly rises up, then overflows into the next cell. Optimally, each cell stage has its own metering pump in, so that the system does not rely on gravity alone. In practice, only four cells were used on a very slow flow set-up (total residence time 35 minutes), but more cells or larger cells can be used for a faster through-put.
  • a solution of the hydroxylamide is prepared at ambient temperature, and fed into a series of four cells suspended in a bath at 80 °C for a period between 25 and 50 minutes residence time, then immediately taken through a cold bath at ice temperature and diluted, at which point a solvent such as ethyl acetate or isopropyl acetate is introduced and put through a static mixer, then sent cold to a receiver. There the first extraction is removed, and the aqueous layer extracted twice more with the same solvent. The combined extracts are then washed with brine twice to remove residual HCI, and the crude chloroisooxazole is recovered by removal of the solvent.
  • This method has the advantage of a small footprint, is a continuous operation, and is capable of considerable scaling up.
  • this can be run batch-wise, with the concentrated HCI solution being introduced into a larger volume of water, where it is diluted. When the HCI concentration reaches 2 M, the mixture is extracted as described above.
  • the amination can be run with between 20 and 30 equivalents of ammonium hydroxide in the absence of organic co-solvents at 20-25 °C.
  • Organic cosolvents strongly promote dimer or trimer formation.
  • the residual ammonium hydroxide is removed with good vacuum below 45 °C, to give the crude muscimol. These conditions promote decomposition of the muscimol as the scale increases, even though they work quite well on the 100 g scale.
  • the pH may be adjusted to about pH 3 with concentrated HCI, releasing the N-BOC muscimol. This may be recovered by extraction, leaving clean mono BOC muscimol as a solid after solvent removal. As the N-BOC muscimol is unstable to prolonged exposure to low pH, this must be done expeditiously. This step removes the residual latent ammonia that appeared in the product of previous preparations.
  • the crude N-BOC muscimol may be further purified by recrystallization from a solvent system like MTBE/hexanes or ethyl acetate/hexanes.
  • the reaction mixture was cooled down to room temperature, then concentrated by half using a rotary evaporator.
  • the residue was neutralized by slow addition of the concentrate to a suspension of sodium carbonate (194 g, 1 .826 mol. 0.55 eq) in 8 L water.
  • the neutralized reaction mixture is extracted 3 times with a 1 :1 mixture of hexanes/ ethyl acetate (5 L each).
  • the combined extracts were dried over sodium sulfate, filtered, then concentrated to give the crude Methyl 4-chloro-3,3-dimethoxy butanoate, 5.8 Kg, 89%.
  • a small 3 neck flask was set up with a magnetic stirrer, dropping funnel, thermoprobe, and empty ice bath. To the flask was added methyl 4-chloro-3,3- dimethylbutanoate (2g, 10 mmol) and methanol (3.3 g, 4.16 mL). The mixture was cooled to 15 °C, and hydroxylamine hydrochloride (1.02 g, 14.7 mmol) was added all at once. Sodium methoxide, 30% in methanol (5.327 g, 29.6 mmol) was charged to the addition funnel and added over 2-3 hrs, while keeping the temperature between 15 and 25 °C. The reaction was then stirred at 20 °C for 12 hrs.
  • the mixture was diluted with a little n-butanol, then re-concentrated, removing about 80% of the volume. 6 L of 88:1 ethyl acetate: methanol were added, then the mixture was reconcentrated. Then 7 L ethyl acetate were added, and the mixture brought to 55 °C. The mixture was cooled to 0 °C, then filtered. The mother liquors were concentrated ands cooled as before, giving a second crop. 4.2 K 87.5% yield.
  • a 22-L round-bottom flask was set up with a mechanical stirrer, addition funnel, and thermoprobe.
  • a solution of methyl 4-chloro-3,3-dimethoxy-butanoate (1 .0 Kg, 5.1 mol) in methanol (2 L) was charged to the flask.
  • Hydroxylamine hydrochloride (509 g, 7.32 mol, 1 .44 eq) was added to the flask all at once, with stirring.
  • Sodium methoxide, 30 % in methanol (2.65 kg solution, 14.75 mol, 2 eq vs ketal) was charged to the addition funnel, and added slowly over 2 hrs, 45 minutes. Temperature at end of addition: 17.1 °C.
  • n-Butanol 400 mL was added, and the mixture reconcentrated as much as possible. Then a mixture of 88% ethyl acetate/12% methanol was added; this was then stripped down nearly completely. Finally, ethyl acetate (8 L) was added, and the mixture heated at 45 °C to dissolve the crude product as much as possible; this mixture was then brought to 0 °C, and kept there until the product had fully crystallized. The mixture was filtered to harvest a first crop of product. The mother liquors were concentrated, cooled as before, and a second crop of product obtained. These were combined, and dried, giving 870 g, 87% yield of 4- chloro-N-hydroxy-3,3-dimethoxybutanamide.
  • the flask was charged with 4-chloro-N-hydroxy-3,3- dimethoxybutanamide (10 g, 50.7 mmol) prepared by the improved method, and 50 mL 12 M HCI. After 10 minutes at 80 °C, HPLC analysis of a sample showed 93% product. The reaction was stopped and cooled, diluted with water, then extracted three times with ethyl acetate.
  • a mixture of 4-chloro-N-hydroxy-3,3-dimethoxybutanamide (50 g, 0.308 mol) and 10 M HCI (370 mL, 10 eq’s) was prepared, and metered into the series of flow reactors over approximately 1 hr. To chase the system, another 400 mL of brine was then metered through, while still at 80 °C. When the brine flush had completed, the mixture in the receiver was thoroughly mixed, and the isopropyl acetate removed. The aqueous layer was extracted twice more with isopropyl acetate (300 mL), giving a solution of crude 5-(chloromethyl)isoxazol-3-ol.
  • the organic phase was extracted twice with 0.3M sodium carbonate, drawing the product into the aqueous phase.
  • the aqueous phase was washed with MTBE, then acidified with 2 NHCI and extracted twice with ethyl acetate. The product is now in the ethyl acetate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne des intermédiaires pharmaceutiques et des procédés de préparation efficace de muscimol mono-BOC et de ses dérivés dans la synthèse de muscimol et de congénères et de dérivés de ceux-ci.
PCT/US2023/083997 2023-12-14 2023-12-14 Intermédiaires pharmaceutiques et leurs procédés de préparation dans la synthèse de muscimol et de congénères et leurs dérivés Pending WO2025128106A1 (fr)

Priority Applications (1)

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PCT/US2023/083997 WO2025128106A1 (fr) 2023-12-14 2023-12-14 Intermédiaires pharmaceutiques et leurs procédés de préparation dans la synthèse de muscimol et de congénères et leurs dérivés

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11998531B1 (en) * 2023-12-14 2024-06-04 William Allen Boulanger Pharmaceutical intermediates and methods for preparing the same in the synthesis of muscimol and congeners and derivatives thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11998531B1 (en) * 2023-12-14 2024-06-04 William Allen Boulanger Pharmaceutical intermediates and methods for preparing the same in the synthesis of muscimol and congeners and derivatives thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHIARINO D, NAPOLETANO M, SALA A: "A convenient synthesis of muscimol by a 1,3-dipolar cycloaddition reaction", TETRAHEDRON LETTERS, vol. 27, no. 27, 1 January 1986 (1986-01-01), AMSTERDAM, NL, pages 3181 - 3182, XP002952885, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(00)84748-6 *
FRÀTER‐SCHRÖDER M., GOOD R., EUGSTER C. H.: "81. zur Kenntnis der VAN SLYKE-Reaktion des Muscimols und anderer 3-hydroxyisoxazole", HELVETICA CHIMICA ACTA, vol. 52, no. 3, 1 January 1969 (1969-01-01), Hoboken, USA, pages 720 - 724, XP093324055, ISSN: 0018-019X, DOI: 10.1002/hlca.19690520321 *
MICHAEL FREY, VOLKER JAEGER: "Synthesis of N-substituted muscimol derivatives including N-glycylmuscimol", SYNTHESIS, vol. 1985, no. 12, 1 December 1985 (1985-12-01), pages 1100 - 1104, XP002523155, ISSN: 0039-7881, DOI: 10.1055/s-1985-31439 *
NAKAMURA N.: "Improved syntheses of dl-ibotenic acid and muscimol", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 19, 1 January 1971 (1971-01-01), pages 46 - 51, XP093324041 *

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