GB2587997A - A semisynthetic method of preparing neosaxitoxin - Google Patents

A semisynthetic method of preparing neosaxitoxin Download PDF

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GB2587997A
GB2587997A GB2018189.7A GB202018189A GB2587997A GB 2587997 A GB2587997 A GB 2587997A GB 202018189 A GB202018189 A GB 202018189A GB 2587997 A GB2587997 A GB 2587997A
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solution
extract
volume
gtx1
isolate
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Ian Selwood Andrew
Van Ginkel Roelof
Alan Waugh Craig
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Cawthron Institute Trust Board
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    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
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    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
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Abstract

A semisynthetic method of preparing neosaxitoxin in quantities of a purity sufficient to allow the compound to be used as an active pharmaceutical ingredient (API) is described. The scalable method includes the reductive desulfonation of an unresolved mixture of gonyautoxin 1 (GTX1) and gonyautoxin 4 (GTX4) isolated from an extract of a culture of Alexandrium pacificum grown to high cell densities in aerated vertical columns of amended sea water.

Claims (10)

1) A method of preparing a quantity of neoSTX comprising the steps of: (a) contacting in solution in a reaction solvent a quantity of purified GTX1,4 and a quantity of dithiol for a period of time and at a temperature sufficient to provide a reaction product in which greater than 97.5% (w/w) of the GTX1,4 has been converted to neoSTX; and then (b) applying the reaction product to a silica based weak cation exchange sorbent and eluting with an aqueous weak organic acid to separate the neoSTX from the dithiol and provide the quantity of neoSTX, where the pH of the solution is in the range 7.4 to 7.6.
2) The method of claim 1 where the reaction solvent is buffered aqueous acetic acid.
3) The method of claim 1 or 2 where the dithiol is selected from the group consisting of dithiothreitol (DTT) and dithiobutylamine (DTBA) .
4) The method of claim 1 where the dithiol is dithiothreitol (DTT) .
5) A method of fractionating a volume of concentrated aqueous extract to provide a solution of partially purified GXT1,4 comprising the steps: (a) Reducing the volume of the aqueous extract by ultrafiltration to provide a reduced volume; (b) Loading the reduced volume on a column of activated carbon sorbent to provide a loaded column; and (c) Eluting the loaded column with a stepwise gradient of water followed by aqueous acetic acid/acetonitrile to provide the solution of partially purified GTX1,4, where the volume of concentrated aqueous extract is an extract of a culture of a dinoflagellate .
6) A method of preparing a volume of concentrated aqueous extract for use in the preparation of a quantity of GTX1,4 comprising the steps: (a) Culturing a selected isolate of a dinoflagellate in a vertical column of aerated amended seawater for a period of time and at a temperature sufficient to provide a culture having a predetermined cell density; (b) Harvesting the cells from the culture having the predetermined cell density to provide a quantity of cellular biomass; (c) Resuspending the quantity of cellular biomass in an aqueous solution of a weak organic acid for a period of time and at a temperature sufficient to provide a mixture of residual biomass and an extract in solution; (d) Separating the residual biomass from the extract in solution; and then (e) Reducing the volume of the extract in solution to provide the volume of concentrated aqueous extract, where the selected isolate has been selected to produce a ratio of GTX2,3 to GTX1,4 of less than 0.1, the amended seawater is seawater amended with a nutrient medium, and the predetermined cell density is in the range 7 x 104 to 105 cells/mL.
7) The method of claim 6 where the selected isolate is an isolate of the dinoflagellate Alexandrium pacificum.
8) The method of claim 7 where the isolate is an isolate of the dinoflagellate Alexandrium pacificum that produces a ratio of GTX2,3 to GTX1,4 of less than 0.01.
9) The method of any one of claims 6 to 8 where the aqueous solution of a weak organic acid is 0.25 to 0.75% acetic acid.
10) A quantity of neoSTX having a purity greater than 99.5% (w/w) where the quantity is greater than 100 mg.
GB2018189.7A 2018-09-21 2018-09-21 A semisynthetic method of preparing neosaxitoxin Active GB2587997B (en)

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PCT/IB2018/057274 WO2020058750A1 (en) 2018-09-21 2018-09-21 A semisynthetic method of preparing neosaxitoxin

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JP (1) JP7110403B2 (en)
CN (1) CN113166164B (en)
CA (1) CA3113727A1 (en)
CL (1) CL2020003015A1 (en)
GB (1) GB2587997B (en)
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CA3113727A1 (en) * 2018-09-21 2020-03-26 The Cawthron Institute Trust Board A semisynthetic method of preparing neosaxitoxin
US12018034B2 (en) 2018-09-21 2024-06-25 The Cawthron Institute Trust Board Semisynthetic methods of preparing GTX1,4 and neosaxitoxin
CN112461913B (en) * 2020-11-06 2022-02-22 华南农业大学 Method for improving identification capability of isomer compound
FR3130842A1 (en) 2021-12-22 2023-06-23 CarbonWorks METHOD FOR CAPTURING PHYTOTOXINS IN A BIOLOGICAL REACTOR

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JP7110403B2 (en) 2022-08-01
CN113166164B (en) 2024-01-30
WO2020058949A1 (en) 2020-03-26
US11028094B2 (en) 2021-06-08
WO2020058750A1 (en) 2020-03-26
GB202018189D0 (en) 2021-01-06
CA3113727A1 (en) 2020-03-26
US20200407367A1 (en) 2020-12-31
GB2587997B (en) 2023-05-10
JP2021526539A (en) 2021-10-07
CL2020003015A1 (en) 2021-06-25
US10822344B2 (en) 2020-11-03
CN113166164A (en) 2021-07-23
US20200255441A1 (en) 2020-08-13

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