CN107325033A - A kind of method of high stereoselectivity synthesis aplysiatoxin Dap fragments - Google Patents
A kind of method of high stereoselectivity synthesis aplysiatoxin Dap fragments Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a kind of synthetic method for preparing aplysiatoxin Dap fragments：Including step：With the ketone (III) of 3 propionyl oxazolidine of (L) N tertbutyloxycarbonyl dried meat ammonium aldehyde (II) and (R) 4 benzyls 2 for raw material, intermediate (I) is prepared；Intermediate (I) obtains intermediate (IV) after hydrolysis；Intermediate (IV) obtains the aplysiatoxin Dap fragments of highly-solid selectively through methylation reaction；Or, the intermediate (I) prepared can also first pass through methylation reaction generation intermediate (V), intermediate (V) obtains the aplysiatoxin Dap fragments of highly-solid selectively through hydrolysis.The preparation method of the present invention is with low cost, easy to operate, and stereoselectivity is high.
Description
Technical field
The invention belongs to pharmacy synthesis technology field, and in particular to a kind of high stereoselectivity synthesis aplysiatoxin 10
(D10) method of Dap fragments.
Background technology
Aplysiatoxin be it is a kind of from food algae mollusk long-tail the back of the body anus sea hare glandula digestive find marine biotoxins it
One, therefore it is named as aplysiatoxin.Aplysiatoxin has a variety of hypotypes, and wherein D10 is one kind of most study, is aplysiatoxin
Representative.Aplysiatoxin is a kind of cellular tubulin inhibitor of strength, has stronger lethal effect to tumour cell, now
The existing antibody coupling medicine list marketing using aplysiatoxin as carrier, to treating cancer.Aplysiatoxin by Dov, Vil,
Dap, Dap, Doe fragment are constituted, and wherein Dap fragments include three chiral centres, and the asymmetric syntheses to Dap fragments is synthesis sea
One of key issue that rabbit toxin is faced.It is related to the report of the synthetic method of Dap fragments successively in the prior art, for example：
(" the The Dolastatins such as George R.Pettit；18:Stereospcific Synthesis of Dolaproine”,
SYNTHESIS,1996,06,719-725).The Dap fragments stereoselectivity synthesized with the method is not high, it is necessary to separate isomers
Purpose product can be just obtained, and raw material is costly, post-processes more complicated.
The content of the invention
It is an object of the invention to provide a kind of method of high stereoselectivity synthesis aplysiatoxin Dap fragments, the present invention
Method raw material it is cheap and easy to get, accessory substance is few, and stereoselectivity is high, it is easy to industrialized production.
The synthetic method of aplysiatoxin Dap fragments of the present invention, comprises the following steps：
(1) in organic solvent, with compound (II) (L)-N- tertbutyloxycarbonyl dried meat ammonium aldehydes and compound (III) (R) -4-
Benzyl -3- propionyl oxazolidine -2- ketone is raw material, in the presence of alkali and auxiliary agent, carries out aldol reaction, obtains intermediate
(I)；
The intermediate (I) of preparation can prepare target compound Dap fragments by following two methods：
Method one：
(2) in a solvent, in the presence of alkali and auxiliary agent, intermediate (I) obtains intermediate (IV) through hydrolysis；
(3) in organic solvent, with alkali, methylating reagent methylation reaction occurs for intermediate (IV), obtains high three-dimensional choosing
Selecting property product aplysiatoxin Dap fragments.
Method two：
(4) in organic solvent, in the presence of drier, acid binding agent and methylating reagent, intermediate (I) is through methylating
Reaction, the intermediate (V) methylated；
(5) in a solvent, in the presence of alkali and auxiliary agent, intermediate (V) is produced through hydrolysis generation highly-solid selectively
Thing aplysiatoxin Dap fragments.
Shown in the course of reaction such as route (1)：
In step (1), the organic solvent is selected from dimethylformamide, dichloromethane, tetrahydrofuran chloroform, dioxy six
One or more in ring, dimethyl sulfoxide (DMSO), 1,2- dichloroethanes etc.；Preferably, it is dichloromethane or tetrahydrofuran.
In step (1), the alkali in DIPEA, triethylamine, sodium carbonate, potassium carbonate, LiHMDS, sodium hydride etc. one
Plant or a variety of；Preferably, it is triethylamine.
In step (1), one kind in the fourth boron of trifluoromethanesulfonic acid two, titanium tetrachloride, alchlor etc. of the auxiliary agent or
It is a variety of；Preferably, it is the fourth boron of trifluoromethanesulfonic acid two.
In step (1), compound (II), compound (III), auxiliary agent, the mol ratio of alkali are 0.8：(0.8-1.5)：(0.8-
1.5)：(0.8-1.5)；Preferably, it is 0.8：0.9：1.0：1.1.
In step (1), the temperature of the aldol reaction is -80 DEG C--20 DEG C；Preferably, it is -75 DEG C.
In step (1), the time of the aldol reaction is -5 hours 1 hour；Preferably, it is 3 hours.
In step (1), the aldol reaction is preferably carried out under nitrogen protection.
In step (1), the step of can also including reaction is quenched after the completion of the aldol reaction；The quencher choosing
One or more from hydrogen peroxide, methanol, ethanol, isopropanol etc.；Preferably, it is hydrogen peroxide, methanol or its mixed solution, its
In, when being mixed solution, the volume ratio of the hydrogen peroxide and methanol is 1：1-1：4, it is therefore preferable to 1：2.
In an embodiment, step (1) includes：(R) -4- benzyl -3- propionyl oxazolidine -2- ketone is added and reacted
Bottle, is added in organic solvent, stirring and dissolving is cooled to 0 DEG C, and gas in reaction bulb is changed into nitrogen protection gas, alkali is added, adds
The fourth boron of trifluoromethanesulfonic acid two, reacts 45 minutes, continues to be cooled to -75 DEG C, be slowly added to (L)-N- tertbutyloxycarbonyl dried meat ammonium aldehydes, instead
Answer 1 hour, be warming up to 0 DEG C, react 2 hours, LC-MS detection reaction carry out degree, after the completion of add the mixed of hydrogen peroxide and methanol
Close solution and reaction is quenched.Rotation removes organic solvent, is extracted twice with dichloromethane, merges organic phase, with sodium acid carbonate and sodium chloride
Wash twice, with anhydrous sodium sulfate drying, column chromatography can obtain intermediate (I).
In step (2), one or more of the solvent in tetrahydrofuran, water, methanol, ethanol, dioxane etc.；
Preferably, it is the mixed solvent of tetrahydrofuran and water, wherein, the volume ratio of the tetrahydrofuran and water is (1-5)：1, preferably
For 4：1.
In step (2), one or more of the alkali in lithium hydroxide, sodium hydroxide, potassium hydroxide etc.；It is preferred that
Ground, is lithium hydroxide.
In step (2), the auxiliary agent is hydrogen peroxide；Preferably, it is the hydrogen peroxide of mass fraction 30%.
In step (2), the intermediate (I), auxiliary agent, the mol ratio of alkali are 1：(3-10)：(1-2)；Preferably, it is 1：
7.2：1.6.
In step (2), the temperature of the hydrolysis is 0 DEG C -20 DEG C；Preferably, it is 0 DEG C.
In step (2), the time of the hydrolysis is 3-10 hours；Preferably, it is 4 hours.
In step (2), after reaction terminates, in addition to the step of reaction is quenched in quencher is used；Wherein, the quencher is
Reducing agent, selected from sodium thiosulfate and/or sodium sulfite；Preferably, it is sodium thiosulfate, sodium sulfite or its saturated solution.
Wherein, the volume ratio of the quencher and reaction solution is 1：4-4：1；Preferably, it is 1：1.
In an embodiment, step (2) includes：Intermediate (I) is put into reaction bulb, tetrahydrofuran and water is added
Mixed solution dissolving, cooled with ice-water bath, add hydrogen peroxide, add lithium hydroxide solution.Monitored and reacted with thin-layer chromatography, greatly
React and complete after about 2 hours, add sodium thiosulfate or reaction is quenched in sodium sulfite solution.Rotation removes volatile solvent, with organic
Solvent is washed three times, collects aqueous phase, with hydrochloric acid water transfer phase PH=3, is extracted three times with organic solvent, is merged organic phase, eaten with saturation
Salt is washed, and organic phase is dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and rotation is that can obtain (IV) except organic solvent.
Wherein, the concentration of hydrochloric acid used in extraction is 0.1-10M；Preferably, it is 1M.
Wherein, the organic solvent used in extraction is in dichloromethane, ethyl acetate, ether, the tertiary ether of first, methyl phenyl ethers anisole etc.
One or more；Preferably, it is ethyl acetate.
In step (3), the organic solvent is selected from dimethylformamide, tetrahydrofuran, dichloromethane, dioxane, two
One or more in methyl sulfoxide etc.；Preferably, it is dimethylformamide or tetrahydrofuran；It is further preferred that being anhydrous
Dimethylformamide or anhydrous tetrahydro furan.
In step (3), one kind in sodium hydride, LiHMDS, n-BuLi, lithium diisopropyl amido etc. of the alkali or
It is a variety of；Preferably, it is sodium hydride.
In step (3), the methylating reagent is selected from iodomethane and/or dimethyl suflfate；Preferably, it is iodomethane.
In step (3), intermediate (IV), alkali, the mol ratio of methylating reagent are (1)：(2-10)：(3-20)；Preferably,
For 1：4.5：17.
In step (3), intermediate (IV) is dissolved in organic solvent, then ice-water bath cooling adds sodium hydride, iodine first
Alkane；Preferably, after adding sodium hydride stirring 30 minutes, iodomethane is added,
In step (3), the temperature of the methylation reaction is 0-20 DEG C；Preferably, it is 0 DEG C.
In step (3), the time of the methylation reaction is 5-24 hours；Preferably, it is 10 hours.
In step (3), the methylation reaction is carried out preferably under inert gas shielding.
In step (3), intermediate (IV) first uses alkali process, then carries out methylation reaction；Preferably, it is 30 points of alkali process
Clock, then carry out methylation reaction；Wherein described alkali includes sodium hydride, LiHMDS, n-BuLi, lithium diisopropyl amido.
In step (3), the step of reaction can also being quenched including the use of frozen water after reaction completely.
Wherein, the step of also including extraction after reaction is quenched；Wherein, the organic solvent used in extraction is selected from dichloromethane
The tertiary ether of alkane, ethyl acetate, ether, first, methyl phenyl ethers anisole；Preferably, it is ethyl acetate.
In an embodiment, step (3) includes：Intermediate (IV) is dissolved in tetrahydrofuran, ice-water bath cooling,
Sodium hydride is added, is stirred 30 minutes, iodomethane is added, is stirred overnight at a temperature of 0 DEG C, is detected and reacted using TLC, reaction is completed
Reaction is quenched using frozen water afterwards, is washed with ethyl acetate once, phase of fetching water adjusts pH=3 with hydrochloric acid, three are extracted with organic solvent
It is secondary, merge organic phase, be spin-dried for, column chromatography can obtain Dap fragments.Wherein, the organic solvent used in extraction is selected from dichloromethane,
Ethyl acetate, ether, the tertiary ether of first, methyl phenyl ethers anisole；Preferably, it is ethyl acetate.
In step (4), the organic solvent is selected from dimethylformamide, DMSO, dichloromethane, 1,2- dichloromethane
One or more in；Preferably, it is dimethylformamide, DMSO or its mixed solution, dichloromethane, DMSO
Or its mixed solution；It is further preferred that being dichloromethane, the mixed solution of DMSO, dichloromethane, the body of DMSO
Product is than being (1-5)：1, it is preferable that be 4：1.
In step (4), the drier is selected from molecular sieve, anhydrous sodium sulfate, anhydrous magnesium sulfate；Preferably, it is molecular sieve.
Wherein, the molecular sieve refers to uniform micropore, its aperture class material suitable with general molecular size.The present invention's
Molecular sieve can select the molecular sieve for being widely used as efficient drying agent, selective absorbent, catalyst, ion-exchanger etc..
In step (4), the acid binding agent is selected from proton sponge (1,8- double dimethylamino naphthalenes), sodium acid carbonate, saleratus；
Preferably, it is proton sponge (1,8- double dimethylamino naphthalenes).
In step (4), the methylating reagent is trimethyl oxygen tetrafluoro boric acid.
In step (4), the intermediate (I), acid binding agent, the mol ratio of methylating reagent are 1：(1-3)：(1-3)；It is preferred that
Ground, is 1：2.5：2.6.
In step (4), the temperature of the methylation reaction is 0-25 DEG C；Preferably, it is 0 DEG C.
In step (4), the time of the methylation reaction is 8-20 hours；Preferably, it is 12 hours.
In step (4), the methylation reaction is carried out preferably under inert gas shielding.
In an embodiment, step (4) includes：Intermediate (I) is dissolved in dimethylformamide and DMSO
Mixed solution in, be cooled to 0 DEG C, add molecular sieve, stir 20 minutes, sequentially add proton sponge, trimethyl oxygen tetrafluoro
Boric acid, is stirred overnight at 0 DEG C, filters off molecular sieve, and vacuum rotation removes organic phase, and column chromatography can obtain intermediate (V).
In step (5), one or more of the solvent in tetrahydrofuran, water, methanol, ethanol, dioxane etc.；
Preferably, it is tetrahydrofuran, water or its mixed solution, when for mixed solution, the volume ratio of the tetrahydrofuran and water is (1-
5)：1, it is therefore preferable to 4：1.
In step (5), one or more of the alkali in lithium hydroxide, sodium hydroxide, potassium hydroxide etc.；It is preferred that
Ground, is lithium hydroxide.
In step (5), the auxiliary agent is hydrogen peroxide；Preferably, it is the hydrogen peroxide of mass fraction 30%.
In step (5), after reaction terminates, in addition to the step of reaction is quenched in quencher is used；Wherein, the quencher is
Reducing agent, selected from sodium thiosulfate and/or sodium sulfite；Preferably, it is sodium thiosulfate, sodium sulfite or its saturated solution.
Wherein, it is 1 to add the volume of quencher and the volume ratio of reaction solution：4-4：1, it is preferable that be 1：1.
In step (5), intermediate (V), auxiliary agent, the mol ratio of alkali are 1：(3-10)：(1-2)；Preferably, it is 1：7.2：
1.6。
In step (5), the temperature of the hydrolysis is 0-20 DEG C；Preferably, it is 0 DEG C.
In step (5), the time of the hydrolysis is 3-10 hours；Preferably, it is 4 hours.
In an embodiment, step (5) includes：Intermediate (V) is put into reaction bulb, tetrahydrofuran and water is added
Mixed solution dissolving, cooled with ice-water bath, add hydrogen peroxide, add lithium hydroxide solution.Monitored and reacted with thin-layer chromatography, greatly
React and complete after about 2 hours, add sodium thiosulfate or reaction is quenched in sodium sulfite solution.Rotation removes volatile solvent, with organic
Solvent is washed three times, collects aqueous phase, with hydrochloric acid water transfer phase PH=3, is extracted three times with organic solvent, is merged organic phase, eaten with saturation
Salt is washed, and organic phase is dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and rotation is that can obtain the aplysiatoxin Dap except organic solvent
Fragment.
Wherein, it is 1 to add the volume of sodium sulfite saturated solution and the ratio of reaction solution：4-4：1, it is preferable that be 1：1.
Wherein, the organic solvent used in extraction is selected from dichloromethane, ethyl acetate, ether, the tertiary ether of first, methyl phenyl ethers anisole；It is excellent
Selection of land, is ethyl acetate.
Wherein, the concentration of hydrochloric acid is 0.1-10M；Preferably, it is 1M.
In a specific embodiment, the reaction scheme of the synthetic method of the aplysiatoxin Dap fragments is as follows：
The invention also provides a kind of N- tertbutyloxycarbonyls proline Yan Sheng oxazolidinone compounds, its structure is as follows
Shown in formula (I)：
The invention also provides prepared by N- tertbutyloxycarbonyls proline Yan Sheng oxazolidinone compounds shown in formula (I)
Application in aplysiatoxin Dap fragments.
The beneficial effects of the present invention are, the present invention with (L)-N- tertbutyloxycarbonyl dried meat ammonium aldehydes (II) and (R) -4- benzyls -
3- propionyl oxazolidine -2- ketone (III) is raw material, prepares intermediate (I)；Intermediate (I) obtains intermediate (IV) after hydrolysis；In
Mesosome (IV) obtains the aplysiatoxin Dap fragments of highly-solid selectively through methylation reaction；Or, the intermediate (I) prepared also may be used
To first pass through methylation reaction generation intermediate (V), intermediate (V) obtains the aplysiatoxin of highly-solid selectively through hydrolysis
Dap fragments.The preparation method of the present invention is with low cost, easy to operate, and stereoselectivity is high.
Embodiment
With reference to specific examples below, the present invention is described in further detail, implement the present invention process, condition,
Reagent, experimental method etc., are the universal knowledege and common knowledge of this area, this hair in addition to the following content specially referred to
It is bright that content is not particularly limited.
Embodiment 1
(1) synthesis of intermediate (I)
2.4g compounds (III) are dissolved in 30ml dichloroethanes, ice-water bath is cooled to 0 DEG C, by air in reaction system
Take out to the greatest extent, add nitrogen protection, add the 5ml 1mol/L fourth boron of trifluoromethanesulfonic acid two, solution is changed into kermesinus, adds 0.8ml
Triethylamine, solution is changed into faint yellow clear.Reacted 45 minutes at 0 DEG C.Reaction system is cooled to -75 DEG C, slow drop
Plus 1.9g reactants (IV), reacted 1 hour at -75 DEG C after being added dropwise to complete, be warming up to 0 DEG C, reacted 2 hours, be warming up to after room temperature
TLC detection reactions, can complete reaction for general 1 hour.15ml methanol is added after the completion of reaction：Hydrogen peroxide (30%)=2：1 quenches
Go out reaction, solution becomes colorless, and a small amount of muddiness is arranged at bottom.Extracted three times with 25ml dichloromethane, merge organic phase, use 25ml carbon
Sour hydrogen sodium saturated solution is washed twice, and saturated common salt is washed once, and rotation removes dry method loading after organic solvent, uses petroleum ether：Acetic acid second
Ester=5：1 column chromatography, can obtain the solid of white blister, as intermediate (I) (3.5g, 86%).
1H NMR (400MHz, DMSO) δ 7.36-7.15 (m, 5H), 5.10-4.90 (m, 1H), 4.65 (dd, J=31.4,
12.6Hz, 1H), 4.32 (t, J=8.4Hz, 1H), 4.22 (dd, J=8.9,2.2Hz, 1H), 3.91 (s, 1H), 3.67 (s,
2H), 3.34 (s, 2H), 2.98 (d, J=4.9Hz, 3H), 1.93-1.74 (m, 2H), 1.62 (dd, J=25.9,7.8Hz, 2H),
1.40(s,9H),1.28–1.12(m,4H).
(2) intermediate (I) hydrolysis intermediate (IV)
600mg intermediates (I) are dissolved in 8ml tetrahydrofurans, 2ml water is added, ice-water bath adds the dioxygens of 1.2ml 30%
Water, adds the solution that 3ml dissolves the hydronium(ion) lithias of 95mg mono-, and TLC monitoring reactions are reacted after about 4 hours and completed, add
10ml saturated sodium bisulfite solutions, are warming up to room temperature, and reaction is stayed overnight.Rotation removes organic solvent, is washed with 6ml dichloromethane three times, protects
Aqueous phase is stayed, aqueous phase ph=3 is adjusted with 1M hydrochloric acid solution, with 6ml dichloromethane solutions aqueous phase extracted four times, merges organic phase,
Rotation removes organic solvent, you can obtain intermediate (IV) (329mg, 86%).
1H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 5.75 (s, 1H), 3.82 (dt, J=19.4,9.7Hz, 1H),
3.67 (s, 1H), 3.33-3.29 (m, 1H), 3.11 (s, 1H), 2.25 (d, J=5.5Hz, 1H), 1.97-1.87 (m, 1H),
(d, J=6.9Hz, the 3H) of 1.83 (ddd, J=17.7,10.8,5.7Hz, 1H), 1.69 (s, 2H), 1.39 (s, 9H), 1.09
(3) intermediate (IV) methyl is combined to target product aplysiatoxin Dap fragments
300mg intermediates (IV) are dissolved in 6ml tetrahydrofurans, 0 DEG C is cooled to, 0.2g sodium hydrides are added, 30 points are stirred
Clock, adds 1.2ml iodomethane, and continuation is stirred overnight at 0 DEG C.TLC monitoring reactions.15ml water quenchings are added after the completion of reaction to go out instead
Should, rotation removes tetrahydrofuran, is washed with ethyl acetate once, phase of fetching water, and adjusts pH=3 using hydrochloric acid, is extracted with 15ml ethyl acetate
Three times, merge organic phase and be spin-dried for, use petroleum ether：Ethyl acetate=6：1 column chromatography.Dap (289mg, 91%) can be obtained.
1H NMR(400MHz,CDCl3) δ 7.27 (s, 1H), 4.17-4.08 (m, 1H), 3.45 (s, 3H), 2.53 (d, J=
6.8Hz,1H),1.99–1.70(m,4H),1.54–1.41(m,9H),1.26–1.24(m,3H).
(4) intermediate (I) methylates synthetic intermediate (V)
Intermediate (I) is dissolved in the mixed solution of 2ml dichloromethane and 0.5ml DMSOs, 0 DEG C, addition is cooled to
200mg 4A molecular sieve, is stirred 20 minutes, adds 260mg proton sponges, and 171mg trimethyl oxygen tetrafluoro boric acids reacted
Night, TLC monitoring reactions.Molecular sieve is first filtered to remove after the completion of reaction, organic solvent is spin-dried for, petroleum ether is used：Ethyl acetate=
10：1 column chromatography can obtain intermediate (V) (82mg, 80%).
1HNMR(400MHz,CDCl3) δ=7.27 (s, 1H), 4.17-4.08 (m, 1H), 3.45 (s, 3H), 2.53 (d, J=
6.8,1H),1.99–1.70(m,4H),1.54–1.41(m,9H),1.26–1.24(m,3H).
(5) intermediate (V) hydrolysis target product aplysiatoxin Dap fragments
150mg intermediates (V) are dissolved in 2ml tetrahydrofurans, ice-water bath, add 1ml water, add 0.6ml hydrogen peroxide, will
The hydronium(ion) lithias of 28mg mono- are dissolved in 1.5ml water, add reaction system.TLC monitoring reactions, react after 4 hours and complete, add
The saturated solution of 10ml sodium thiosulfate, reaction is stayed overnight, and rotation removes tetrahydrofuran, is washed with 5ml dichloromethane three times, phase of fetching water, and is used
1M hydrochloric acid adjusts pH=3, and 5ml ethyl acetate extracts three times, is spin-dried for that product Dap (86mg, 91%) can be obtained.
1H NMR(400MHz,CDCl3) δ 7.27 (s, 1H), 4.17-4.08 (m, 1H), 3.45 (s, 3H), 2.53 (d, J=
6.8Hz,1H),1.99–1.70(m,4H),1.54–1.41(m,9H),1.26–1.24(m,3H).
The protection content of the present invention is not limited to above example.Under the spirit and scope without departing substantially from inventive concept, this
Art personnel it is conceivable that change and advantage be all included in the present invention, and using appended claims as protect
Protect scope.
Claims (18)
1. a kind of synthetic method of aplysiatoxin Dap fragments, it is characterised in that the described method comprises the following steps：
(1) in organic solvent, with compound (II) (L)-N- tertbutyloxycarbonyl dried meat ammonium aldehydes and compound (III) (R) -4- benzyls
Base -3- propionyl oxazolidine -2- ketone is raw material, in the presence of alkali and auxiliary agent, carries out aldol reaction, obtains intermediate (I)；
The intermediate (I) of preparation can prepare target compound aplysiatoxin Dap fragments by following two methods：
Method one：
(2) in a solvent, in the presence of alkali and auxiliary agent, intermediate (I) obtains intermediate (IV) through hydrolysis；
(3) in organic solvent, with alkali, methylating reagent methylation reaction occurs for intermediate (IV), obtains the aplysiatoxin
Dap fragments；
Method two：
(4) in organic solvent, in the presence of drier, acid binding agent and methylating reagent, intermediate (I) is anti-through methylating
Should, the intermediate (V) methylated；
(5) in a solvent, in the presence of alkali and auxiliary agent, intermediate (V) generates the aplysiatoxin Dap pieces through hydrolysis
Section；Shown in the course of reaction such as route (1)：
2. the method as described in claim 1, it is characterised in that in step (1), the organic solvent is selected from dimethyl formyl
One or more in amine, dichloromethane, tetrahydrofuran chloroform, dioxane, dimethyl sulfoxide (DMSO), 1,2- dichloroethanes；With/
Or, one or more of the alkali in DIPEA, triethylamine, sodium carbonate, potassium carbonate, LiHMDS, sodium hydride；And/or, institute
State one or more of the auxiliary agent in the fourth boron of trifluoromethanesulfonic acid two, titanium tetrachloride, alchlor.
3. the method as described in claim 1, it is characterised in that in step (1), the compound (II), compound (III),
Auxiliary agent, the mol ratio of alkali are 0.8：(0.8-1.5)：(0.8-1.5)：(0.8-1.5)；And/or, the temperature of the aldol reaction
Spend for -80 DEG C--20 DEG C；And/or, the aldol reaction is carried out under nitrogen protection；And/or, the aldol condensation is anti-
Should after the completion of also include the step of reaction is quenched, one kind in hydrogen peroxide, methanol, ethanol, isopropanol of the quencher or
It is a variety of.
4. the method as described in claim 1, it is characterised in that step (1) includes：By (R) -4- benzyl -3- propionyl oxazolidine -
2- ketone adds reaction bulb, adds in organic solvent, stirring and dissolving is cooled to 0 DEG C, and gas in reaction bulb is changed into nitrogen protection
Gas, adds alkali, adds the fourth boron of trifluoromethanesulfonic acid two, reacts 45 minutes, continues to be cooled to -75 DEG C, be slowly added to the tertiary fourths of (L)-N-
Oxygen carbonyl dried meat ammonium aldehyde, reacts 1 hour, is warming up to 0 DEG C, reacts 2 hours, LC-MS detection reaction carry out degree, after the completion of add it is double
Reaction is quenched in the mixed solution of oxygen water and methanol；Rotation removes organic solvent, is extracted twice with dichloromethane, merges organic phase, use carbon
Sour hydrogen sodium and sodium chloride are washed twice, and with anhydrous sodium sulfate drying, column chromatography obtains intermediate (I).
5. the method as described in claim 1, it is characterised in that in step (2), the solvent is selected from tetrahydrofuran, water, first
One or more in alcohol, ethanol, dioxane；And/or, the alkali is in lithium hydroxide, sodium hydroxide, potassium hydroxide
It is one or more；And/or, the auxiliary agent is hydrogen peroxide.
6. the method as described in claim 1, it is characterised in that in step (2), the intermediate (I), auxiliary agent, mole of alkali
Than for 1：(3-10)：(1-2)；And/or, the temperature of the hydrolysis is 0 DEG C -20 DEG C；And/or, step (2) reaction terminates
Afterwards, in addition to using quencher the step of reaction being quenched, the quencher is reducing agent, selected from sodium thiosulfate and/or sulfurous
Sour sodium, the volume ratio of the quencher and reaction solution is 1：4-4：1.
7. the method as described in claim 1, it is characterised in that step (2) includes：Intermediate (I) is put into reaction bulb, added
The mixed solution dissolving of tetrahydrofuran and water, is cooled with ice-water bath, adds hydrogen peroxide, add lithium hydroxide solution；Use thin layer color
Spectrum monitoring reaction is completed, and adds sodium thiosulfate or reaction is quenched in sodium sulfite solution；Rotation removes volatile solvent, uses organic solvent
Wash three times, collect aqueous phase, with hydrochloric acid water transfer phase PH=3, extracted three times with organic solvent, merge organic phase, use saturated aqueous common salt
Wash, organic phase is dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, rotation obtains the intermediate (IV) except organic solvent；
Wherein, the concentration of hydrochloric acid used in extraction is 0.1-10M；
The one kind or many of the organic solvent used in extraction in dichloromethane, ethyl acetate, ether, the tertiary ether of first, methyl phenyl ethers anisole
Kind.
8. the method as described in claim 1, it is characterised in that in step (3), the organic solvent is selected from dimethyl formyl
One or more in amine, tetrahydrofuran, dichloromethane, dioxane, dimethyl sulfoxide (DMSO)；And/or, the alkali is selected from hydrogenation
One or more in sodium, LiHMDS, n-BuLi, lithium diisopropyl amido；And/or, the methylating reagent is selected from iodine first
Alkane and/or dimethyl suflfate.
9. the method as described in claim 1, it is characterised in that in step (3), intermediate (IV), alkali, methylating reagent rub
You are than being (1)：(2-10)：(3-20)；And/or, the temperature of the methylation reaction is 0-20 DEG C；And/or, it is described to methylate instead
It should be carried out under inert gas shielding.
10. the method as described in claim 1, it is characterised in that in step (3), intermediate (IV) first uses 30 points of alkali process
Clock, then methylation reaction is carried out, the alkali includes sodium hydride, LiHMDS, n-BuLi, lithium diisopropyl amido；And/or, step
Suddenly the step of the step of reaction also being quenched including the use of frozen water after (3) reaction completely and extraction, the organic solvent used in extraction
Selected from dichloromethane, ethyl acetate, ether, the tertiary ether of first, methyl phenyl ethers anisole.
11. the method as described in claim 1, it is characterised in that step (3) includes：Intermediate (IV) is dissolved in tetrahydrofuran
In, ice-water bath cooling is added sodium hydride, stirred 30 minutes, added iodomethane, be stirred overnight, examined using TLC at a temperature of 0 DEG C
Reaction is surveyed, reaction is quenched using frozen water after the completion of reaction, is washed with ethyl acetate once, phase of fetching water adjusts pH=3 with hydrochloric acid, used
Organic solvent is extracted three times, is merged organic phase, is spin-dried for, column chromatography can obtain the aplysiatoxin Dap fragments；Wherein, in extraction
The organic solvent used is selected from dichloromethane, ethyl acetate, ether, the tertiary ether of first, methyl phenyl ethers anisole.
12. the method as described in claim 1, it is characterised in that in step (4), the organic solvent is selected from dimethyl formyl
One or more in amine, DMSO, dichloromethane, 1,2- dichloromethane；And/or, the drier is selected from molecular sieve, nothing
Aqueous sodium persulfate, anhydrous magnesium sulfate；And/or, the acid binding agent is selected from proton sponge, sodium acid carbonate, saleratus；And/or, it is described
Methylating reagent is trimethyl oxygen tetrafluoro boric acid.
13. the method as described in claim 1, it is characterised in that in step (4), the intermediate (I), acid binding agent, methylate
The mol ratio of reagent is 1：(1-3)：(1-3)；And/or, the temperature of the methylation reaction is 0-25 DEG C；And/or, the methyl
Change reaction to carry out under inert gas shielding.
14. the method as described in claim 1, it is characterised in that step (4) includes：Intermediate (I) is dissolved in dimethyl formyl
In the mixed solution of amine and DMSO, 0 DEG C is cooled to, molecular sieve is added, stirs 20 minutes, sequentially adds proton sponge, three
Methyl oxygen tetrafluoro boric acid, is stirred overnight at 0 DEG C, filters off molecular sieve, and vacuum rotation removes organic phase, and column chromatography can obtain the centre
Body (V).
15. the method as described in claim 1, it is characterised in that in step (5), the solvent is selected from tetrahydrofuran, water, first
One or more in alcohol, ethanol, dioxane；And/or, the alkali is in lithium hydroxide, sodium hydroxide, potassium hydroxide
It is one or more；And/or, the auxiliary agent is hydrogen peroxide.
16. the method as described in claim 1, it is characterised in that in step (5), intermediate (V), auxiliary agent, the mol ratio of alkali are
1：(3-10)：(1-2)；And/or, the temperature of the hydrolysis is 0-20 DEG C；And/or, after step (5) reaction terminates, also wrap
The step of reaction is quenched using quencher is included, the quencher is reducing agent, selected from sodium thiosulfate and/or sodium sulfite, plus
It is 1 to enter the volume of quencher and the volume ratio of reaction solution：4-4：1.
17. the method as described in claim 1, it is characterised in that step (5) includes：Intermediate (V) is put into reaction bulb, plus
Enter the mixed solution dissolving of tetrahydrofuran and water, cooled with ice-water bath, add hydrogen peroxide, add lithium hydroxide solution；Use thin layer
Chromatogram monitoring reaction is completed, and adds sodium thiosulfate or reaction is quenched in sodium sulfite solution；Rotation removes volatile solvent, with organic molten
Agent is washed three times, collects aqueous phase, with hydrochloric acid water transfer phase PH=3, is extracted three times with organic solvent, is merged organic phase, use saturated common salt
Washing, organic phase is dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and rotation is that can obtain the aplysiatoxin Dap pieces except organic solvent
Section；Wherein, it is 1 to add sodium thiosulfate or the volume of sodium sulfite saturated solution and the ratio of reaction solution：4-4：1；In extraction
The organic solvent used is selected from dichloromethane, ethyl acetate, ether, the tertiary ether of first, methyl phenyl ethers anisole, and the concentration of hydrochloric acid is 0.1-10M.
A kind of raw oxazolidinone compounds 18. N- tertbutyloxycarbonyls proline spreads out, it is characterised in that its structure such as following formula
(I) shown in：
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| CN105143199A (en) * | 2013-04-25 | 2015-12-09 | 皮埃尔法布雷医药公司 | Derivatives of dolastatin 10 and auristatins |
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| CN105143199A (en) * | 2013-04-25 | 2015-12-09 | 皮埃尔法布雷医药公司 | Derivatives of dolastatin 10 and auristatins |
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| CLAUDIA NERI ET AL.: "New Routes to chiral evans auxiliaries by enzymatic desymmetrisation and resolution strategies", 《ADV. SYNTH. CATAL.》 * |
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| CN113804789A (en) * | 2021-09-18 | 2021-12-17 | 湖北石河医药科技有限公司 | Separation and detection method of compound A with multiple chiral sites and chiral isomer thereof and application of compound A in synthesis process |
| CN113804789B (en) * | 2021-09-18 | 2023-04-18 | 湖北石河医药科技有限公司 | Separation and detection method of compound A with multiple chiral sites and chiral isomer thereof and application of compound A in synthesis process |
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