CN106349243A - 8, 8-difluoro-swainsonine [(-)-Swainsonine] derivative and preparation method thereof - Google Patents
8, 8-difluoro-swainsonine [(-)-Swainsonine] derivative and preparation method thereof Download PDFInfo
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- CN106349243A CN106349243A CN201610658114.4A CN201610658114A CN106349243A CN 106349243 A CN106349243 A CN 106349243A CN 201610658114 A CN201610658114 A CN 201610658114A CN 106349243 A CN106349243 A CN 106349243A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention provides a 8, 8-difluoro-swainsonine [(-)-Swainsonine] derivative and a preparation method thereof. The preparation method includes following steps: reacting S-tert-butyl sulfonamide with acrolein to prepare S-sulfoximine; reacting S-sulfoximine, zinc powder and difluro ethyl bromoacetate (BrCF2CO2Et) to generate a compound shown as a formula 4; reducing the compound shown as the formula 4 to obtain aldehyde; subjecting aldehyde directly to Wittig reaction to obtain alpha, beta-unsaturated ester; reducing the alpha, beta-unsaturated ester to obtain primary alcohol; adding mesyl on primary hydroxyl of the primary alcohol; enablig an obtained compound to be in intramolecular nucleophilic substitution reaction to obtain a compound shown as a formula 11; removing sulfinyl from the compound shown as the formula 11 to obtain a hydrochloride; adding allyl on the hydrochloride to obtain a compound shown as a formula 3; using the compound shown as the formula 11 as a raw material to prepare a target product. The compound prepared serves as both a glycosidase inhibitor and monosaccharide having inhibition selectivity.
Description
Technical field
The present invention relates to the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-swainsonine] derivant and preparation method thereof.
Background technology
Azabicyclo class nitrogen sugar (.+-.)-Swainsonine [(-)-swainsonine], castanospermine [(+)-castanospermine] and
Its analog be efficient α-, beta-glucosidase enzyme inhibitor, and there is good antiviral and anti-tumor activity.Therefore, close
In the complete synthesis of them and structure activity relationship research by extensive concern.
(+) in the research of-castanospermine structure activity relationship, a large amount of and system work has been done by Taylor p.c. group
Make.Wherein, this group in 1995,1997 respectively to (+) c-8, c-1 and c-7 position hydroxyl of-castanospermine carries out
Find after modification: (+) c-1 position hydroxyl in-castanospermine molecular structure and its configuration be to affect its biological activity
Critical sites, its chirality is the key to nitrogen sugar identification for the glycosidase, and the disappearance of this hydroxyl can lead to the forfeiture of activity.And c-7 position
It is not very big with c-8 position hydroxyl for the impact of physiologically active.Though the transformation to them can make the biological activity of molecule slightly drop
Low, but the suppression selectivity to different glycosidase for the molecule can be improved.Therefore, will (+) the c-7 position of-castanospermine
It transform other groups as with c-8 position hydroxyl or change its chirality it is possible to search out the dissimilar glycosidase of Selective depression
Nitrogen sugar.
Up to now, for (-) research of-swainsonine structure activity relationship have not been reported.In order to search out one
Class is good glycosidase inhibitor, is again to have excellent suppression selective nitrogen sugar simultaneously, the present invention to (-)-
Swainsonine carries out fluorine-containing transformation, introduces together with difluoro methylene in its c-8 position, to by introducing fluorine atom effectively
Ground improves the suppression selectivity to different glycosidase for the nitrogen sugar.
Content of the invention
The system of [(-)-swainsonine] derivant it is an object of the invention to provide a kind of 8,8- bis- fluoro- (.+-.)-Swainsonine
Preparation Method is it is characterised in that prepared by below scheme:
Described preparation method comprises the steps of
Step 1: by the s- t-butyl sulfonamide of formula 5 and the acrolein reaction of formula 6, the s- tert-butyl group Asia sulphur of formula 7
Acid imide；
Step 2: by the s- tert-butyl group sulfenimide of formula 7, zinc powder and ethyl bromide difluoride (brcf2co2Et) occur to add
Become the compound of reaction production 4；
Step 3: using the ester group in the compound of diisobutyl aluminium hydride (dibal-h) reduction-type 4, obtain the aldehyde of formula 8；
Step 4: the aldehyde of the formula 8 of gained is directly carried out the α that Wittig (wittig) reaction obtains formula 9, beta-unsaturated esters；
Step 5: adopt lialh4Ester group in the alpha, beta-unsaturated esters of reduction-type 9, obtains the primary alconol of formula 10；
Step 6: to mesyl on the primary hydroxyl of the primary alconol of formula 10, obtained compound is directly in potassium tert-butoxide (t-
Buok there is intramolecular nucleophilic substitution reaction in the presence of), obtain the compound of formula 11；
Step 7: the compound of formula 11 is sloughed sulfinyl, obtains the hydrochlorate of formula 12；
Step 8: to pi-allyl on the hydrochlorate of the formula 12 of gained, obtain the compound of formula 3；
Step 9: with the compound of formula 3 as raw material, add camphorsulfonic acid (csa), in the secondary catalysis of Ge Labu (grubbs ')
Under the catalysis of agent, carry out back flow reaction, be subsequently adding solid k2co3The target product of formula 1 is obtained after process.
Wherein, the reaction condition of step 1 is: add butyl titanate (ti (oet) 4), solvent is dichloromethane (dcm),
Room temperature, overnight；Step 2 includes the zinc powder activating is added in dry oxolane (thf), is heated to fully flowing back
Afterwards, by the s- tert-butyl group sulfenimide of formula 7 and ethyl bromide difluoride (brcf2co2Et thf solution) adds to wherein, formula 7
S- tert-butyl group sulfenimide there is thunder formal thatch base with the ethyl bromide difluoride zincon that locally produces
(reformatskii) ester of additive reaction production 4；The reaction condition of step 3 is: solvent is dcm, and reaction temperature is -78
DEG C, the response time is 1h；The reaction condition of step 4 is: adds bromo triphenylphosphine ethyl acetate (brph3pch2co3Et), three
Ethamine (et3N), solvent is thf；The reaction condition of step 5 is: solvent is thf, and reaction temperature is 0 DEG C and arrives room temperature；Step 6
Reaction condition is: adds mesyl chloride (mscl), dimethyl aminopyridine (dmap), et3N carries out upper mesyl reaction, molten
Agent is dcm, and reaction temperature is 0 DEG C and arrives room temperature, the solvent of intramolecular nucleophilic substitution reaction is dcm, and reaction temperature is 0 DEG C；Step 7
Reaction condition be: reaction in (hcl-dioxane) in the dioxane solution of hcl, add methanol (meoh), room temperature reaction
2h.
Wherein, the reaction condition of step 8 is: with k2co3Make alkali, dmf be solvent, room temperature or 50 DEG C reaction.
Wherein, the reaction condition of step 8 is: add 3- bromopropene (3-bromoprop-1-ene), with nah (60%, point
It is dispersed in oil) make alkali, thf and dmf (volume ratio 2:1) is solvent, and 50 DEG C of reactions are overnight.
The present invention also provide a kind of using above-mentioned preparation method preparation formula 1 the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-
Swainsonine] derivant, its molecular structure is as follows:
The present invention also provides a kind of preparation method of fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-swainsonine] derivant, its
It is characterised by, by the preparation of following approach:
Described preparation method comprises the steps of
Step 1: by the s- t-butyl sulfonamide of formula 5 and the acrolein reaction of formula 6, the s- tert-butyl group Asia sulphur of formula 7
Acid imide；
Step 2: by the s- tert-butyl group sulfenimide of formula 7, zinc powder and ethyl bromide difluoride (brcf2co2Et) occur to add
Become the compound of reaction production 4；
Step 3: using the ester group in the compound of diisobutyl aluminium hydride (dibal-h) reduction-type 4, obtain the aldehyde of formula 8；
Step 4: the aldehyde of the formula 8 of gained is directly carried out the α that Wittig (wittig) reaction obtains formula 9, beta-unsaturated esters；
Step 5: adopt lialh4Ester group in the alpha, beta-unsaturated esters of reduction-type 9, obtains the primary alconol of formula 10；
Step 6: to mesyl on the primary hydroxyl of the primary alconol of formula 10, obtained compound is directly in potassium tert-butoxide (t-
Buok there is intramolecular nucleophilic substitution reaction in the presence of), obtain the compound of formula 14；
Step 7:: react with 3- alkene butanoic acid after the compound removing sulfinyl of formula 14, obtain the cyclization precursor of formula 15；
Step 8: the target product of cyclization precursor production 16 under the catalysis of the secondary catalyst of Ge Labu of formula 15.
Wherein, the reaction condition of step 1 is: add butyl titanate (ti (oet) 4), solvent is dichloromethane (dcm),
Room temperature, overnight；Step 2 includes the zinc powder activating is added in dry oxolane (thf), is heated to fully flowing back
Afterwards, by the s- tert-butyl group sulfenimide of formula 7 and ethyl bromide difluoride (brcf2co2Et thf solution) adds to wherein, formula 7
S- tert-butyl group sulfenimide there is thunder formal thatch base with the ethyl bromide difluoride zincon that locally produces
(reformatskii) ester of additive reaction production 4；The reaction condition of step 3 is: solvent is dcm, and reaction temperature is -78
DEG C, the response time is 1h；The reaction condition of step 4 is: adds brph3pch2co3Et, triethylamine (et3N), solvent is thf；Step
Rapid 5 reaction condition is: solvent is thf, and reaction temperature is 0 DEG C and arrives room temperature；The reaction condition of step 6 is: adds mesyl chloride
(mscl), dimethyl aminopyridine (dmap), et3N carries out upper mesyl reaction, and solvent is dcm, and reaction temperature arrives for 0 DEG C
Room temperature, the solvent of intramolecular nucleophilic substitution reaction is dcm, and reaction temperature is 0 DEG C；Step 7 removing sulfinyl is in hcl/
Carry out in meoh (methanol) solution, when reacting with 3- alkene butanoic acid, add dedc, et3N, dmf；Step 8 is to enter in toluene solution
Row；The reaction condition of step 9 is: adds pd/c, meoh, hcooh.
The present invention also provide a kind of using above-mentioned preparation method preparation formula 16 the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-
Swainsonine] derivant, its molecular structure is as follows:
The present invention also provides a kind of preparation method of fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-swainsonine] derivant, presses
Following approach preparation:
Described preparation method comprises the steps of
Step 1: by the s- t-butyl sulfonamide of formula 5 and the acrolein reaction of formula 6, the s- tert-butyl group Asia sulphur of formula 7
Acid imide；
Step 2: by the s- tert-butyl group sulfenimide of formula 7, zinc powder and ethyl bromide difluoride (brcf2co2Et) occur to add
Become the compound of reaction production 4；
Step 3: using the ester group in the compound of diisobutyl aluminium hydride (dibal-h) reduction-type 4, obtain the aldehyde of formula 8；
Step 4: the aldehyde of the formula 8 of gained is directly carried out the α that Wittig (wittig) reaction obtains formula 9, beta-unsaturated esters；
Step 5: adopt lialh4Ester group in the alpha, beta-unsaturated esters of reduction-type 9, obtains the primary alconol of formula 10；
Step 6: to mesyl on the primary hydroxyl of the primary alconol of formula 10, obtained compound is directly in potassium tert-butoxide (t-
Buok there is intramolecular nucleophilic substitution reaction in the presence of), obtain the compound of formula 14；
Step 7:: react with 3- alkene butanoic acid after the compound removing sulfinyl of formula 14, obtain the cyclization precursor of formula 15；
Step 8: the compound of cyclization precursor production 16 under the catalysis of the secondary catalyst of Ge Labu of formula 15；
Step 9: after the double bond of the compound of hydro-reduction formula 16, obtain the target product of formula 17.
The present invention also provide a kind of using above-mentioned preparation method preparation formula 17 the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-
Swainsonine] derivant, its molecular structure is as follows:
The compound of formula 1, formula 6 and formula 17 of present invention preparation is good glycosidase inhibitor, be simultaneously again have excellent
Good suppression selective nitrogen sugar.
It is that above and other objects of the present invention, feature and advantage can be become apparent, preferred embodiment cited below particularly,
It is described in detail below.
Specific embodiment
Embodiment 1
A kind of preparation of the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-swainsonine] derivant
Step 1: reacted with acrylic aldehyde 6 by s- t-butyl sulfonamide 5, prepare s- tert-butyl group sulfenimide 7.Specifically anti-
The condition is answered to be: to add butyl titanate (ti (oet)4), solvent is dichloromethane (dcm), room temperature, overnight.The tertiary fourth of s- of gained
The yield of base sulfenimide 7 is 77%.
Step 2: the zinc powder activating is added in dry oxolane (thf), after being heated to fully flowing back, by s-
Tert-butyl group sulfenimide 7 and ethyl bromide difluoride (brcf2co2Et thf solution) adds to wherein, s- tert-butyl group sulfenyl
There is thunder formal thatch base (reformatskii) additive reaction with the ethyl bromide difluoride zincon locally producing in imines 7
Generate ester 4.Concrete reaction condition is: backflow 1h.After reaction is quenched, system composes detection, the diastereomer dr ratio of ester 4 through fluorine
Example is about 6.5:1, and both can not be separated by column chromatography.The yield of ester 4 is 65%.
Step 3: using the ester group in diisobutyl aluminium hydride (dibal-h) reducing compound 4, obtain aldehyde 8.Concrete reaction
Condition is: solvent is dcm, and reaction temperature is -78 DEG C, and the response time is 1h.
Step 4: the aldehyde 8 of gained is directly carried out Wittig (wittig) reaction and obtains α, beta-unsaturated esters 9.Concrete reaction
Condition is: adds brph3pch2co3Et, triethylamine (et3N), solvent is thf.α, two diastereomers of beta-unsaturated esters 9 mix
Compound can not be separated by column chromatography.α, the yield of beta-unsaturated esters 9 is 57%.
Step 5: adopt lialh4Ester group in reduction alpha, beta-unsaturated esters 9, obtaining equally can not be conveniently by post layer
Analysis in addition detached primary alconol 10.Concrete reaction condition is: solvent is thf, and reaction temperature is 0 DEG C and arrives room temperature.The yield of primary alconol 10
For 83%.
Step 6: to mesyl (ms) on the primary hydroxyl of primary alconol 10, concrete reaction condition is: add mesyl chloride
(mscl), dimethyl aminopyridine (dmap), et3N, solvent is dcm, and reaction temperature is 0 DEG C and arrives room temperature；Obtained compound
Directly in the presence of potassium tert-butoxide (t-buok), there is intramolecular nucleophilic substitution reaction, obtain compound 11 and another amount is few
Isomer 14 (concrete structure is referring to embodiment 3).Concrete reaction condition is: solvent is dcm, and reaction temperature is 0 DEG C.By post
Isomer 14 few with another amount for compound 11 can easily be separated by chromatography.The yield of compound 11 is 55%.
Step 7: compound 11 is sloughed sulfinyl in the presence of hcl, obtains hydrochlorate 12, concrete reaction condition
For: in the dioxane solution of hcl (hcl-dioxane), add methanol (meoh), room temperature reaction 2h.
Step 8: to pi-allyl on the hydrochlorate 12 of gained, obtain diene 3.Concrete reaction condition is: with k2co3Make alkali,
Dmf be solvent, room temperature or 50 DEG C reaction.Substrate 12 also only obtains cyclization precursor 3 with 30% about yield with this understanding.Change
For next step reaction after compound 3 is treated, post purifies excessively.The boiling point of compound 3 is not high, and post-treated, mistake post damages after purifying
Lose very big.
Step 9: the compound 3 after being purified with treated, mistake post, as raw material, is solvent using dichloromethane, with reference to d.g.
Method (dechamps, the i. of report more than Paar；pardo,d.g.；Cossy, j.tetrahedron 2007,63,9082), add
Plus 1.1 equivalent camphorsulfonic acid (csa), under the catalysis of the secondary catalyst of Ge Labu (grubbs '), back flow reaction 1 hour, point
Plate shows that raw material is reacted completely.Add solid k2co3After process, cyclization product 1 is obtained with 45% separation yield.At this
In, the effect adding csa is and the nitrogen-atoms complexation in substrate, to avoid nitrogen-atoms and catalyst complexation, to affect catalytic effect.
The compound 1 of this embodiment preparation is good glycosidase inhibitor, is to have excellent suppression to select simultaneously again
Property nitrogen sugar.
Embodiment 2
A kind of preparation of the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-swainsonine] derivant
Step 1: reacted with acrylic aldehyde 6 by s- t-butyl sulfonamide 5, prepare s- tert-butyl group sulfenimide 7.Specifically anti-
The condition is answered to be: to add butyl titanate (ti (oet)4), solvent is dichloromethane (dcm), room temperature, overnight.The tertiary fourth of s- of gained
The yield of base sulfenimide 7 is 77%.
Step 2: the zinc powder activating is added in dry oxolane (thf), after being heated to fully flowing back, by s-
Tert-butyl group sulfenimide 7 and ethyl bromide difluoride (brcf2co2Et thf solution) adds to wherein, s- tert-butyl group sulfenyl
There is thunder formal thatch base (reformatskii) additive reaction with the ethyl bromide difluoride zincon locally producing in imines 7
Generate ester 4.Concrete reaction condition is: backflow 1h.After reaction is quenched, system composes detection, the diastereomer dr ratio of ester 4 through fluorine
Example is about 6.5:1, and both can not be separated by column chromatography.The yield of ester 4 is 65%.
Step 3: using the ester group in diisobutyl aluminium hydride (dibal-h) reducing compound 4, obtain aldehyde 8.Concrete reaction
Condition is: solvent is dcm, and reaction temperature is -78 DEG C, and the response time is 1h.
Step 4: the aldehyde 8 of gained is directly carried out Wittig (wittig) reaction and obtains α, beta-unsaturated esters 9.Concrete reaction
Condition is: adds brph3pch2co3Et, triethylamine (et3N), solvent is thf.α, two diastereomers of beta-unsaturated esters 9 mix
Compound can not be separated by column chromatography.α, the yield of beta-unsaturated esters 9 is 57%.
Step 5: adopt lialh4Ester group in reduction alpha, beta-unsaturated esters 9, obtaining equally can not be conveniently by post layer
Analysis in addition detached primary alconol 10.Concrete reaction condition is: solvent is thf, and reaction temperature is 0 DEG C and arrives room temperature.The yield of primary alconol 10
For 83%.
Step 6: to mesyl (ms) on the primary hydroxyl of primary alconol 10, concrete reaction condition is: add mesyl chloride
(mscl), dimethyl aminopyridine (dmap), et3N, solvent is dcm, and reaction temperature is 0 DEG C and arrives room temperature；Obtained compound
Directly in the presence of potassium tert-butoxide (t-buok), there is intramolecular nucleophilic substitution reaction, obtain compound 11 and another amount is few
Isomer 14 (concrete structure is referring to embodiment 3).Concrete reaction condition is: solvent is dcm, and reaction temperature is 0 DEG C.By post
Isomer 14 few with another amount for compound 11 can easily be separated by chromatography.The yield of compound 11 is 55%.
Step 7: compound 11 is sloughed sulfinyl in the presence of hcl, obtains hydrochlorate 12, concrete reaction condition
For: in the dioxane solution of hcl (hcl-dioxane), add methanol (meoh), room temperature reaction 2h.
Step 8: to pi-allyl on the hydrochlorate 12 of gained, obtain diene 3.Concrete reaction condition is to add 3- bromopropene
(3-bromoprop-1-ene), alkali is made with nah (60%, be dispersed in oil), thf and dmf (volume ratio 2:1) is solvent, 50 DEG C
Reaction is overnight.Two steps diene 3 can be obtained with 84% thick yield.Diene 3 does not purify, and is directly used in next step reaction.
Step 4): with diene 3 as raw material, it is solvent using dichloromethane, more than reference d.g. Paar, the method for report, adds
The camphorsulfonic acid (csa) of 1.1 equivalents, under the catalysis of the secondary catalyst of Ge Labu (grubbs '), back flow reaction 1 hour, put plate
Show that raw material is reacted completely.Add solid k2co3After process, cyclization product 1 is obtained with 45% separation yield.Here,
The effect adding csa is and the nitrogen-atoms complexation in substrate, to avoid nitrogen-atoms and catalyst complexation, to affect catalytic effect.
The compound 1 of this embodiment preparation is good glycosidase inhibitor, is to have excellent suppression to select simultaneously again
Property nitrogen sugar.
Embodiment 3
A kind of preparation of the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-swainsonine] derivant
Step 1: reacted with acrylic aldehyde 6 by s- t-butyl sulfonamide 5, prepare s- tert-butyl group sulfenimide 7.Specifically anti-
The condition is answered to be: to add butyl titanate (ti (oet)4), solvent is dichloromethane (dcm), room temperature, overnight.The tertiary fourth of s- of gained
The yield of base sulfenimide 7 is 77%.
Step 2: the zinc powder activating is added in dry oxolane (thf), after being heated to fully flowing back, by s-
Tert-butyl group sulfenimide 7 and ethyl bromide difluoride (brcf2co2Et thf solution) adds to wherein, s- tert-butyl group sulfenyl
There is thunder formal thatch base (reformatskii) additive reaction with the ethyl bromide difluoride zincon locally producing in imines 7
Generate ester 4.Concrete reaction condition is: backflow 1h.After reaction is quenched, system composes detection, the diastereomer dr ratio of ester 4 through fluorine
Example is about 6.5:1, and both can not be separated by column chromatography.The yield of ester 4 is 65%.
Step 3: using the ester group in diisobutyl aluminium hydride (dibal-h) reducing compound 4, obtain aldehyde 8.Concrete reaction
Condition is: solvent is dcm, and reaction temperature is -78 DEG C, and the response time is 1h.
Step 4: the aldehyde 8 of gained is directly carried out Wittig (wittig) reaction and obtains α, beta-unsaturated esters 9.Concrete reaction
Condition is: adds brph3pch2co3Et, triethylamine (et3N), solvent is thf.α, two diastereomers of beta-unsaturated esters 9 mix
Compound can not be separated by column chromatography.α, the yield of beta-unsaturated esters 9 is 57%.
Step 5: adopt lialh4Ester group in reduction alpha, beta-unsaturated esters 9, obtaining equally can not be conveniently by post layer
Analysis in addition detached primary alconol 10.Concrete reaction condition is: solvent is thf, and reaction temperature is 0 DEG C and arrives room temperature.The yield of primary alconol 10
For 83%.
Step 6: to mesyl (ms) on the primary hydroxyl of primary alconol 10, concrete reaction condition is: add mesyl chloride
(mscl), dimethyl aminopyridine (dmap), et3N, solvent is dcm, and reaction temperature is 0 DEG C and arrives room temperature；Obtained compound
Directly in the presence of potassium tert-butoxide (t-buok), there is intramolecular nucleophilic substitution reaction, obtain compound 14 and another isomery
Body 11 (concrete structure is referring to embodiment 1 and 2).Concrete reaction condition is: solvent is dcm, and reaction temperature is 0 DEG C.By post layer
Compound 14 can easily be separated by analysis with another isomer 11.
Step 7: react with 3- alkene butanoic acid after compound 14 removing sulfinyl, obtain cyclization precursor 15.Removing sulfenyl
Base is to carry out in hcl/meoh (methanol) solution.When reacting with 3- alkene butanoic acid, add dedc, et3N, dmf, before obtaining cyclization
The yield of body 15 is 65%.
Step 8: cyclization precursor 15 generates compound 16 under the catalysis of the secondary catalyst of Ge Labu in toluene solution.Change
The yield of compound 16 is 75%.
The compound 16 of this embodiment preparation is good glycosidase inhibitor, is to have excellent suppression to select simultaneously again
Property nitrogen sugar.
Embodiment 4
A kind of preparation of the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-swainsonine] derivant
Step 1: reacted with acrylic aldehyde 6 by s- t-butyl sulfonamide 5, prepare s- tert-butyl group sulfenimide 7.Specifically anti-
The condition is answered to be: to add butyl titanate (ti (oet)4), solvent is dichloromethane (dcm), room temperature, overnight.The tertiary fourth of s- of gained
The yield of base sulfenimide 7 is 77%.
Step 2: the zinc powder activating is added in dry oxolane (thf), after being heated to fully flowing back, by s-
Tert-butyl group sulfenimide 7 and ethyl bromide difluoride (brcf2co2Et thf solution) adds to wherein, s- tert-butyl group sulfenyl
There is thunder formal thatch base (reformatskii) additive reaction with the ethyl bromide difluoride zincon locally producing in imines 7
Generate ester 4.Concrete reaction condition is: backflow 1h.After reaction is quenched, system composes detection, the diastereomer dr ratio of ester 4 through fluorine
Example is about 6.5:1, and both can not be separated by column chromatography.The yield of ester 4 is 65%.
Step 3: using the ester group in diisobutyl aluminium hydride (dibal-h) reducing compound 4, obtain aldehyde 8.Concrete reaction
Condition is: solvent is dcm, and reaction temperature is -78 DEG C, and the response time is 1h.
Step 4: the aldehyde 8 of gained is directly carried out Wittig (wittig) reaction and obtains α, beta-unsaturated esters 9.Concrete reaction
Condition is: adds brph3pch2co3Et, triethylamine (et3N), solvent is thf.α, two diastereomers of beta-unsaturated esters 9 mix
Compound can not be separated by column chromatography.α, the yield of beta-unsaturated esters 9 is 57%.
Step 5: adopt lialh4Ester group in reduction alpha, beta-unsaturated esters 9, obtaining equally can not be conveniently by post layer
Analysis in addition detached primary alconol 10.Concrete reaction condition is: solvent is thf, and reaction temperature is 0 DEG C and arrives room temperature.The yield of primary alconol 10
For 83%.
Step 6: to mesyl (ms) on the primary hydroxyl of primary alconol 10, concrete reaction condition is: add mesyl chloride
(mscl), dimethyl aminopyridine (dmap), et3N, solvent is dcm, and reaction temperature is 0 DEG C and arrives room temperature；Obtained compound
Directly in the presence of potassium tert-butoxide (t-buok), there is intramolecular nucleophilic substitution reaction, obtain compound 14 and another isomery
Body 11 (concrete structure is referring to embodiment 1 and 2).Concrete reaction condition is: solvent is dcm, and reaction temperature is 0 DEG C.By post layer
Compound 14 can easily be separated by analysis with another isomer 11.
Step 7: react with 3- alkene butanoic acid after compound 14 removing sulfinyl, obtain cyclization precursor 15.Removing sulfenyl
Base is to carry out in hcl/meoh (methanol) solution.When reacting with 3- alkene butanoic acid, add dedc, et3N, dmf, before obtaining cyclization
The yield of body 15 is 65%.
Step 8: cyclization precursor 15 generates compound 16 under the catalysis of the secondary catalyst of Ge Labu in toluene solution.Change
The yield of compound 16 is 75%.
Step 9: after the double bond of hydro-reduction 16, obtain compound 17.Concrete reaction condition is: add pd/c, meoh,
hcooh.The yield of compound 17 is 70%.
The compound 17 of this embodiment preparation is good glycosidase inhibitor, is to have excellent suppression to select simultaneously again
Property nitrogen sugar.
In description above, numeral all represents the molecular formula of corresponding compound.
Although the present invention is disclosed as above with preferred embodiment, so it is not limited to the present invention, any affiliated technology
The technical staff in field, without departing from the spirit and scope of the present invention, when can make a little change and improvement, the therefore present invention
Protection domain when being defined depending on as defined in claim.
Claims (10)
1. one kind 8, the preparation method of the fluoro- (.+-.)-Swainsonine of 8- bis- [(-)-swainsonine] derivant it is characterised in that by with
Lower flow process preparation:
Described preparation method comprises the steps of
Step 1: by the s- t-butyl sulfonamide of formula 5 and the acrolein reaction of formula 6, the s- tert-butyl group sulfenyl of formula 7 is sub-
Amine；
Step 2: by the s- tert-butyl group sulfenimide of formula 7, zinc powder and ethyl bromide difluoride (brcf2co2Et) occur addition anti-
Answer the compound of production 4；
Step 3: using the ester group in the compound of diisobutyl aluminium hydride (dibal-h) reduction-type 4, obtain the aldehyde of formula 8；
Step 4: the aldehyde of the formula 8 of gained is directly carried out the α that Wittig (wittig) reaction obtains formula 9, beta-unsaturated esters；
Step 5: adopt lialh4Ester group in the alpha, beta-unsaturated esters of reduction-type 9, obtains the primary alconol of formula 10；
Step 6: to mesyl on the primary hydroxyl of the primary alconol of formula 10, obtained compound is directly at potassium tert-butoxide (t-buok)
In the presence of occur intramolecular nucleophilic substitution reaction, obtain the compound of formula 11；
Step 7: the compound of formula 11 is sloughed sulfinyl, obtains the hydrochlorate of formula 12；
Step 8: to pi-allyl on the hydrochlorate of the formula 12 of gained, obtain the compound of formula 3；
Step 9: with the compound of formula 3 as raw material, add camphorsulfonic acid (csa), in the secondary catalyst of Ge Labu (grubbs ')
Under catalysis, carry out back flow reaction, be subsequently adding solid k2co3The target product of formula 1 is obtained after process.
2. preparation method according to claim 1 is it is characterised in that the reaction condition of step 1 is: adds butyl titanate
(ti (oet) 4), solvent is dichloromethane (dcm), room temperature, overnight；Step 2 includes being added to the zinc powder activating dry
In oxolane (thf), after being heated to fully flowing back, by the s- tert-butyl group sulfenimide of formula 7 and ethyl bromide difluoride
(brcf2co2Et thf solution) adds to wherein, the s- tert-butyl group sulfenimide of formula 7 i.e. with the difluoro bromoacetic acid locally producing
There is the ester of thunder formal thatch base (reformatskii) additive reaction production 4 in ethyl ester zincon；The reaction condition of step 3
For: solvent is dcm, and reaction temperature is -78 DEG C, and the response time is 1h；The reaction condition of step 4 is: adds bromo triphenylphosphine
Ethyl acetate (brph3pch2co3Et), triethylamine (et3N), solvent is thf；The reaction condition of step 5 is: solvent is thf, instead
Answer temperature to be 0 DEG C and arrive room temperature；The reaction condition of step 6 is: add mesyl chloride (mscl), dimethyl aminopyridine (dmap),
et3N carries out upper mesyl reaction, and solvent is dcm, and reaction temperature is 0 DEG C and arrives room temperature, the solvent of intramolecular nucleophilic substitution reaction
For dcm, reaction temperature is 0 DEG C；The reaction condition of step 7 is: anti-in the dioxane solution of hcl (hcl-dioxane)
Should, add methanol (meoh), room temperature reaction 2h.
3. preparation method according to claim 1 is it is characterised in that the reaction condition of step 8 is: with k2co3Make alkali, dmf
For solvent, room temperature or 50 DEG C of reactions.
4. preparation method according to claim 1 is it is characterised in that the reaction condition of step 8 is: adds 3- bromopropene
(3-bromoprop-1-ene), alkali is made with nah (60%, be dispersed in oil), thf and dmf (volume ratio 2:1) is solvent, 50 DEG C
Reaction is overnight.
5. the fluoro- (.+-.)-Swainsonine of 8,8- bis- of the formula 1 of preparation method preparation any one of a kind of employing claim 1-4
[(-)-swainsonine] derivant, its molecular structure is as follows:
6. one kind 8, the preparation method of the fluoro- (.+-.)-Swainsonine of 8- bis- [(-)-swainsonine] derivant it is characterised in that by with
Lower approach preparation:
Described preparation method comprises the steps of
Step 1: by the s- t-butyl sulfonamide of formula 5 and the acrolein reaction of formula 6, the s- tert-butyl group sulfenyl of formula 7 is sub-
Amine；
Step 2: by the s- tert-butyl group sulfenimide of formula 7, zinc powder and ethyl bromide difluoride (brcf2co2Et) occur addition anti-
Answer the compound of production 4；
Step 3: using the ester group in the compound of diisobutyl aluminium hydride (dibal-h) reduction-type 4, obtain the aldehyde of formula 8；
Step 4: the aldehyde of the formula 8 of gained is directly carried out the α that Wittig (wittig) reaction obtains formula 9, beta-unsaturated esters；
Step 5: adopt lialh4Ester group in the alpha, beta-unsaturated esters of reduction-type 9, obtains the primary alconol of formula 10；
Step 6: to mesyl on the primary hydroxyl of the primary alconol of formula 10, obtained compound is directly at potassium tert-butoxide (t-buok)
In the presence of occur intramolecular nucleophilic substitution reaction, obtain the compound of formula 14；
Step 7:: react with 3- alkene butanoic acid after the compound removing sulfinyl of formula 14, obtain the cyclization precursor of formula 15；
Step 8: the target product of cyclization precursor production 16 under the catalysis of the secondary catalyst of Ge Labu of formula 15.
7. preparation method according to claim 6 is it is characterised in that the reaction condition of step 1 is: adds butyl titanate
(ti (oet) 4), solvent is dichloromethane (dcm), room temperature, overnight；Step 2 includes being added to the zinc powder activating dry
In oxolane (thf), after being heated to fully flowing back, by the s- tert-butyl group sulfenimide of formula 7 and ethyl bromide difluoride
(brcf2co2Et thf solution) adds to wherein, the s- tert-butyl group sulfenimide of formula 7 i.e. with the difluoro bromoacetic acid locally producing
There is the ester of thunder formal thatch base (reformatskii) additive reaction production 4 in ethyl ester zincon；The reaction condition of step 3
For: solvent is dcm, and reaction temperature is -78 DEG C, and the response time is 1h；The reaction condition of step 4 is: adds
brph3pch2co3Et, triethylamine (et3N), solvent is thf；The reaction condition of step 5 is: solvent is thf, and reaction temperature is 0
DEG C arrive room temperature；The reaction condition of step 6 is: adds mesyl chloride (mscl), dimethyl aminopyridine (dmap), et3On n is carried out
Mesyl reacts, and solvent is dcm, and reaction temperature is 0 DEG C and arrives room temperature, the solvent of intramolecular nucleophilic substitution reaction is dcm, reaction
Temperature is 0 DEG C；Step 7 removing sulfinyl is to carry out in hcl/meoh (methanol) solution, when reacting with 3- alkene butanoic acid, adds
dedc、et3N, dmf；Step 8 is carried out in toluene solution；The reaction condition of step 9 is: add pd/c, meoh,
hcooh.
8. described in a kind of employing claim 6 or 7 preparation method preparation formula 16 the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-
Swainsonine] derivant, its molecular structure is as follows:
9. one kind 8, the preparation method of the fluoro- (.+-.)-Swainsonine of 8- bis- [(-)-swainsonine] derivant it is characterised in that by with
Lower approach preparation:
Described preparation method comprises the steps of
Step 1: by the s- t-butyl sulfonamide of formula 5 and the acrolein reaction of formula 6, the s- tert-butyl group sulfenyl of formula 7 is sub-
Amine；
Step 2: by the s- tert-butyl group sulfenimide of formula 7, zinc powder and ethyl bromide difluoride (brcf2co2Et) occur addition anti-
Answer the compound of production 4；
Step 3: using the ester group in the compound of diisobutyl aluminium hydride (dibal-h) reduction-type 4, obtain the aldehyde of formula 8；
Step 4: the aldehyde of the formula 8 of gained is directly carried out the α that Wittig (wittig) reaction obtains formula 9, beta-unsaturated esters；
Step 5: adopt lialh4Ester group in the alpha, beta-unsaturated esters of reduction-type 9, obtains the primary alconol of formula 10；
Step 6: to mesyl on the primary hydroxyl of the primary alconol of formula 10, obtained compound is directly at potassium tert-butoxide (t-buok)
In the presence of occur intramolecular nucleophilic substitution reaction, obtain the compound of formula 14；
Step 7:: react with 3- alkene butanoic acid after the compound removing sulfinyl of formula 14, obtain the cyclization precursor of formula 15；
Step 8: the compound of cyclization precursor production 16 under the catalysis of the secondary catalyst of Ge Labu of formula 15；
Step 9: after the double bond of the compound of hydro-reduction formula 16, obtain the target product of formula 17.
10. described in a kind of employing claim 9 preparation method preparation formula 17 the fluoro- (.+-.)-Swainsonine of 8,8- bis- [(-)-
Swainsonine] derivant, its molecular structure is as follows:
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| Title |
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| CHANG-MEI SI, ET AL.: "Divergent Method to trans-5-Hydroxy-6-alkynyl/alkenyl-2-piperidinones: Syntheses of (-)-Epiquinamide and (+)-Swainsonine", 《J. ORG. CHEM.》 * |
| GIORDANO LESMA,ET AL.: "A chemoenzymatic-RCM strategy for the enantioselective synthesis of new dihydroxylated 5-hydroxymethyl-indolizidines and 6-hydroxymethyl-quinolizidines", 《TETRAHEDRON: ASYMMETRY》 * |
| LIANG WU, ET AL.: "Pd(II)-Catalyzed Aminofluorination of Alkenes in Total Synthesis 6-(R)-Fluoroswainsonine and 5-(R)-Fluorofebrifugine", 《ORGANIC LETTERS》 * |
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