CN109748924A - A kind of asymmetric syntheses new method of biotin chiral lactone - Google Patents
A kind of asymmetric syntheses new method of biotin chiral lactone Download PDFInfo
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Abstract
The invention discloses a kind of asymmetric syntheses new methods of biotin chiral lactone, for the method using cyclic acid anhydride as starting material, asymmetric lactone (3S, 6R) -1 is made in chosen property alcoholysis, reduction, cyclization, 3- dibenzyl tetrahydrofuran and imidazole-2,4-diones.Present invention process route is simple, raw material is cheap and easy to get, the basic catalyst is practically insoluble in water, by simply extracting realization recovery, reduce production cost, improves the diastereoselective of alcoholysis reaction, method of the invention is easy to operate, the advantage that reaction condition is mild, easy to operate, high income, stereoselectivity are good, there is preferable application value and economic benefit.
Description
(1) technical field
The present invention relates to a kind of methods that stereoselective syntheses lead to the biotin chiral lactone of formula (I).
(2) technical background
Biotin is a kind of water-soluble sulfur-bearing B family vitamin, is widely present in the tissue of animals and plants and microorganism,
Biotin plays a significant role in terms of the metabolism such as carbohydrate, protein and fat, is that fat metabolism and its carboxylation are anti-
The important coenzyme answered is the important trophic factors for maintaining animals and plants normal growth and development indispensable, is widely used in medicine
There is great market demand in the fields such as product, cosmetics, food additives, feed addictive, therefore by numerous synthesis chemists
Research interest.
Optically active lactone (I) according to the present invention is the key intermediate of synthesizing biotinylated, at present to the conjunction of lactone
At being broadly divided into three kinds: chemical resolution, asymmetric syntheses, biosynthesis.It is tried in chemical resolution method using expensive fractionation
Agent, split process is cumbersome, splits the reasons such as low efficiency, seldom uses in existing industrialized production, and the ee value of biological synthesis process
It is all relatively low with yield, have much room for improvement and promoted, is unsuitable for industrialized production.
Document (Tetrahedron Lett.1993,34 (7): 1167-1170) is disappeared using (R)-BINAL-H reagent by interior
Cyclic acid anhydride direct-reduction is revolved, asymmetric lactone is obtained with 76% yield and 90%ee value, but yield and stereoselectivity are relatively low, no
It is suitable for industrialized production.
2013, document (Org.Lett.2013,15,1740-1743) was reported with the compound examination of Ir-C3*-TunePhos
Agent is Stereoselective reduction catalyst, and meso cyclic acid anhydride is reduced directly, is obtained with 96% high yield and 96%ee value
Chiral lactones.Although the reaction yield and stereoselectivity are higher, the expensive iridium metals of the reactive applications are catalysis
Agent, production cost is higher, is unfavorable for industrialized production.
Seebach etc. (J.Org.Chem.1998,63:1190-1197) utilizes chiral catalyst Ti-TAADOL derivative
By meso cyclic acid anhydride under conditions of -20 DEG C, required chiral half ester is obtained with 80% yield and 26%ee value.
Deng et al. (Synthesis.2001,1737) uses the quinine dimer DHQD-PHN conduct of anthraquinone connection
Chiral catalyst carries out asymmetry catalysis alcoholysis reaction to meso cyclic acid anhydride 6, obtains chiral half ester with 93%ee value, recycles
Cyanuric chloride, N- methylmorphine and sodium borohydride restore lactones, through sour water solution cyclization, with 82% yield and 91% high ee
Value obtains chiral lactones 8.
Chen Fener seminar is using cinchona alkaloid quinine as catalyst, using enantioselective ring-opening alcoholysis as key technology
Biotin asymmetric syntheses route, meso cyclic acid anhydride is under the catalysis of cinchona alkaloid quinine 31, with 75% yield
97% is up to ee value and obtains chiral half ester 30, through potassium borohydride reduction, the chiral lactones 8 of sour water solution cyclization.
Chinese patent (CN 1473832) is with by-product (1S, 2S)-d- Su Shi -1- (p-nitrophenyl in production of chloramphenicol
Base) -2- amino-1,3-propanediol derivative be catalyst, meso cyclic acid anhydride occurs in methanol solution asymmetry monoesters
Change ring-opening reaction, generate chiral monoester, is restored through potassium borohydride and Calcium Chloride System, through sour hydrolysis process cyclization, with 88%
Yield and 98.5% ee are worth chiral lactones.
Chen Fener group (Adv.Synth.Catal.2009,351,547) is using chiral thiourea as catalyst, by meso ring
Acid anhydrides asymmetry mono-esterification, then restored, hydrolyzed, asymmetric lactone is worth with the ee of 98% yield and 82%.
Currently, existing asymmetric lactone synthetic method exists, catalyst amount is big, stereoselectivity is not high, the reaction time
Therefore the disadvantages of long is still current research hotspot and difficult point by cyclic dicarboxylic acid anhydride high stereoselectivity synthesis asymmetric lactone.
(3) summary of the invention
The present invention provides the preparation method of one kind (3S, 6R) -1,3- dibenzyl tetrahydrofuran and imidazole-2,4-diones, gram
The problems such as reaction yield existing in the prior art is low, stereoselectivity is bad is taken.
To achieve the above object, the present invention uses following technology path:
Using cyclic acid anhydride shown in Formula II as starting material, chosen property alcoholysis, reduction, cyclization be made asymmetric lactone (3S,
6R) -1,3- dibenzyl tetrahydrofuran and imidazole-2,4-diones, specific synthetic method carry out as follows:
(a) Formula II compound represented is dissolved in organic solvent A, chiral alcohol shown in formula (VI) is added, stirs evenly
Afterwards, basic catalyst shown in formula (V) is slowly added dropwise wherein, controls temperature at -50~80 DEG C, is stirred to react 5~20 hours,
It is filtered to after reaction, obtain reaction solution A, it is dry, obtain formula III compound represented；Chemical combination shown in the Formula II
The ratio between object and the amount of substance of chiral alcohol shown in basic catalyst shown in formula (V), formula (VI) are 1:0.05~0.25:1~2；
(b) the formula III compound represented that step (a) obtains is dissolved in organic solvent B, at 0~60 DEG C, is added also
Original reagent is stirred to react 5~12 hours, obtains that reaction solution B is post-treated to obtain formula IV compound represented；The formula III institute
The ratio between amount of substance of the compound and reducing agent that show is 1:1.0~4.0；The reducing agent is hydroboron；
(c) acid is added into formula IV compound represented IV obtained by step (b), is reacted 1~5 hour at 20~120 DEG C, to
After reaction, it obtains reaction liquid C and is cooled to room temperature, filter, is dry, obtaining Formulas I compound represented；Change shown in the formula IV
Closing the ratio between amount of substance of object and acid is 1:1.0~4.0；
In formula (V): n is the number of unit group, and n takes 0~4；
The R2、R3、R4Or R5Respectively stand alone as C1-C12Alkyl, phenyl.
In formula (VI), two R6It is identical, be the residue of formula (VII a) or (VIIb):
In the formula (VII a) or (VIIb): R7It is hydrogen, fluorine, chlorine, C1-C6Alkyl or C1-C6Alkoxy.
Further, in step (a), the organic solvent A is aromatic hydrocarbons such as benzene,toluene,xylene, isopropylbenzene, methyl phenyl ethers anisole
Or chlorobenzene, ether for example ether, tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, monoglyme, diethylene glycol dimethyl ether or
Triglyme, halogenated hydrocarbons such as methylene chloride, 1,2- dichloroethanes or chloroform and dimethylformamide, dimethyl sulfoxide,
Acetonitrile or acetone, preferably toluene or methylene chloride.
Further, in step (a), the volumetric usage of the organic solvent A is in terms of the quality of Formula II compound represented
For 3-10mL/g.
Further, in step (a), basic catalyst shown in the formula (V) is preferably N, N, N, N- tetrapropyl -1,3- third
Diamines, N, N, N, the N- tetrabutyl -1,4- butanediamine, N, N, N, tetra- octyl -1,8- of tetra- hexyl -1,6- hexamethylene diamine of N- or N, N, N, N-
Octamethylenediamine.
Further, in step (a), the amount of the Formulas I compound represented and the substance of basic catalyst shown in formula (V)
The ratio between preferably 1:0.1-0.15.
Further, in step (a), chiral alcohol shown in the formula (VI) is preferably (S) -1,1- dinaphthyl -1,2- the third two
Alcohol.
Further, in step (a), the ratio between the amount of substance of the Formula II compound represented and chiral alcohol shown in formula (VI)
Preferably 1:1.2.
According to the present invention, the enantiomeric purity of chiral alcohol is preferably at least 90%ee, more preferably at least 98%ee, special
It You Xuanweizhishao not 99%ee.
Further, in step (a), the reaction temperature is preferably -20-50 DEG C.
Further, in step (b), the organic solvent B is ether such as tetrahydrofuran, 2- methyltetrahydrofuran, dioxy six
Ring, monoglyme, glycol dimethyl ether, glycol monoethyl ether or triglyme；Alcohol for example methanol, ethyl alcohol, isopropanol,
N-butanol or ethylene glycol.
Further, in step (b), the volumetric usage of the organic solvent B is in terms of the quality of formula III compound represented
For 5-10mL/g.
Further, in step (b), the reducing agent is LiBH4、NaBH4、KBH4、Zn(BH4)2、Ca(BH4)2、NaBH
(OAc)3、NaBH3CN, preferably KBH4。
Further, in step (b), the ratio between amount of substance of the formula III compound represented and reducing agent is preferably 1:
2.0-3.0。
Further, in step (b), the reaction temperature is preferably 20-40 DEG C.
Further, in step (b), the post-processing approach of the reaction solution B are as follows: water is added in the reaction solution B of Xiang Suoshu
And toluene, toluene phase is separated, water phase concentration filters, is dried to obtain formula IV compound represented.
Further, in step (c), the acid is hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, hydrobromic acid, hydroiodic acid or to first
Benzene sulfonic acid, preferably sulfuric acid.
Further, in step (c), the ratio between amount of substance of the formula IV compound represented acid is preferably 1:1.5-2.5.
Further, in step (c), the reaction temperature is preferably 50-90 DEG C.
Compared with prior art, the beneficial effects of the present invention are:
Present invention process route is simple, and raw material is cheap and easy to get, and the basic catalyst is practically insoluble in water, by simple
Extraction realize recovery, reduce production cost, improve the diastereoselective of alcoholysis reaction, method of the invention
Advantage easy to operate, that reaction condition is mild, easy to operate, high income, stereoselectivity are good, there is preferable application value and warp
Ji benefit.
(4) specific embodiment
Following examples describe according to the method for the present invention:
The diastereomeric purity and enantiomeric purity of intermediate and final products can by such as routine HPLC analyze come
It determines.This method is well known to those skilled in the art
Embodiment 1: the preparation of compound III
At 10 DEG C, compound II (10g, 29.7mmol) is dissolved in 50mL toluene, dinaphthyl -1 (S) -1,1- is added,
2- propylene glycol (12.7g, 35.7mmol), after mixing evenly, by N, N, N, N- tetrapropyl -1,3- propane diamine (0.83g,
It 4.455mmol) is slowly dropped in reaction solution, controls temperature at -50~80 DEG C, continue stirring 5~20 hours, to the end of reacting
Afterwards, reaction solution is filtered, filter residue is washed with the toluene of 20mL, and dry filter residue, obtaining desired diastereomeric purity is 100%
Compound III 19g, yield 96%.
Embodiment 2: the preparation of compound III
At 10 DEG C, compound II (5g, 14.8mmol) is dissolved in 25mL toluene, dinaphthyl -1 (S) -1,1- is added,
2- propylene glycol (6.35g, 17.8mmol), after mixing evenly, by N, N, N, the N- tetrabutyl-Putriscine (0.321g,
It 2.2275mmol) is slowly dropped in reaction solution, controls temperature at -50~80 DEG C, continue stirring 15~20 hours, wait react knot
Shu Hou filters reaction solution, and filter residue is washed with the toluene of 10mL, and dry filter residue, obtaining desired diastereomeric purity is
100% compound III 9.72g, yield 95%.
Embodiment 3: the preparation of compound III
At 10 DEG C, compound II (5g, 14.8mmol) is dissolved in 25mL toluene, dinaphthyl -1 (S) -1,1- is added,
2- propylene glycol (6.35g, 17.8mmol), after mixing evenly, by N, N, N, tetra- hexyl -1,6- hexamethylene diamine of N- (1g,
It 2.2275mmol) is slowly dropped in reaction solution, controls temperature at -50~80 DEG C, continue stirring 15~20 hours, wait react knot
Shu Hou filters reaction solution, and filter residue is washed with the toluene of 10mL, and dry filter residue, obtaining desired diastereomeric purity is
100% compound III 9.91g, yield 96.5%.
Embodiment 4: the preparation of compound III
At 10 DEG C, compound II (6.7g, 20mmol) is dissolved in 25mL toluene, dinaphthyl -1 (S) -1,1- is added,
2- propylene glycol (8.54g, 24mmol), after mixing evenly, by N, N, N, tetra- octyl -1,8- octamethylenediamine (1.77g, 3mmol) of N- is slow
Slowly it is added drop-wise in reaction solution, controls temperature at -50~80 DEG C, continue stirring 10~20 hours, to after reaction, by reaction solution
It filters, filter residue is washed with the toluene of 10mL, and dry filter residue, obtaining desired diastereomeric purity is 100% compound III
13.42g yield 97%.
Embodiment 5: the preparation of compound III
At 10 DEG C, compound II (10g, 29.7mmol) is dissolved in 80mL methylene chloride, (S) -1,1- dinaphthyl is added
Base -1,2-PD (12.7g, 35.7mmol), after mixing evenly, by N, N, N, N- tetrapropyl -1,3- propane diamine (0.83g,
It 4.455mmol) is slowly dropped in reaction solution, controls temperature at -50~80 DEG C, continue stirring 10~20 hours, wait react knot
Shu Hou washes reaction solution, saturated common salt washing, organic phase concentration, column chromatograph to obtain desired diastereomeric purity be
100% compound III 18.49g, yield 90%.
Embodiment 6: the preparation of compound III
At 10 DEG C, compound II (5g, 14.8mmol) is dissolved in 25mL toluene, dinaphthyl -1 (S) -1,1- is added,
2- propylene glycol (6.35g, 17.8mmol), after mixing evenly, by N, N, N, tetra- hexyl -1,6- hexamethylene diamine of N- (0.137g,
It 0.74mmol) is slowly dropped in reaction solution, controls temperature at -50~80 DEG C, continue stirring 15~20 hours, to the end of reacting
Afterwards, reaction solution is filtered, filter residue is washed with the toluene of 10mL, and dry filter residue, obtaining desired diastereomeric purity is 100%
Compound III 8.622g, yield 70%.
Embodiment 7: the preparation of compound III
At 10 DEG C, compound II (5g, 14.8mmol) is dissolved in 25mL toluene, dinaphthyl -1 (S) -1,1- is added,
2- propylene glycol (6.35g, 14.8mmol), after mixing evenly, by N, N, N, tetra- hexyl -1,6- hexamethylene diamine of N- (0.689g,
It 3.7mmol) is slowly dropped in reaction solution, controls temperature at -50~80 DEG C, continue stirring 15~20 hours, to the end of reacting
Afterwards, reaction solution is filtered, filter residue is washed with the toluene of 10mL, and dry filter residue, obtaining desired diastereomeric purity is 100%
Compound III 9.73g, yield 95%.
Embodiment 8: the preparation of compound III
At 10 DEG C, compound II (10g, 29.7mmol) is dissolved in 50mL toluene, dinaphthyl -1 (S) -1,1- is added,
2- propylene glycol (10.58g, 29.7mmol), after mixing evenly, by N, N, N, N- tetrapropyl -1,3- propane diamine (0.83g,
It 4.455mmol) is slowly dropped in reaction solution, controls temperature at -50~80 DEG C, continue stirring 5~20 hours, to the end of reacting
Afterwards, reaction solution is filtered, filter residue is washed with the toluene of 20mL, and dry filter residue, obtaining desired diastereomeric purity is 100%
Compound III 18.9g, yield 92%.
Embodiment 9: the preparation of compound III
At 10 DEG C, compound II (5g, 14.8mmol) is dissolved in 25mL toluene, dinaphthyl -1 (S) -1,1- is added,
2- propylene glycol (10.58g, 29.7mmol), after mixing evenly, by N, N, N, tetra- hexyl -1,6- hexamethylene diamine of N- (0.412g,
It 2.22mmol) is slowly dropped in reaction solution, controls temperature at -50~80 DEG C, continue stirring 15~20 hours, to the end of reacting
Afterwards, reaction solution is filtered, filter residue is washed with the toluene of 10mL, and dry filter residue, obtaining desired diastereomeric purity is 100%
Compound III 9.31g, yield 91%.
Embodiment 10: the preparation of compound IV
Compound III (5g, 7.22mmol) is entered into the solution in 50mL tetrahydrofuran, is slowly added at 10 DEG C
LiBH4 (0.38g, 18.05mmol) controls 0~60 DEG C of temperature, continues stirring 5~12 hours, and reaction terminates, and 50mL water is added
With 50mL toluene, after stirring 30 minutes, water phase is separated, water phase 50m1 toluene extracts three times, merges organic phase, and be concentrated, obtain
(the S) -1,1- dinaphthyl -1,2- propylene glycol for being 85% to 2.18g theory total recovery.Merge water phase, compound is concentrated under reduced pressure to obtain
IV2.08g, 85%.
Embodiment 11: the preparation of compound IV
Compound III (6.9g, 10mmol) is entered into the solution in 70mL tetrahydrofuran, is slowly added at 10 DEG C
NaBH4(0.95g, 25mmol), control 0~60 DEG C of temperature, continue stirring 5~12 hours, reaction terminates, be added 70mL water and
70mL toluene after stirring 30 minutes, separates water phase, and water phase 70m1 toluene extracts three times, merges organic phase, and be concentrated, obtain
(S) -1,1- dinaphthyl -1,2- propylene glycol that 3g theory total recovery is 86%.Merge water phase, compound is concentrated under reduced pressure to obtain
IV2.92g, 86%.
Embodiment 12: the preparation of compound IV
Compound III (13.8g, 20mmol) is entered into the solution in 100mL tetrahydrofuran, is slowly added at 10 DEG C
KBH4(2.69g, 50mmol), control 0~60 DEG C of temperature, continue stirring 5~12 hours, reaction terminates, be added 100mL water and
100mL toluene after stirring 30 minutes, separates water phase, and water phase 100m1 toluene extracts three times, merges organic phase, and be concentrated, obtain
(the S) -1,1- dinaphthyl -1,2- propylene glycol for being 89% to 6.3g theory total recovery.Merge water phase, compound is concentrated under reduced pressure to obtain
IV5.98g, 88%.
Embodiment 13: the preparation of compound IV
Compound III (13.8g, 20mmol) is entered into the solution in 100mL tetrahydrofuran, is slowly added at 10 DEG C
KBH4(1.08g, 20mmol), control 0~60 DEG C of temperature, continue stirring 5~12 hours, reaction terminates, be added 100mL water and
100mL toluene after stirring 30 minutes, separates water phase, and water phase 100m1 toluene extracts three times, merges organic phase, and be concentrated, obtain
(the S) -1,1- dinaphthyl -1,2- propylene glycol for being 89% to 6.3g theory total recovery.Merge water phase, compound is concentrated under reduced pressure to obtain
IV5.44g, 80%.
Embodiment 14: the preparation of compound IV
Compound III (13.8g, 20mmol) is entered into the solution in 100mL tetrahydrofuran, is slowly added at 10 DEG C
KBH4(4.3g, 80mmol), control 0~60 DEG C of temperature, continue stirring 5~12 hours, reaction terminates, be added 100mL water and
100mL toluene after stirring 30 minutes, separates water phase, and water phase 100m1 toluene extracts three times, merges organic phase, and be concentrated, obtain
(the S) -1,1- dinaphthyl -1,2- propylene glycol for being 89% to 6.3g theory total recovery.Merge water phase, compound is concentrated under reduced pressure to obtain
IV5.78g, 85%.
Embodiment 15: the preparation of compound I
Compound IV (10g, 29.4mmol) is added in the 4M hydrochloric acid solution of 40ml, is stirred 1 hour at 90 DEG C.It takes out
Filter is washed (50ml), and filter cake vacuum drying obtains lactone compound I 9.27g, 98%, chiral purity 98.5%ee
(HPLC)。
Embodiment 16: the preparation of compound I
Compound IV (5g, 14.7mmol) is added in the 2M hydrochloric acid solution of 30ml, is stirred 3 hours at 90 DEG C.It takes out
Filter is washed (50ml), and filter cake vacuum drying obtains lactone compound I 4.44g, 94%, chiral purity 98.5%ee
(HPLC)。
Embodiment 17: the preparation of compound I
Compound IV (15g, 44.1mmol) is added in the 4M sulfuric acid solution of 50ml, is stirred 1 hour at 90 DEG C.It takes out
Filter is washed (50ml), and filter cake vacuum drying obtains lactone compound I 13.6g, and 96%, chiral purity is 97%ee (HPLC).
Embodiment 18: the preparation of compound I
Compound IV (10g, 29.4mmol) is added in the 2M sulfuric acid solution of 50ml, is stirred 3 hours at 90 DEG C.It takes out
Filter is washed (50ml), and filter cake vacuum drying obtains lactone compound I 8.7g, and 92%, chiral purity is 97%ee (HPLC).
Embodiment 19: the preparation of compound I
Compound IV (5g, 14.7mmol) is added in the 4M p-methyl benzenesulfonic acid solution of 30ml, it is small that 4 are stirred at 90 DEG C
When.It filters, washes (50ml), filter cake vacuum drying obtains lactone compound I4.49g, 95%, chiral purity 98%ee
(HPLC)。
Embodiment 20: the preparation of compound I
Compound IV (15g, 44.1mmol) is added in the 2M p-methyl benzenesulfonic acid solution of 100ml, stirs 5 at 90 DEG C
Hour.It filtering, washes (100ml), filter cake vacuum drying obtains lactone compound I12.78g, and 90%, chiral purity 98%
ee(HPLC)。
Claims (10)
1. a kind of asymmetric syntheses new method of biotin chiral lactone, it is characterised in that: the method is in accordance with the following steps
It carries out:
(a) Formula II compound represented is dissolved in organic solvent A, chiral alcohol shown in formula (VI) is added, it after mixing evenly, will
Basic catalyst shown in formula (V) is slowly added dropwise wherein, controls temperature at -50~80 DEG C, is stirred to react 5~20 hours, to anti-
After answering, obtains reaction solution A and filtered, it is dry, obtain formula III compound represented；The Formula II compound represented with
The ratio between amount of substance of basic catalyst shown in formula (V), chiral alcohol shown in formula (VI) is 1:0.05~0.25:1~2；
(b) the formula III compound represented that step (a) obtains is dissolved in organic solvent B, at 0~60 DEG C, reduction is added
Agent is stirred to react 5~12 hours, obtains that reaction solution B is post-treated to obtain formula IV compound represented；Shown in the formula III
The ratio between amount of substance of compound and go back original reagent is 1:1.0~4.0；The reducing agent is hydroboron；
(c) acid is added into formula IV compound represented IV obtained by step (b), is reacted 1~5 hour at 20~120 DEG C, wait react
After, it obtains reaction liquid C and is cooled to room temperature, filter, is dry, obtaining Formulas I compound represented；The formula IV compound represented
The ratio between amount of substance with acid is 1:1.0~4.0；
In formula (V): n is the number of unit group, and n takes 0~4；
The R2、R3、R4Or R5Respectively stand alone as C1-C12Alkyl or phenyl.
In formula (VI), two R6It is identical, be the residue of formula (VIIa) or (VIIb):
In the formula (VIIa) or (VIIb): R7It is hydrogen, fluorine, chlorine, C1-C6Alkyl or C1-C6Alkoxy.
2. the method as described in claim 1, it is characterised in that: in step (a), the organic solvent A is benzene, toluene, two
Toluene, isopropylbenzene, methyl phenyl ethers anisole, chlorobenzene, ether, tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, monoglyme, two
Glyme, triglyme, methylene chloride, 1,2- dichloroethanes, chloroform, dimethylformamide, dimethyl sulfoxide, second
Nitrile or acetone.
3. the method as described in claim 1, it is characterised in that: in step (a), the volumetric usage of the organic solvent A with
The quality of Formula II compound represented is calculated as 3-10mL/g.
4. the method as described in claim 1, it is characterised in that: in step (a), basic catalyst shown in the formula (V) is
N, N, N, N- tetrapropyl -1,3- propane diamine, N, N, N, the N- tetrabutyl -1,4- butanediamine, N, N, N, tetra- hexyl -1,6- hexamethylene diamine of N-
Or tetra- octyl -1,8- octamethylenediamine of N, N, N, N-.
5. the method as described in claim 1, it is characterised in that: in step (a), chiral alcohol shown in the formula (VI) is (S)-
1,1- dinaphthyl -1,2- propylene glycol.
6. the method as described in claim 1, it is characterised in that: in step (b), the organic solvent B is tetrahydrofuran, 2-
Methyltetrahydrofuran, dioxane, monoglyme, glycol dimethyl ether, glycol monoethyl ether, triglyme, first
Alcohol, ethyl alcohol, isopropanol, n-butanol or ethylene glycol.
7. the method as described in claim 1, it is characterised in that: in step (b), the volumetric usage of the organic solvent B with
The quality of formula III compound represented is calculated as 5-10mL/g.
8. the method as described in claim 1, it is characterised in that: in step (b), the reducing agent is LiBH4、NaBH4、
KBH4、Zn(BH4)2、Ca(BH4)2、NaBH(OAc)3Or NaBH3CN4。
9. the method as described in claim 1, it is characterised in that: in step (b), the post-processing approach of the reaction solution B are as follows: to
Water and toluene are added in the reaction solution B, separates toluene phase, water phase concentration filters, is dried to obtain chemical combination shown in formula IV
Object.
10. the method as described in claim 1, it is characterised in that: in step (c), the acid is hydrochloric acid, sulfuric acid, phosphoric acid, height
Chloric acid, hydrobromic acid, hydroiodic acid or p-methyl benzenesulfonic acid.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110804062A (en) * | 2019-11-06 | 2020-02-18 | 浙江工业大学 | Synthesis method of (3S,6R) -1, 3-dibenzyl tetrahydrofuran imidazole-2, 4-diketone |
| CN113549084A (en) * | 2020-04-24 | 2021-10-26 | 杭州科兴生物化工有限公司 | Method for stereoselectively synthesizing chiral lactone |
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| CN110804062A (en) * | 2019-11-06 | 2020-02-18 | 浙江工业大学 | Synthesis method of (3S,6R) -1, 3-dibenzyl tetrahydrofuran imidazole-2, 4-diketone |
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| CN113549084A (en) * | 2020-04-24 | 2021-10-26 | 杭州科兴生物化工有限公司 | Method for stereoselectively synthesizing chiral lactone |
| CN113549084B (en) * | 2020-04-24 | 2023-02-28 | 杭州科兴生物化工有限公司 | Method for stereoselectively synthesizing chiral lactone |
| CN114560865A (en) * | 2022-02-25 | 2022-05-31 | 复旦大学 | Continuous flow synthesis method of (3aS,6aR) -lactone |
| CN114634515A (en) * | 2022-02-25 | 2022-06-17 | 复旦大学 | Stereoselective synthesis method of (3aS,6aR) -lactone |
| CN114560865B (en) * | 2022-02-25 | 2024-02-02 | 复旦大学 | Continuous flow synthesis method of (3 aS,6 aR) -lactone |
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