CN108059579A - A kind of borane reagent combination solution, preparation method and the usage containing stabilizer - Google Patents
A kind of borane reagent combination solution, preparation method and the usage containing stabilizer Download PDFInfo
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- CN108059579A CN108059579A CN201710995960.XA CN201710995960A CN108059579A CN 108059579 A CN108059579 A CN 108059579A CN 201710995960 A CN201710995960 A CN 201710995960A CN 108059579 A CN108059579 A CN 108059579A
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- Prior art keywords
- borane
- stabilizer
- ether complexes
- tetrahydrofuran
- borane dimethylsulfide
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- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 title claims abstract description 108
- 229910000085 borane Inorganic materials 0.000 title claims abstract description 70
- 239000003381 stabilizer Substances 0.000 title claims abstract description 68
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 179
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 90
- -1 borane dimethylsulfide ether complexes Chemical class 0.000 claims abstract description 79
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 33
- 239000012279 sodium borohydride Substances 0.000 claims description 33
- 238000006722 reduction reaction Methods 0.000 claims description 25
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 10
- 229910052700 potassium Inorganic materials 0.000 claims description 10
- 239000011591 potassium Substances 0.000 claims description 10
- 239000012448 Lithium borohydride Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 8
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 6
- 229910052796 boron Inorganic materials 0.000 claims description 6
- MCYCSIKSZLARBD-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)phenyl]ethanone Chemical class CC(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MCYCSIKSZLARBD-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000010926 purge Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 230000009467 reduction Effects 0.000 abstract description 20
- 239000000243 solution Substances 0.000 description 107
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229910010277 boron hydride Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005661 deetherification reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- 238000006197 hydroboration reaction Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000002560 nitrile group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- GVPVKKWXJXESIC-UHFFFAOYSA-N 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC(Cl)=C(N)C(C(F)(F)F)=C1 GVPVKKWXJXESIC-UHFFFAOYSA-N 0.000 description 1
- VYOROBFIZJMFTO-UHFFFAOYSA-N 3,3,3-trifluoro-1-phenyl-2-(trifluoromethyl)propan-1-one Chemical class FC(F)(F)C(C(F)(F)F)C(=O)C1=CC=CC=C1 VYOROBFIZJMFTO-UHFFFAOYSA-N 0.000 description 1
- 238000005750 Corey-Bakshi-Shibata reduction reaction Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- NVXLIZQNSVLKPO-UHFFFAOYSA-N Glucosereductone Chemical compound O=CC(O)C=O NVXLIZQNSVLKPO-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
- C07B41/02—Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The present invention provides a kind of borane reagent combination solutions containing stabilizer, wherein, the borane reagent combination solution includes borane dimethylsulfide ether complexes, tetrahydrofuran and stabilizer, wherein concentration of the borane dimethylsulfide ether complexes in tetrahydrofuran is 1~10 mol/L, and the molar ratio of borane dimethylsulfide ether complexes and stabilizer is 100:1~1000:1.The combination solution concentration higher of the present invention, thermal stability is more preferable, can more efficiently utilize reaction vessel, tetrahydrofuran reagent is saved, to reduce cost；During applied to Corey asymmetric reductions, the enantioselectivity of reaction is more preferable, enantiomeric excess value (%ee) higher of product.
Description
Technical field
The present invention relates to a kind of combination solution, specifically, be related to a kind of borane reagent combination solution containing stabilizer, its
Preparation method and use.
Background technology
Diborane (B2H6) it is toxic, pyrophoric gas, it is highly susceptible to hydrolyzing and aoxidizes.It is carried out to handle necessary pole
Degree is careful and must transport and store at a temperature of less than -20 DEG C.In order to reduce the danger for using diborane, usually make
With borine (BH3) with the complex compounds of the donor melecules such as tetrahydrofuran, thioether, amine and hydrogen phosphide organic reaction is carried out, especially
Hydroboration for the reduction of functional group and with alkene and alkynes.The functional group reduced by these borane complexes wraps
Include aldehyde, ketone, lactones, epoxides, ester, amide, oxime, imines and nitrile group.
The most common commercial source of borine is tetrahydrofuran (THF) solution of borine tetrahydrofuran complex (BTHF),
It can buy on the market and concentration is usually 1 mol/L.However, due to the ether cleavage of tetrahydrofuran ring, borine tetrahydrochysene furan
Complex compound of muttering is easy to be thermally decomposed.By inventor the study found that at a temperature of 25 DEG C, the borine tetrahydrofuran network of 1 mol/L
Polymer solution after 15 days concentration have dropped 18%, at a temperature of 35 DEG C, the borine tetrahydrofuran complex solution 15 of 1 mol/L
Concentration has dropped 24% after it, and this poor thermal stability greatly affected the transport of product, storage and application.
When borine tetrahydrofuran (BTHF) complex solution of this low concentration participates in organic reaction, due to borane concentration
Relatively low, dosage is larger, can occupy more reaction compartments, causes the waste of production capacity；Tetrahydrofuran solvent dosage is larger, cost compared with
It is high；The enantioselectivity reacted during applied to Corey asymmetric reductions is poor, with reference to US6218585, when sodium borohydride stabilized
Borine tetrahydrofuran complex solution for acetophenone Me-CBS catalysis reduction when, be only capable of in reduction obtain 80% to
95% %ee values.
Amine borine reactivity be usually not enough to reduce special functional group, moreover, such complexing agent be difficult to sometimes from
It is removed in reaction mixture, causes purifying products relatively difficult so that its business application is restricted.
On the other hand, the thioethers borine such as borane dimethylsulfide ether complexes (BDMS) is high concentration, such as borane dimethylsulfide
Ether complexes concentration can reach 10 mol/Ls.Borane dimethylsulfide ether complexes are equally applicable to Corey asymmetric reductions, example
When being such as applied to reduction 3 ', 5 '-bis- (trifluoromethyls) acetophenone, just good reduction effect can be obtained
(J.AM.CHEM.SOC. 2003,125,2129-2135).But since the borane dimethylsulfide ether complexes height of high concentration is inflammable,
It is violent to meet water reaction, is highly susceptible to releasing spontaneously inflammable inflammable gas, the security risk for cause its storage, transporting and using is very
Greatly.
The tetrahydrofuran solution of the borane dimethylsulfide ether complexes of 1.5~5 mol/Ls is compared to commercialized borine tetrahydrochysene
The tetrahydrofuran solution concentration of furans complex compound is higher, and for reaction efficiency during 3 ', 5 '-bis- (trifluoromethyl) acetophenones of reduction
Higher.But by inventor the study found that at a temperature of 35 DEG C, the tetrahydrochysene of the borane dimethylsulfide ether complexes of 2 mol/Ls
Tetrahydrofuran solution after 28 days concentration have dropped 3.3%, it was demonstrated that the stability of the tetrahydrofuran solution of borane dimethylsulfide ether complexes is not
It reaches.
It, can by adding a small amount of hydride source, such as sodium borohydride, potassium borohydride, lithium borohydride with reference to US3634277
With borine tetrahydrofuran complex solution known to raising in the storage stability of various concentration.
But it is added into the tetrahydrofuran solution of borane dimethylsulfide ether complexes produced by after the stabilizers such as boron hydride
Influence have not been reported, therefore, the stability of the tetrahydrofuran solution of the borane dimethylsulfide ether complexes containing boron hydride and also
Originality energy, e.g., the influence for the enantioselectivity of asymmetric reduction reaction is not apparent.
The content of the invention
Inventor has found that borane dimethylsulfide ether complexes can also have an effect with tetrahydrofuran, cause tetrahydrochysene
The ether cleavage of furan nucleus, the tetrahydrofuran solution of borane dimethylsulfide ether complexes are equally easy to be thermally decomposed.It is existing in order to overcome
The defects of technology, the present invention provides a kind of safe and stable and efficient borane reagent combination solutions.In order to realize the present invention
Purpose, technical scheme is as follows：
The present invention provides a kind of borane reagent combination solution containing stabilizer, wherein, the borane reagent combination solution
Including borane dimethylsulfide ether complexes, tetrahydrofuran and stabilizer, wherein borane dimethylsulfide ether complexes are in tetrahydrofuran
Concentration is 1~10 mol/L, and the molar ratio of borane dimethylsulfide ether complexes and stabilizer is 100:1~1000:1, it is described steady
Determine the one kind or its combination of agent in sodium borohydride, lithium borohydride or potassium borohydride.
In the preferred embodiment of the present invention, wherein, concentration of the borane dimethylsulfide ether complexes in tetrahydrofuran is
1.5~5 mol/Ls.
In the preferred embodiment of the present invention, wherein, the molar ratio of borane dimethylsulfide ether complexes and stabilizer is
200:1~500:1.
In the preferred embodiment of the present invention, wherein, the stabilizer is sodium borohydride.
The present invention provides a kind of preparation method of the borane reagent combination solution containing stabilizer, wherein, the preparation side
Method comprises the following steps：
(1) suitable dimethyl sulphide is simultaneously packed into simultaneously with nitrogen purging glass reaction bottle, control reaction bulb temperature at 0 DEG C,
The diborane of 0.5 equivalent is bubbled into reaction bulb through several hours, during being bubbled into, controls temperature at 0~5 DEG C,
After treating that diborane is passed through, continue to be stirred to react 10~20 minutes, borane dimethylsulfide ether complexes are made；
(2) using tetrahydrofuran by the borane dimethylsulfide ether complexes obtained in step (1) be diluted to 1~10 mole/
It rises, the tetrahydrofuran solution of borane dimethylsulfide ether complexes is made；
(3) stabilizer is added in into the tetrahydrofuran solution of the borane dimethylsulfide ether complexes obtained by step (2), so as to
Borane reagent combination solution is made, the wherein molar ratio of borane dimethylsulfide ether complexes and stabilizer is 100:1~1000:1, institute
State the one kind or its combination of stabilizer in sodium borohydride, lithium borohydride or potassium borohydride.
In the preferred embodiment of the present invention, wherein in step (2), the tetrahydrofuran of borane dimethylsulfide ether complexes
Solution concentration is 1.5~5 mol/Ls.
In the preferred embodiment of the present invention, wherein in step (3), borane dimethylsulfide ether complexes and stabilizer
Molar ratio is 200:1~500:1.
The present invention also provides use of the borane reagent combination solution in Corey asymmetric reduction reactions containing stabilizer
On the way, wherein when the combination solution reduces 3 ', 5 '-bis- (trifluoromethyl) acetophenones, the enantioselectivity of reaction is good, product yield
Up to 93%, %ee values are up to more than 99%.
The present invention is that boron hydride is added into the tetrahydrofuran solution of borane dimethylsulfide ether complexes as stabilizer
To increase the stability of combination solution.Therefore, the borane reagent containing stabilizer of the present invention is combined at different conditions
The stability of solution is studied.For example, Fig. 1 compared under the conditions of existing for different types of stabilizer, 2 mol/Ls
Stability data of the tetrahydrofuran solution of borane dimethylsulfide ether complexes under the conditions of 35 DEG C, it can be seen from the figure that stablizing
Under the conditions of agent (sodium borohydride, potassium borohydride, lithium borohydride) is existing, the tetrahydrofuran solution of borane dimethylsulfide ether complexes is steady
It is qualitative to significantly improve；Fig. 2 compared under the conditions of stabilizer (sodium borohydride) is existing, the borane dimethylsulf iotade network of 2 mol/Ls
The tetrahydrofuran solution of the tetrahydrofuran solution of conjunction object and the borine tetrahydrofuran complex of 2 mol/Ls is under the conditions of 35 DEG C
Stability data, it can be seen from the figure that under conditions of equally containing stabilizer, the tetrahydrofuran of borane dimethylsulfide ether complexes
Solution is more more stable than the tetrahydrofuran solution of borine tetrahydrofuran complex；Fig. 3 compared the sodium borohydride in different mol ratio
Under the conditions of existing, the stability number of the tetrahydrofuran solutions of the borane dimethylsulfide ether complexes of 2 mol/Ls under the conditions of 35 DEG C
According to, it was demonstrated that borane dimethylsulfide ether complexes are with stabilizer molar ratio 100:1~1000:In the range of 1, of the present invention group
It is stable to close object；Fig. 4 compared under the conditions of existing for stabilizer, the tetrahydrochysene of the borane dimethylsulfide ether complexes of various concentration
Stability data of the tetrahydrofuran solution under the conditions of 35 DEG C, it was demonstrated that under the conditions of existing for stabilizer, the borine two of various concentration
The tetrahydrofuran solution of dimethylsulfide complex is all stable；Fig. 5 shown under the conditions of existing for stabilizer, 2 mol/Ls
Stability data of the tetrahydrofuran solution of borane dimethylsulfide ether complexes under the conditions of 2-8 DEG C, statistics indicate that, it is deposited in stabilizer
Under the conditions, composition of the present invention can be stablized for a long time.
Borane reagent combination solution provided by the invention have numerous advantages, for example, 1) can store at low temperature to
It is 1 year few, reference implementation example 6, and also the borane reagent stablized will not cause because gas is generated in steel cylinder during storage
Pressure increases, and compared with the thioether borine of high concentration, significantly reduces the security risk of storage；2) transport for a long time at high temperature
Defeated (reference implementation example 3) will not go bad, and without Refrigerated Transport, can reduce transportation cost, after shipping or use it
It is preceding to economize on resources also without detection is repeated, reduce waste；3) with the borine tetrahydrofuran complex of common 1 mol/L
Tetrahydrofuran solution compare, combination solution concentration higher of the invention, thermal stability is more preferable, can more efficiently using reaction
Container saves tetrahydrofuran reagent, to reduce cost；4) when participating in Corey asymmetric reduction reactions, the enantioselectivity of reaction
More preferably, referring to the experimental result of embodiment 7-10, as shown in table 5, make reducing agent using borane dimethylsulfide ether complexes and participate in instead
At once compared with the experimental result of borine tetrahydrofuran complex, obtained product yield is not much different, and enantiomeric excess value
(%ee) higher.
The present invention borane reagent combination solution can stablize at least 28 days at 35 DEG C or can stablize at 2-8 DEG C to
It is 1 year few.This combination solution of the present invention can be used for a variety of organic conversions.Example is the reduction of functional group, passes through this borine
The functional group of complex compound reduction includes aldehyde, ketone, lactones, epoxides, ester, amide, oxime, imines and nitrile group.
Corey-Bakshi-Shibata reduction (i.e. Corey asymmetric reductions) (E.J.Corey, R.K.Bakshi,
S.Shibata, J. Am.Chem.Soc.1987,109,5551-5553) refer to utilize borine and borane of chiral oxazole catalyst
The reductone of enantioselectivity obtains corresponding chiral alcohol.It is this to go back due to its high enantioselectivity, predictability and high yield
Original reaction effectively can be competed mutually with enzyme and transition metal-catalyzed hydrogenation.This reduction reaction reduction efficiency it is very high and
It is easy to operate, therefore it is highly suitable for industrial production.This borane reagent combination solution of the present invention is equally applicable to this
Kind of reduction reaction, moreover, compared with using the borine tetrahydrofuran complex solution of sodium borohydride stabilized as reducing agent, this hair
Higher enantiomeric excess value can be obtained in reduction for the bright combination solution or even the presence of sodium borohydride is not also dropped
The enantioselectivity of the low reaction.
The present invention can prepare the tetrahydrofuran solution of stable borane dimethylsulfide ether complexes, can be widely applied to
Corey asymmetric reductions selectively reduce prochiral ketones and obtain corresponding chiral alcohol.The present invention combination solution in
Boron hydride is added in the tetrahydrofuran solution of borane dimethylsulfide ether complexes as stabilizer to increase the stabilization of combination solution
Property.Borane reagent combination solution disclosed by the invention containing stabilizer can be applied to Corey asymmetric reductions.
The present invention provides a kind of borane reagent combination solution containing stabilizer, which is a kind of with good
The efficient borane reagent of stability, security and reactivity, has very big commercial application value.
Description of the drawings
Fig. 1 compared under the conditions of existing for different types of stabilizer, the borane dimethylsulfide ether complexes of 2 mol/Ls
Stability data of the tetrahydrofuran solution under the conditions of 35 DEG C
Fig. 2 compared under the conditions of existing for stabilizer, the tetrahydrofuran of the borane dimethylsulfide ether complexes of 2 mol/Ls
Stability data of the tetrahydrofuran solution of solution and the borine tetrahydrofuran complex of 2 mol/Ls under the conditions of 35 DEG C
Fig. 3 shows the borane dimethylsulf iotade of stabilizer 2 mol/Ls different from borane dimethylsulfide ether complexes molar ratio
Stability of the tetrahydrofuran solution of complex compound under the conditions of 35 DEG C；
Fig. 4 shown under the conditions of existing for stabilizer, the tetrahydrofuran of the borane dimethylsulfide ether complexes of various concentration
Stability of the solution under the conditions of 35 DEG C；
Fig. 5 shown under the conditions of existing for stabilizer, the tetrahydrofuran of the borane dimethylsulfide ether complexes of 2 mol/Ls
Stability of the solution under the conditions of 2-8 DEG C.
Specific embodiment
Following embodiment illustration present invention are without being limited.According to Brown, H.C.；Kramer,G.W.；Levy,
A.B.； Midland,M.M.in Organic Synthesis via Boranes,John Wiley and Sons,Inc.,
New York 1973, the method described in the 241-244 pages measure borane concentration by acidometric titration borine.
The instrument of the enantiomeric excess value (%ee) of the present invention is measured as high performance liquid chromatograph, chromatographic column is：
CHIRALCEL OD-H (0.46cm I.D.*25cm L*5 μm), mobile phase are n-hexane and isopropanol.
The preparation of 1 borane dimethylsulfide ether complexes (BDMS) of embodiment
660 grams of dimethyl sulphides are packed into nitrogen purging glass reaction bottle and simultaneously, temperature in reaction bulb are down to 0 DEG C, through 1
138 grams of diboranes are bubbled into reaction bulb by hour, and during being bubbled into, control temperature treats diborane at 0~5 DEG C
After being passed through, continue to be stirred to react 15 minutes.After testing, the density of borane dimethylsulfide ether complexes obtained by the reaction is 0.80
Grams per milliliter, borine (i.e. borane dimethylsulfide ether complexes) concentration are 10.08 mol/Ls (M).
The preparation of 2 borine tetrahydrofuran complex (BTHF) of embodiment
353.8 grams of tetrahydrofurans are packed into nitrogen purging glass reaction bottle and simultaneously, temperature in reaction bulb are down to 0 DEG C,
Through 0.5 it is small when diborane (11.8 grams) is bubbled into reaction bulb, during being bubbled into, control temperature is treated at 0~5 DEG C
After diborane is passed through, continue to be stirred to react 15 minutes.After testing, the density of solution is 0.87 grams per milliliter after reaction, borine
(i.e. borine tetrahydrofuran complex) concentration is 2 mol/Ls.
Sodium borohydride is added in into borine tetrahydrofuran complex solution obtained above so that sodium borohydride is in the solution
Ultimate density for 0.005M, i.e. the molar ratio of sodium borohydride and borine tetrahydrofuran complex is 1:400.Hydroboration is added
After sodium, by solution stirring 1 it is small when so that sodium borohydride dissolve, obtain solution A.Finally the solution for adding in sodium borohydride is positioned over
Stability study is carried out in the stability test case of constant temperature (35 DEG C).
3 stabilizer type of embodiment (sodium borohydride, potassium borohydride and lithium borohydride) is to borane dimethylsulfide ether complexes
Under the influence of the stability of tetrahydrofuran solution and the same terms, the tetrahydrofuran solution and boron of borine tetrahydrofuran complex
The comparison of the stability of the tetrahydrofuran solution of alkane dimethylsulfide complex
Using tetrahydrofuran as solvent, by the borane dimethylsulfide ether complexes obtained in embodiment 1 be diluted to about 2 moles/
It rises, the solution after dilution is then divided into quarter, adds sodium borohydride, potassium borohydride, boron respectively in three parts of solution thereto
Lithium hydride so that the ultimate density of three kinds of stabilizers in the solution is 0.005M, i.e. borane dimethylsulfide ether complexes and boron hydrogen
The molar ratio for changing sodium is 400:1.After adding sodium borohydride and lithium borohydride, by solution stirring 1 it is small when so that stabilizer dissolves, obtain
To solution B and C；Add potassium borohydride after, by solution stirring 24 it is small when so that stabilizer dissolve, obtain solution D.To finally it add
The tetrahydrofuran solution (solution E) for the borane dimethylsulfide ether complexes for adding stabilizer and being not added with stabilizer is placed in constant temperature (35
DEG C) stability test case in carry out stability study.Experimental result is displayed in table 1 and Fig. 1, Fig. 2, it can be seen that
Under the conditions of existing for stabilizer, the tetrahydrofuran solution of borane dimethylsulfide ether complexes is more stable and than under similarity condition
The tetrahydrofuran solution of borine tetrahydrofuran complex is more stable.
1 stabilizer type of table (sodium borohydride, potassium borohydride and lithium borohydride) is to the tetrahydrochysene of borane dimethylsulfide ether complexes
The influence of the stability of tetrahydrofuran solution
And under the same terms, tetrahydrofuran solution and the borane dimethylsulfide ether complexes of borine tetrahydrofuran complex
The comparison of tetrahydrofuran solution stability
4 stabilizer of embodiment (sodium borohydride) concentration is to the stability of the tetrahydrofuran solution of borane dimethylsulfide ether complexes
Influence
Using tetrahydrofuran as solvent, the borane dimethylsulfide ether complexes obtained in embodiment 1 are diluted to 2 mol/Ls,
Then solution is divided into quarter, respectively using the molar ratio of borane dimethylsulfide ether complexes and sodium borohydride as 1000:1、400:
1、200:1、100:1 adds in stabilizer sodium borohydride thereto so that the ultimate density of sodium borohydride in the solution is respectively
0.002M (solution F), 0.005M (solution B), 0.01M (solution G) and 0.02M (Solution H), into solution, addition molar ratio is
100:During 1 sodium borohydride, it is desirable that the stirring longer time, so that sodium borohydride dissolving, the solution for having added sodium borohydride was put
It is placed in the stability test case of constant temperature (35 DEG C) and carries out stability study.Experimental result is displayed in table 2 and Fig. 3, can
To find out, borane dimethylsulfide ether complexes are with stabilizer mole molar ratio 100：1~1000：In the range of 1, group of the invention
It is stable to close solution.
2 stabilizer of table (sodium borohydride) concentration is to the shadow of the stability of the tetrahydrofuran solution of borane dimethylsulfide ether complexes
It rings
5 stabilizer of embodiment is to the shadow of the stability of the tetrahydrofuran solution of the borane dimethylsulfide ether complexes of various concentration
It rings
Using tetrahydrofuran as solvent, the borane dimethylsulfide ether complexes obtained in embodiment 1 are diluted to 1.5 respectively and are rubbed
That/liter (solution I), 2 mol/Ls (solution B) and 5 mol/Ls (solution J), then with borane dimethylsulfide ether complexes and stabilization
The molar ratio of agent is 400:1 addition sodium borohydride makees stabilizer, and the solution for adding in sodium borohydride is placed in constant temperature (35 DEG C)
Stability test case in carry out stability study.Experimental result is displayed in table 3 and Fig. 4, it can be seen that in stabilizer
Under the conditions of existing, the tetrahydrofuran solution of the borane dimethylsulfide ether complexes of various concentration is stable.
Stability experiment of the tetrahydrofuran solution of the borane dimethylsulfide ether complexes of 3 various concentration of table under the conditions of 35 DEG C
As a result
Stability change of the tetrahydrofuran solution of 6 borane dimethylsulfide ether complexes of embodiment under the conditions of 2-8 DEG C
Using tetrahydrofuran as solvent, the borane dimethylsulfide ether complexes obtained in embodiment 1 are diluted to 2 mol/Ls,
Then using the molar ratio of borane dimethylsulfide ether complexes and stabilizer as 400:1 addition sodium borohydride makees stabilizer, will add in boron
The solution of sodium hydride is placed in carrying out stability study in the stability test case of low temperature (2~8 DEG C).Experimental result is shown in table
In 4 and Fig. 5, it can be seen that under the conditions of existing for stabilizer, composition solution of the invention can be stablized at 2-8 DEG C
For a long time.
Stability change of the tetrahydrofuran solution of 4 borane dimethylsulfide ether complexes of table under the conditions of 2-8 DEG C
The different types of borane reagents of embodiment 7-10 as reducing agent for 3 ', 5 '-bis- (trifluoromethyl) acetophenones
The Performance of asymmetric reduction
At 0~5 DEG C by syringe pump through 2 it is small when by 3 ', 5 '-(3.1 milliliters at 17 milliliters for bis- (trifluoromethyl) acetophenones
In THF, i.e., 17 mMs) be added separately to 5 milliliters of 2M (i.e. 10 mMs) different borane reagents and 0.85 milliliter (5 rub
Your % compared with 3 ', 5 '-bis- (trifluoromethyl) acetophenones) 1M (R)-MeCBS toluene solutions mixed solution in.3 ' are added in,
It is stirred after 5 '-bis- (trifluoromethyl) acetophenones 30 minutes, is then added dropwise in hydrochloric acid (1M, 4.2 milliliters) to quench into reaction solution
It goes out reaction.Reaction solution organic phase is extracted with 20 milliliters of methyl tertiary butyl ether(MTBE)s, with water and saturated common salt water washing organic layer, use is anhydrous
Na2SO4It is dry, finally, organic phase is evaporated, obtains product.[3,5- is double (trimethyl) by (the S) -1- detected with chiral HPLC
Phenyl] ethyl alcohol enantiomeric excess value (%ee), the results are shown in tables 5.Make reducing agent selective reduction 3 ', 5 '-bis- with BTHF
During (trifluoromethyl) acetophenone, obtained product %ee values are relatively low, moreover, adding in influence of the sodium borohydride to product %ee values very
Greatly；And when making reducing agent selective reduction 3 ', 5 '-bis- (trifluoromethyls) acetophenone with BDMS, %ee values are very high, moreover, boron hydrogen
Changing the presence of sodium does not reduce the %ee values of the reaction yet.
The reduction result of the different borane reagents of table 5
Claims (8)
1. a kind of borane reagent combination solution containing stabilizer, wherein, the borane reagent combination solution includes borane dimethylsulfide
Ether complexes, tetrahydrofuran and stabilizer, wherein concentration of the borane dimethylsulfide ether complexes in tetrahydrofuran rub for 1~10
You/liter, the molar ratio of borane dimethylsulfide ether complexes and the stabilizer is 100:1~1000:1, the stabilizer is selected from boron
One kind or its combination in sodium hydride, lithium borohydride or potassium borohydride.
2. the borane reagent combination solution containing stabilizer as described in claim 1, wherein, borane dimethylsulfide ether complexes are four
Concentration in hydrogen furans is 1.5~5 mol/Ls.
3. the borane reagent combination solution containing stabilizer as described in claim 1, wherein, borane dimethylsulfide ether complexes with it is steady
The molar ratio for determining agent is 200:1~500:1.
4. the borane reagent combination solution containing stabilizer as described in claim 1, wherein, the stabilizer is sodium borohydride.
5. the preparation method of the borane reagent combination solution containing stabilizer as described in claim 1, wherein, the preparation method
Comprise the following steps：
(1) suitable dimethyl sulphide is simultaneously packed into simultaneously with nitrogen purging glass reaction bottle, control reaction bulb temperature at 0 DEG C, if through
The diborane of 0.5 equivalent is bubbled into reaction bulb by dry hour, and during being bubbled into, control temperature treats second at 0~5 DEG C
After borine is passed through, continue to be stirred to react 10~20 minutes, borane dimethylsulfide ether complexes are made；
(2) the borane dimethylsulfide ether complexes obtained in step (1) are diluted to by 1~10 mol/L using tetrahydrofuran, made
Obtain the tetrahydrofuran solution of borane dimethylsulfide ether complexes；
(3) stabilizer is added in into the tetrahydrofuran solution of the borane dimethylsulfide ether complexes obtained by step (2), so as to be made
Borane reagent combination solution of the present invention, the wherein molar ratio of borane dimethylsulfide ether complexes and stabilizer are 100:1~
1000:1, the one kind or its combination of the stabilizer in sodium borohydride, lithium borohydride or potassium borohydride.
6. preparation method as claimed in claim 5, wherein in step (2), the tetrahydrofuran of borane dimethylsulfide ether complexes
Solution concentration is 1.5~5 mol/Ls.
7. preparation method as claimed in claim 5, wherein in step (3), borane dimethylsulfide ether complexes and stabilizer
Molar ratio is 200:1~500:1.
8. the borane reagent combination solution containing stabilizer can be applied to Corey asymmetric reduction reactions as described in claim 1,
Wherein, when the combination solution reduces 3 ', 5 '-bis- (trifluoromethyl) acetophenones, the enantioselectivity of reaction is good, product yield high
More than 99% is up to up to 93%, %ee values.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113651842A (en) * | 2021-08-31 | 2021-11-16 | 河南师范大学 | Borane compound K [ BH3S(CH3)BH3]Method of synthesis of |
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|---|---|---|---|---|
| US3634277A (en) * | 1969-03-20 | 1972-01-11 | Herbert C Brown | Stabilized tetrahydrofuran solutions of diborane |
| US4320027A (en) * | 1980-05-02 | 1982-03-16 | Aldrich-Boranes, Inc. | Process for producing highly stabilized borane-tetrahydrofuran solutions |
| US20080275255A1 (en) * | 2004-08-12 | 2008-11-06 | Sigma-Aldrich Co. | Stabilized Borane-Tetrahydrofuran Complex |
| WO2014019166A1 (en) * | 2012-08-01 | 2014-02-06 | 上海威智医药科技有限公司 | Industrial production method for high-activity borane compound |
| CN105461602A (en) * | 2015-11-27 | 2016-04-06 | 东华大学 | Preparation method of chiral S/R-3-ethoxy-4-methoxy-alpha[(methylsulfonyl)methyl] benzyl alcohol |
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2017
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3634277A (en) * | 1969-03-20 | 1972-01-11 | Herbert C Brown | Stabilized tetrahydrofuran solutions of diborane |
| US4320027A (en) * | 1980-05-02 | 1982-03-16 | Aldrich-Boranes, Inc. | Process for producing highly stabilized borane-tetrahydrofuran solutions |
| US20080275255A1 (en) * | 2004-08-12 | 2008-11-06 | Sigma-Aldrich Co. | Stabilized Borane-Tetrahydrofuran Complex |
| WO2014019166A1 (en) * | 2012-08-01 | 2014-02-06 | 上海威智医药科技有限公司 | Industrial production method for high-activity borane compound |
| CN105461602A (en) * | 2015-11-27 | 2016-04-06 | 东华大学 | Preparation method of chiral S/R-3-ethoxy-4-methoxy-alpha[(methylsulfonyl)methyl] benzyl alcohol |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113651842A (en) * | 2021-08-31 | 2021-11-16 | 河南师范大学 | Borane compound K [ BH3S(CH3)BH3]Method of synthesis of |
| CN113651842B (en) * | 2021-08-31 | 2024-01-30 | 河南师范大学 | Borane compound K BH 3 S(CH 3 )BH 3 ]Is synthesized by the method of (2) |
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