CN106749157A - A kind of step of use DDB one prepares the new method of bicyclic alcohols - Google Patents
A kind of step of use DDB one prepares the new method of bicyclic alcohols Download PDFInfo
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- CN106749157A CN106749157A CN201710017517.5A CN201710017517A CN106749157A CN 106749157 A CN106749157 A CN 106749157A CN 201710017517 A CN201710017517 A CN 201710017517A CN 106749157 A CN106749157 A CN 106749157A
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- Prior art keywords
- sodium borohydride
- reducing agent
- bicyclic alcohols
- ddb
- borohydride
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- -1 bicyclic alcohols Chemical class 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 34
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 17
- 239000012279 sodium borohydride Substances 0.000 claims description 17
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 11
- 239000004305 biphenyl Substances 0.000 claims description 11
- 235000010290 biphenyl Nutrition 0.000 claims description 11
- 239000011591 potassium Substances 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
- 229910052700 potassium Inorganic materials 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- 238000006197 hydroboration reaction Methods 0.000 claims 1
- 239000012044 organic layer Substances 0.000 claims 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Inorganic materials [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 abstract description 9
- 230000000977 initiatory effect Effects 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- KXMTXZACPVCDMH-UHFFFAOYSA-N methyl 4-[5-(hydroxymethyl)-7-methoxy-1,3-benzodioxol-4-yl]-7-methoxy-1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1CO KXMTXZACPVCDMH-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000006136 alcoholysis reaction Methods 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 231100000481 chemical toxicant Toxicity 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 238000011017 operating method Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 102000017278 Glutaredoxin Human genes 0.000 description 1
- 108050005205 Glutaredoxin Proteins 0.000 description 1
- 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 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LEXBBZCFWJNTGC-UHFFFAOYSA-N gallicin Natural products C1CC(=C)C(O)CCC(C)=CC2OC(=O)C(C)C21 LEXBBZCFWJNTGC-UHFFFAOYSA-N 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a kind of such as structural formula（Ⅰ）The shown new preparation process for being combined to thing bicyclic alcohols, the method is with DDB（Ⅱ）It is initiation material, under reducing agent existence condition, a step reduction reaction produces to obtain bicyclic alcohols（Ⅰ）, the method reactions steps are short, and easy to operate, high income, low cost is environment-friendly, are adapted to industrialized production, and advantage significantly, there is good application prospect.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to one kind DDB（Ⅱ）One step prepares bicyclic alcohols
（Ⅰ）New method.
Background technology
Bicyclic alcohols（Bicyclol）Double (the methylene-dioxies of chemical entitled 4,4'- dimethoxys -5,6,5', 6'-）-
2- methylol -2'- methoxycarbonyl group biphenyl.Bicyclol（Bicyclol Tablets）Trade name bicyclol tablets, be by China
The product that the Academy of Medical Sciences, China Concord Medical Science University's medicine are developed, is that first, China possesses the one of independent intellectual property right
The anti-hepatitis original new drug of class, in December, 1996 enters clinical test through Ministry of Public Health's approval, and in September, 2001 obtains what original SFDA was issued
New Drug Certificate and production approval text, are produced by Beijing XieHe medicine Factory and listed.
Research shows that bicyclic alcohols have the significant liver function-protecting of comparing to make various clinical and Experimental Hepatic Damage
With its mechanism may have following several：Firstth, chemical toxicant and drug-induced lipid peroxidation are suppressed；Secondth, to mitochondria
The mobility of film has preferable maintenance effect；3rd, polyphenoils thioltransferase level in liver is improved；4th, liver is reduced
Cellular damage, suppresses Apoptosis to accelerate chemical toxicant to decompose；5th, carcinogenic metabolism and removing；6th, regulation and control are participated in
The gene expression of the pathology such as hepatic energy metabolism, Apoptosis, physiology course, its structural formula can be with shown in following formula.
European patent EP 0353358A1 discloses a kind of preparation method of bicyclic alcohols.The synthetic route is with DDB
（Ⅱ）It is initiation material, biphenyl bisgallic acid is obtained by basic hydrolysis, anhydride ester derivs are then obtained with acetic anhydride, acid anhydrides spreads out
Biology is through NaBH4Reduction, p-methyl benzenesulfonic acid process to obtain lactone derivatives, and lactone obtains double in the presence of carboxylate with methyl alcohol reaction
Cyclic alcohol.The final step of the synthetic route is higher to anhydrous condition requirement when carrying out open loop using methyl alcohol and weak base, and by
Cannot be lifted in the limit temperature of methyl alcohol boiling point, cause open loop yield low, conversion ratio is relatively low, and its synthetic route sees below formula：
。
Synthetic route first passes through basic hydrolysis with DDB as initiation material disclosed in Chinese patent CN103242286A
Biphenyl bisgallic acid is obtained, then biphenyl acid anhydrides is obtained with acetic anhydride, then obtain biphenyl lactone through reducing agent reduction, then through hydrogen-oxygen
Change sodium hydrolysis and obtain biphenyl acid alcohol, most obtain bicyclic alcohols through esterification, recrystallizing and refining afterwards, the synthetic route is synthesized using five steps
Bicyclic alcohols, operating procedure is more long, and the dimethyl suflfate that final step is used has severe toxicity, than relatively hazardous, is unfavorable for industrial metaplasia
Produce, its synthetic route sees below formula：
。
Synthetic route disclosed in Chinese patent CN 102617544B is with gallicin as initiation material, by eight
Step reaction, including etherificate, bromination, cyclization, reduction and hydrolysis, esterification condensation, coupling reaction, alcoholysis are finally synthesizing and obtain bicyclic
Alcohol, the synthetic route operating procedure is more long, and side reaction is more, cumbersome, and industrialized production and application are poor, and its synthetic route is shown in
Following formula：
。
Synthetic route disclosed in Chinese patent CN103724317A is, with DDB as initiation material, to first pass through alkaline water
Solution is obtained biphenyl bisgallic acid, then obtains biphenyl acid anhydrides with acetic anhydride, then Biphenyl Ester acid is obtained through alcoholysis esterification, most afterwards through boron
The reduction of alkane dimethyl sulphide obtains bicyclic alcohols, and the synthetic route final step reduction reduces the step of Biphenyl Ester acid with borane dimethylsulf iotade
Suddenly the shortcomings of there are big toxicity, operational hazards, is unfavorable for industrialized production, and its synthetic route sees below formula：
。
In view of bicyclic alcohols significant application value, development is a kind of simple to operate, and lower-cost process route is necessary
's.
It is that process route of the invention is anti-by a step by raw material of DDB with disclosed document difference
Should be that bicyclic alcohols have been prepared in reduction.
The content of the invention
The present invention is directed to existing bicyclic alcohols（Ⅰ）The problem that preparation technology route is present, disclose a kind of reaction condition it is gentle,
Processing step is short, easy to operate, low cost, the bicyclic alcohols of high income（Ⅰ）Preparation method.
The invention discloses a kind of method for preparing bicyclic alcohols, its reaction equation is as follows, it is characterised in that：
。
In organic solvent A, nitrogen protection, cryogenic conditions add reducing agent, heating response, selective reduction DDB
（Ⅱ）Into bicyclic alcohols, reaction is completed, and reaction is quenched, and solvent, plus organic solvent B is evaporated off, and is washed with water, is concentrated, is purified, and obtains bicyclic
Alcohol.
Organic solvent A is tetrahydrofuran, dioxane, methyl alcohol, ethanol.
Organic solvent B is ethyl acetate, dichloromethane, toluene.
Reducing agent is sodium borohydride, potassium borohydride；Reducing agent consumption is 1 to 8 times of DDB molal quantity, preferably 2 to 5
Times.
It is -15 DEG C to 20 DEG C, preferably -5 DEG C to 5 DEG C to add reacting liquid temperature during reducing agent.
Heating response temperature after reducing agent is added is 20 DEG C to 75 DEG C, preferably 60 DEG C to 75 DEG C.
The catalyst of addition is iodine, sulfuric acid, lewis acid or methyl alcohol.
Its new reduction system combination includes：Sodium borohydride/iodine system, potassium borohydride/iodine system, sodium borohydride/sulfuric acid
System, potassium borohydride/sulfuric acid system, sodium borohydride/lithium chloride system, potassium borohydride/lithium chloride system, sodium borohydride/chlorination
Zinc/tertiary amine system, potassium borohydride/zinc chloride/tertiary amine system, sodium borohydride/methanol system, potassium borohydride/methanol system.
Specific embodiment
More preferably to illustrate technical scheme, spy provides following examples, but the present invention is not limited to this.
Embodiment 1
Under nitrogen protection, DDB 10.0g is weighed, is added in 250ml there-necked flasks, add tetrahydrofuran 50ml, stirring is cold
But to 0 DEG C, sodium borohydride 2.3g is added, then 4.5g iodine is dissolved in 50ml tetrahydrofurans, instill there-necked flask, 0 DEG C -3 DEG C of temperature control, drop
Add complete, be heated to reflux, completed to reaction, the watery hydrochloric acid that reaction solution is cooled to 0 DEG C of addition 1mol/L is quenched reaction, concentration is molten
Agent, obtains white solid, adds ethyl acetate 100ml, and distilled water is washed twice, and is concentrated to give bicyclic alcohols crude product, column chromatography purifying
（Methylene chloride-methanol）, dry bicyclic alcohols 5.2g, yield 52%.Product is white solid, 138-140 DEG C of fusing point, product
Nuclear magnetic data is as follows：
1H NMR (400 MHz, CDCl3):δ ppm3.71 (s, 3 H), 3.95 (s, 3 H), 3.97 (s, 3 H),
4.36 (d, J=12.0HZ, 2H), 5.91 (s, 2 H), 6.02 (d, J=8.2 Hz, 2H), 6.77 (s, 1 H), 7.34
(s, 1 H).
Embodiment 2
Under nitrogen protection, DDB 10.0g is weighed, is added in 250ml there-necked flasks, add tetrahydrofuran 50ml, stirring is cold
But to 0 DEG C, sodium borohydride 2.3g is added, then 2.5g iodine is dissolved in 50ml tetrahydrofurans, instill there-necked flask, 0 DEG C -3 DEG C of temperature control, drop
Add complete, reaction is heated to reflux, completed to reaction, the watery hydrochloric acid that reaction solution is cooled to 0 DEG C of addition 1mol/L is quenched reaction, it is dense
Contracting solvent, obtains white solid, adds ethyl acetate 100ml, and distilled water is washed twice, and is concentrated to give bicyclic alcohols crude product, acetonitrile weight
Crystallization, ethyl acetate-light petrol recrystallization, dry bicyclic alcohols 4.2g, yield 42%.Product is white solid, fusing point 138-
140 DEG C, the nuclear magnetic data of product is with embodiment 1.
Embodiment 3
Under nitrogen protection, DDB 10.0g is weighed, is added in 250ml there-necked flasks, add tetrahydrofuran 100ml, stirred,
0 DEG C is cooled to, sodium borohydride 2.6g is added, lithium chloride 2.4g, charging is finished, and reaction is heated to reflux, completed to reaction, will reacted
The watery hydrochloric acid that liquid is cooled to 0 DEG C of addition 1mol/L is quenched reaction, and concentrated solvent obtains white solid, adds ethyl acetate
100ml, distilled water is washed twice, and is concentrated to give bicyclic alcohols crude product, and recrystallized from acetonitrile, ethyl acetate-hexane is recrystallized, dry
Bicyclic alcohols 4.1g, yield 41%.Product is white solid, 138-140 DEG C of fusing point, and the nuclear magnetic data of product is with embodiment 1.
Embodiment 4
Under nitrogen protection, DDB 10.0g is weighed, is added in 250ml there-necked flasks, add tetrahydrofuran 50ml, stirring is cold
But to 0 DEG C, add sodium borohydride 2.3g, concentrated sulfuric acid 5.6g to be dissolved in 50ml tetrahydrofurans, instill there-necked flask, 0 DEG C -3 DEG C of temperature control, drop
Add complete, be heated to reflux, completed to reaction, the watery hydrochloric acid that reaction solution is cooled to 0 DEG C of addition 1mol/L is quenched reaction, concentration is molten
Agent, obtains white solid, adds ethyl acetate 100ml, and distilled water is washed twice, and is concentrated to give bicyclic alcohols crude product, recrystallized from acetonitrile,
Ethyl acetate-hexane is recrystallized, dry bicyclic alcohols 4.3g, yield 43%.Product is white solid, 138-140 DEG C of fusing point,
The nuclear magnetic data of product is with embodiment 1.
Claims (8)
1. one kind DDB（Ⅱ）One step prepares bicyclic alcohols（Ⅰ）Method, its reaction equation is as follows：
It is characterized in that：In sealed reactor added with organic solvent A, nitrogen protection is filled with, reducing agent is added under cryogenic conditions
After corresponding catalyst, heating continues to react, DDB（Ⅱ）It is reduced into bicyclic alcohols（Ⅰ）Afterwards, reaction is quenched with acid, is evaporated off molten
Agent, plus organic solvent B dissolving, are washed with water, organic layer concentration, and recrystallization purification is dried, and obtains final product bicyclic alcohols（Ⅰ）.
2. according to claim 1, it is characterised in that：Organic solvent A is tetrahydrofuran, dioxane, methyl alcohol, ethanol.
3. according to claim 1, it is characterised in that：Organic solvent B is ethyl acetate, dichloromethane, toluene.
4. according to claim 1, it is characterised in that：Reducing agent is sodium borohydride, potassium borohydride；Reducing agent consumption is biphenyl
1 to 8 times of dibasic acid esters molal quantity, preferably 2 to 5 times.
5. according to claim 1, it is characterised in that：It is -15 DEG C to 20 DEG C to add reacting liquid temperature during reducing agent, excellent
- 5 DEG C to 5 DEG C of choosing.
6. method according to claim 1, it is characterised in that：Heating response temperature after reducing agent is added is 20 DEG C to 75
DEG C, preferably 60 DEG C to 75 DEG C.
7. according to claim 1, it is characterised in that：The catalyst of addition is iodine, sulfuric acid, lewis acid or methyl alcohol.
8. according to claim 1, it is characterised in that its new reduction system combination includes：Sodium borohydride/iodine system, boron
Hydrofining/iodine system, sodium borohydride/sulfuric acid system, potassium borohydride/sulfuric acid system, sodium borohydride/lithium chloride system, hydroboration
Potassium/lithium chloride system, sodium borohydride/zinc chloride/tertiary amine system, potassium borohydride/zinc chloride/tertiary amine system, sodium borohydride/methyl alcohol
System, potassium borohydride/methanol system.
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| CN201710017517.5A CN106749157A (en) | 2017-01-11 | 2017-01-11 | A kind of step of use DDB one prepares the new method of bicyclic alcohols |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111205263A (en) * | 2020-04-22 | 2020-05-29 | 北京鑫开元医药科技有限公司 | Preparation method and application of bicyclol |
| CN113754627A (en) * | 2021-09-03 | 2021-12-07 | 西北师范大学白银师科创新研究院 | A kind of preparation method of biphenyl alcohol |
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Cited By (2)
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| CN111205263A (en) * | 2020-04-22 | 2020-05-29 | 北京鑫开元医药科技有限公司 | Preparation method and application of bicyclol |
| CN113754627A (en) * | 2021-09-03 | 2021-12-07 | 西北师范大学白银师科创新研究院 | A kind of preparation method of biphenyl alcohol |
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