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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- 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
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- 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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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
|---|---|---|---|---|
| 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 | Preparation method of biphenylol acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1412185A (en) * | 2002-10-11 | 2003-04-23 | 常俊标 | Production method of halogenated hexahydroxydiphenic derivative and its medicinal application |
| CN1712408A (en) * | 2004-06-21 | 2005-12-28 | 江苏恒瑞医药股份有限公司 | Dicycloalcohol glucoside compound its production and use |
| CN103242286A (en) * | 2013-01-24 | 2013-08-14 | 辽宁亿灵科创生物医药科技有限公司 | Bicyclol medical composition and preparation method thereof |
| CN103724317A (en) * | 2013-12-11 | 2014-04-16 | 西北师范大学 | Method adopting bifendate to prepare bicyclol |
-
2017
- 2017-01-11 CN CN201710017517.5A patent/CN106749157A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1412185A (en) * | 2002-10-11 | 2003-04-23 | 常俊标 | Production method of halogenated hexahydroxydiphenic derivative and its medicinal application |
| CN1712408A (en) * | 2004-06-21 | 2005-12-28 | 江苏恒瑞医药股份有限公司 | Dicycloalcohol glucoside compound its production and use |
| CN103242286A (en) * | 2013-01-24 | 2013-08-14 | 辽宁亿灵科创生物医药科技有限公司 | Bicyclol medical composition and preparation method thereof |
| CN103724317A (en) * | 2013-12-11 | 2014-04-16 | 西北师范大学 | Method adopting bifendate to prepare bicyclol |
Non-Patent Citations (2)
| Title |
|---|
| GOTO, JUNICHI 等: "New type of derivatization reagents for liquid chromatographic resolution of enantiomeric hydroxyl compounds", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
| 姚其正 主编: "《药物合成反应》", 30 September 2012 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 | Preparation method of biphenylol acid |
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