CN103724317A - Method adopting bifendate to prepare bicyclol - Google Patents
Method adopting bifendate to prepare bicyclol Download PDFInfo
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- CN103724317A CN103724317A CN201310669138.6A CN201310669138A CN103724317A CN 103724317 A CN103724317 A CN 103724317A CN 201310669138 A CN201310669138 A CN 201310669138A CN 103724317 A CN103724317 A CN 103724317A
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- bicyclol
- biphenyl
- acid
- biphenylylmethylcarbinol
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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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method adopting bifendate to prepare bicyclol, belongs to the technical field of chemical synthesis, and comprises the following steps: biphenyl diacid is obtained after bifendate, as a starting raw material, is subjected to basic hydrolysis and acidification; biphenyl anhydride is obtained after dehydration; biphenyl acid ester is obtained after alcoholysis and esterification; finally, carboxyl is selectively reduced to alcoholic hydroxyl group, and the bicyclol is obtained. The synthetic product provided by the invention is a white solid body, with the melting point of 138 DEG C to 140 DEG C, and the product subjected to nuclear magnetism detection has been proved to be a pure bicyclol product; compared with the prior art, the method has the characteristics that the raw materials are cheap and easily obtained, the process route is short, the reaction condition is mild, the operation is simple and feasible, the aftertreatment is convenient (column chromatography separation is not needed for the entire route), the cost is low, the yield is high (the four-step total yield is larger than 80%), and the method has prosperous prospect in industrialized application.
Description
Technical field
The invention belongs to chemical combination and become technical field, being specifically related to a kind of preparation method of bicyclol, relating in particular to a kind of utilization and utilize Biphenylylmethylcarbinol to prepare the method for bicyclol.
Background technology
Bicyclol (Bicyclol) is the country that the is used for the treatment of chronic viral hepatitis one class chemistry new drug by Chinese Academy of Sciences's institute of materia medica's independent research, have significant hepatoprotective effect and certain antiviral activity, the transaminase being used for the treatment of due to hepatitis raises.The chemistry of bicyclol is called 4,4 '-dimethoxy-5, and 6,5 ', 6 '-secondary methylenedioxy group-2-methylol-2 '-methoxycarbonyl biphenyl, chemical structural formula is:
Chinese patent CN102617544A discloses a kind of method of preparing bicyclol, is take methyl gallate as starting raw material, through etherificate, and bromination, cyclization, reduction and hydrolysis, esterification condensation, linked reaction, alcoholysis, by the synthetic bicyclol of eight step reactions, total recovery only has 10.8%.The one-tenth route that the disclosed bicyclol of European patent EP 0353358A1 is closed, take Biphenylylmethylcarbinol (II) as starting raw material, through alkaline hydrolysis, obtain dicarboxylic acid, obtain anhydride ester derivs with acetic anhydride again, then anhydride ester derivs obtains lactone derivatives through sodium borohydride reduction, tosic acid processing, and last lactone reacts and obtains bicyclol with methyl alcohol under carboxylate salt exists.The method can be synthesized bicyclol by four steps, but it is more from anhydride ester derivs, to prepare lactone one step side reaction, and yield is very low, and its cost is higher, and applicability is poor.
Chinese patent CN1073438A discloses the improved synthetic method of a kind of Biphenylylmethylcarbinol, and the method, take gallic acid or Weibull as starting raw material, makes Biphenylylmethylcarbinol through esterification, monomethyl ether, bromo, Ullmann linked reaction.The method greatly reduces the synthetic cost of Biphenylylmethylcarbinol.Therefore, adopting Biphenylylmethylcarbinol is ideal selection as bicyclol synthesis material.
Summary of the invention
The object of the invention is the problem existing for prior art, provide a kind of technique simple, the method for reaction conditions gentleness, cost is low, yield is high suitability for industrialized production bicyclol.
The present invention utilizes Biphenylylmethylcarbinol to prepare the method for bicyclol, is take Biphenylylmethylcarbinol as initial feed, first through alkaline hydrolysis, acidifying, makes biphenyl bisgallic acid, through dehydration, obtain biphenyl acid anhydrides again, then through alcoholysis esterification, obtaining Biphenyl Ester acid, is alcoholic extract hydroxyl group finally by selective reduction carboxyl, obtains bicyclol.Concrete technology is as follows:
(1) biphenyl bisgallic acid is synthetic: in solvent, under alkali exists, Biphenylylmethylcarbinol is hydrolyzed at 50～100 ℃; After hydrolysis completely, reaction solution is neutralized to pH=1～2 with mineral acid, separates out solid, filters, and washing, to neutral, obtains biphenyl bisgallic acid solid;
Described solvent is alcohol solution (methyl alcohol, ethanol, Virahol etc.) or the aqueous acetone solution that water, percent by volume are 10～20%;
Described alkali is sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, potassium ethylate; The mass percent of alkali in solvent is 5%～50%;
Described mineral acid is the vitriol oil, concentrated hydrochloric acid.
(2) biphenyl acid anhydrides is synthetic: in organic solvent, dewatering agent carries out biphenyl bisgallic acid dehydration reaction under existing at 100～140 ℃, and question response is completely rear cooling, and steaming desolventizes, and solid recrystallization (benzene or toluene), obtains biphenyl acid anhydrides;
Described organic solvent is diacetyl oxide, benzene,toluene,xylene;
Described dewatering agent is diacetyl oxide, Acetyl Chloride 98Min.; The consumption of dewatering agent is 2～4 times of biphenyl bisgallic acid quality.
(3) Biphenyl Ester acid is synthetic: in anhydrous methanol, by the alcoholysis esterification at 50～70 ℃ of biphenyl acid anhydrides; After alcoholysis esterification completely, steam and desolventize, obtain Biphenyl Ester acid.
(4) bicyclol is synthetic: in organic solvent, under nitrogen protection, reductive agent exist, Biphenyl Ester acid is carried out at-20～20 ℃ to selective reduction reaction; After reacting completely, steam and desolventize, use successively methylene dichloride, saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated, obtains bicyclol;
Described organic solvent is tetrahydrofuran (THF), tirethylene glycol dme;
Reductive agent used: borine dimethyl sulphide, borine tetrahydrofuran (THF), sodium borohydride+boron trifluoride diethyl etherate etc.; The consumption of reductive agent is 1.2～2.0 times of Biphenyl Ester acid quality.
Synthetic product of the present invention is white solid, and fusing point is: 138
~140 ℃; Total recovery is 80～85%, and product detects through nuclear-magnetism, is bicyclol sterling.
The relative prior art of the present invention, raw material is cheap and easy to get, and operational path is short, reaction conditions gentleness; Operation is simple, convenient post-treatment (whole route separates without column chromatography), and cost is low; Productive rate high (four step total recovery >80%), is easy to suitability for industrialized production.
Embodiment
Below by specific embodiment, the synthetic of bicyclol of the present invention elaborated.
Embodiment 1
(1) preparation of biphenyl bisgallic acid (III): take (water 80 mL in the mixed solvent that 10.0 g Biphenylylmethylcarbinols (II) and 2.5 g sodium hydroxide are dissolved in 100 mL water and methyl alcohol, methyl alcohol 20 mL), be heated to 100 ℃, question response is (2h left and right) completely, cooling, be acidified to pH=1 with concentrated hydrochloric acid, filter, be washed to neutrality, dry, obtain 9.3 g biphenyl bisgallic acids (III), yield: 99%.Product is white solid.Nuclear magnetic data is as follows:
1H?NMR?(d6-DMSO,?400?MHz):?
δppm?3.88?(s,?6H),?5.94?(s,?4H),?5.97?(s,?4H),?7.24?(s,?2H),?10.24?(s,?br,?2H)。
(2) preparation of biphenyl acid anhydrides (IV): take 5.0 g biphenyl bisgallic acids (III), be dissolved in 25 mL diacetyl oxides, be heated to 100 ℃.Reaction, to reacting completely, steams solvent, uses toluene recrystallization, obtains 4.3 g biphenyl acid anhydrides (IV), yield: 88%.Product is white solid; The nuclear magnetic data of product is as follows:
1H?NMR?(CDCl
3,?400?MHz):?
δppm?3.97?(s,?6H),?6.05?(s,?2H),?6.16?(s,?2H),?7.02?(s,?2H)。
(3) preparation of Biphenyl Ester acid (V): take 4.0 g biphenyl acid anhydrides, add in 20mL anhydrous methanol, be heated to 60 ℃, reaction is to complete, and steaming desolventizes, and obtains joining 4.2 g Biphenyl Ester acid (V), yield 97%.
(4) bicyclol (I) is synthetic: under nitrogen protection, 2.0 g Biphenyl Ester acid are dissolved in 20 mL anhydrous tetrahydro furans, are cooled to 0
oc, slowly adds 3.7mL borine dimethyl sulphide (2.0 M), and stirring reaction is complete, with methyl alcohol cancellation reaction, steaming desolventizes, and adds 50mL methylene dichloride, with saturated common salt water washing 2 times, organic phase anhydrous sodium sulfate drying, filter concentrated 1.8 g bicyclol, the yield 95% of obtaining.The total recovery of bicyclol is 80.3 %.Product is white solid, and fusing point is: 138～140 ℃; Nuclear magnetic data is as follows:
1H?NMR?(400?MHz,?CDCl
3)?
δppm?3.71?(s,?3H),?3.95?(s,?3H),?3.97?(s,?3H),?4.36?(d,?
J?=?12.0?Hz,?2H),?5.91?(s,?2H),?6.02?(d,?
J?=?8.2?Hz,?2H),?6.77?(s,?1H),?7.34?(s,?1H)。
Embodiment 2
(1) preparation of biphenyl bisgallic acid (III): take 10.0 g Biphenylylmethylcarbinols (II) and 4.0 g sodium hydroxide and be dissolved in 50 mL water, be heated to 80 ℃, question response is complete, cooling, be acidified to pH=1 with concentrated hydrochloric acid, filter, be washed to neutrality, dry, obtain 9.3 g biphenyl bisgallic acids (III), yield: 99%.Product is white solid, and nuclear magnetic data is with embodiment 1.
(2) preparation of biphenyl acid anhydrides (IV): take 5.0 g biphenyl bisgallic acids (III), be dissolved in 25 mL diacetyl oxides, be heated to 120 ℃.Reaction, to reacting completely, steams solvent, uses benzene recrystallization, obtains 4.6 g biphenyl acid anhydrides (IV), yield 96%.Product is white solid, and nuclear magnetic data is with embodiment 1.
(3) preparation of Biphenyl Ester acid (V): take 2.0 g biphenyl acid anhydrides, add in 20 mL anhydrous methanols, be heated to 60 ℃, reaction is to complete, and steaming desolventizes, and obtains joining 2.1 g Biphenyl Ester acid (V), yield 96%.
(4) bicyclol (I) is synthetic: under nitrogen protection, 1.0 g Biphenyl Ester acid are dissolved in 20 mL anhydrous tetrahydro furans, are cooled to 0 ℃; slowly add 2.5 mL borine dimethyl sulphides (2.0 M); stirring reaction is complete, and with methyl alcohol cancellation reaction, steaming desolventizes; add 50 mL methylene dichloride; with saturated common salt water washing 2 times, organic phase anhydrous sodium sulfate drying, filter; concentrated 0.91 g bicyclol, the yield 94% of obtaining.The total recovery of bicyclol is 85%, and product is white solid, and fusing point, nuclear magnetic data and embodiment 1 are same.
Embodiment 3
(1) preparation of biphenyl bisgallic acid (III): take 10.0 g Biphenylylmethylcarbinols (II) and 4.0 g sodium hydroxide and be dissolved in (containing 10% volume acetone) in 50 mL aqueous acetone solutions, be heated to 80 ℃, question response is complete, cooling, be acidified to pH=2 with concentrated hydrochloric acid, filter, be washed to neutrality, dry, obtain 9.1 g biphenyl bisgallic acids (III), yield: 98%.Product is white solid, and nuclear magnetic data is with embodiment 1.
(2) preparation of biphenyl acid anhydrides (IV): take 5.0 g biphenyl bisgallic acids (III), be dissolved in 25 mL diacetyl oxides, be heated to 140 ℃.Reaction, to reacting completely, steams solvent, uses toluene recrystallization, obtains 4.3 g biphenyl acid anhydrides (IV), yield 90%.Product is white solid, and nuclear magnetic data is with embodiment 1.
(3) preparation of Biphenyl Ester acid (V): take 2.0 g biphenyl acid anhydrides, add in 20 mL anhydrous methanols, be heated to 70 ℃, reaction is to complete, and steaming desolventizes, and obtains joining 1.9 g Biphenyl Ester acid (V), yield 97%.
(4) bicyclol (I) is synthetic: under nitrogen protection, 1.0 g Biphenyl Ester acid are dissolved in 10 mL anhydrous tetrahydro furans, are cooled to-20 ℃; slowly add 1.5 mL borine dimethyl sulphides (2.0 M); stirring reaction is complete, and with methyl alcohol cancellation reaction, steaming desolventizes; add 50 mL methylene dichloride; with saturated common salt water washing 2 times, organic phase anhydrous sodium sulfate drying, filter; concentrated 0.92 g bicyclol, the yield 95% of obtaining.The total recovery of bicyclol is 81%, and product is white solid, and fusing point, nuclear magnetic data and embodiment 1 are same.
Embodiment 4
(1) preparation of biphenyl bisgallic acid (III): take 10.0 g Biphenylylmethylcarbinols (II) and 10 g sodium hydroxide and be dissolved in 40 mL water, be heated to 60 ℃, question response is complete, cooling, be acidified to pH=1 with concentrated hydrochloric acid, filter, be washed to neutrality, dry, obtain 9.1 g biphenyl bisgallic acids (III), yield: 97%.Product is white solid, and nuclear magnetic data is with embodiment 1.
(2) preparation of biphenyl acid anhydrides (IV): take 5.0 g biphenyl bisgallic acids (III), be dissolved in 25 mL diacetyl oxides, be heated to 140 ℃.Reaction, to reacting completely, steams solvent, uses toluene recrystallization, obtains 4.3 g biphenyl acid anhydrides (IV), yield 90%.Product is white solid, and nuclear magnetic data is with embodiment 1.
(3) preparation of Biphenyl Ester acid (V): take 2.0 g biphenyl acid anhydrides, add in 20 mL anhydrous methanols, be heated to 60 ℃, reaction is to complete, and steaming desolventizes, and obtains joining 1.9 g Biphenyl Ester acid (V), yield 97%.
(4) bicyclol (I) is synthetic: under nitrogen protection, 1.0 g Biphenyl Ester acid are dissolved in 20 mL anhydrous tetrahydro furans, are cooled to 20 ℃; slowly add 2.0 mL borine dimethyl sulphides (2.0 M); stirring reaction is complete, and with methyl alcohol cancellation reaction, steaming desolventizes; add 50 mL methylene dichloride; with saturated common salt water washing 2 times, organic phase anhydrous sodium sulfate drying, filter; concentrated 0.93 g bicyclol, the yield 96% of obtaining.The total recovery of bicyclol is 81%, and product is white solid, and fusing point, nuclear magnetic data and embodiment 1 are same.
Above-mentioned synthetic reaction formula is as follows:
Claims (10)
1. utilizing Biphenylylmethylcarbinol to prepare a method for bicyclol, is take Biphenylylmethylcarbinol as initial feed, first through alkaline hydrolysis, acidifying, makes biphenyl bisgallic acid, through dehydration, obtain biphenyl acid anhydrides again, then through alcoholysis esterification, obtaining Biphenyl Ester acid, is alcoholic extract hydroxyl group finally by selective reduction carboxyl, obtains bicyclol.
2. utilize as claimed in claim 1 Biphenylylmethylcarbinol to prepare the method for bicyclol, it is characterized in that: concrete technology is as follows:
(1) biphenyl bisgallic acid is synthetic: in solvent, under alkali exists, Biphenylylmethylcarbinol is hydrolyzed at 50～100 ℃; After hydrolysis completely, reaction solution is neutralized to pH=1～2 with mineral acid, separates out solid, filters, and washing, to neutral, obtains biphenyl bisgallic acid solid;
(2) biphenyl acid anhydrides is synthetic: in organic solvent, dewatering agent carries out biphenyl bisgallic acid dehydration reaction under existing at 100～140 ℃, and question response is completely rear cooling, and steaming desolventizes, and benzene or toluene solid recrystallization, obtain biphenyl acid anhydrides;
(3) Biphenyl Ester acid is synthetic: in anhydrous methanol, by biphenyl acid anhydrides in 50
~alcoholysis esterification at 70 ℃; After alcoholysis esterification completely, steam and desolventize, obtain Biphenyl Ester acid;
(4) bicyclol is synthetic: in organic solvent, under nitrogen protection, reductive agent exist, Biphenyl Ester acid is carried out at-20～20 ℃ to selective reduction reaction; After reacting completely, steam and desolventize, use successively methylene dichloride, saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated, obtains bicyclol.
3. utilize as claimed in claim 2 Biphenylylmethylcarbinol to prepare the method for bicyclol, it is characterized in that: in step (1), described solvent is water, percent by volume is the aqueous solution of 10～20% alcohol or the aqueous solution of acetone.
4. utilize as claimed in claim 2 Biphenylylmethylcarbinol to prepare the method for bicyclol, it is characterized in that: in step (1), described alkali is sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, potassium ethylate; The mass percent of alkali in solvent is 5%～50%.
5. utilize as claimed in claim 2 Biphenylylmethylcarbinol to prepare the method for bicyclol, it is characterized in that: in step (1), described mineral acid is the vitriol oil, concentrated hydrochloric acid.
6. utilize as claimed in claim 2 Biphenylylmethylcarbinol to prepare the method for bicyclol, it is characterized in that: in step (2), described organic solvent is diacetyl oxide, benzene,toluene,xylene.
7. utilize as claimed in claim 2 Biphenylylmethylcarbinol to prepare the method for bicyclol, it is characterized in that: in step (2), described dewatering agent is diacetyl oxide, Acetyl Chloride 98Min.; The consumption of dewatering agent is 4～8 times of biphenyl bisgallic acid quality.
8. utilize as claimed in claim 2 Biphenylylmethylcarbinol to prepare the method for bicyclol, it is characterized in that: in step (4), described organic solvent is tetrahydrofuran (THF), tirethylene glycol dme.
9. utilize as claimed in claim 2 Biphenylylmethylcarbinol to prepare the method for bicyclol, it is characterized in that: in step (4), described reductive agent is borine dimethyl sulphide, borine tetrahydrofuran (THF), or the mixture of sodium borohydride and boron trifluoride diethyl etherate.
10. utilize as claimed in claim 9 Biphenylylmethylcarbinol to prepare the method for bicyclol, it is characterized in that: the consumption of reductive agent is 1.2～2.0 times of Biphenyl Ester acid quality.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402856A (en) * | 2014-12-08 | 2015-03-11 | 浙江东亚药业有限公司 | Preparation method of bis(methylenedioxy) biphenyl derivative compound |
| CN106749157A (en) * | 2017-01-11 | 2017-05-31 | 杭州百诚医药科技股份有限公司 | A kind of step of use DDB one prepares the new method of bicyclic alcohols |
| CN112250658A (en) * | 2020-12-21 | 2021-01-22 | 北京鑫开元医药科技有限公司 | Formylated bicyclol and preparation method thereof |
| 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 |
| CN116283886A (en) * | 2021-12-20 | 2023-06-23 | 重庆圣华曦药业股份有限公司 | Preparation method of bicyclo-ethanol and application of bicyclo-ethanol in bicyclo-ethanol tablet |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101456860A (en) * | 2007-12-10 | 2009-06-17 | 中国科学院上海药物研究所 | Process for preparing 4-[9-(6-aminopurine)]-2(S)-hydroxybutyrate methyl ester |
-
2013
- 2013-12-11 CN CN201310669138.6A patent/CN103724317A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101456860A (en) * | 2007-12-10 | 2009-06-17 | 中国科学院上海药物研究所 | Process for preparing 4-[9-(6-aminopurine)]-2(S)-hydroxybutyrate methyl ester |
Non-Patent Citations (4)
| Title |
|---|
| XIAOBO TANG ET AL.: "Synthesis and evaluation of substituted dibenzo[c,e]azepine-5-ones as P-glycoprotein-mediated multidrug resistance reversal agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| XIAOKE GU ET AL.: "Synthesis and biological evaluation of bifendate–chalcone hybrids as a new class of potential P-glycoprotein inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 李媛等: "羧酸的还原方法", 《化学通报》 * |
| 郭瑞云等: "α-联苯双酯酯基的修饰", 《药学学报》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402856A (en) * | 2014-12-08 | 2015-03-11 | 浙江东亚药业有限公司 | Preparation method of bis(methylenedioxy) biphenyl derivative compound |
| CN104402856B (en) * | 2014-12-08 | 2017-05-03 | 浙江东亚药业有限公司 | Preparation method of bis(methylenedioxy) biphenyl derivative compound |
| CN106749157A (en) * | 2017-01-11 | 2017-05-31 | 杭州百诚医药科技股份有限公司 | A kind of step of use DDB one prepares the new method of bicyclic alcohols |
| CN112250658A (en) * | 2020-12-21 | 2021-01-22 | 北京鑫开元医药科技有限公司 | Formylated bicyclol and preparation method thereof |
| 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 |
| CN116283886A (en) * | 2021-12-20 | 2023-06-23 | 重庆圣华曦药业股份有限公司 | Preparation method of bicyclo-ethanol and application of bicyclo-ethanol in bicyclo-ethanol tablet |
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Application publication date: 20140416 |