CN102199138B - Preparation method for 6, 7-di-substituted-2, 3 dihydrobenzofuran - Google Patents
Preparation method for 6, 7-di-substituted-2, 3 dihydrobenzofuran Download PDFInfo
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- CN102199138B CN102199138B CN2010101295098A CN201010129509A CN102199138B CN 102199138 B CN102199138 B CN 102199138B CN 2010101295098 A CN2010101295098 A CN 2010101295098A CN 201010129509 A CN201010129509 A CN 201010129509A CN 102199138 B CN102199138 B CN 102199138B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method for 6, 7-di-substituted-2, 3 dihydrobenzofuran represented by a formula (II). The preparation comprises the following steps: (a) reducing 6, 7-di-substituted coumarone represented by a formula (I) in an alcoholic solvent under the alkaline condition by a reductant of hydrazine hydrate. According to the present invention, the cheap hydrazine hydrate is adopted as a reductant, such that production cost is reduced; and technological operation is simple and controllable so as to be suitable for industrialized production. In the formula, R1 and R2 independently represent an H protecting group and a hydroxy protecting group.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to 6,7-disubstituted-2, the preparation method of 3-Dihydrobenzofuranes also relates to 6,7-dihydroxyl-2, the preparation method of 3-Dihydrobenzofuranes.
Background technology
The Methoxsalen chemistry is by name: 8-methoxyl group-4, and 5:6, the 7-furocoumarin(e) has another name called 8-methoxypsoralen or xanthotoxin, and structural formula is as follows:
Methoxsalen can improve tyrosinase activity, promotes epidermal melanin to form, and impels the melanocyte in hair follicle to move to epidermis, occurs pigmentation on skin thereby make, and clinically is mainly used in treating vitiligo.Methoxsalen also has anti-epidermis proliferation function, suppresses the epidermal cell proliferation of the diseases such as psoriasis (psoriatic), skin is damaged disappear.
The method for preparing at present Methoxsalen is mainly US4129575 and the disclosed synthetic route of US4129576:
Can find out from above-mentioned route, 6,7-dihydroxyl-2, the 3-Dihydrobenzofuranes is the product of the 3rd step reduction reaction, is an important intermediate of synthetic Methoxsalen.The method of synthetic this intermediate of US4129575 and US4129576 report is to use palladium charcoal catalytic hydrogenation, reaction conditions is the pressure of 2atm and the high temperature of 100 ℃, this just needs the working pressure still, and because the solvent that reaction is used is 20% acetic acid/ethyl acetate, the life-time service acetic acid solution easily corrodes autoclave pressure, and the reaction times that reaches in addition 12 hours is also a shortcoming of this method.In addition, the contriver finds under study for action, if substrate 6, the purity of 7-dihydroxyl coumarone words (less than 99%) a little almost, by product obviously can increase, the palladium charcoal is easy inactivation also, and the requirement of bibliographical information palladium charcoal is up to 33%, and the words that the palladium charcoal rate of recovery is low certainly will cause raw materials cost to increase substantially.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, provides a kind of more rational 6,7-dihydroxyl-2, the synthetic method of 3-Dihydrobenzofuranes.
Technical problem to be solved by this invention can be achieved through the following technical solutions:
In a first aspect of the present invention, provide a kind of and prepare suc as formula 6 shown in (II), 7-is disubstituted-2, the method for 3-Dihydrobenzofuranes, it comprises the steps:
In formula, R
1, R
2Be H, hydroxyl protecting group independently of one another, wherein said hydroxyl protecting group is preferably C
1-6Alkyl or benzyl, more preferably methyl or ethyl,
(a) in alcoholic solvent, under alkaline condition, under the effect of reduction reagent hydrazine hydrate, will be suc as formula 6 shown in (I), the disubstituted coumarone of 7-reduces.
In preferred embodiment, described alcoholic solvent is ethylene glycol, glycol ether, Triethylene glycol, preferred ethylene glycol.
In preferred embodiment, described alkali is mineral alkali, preferred potassium hydroxide or sodium hydroxide.
In preferred embodiment, the content of described reduction reagent hydrazine hydrate is more than 40%.
In preferred embodiment, 6 shown in described reduction reagent hydrazine hydrate and formula (I), the mol ratio of the hydroxyl coumarone that 7-is disubstituted is 3～8: 1, preferred 3～4: 1.
In preferred embodiment, the reaction times of step (a) is 3～6 hours, and temperature of reaction is 120～180 ℃.
When selecting hydrazine hydrate reagent, because the operation of design is that the limit coronite steams unnecessary moisture, so the contriver is after the experimental result that the hydrazine hydrate replacement palladium charcoal/hydrogen that uses 100% obtains, trying with industrial content commonly used is that 40%～85% hydrazine hydrate aqueous solution replaces 100% hydrazine hydrate, and result has also obtained similar effect.
By present method obtain 6,7-is disubstituted-2, the yield of 3-Dihydrobenzofuranes can reach more than 85%, product purity can reach more than 95%.
In a second aspect of the present invention, a kind of 6,7-dihydroxyl-2 that prepare are provided, the method for 3-Dihydrobenzofuranes is characterized in that, comprises the steps:
(a) in alcoholic solvent, under alkaline condition, under the effect of reduction reagent hydrazine hydrate, with raw material 6,7-dihydroxyl coumarone reduces;
(b) add the aqueous acid termination reaction, then collect from reaction solution and obtain 6,7-dihydroxyl-2,3-Dihydrobenzofuranes.
In preferred embodiment, described alcoholic solvent is ethylene glycol, glycol ether, Triethylene glycol, preferred ethylene glycol.
In preferred embodiment, described alkali is mineral alkali, preferred potassium hydroxide or sodium hydroxide.
In preferred embodiment, the content of described reduction reagent hydrazine hydrate is more than 40%.
In preferred embodiment, described raw material 6, the purity of 7-dihydroxyl coumarone is more than 85%.
In preferred embodiment, the mol ratio of described reduction reagent hydrazine hydrate and 6,7-dihydroxyl coumarone is 3～8: 1, preferred 3～4: 1.
In preferred embodiment, described aqueous acid is selected from aqueous hydrochloric acid or aqueous sulfuric acid.
In preferred embodiment, the reaction times of step (a) is 3～6 hours, and temperature of reaction is 120～180 ℃.
When selecting hydrazine hydrate reagent, because the operation of design is that the limit coronite steams unnecessary moisture, so the contriver is after the experimental result that the hydrazine hydrate replacement palladium charcoal/hydrogen that uses 100% obtains, trying with industrial content commonly used is that 40%～85% hydrazine hydrate aqueous solution replaces 100% hydrazine hydrate, and result has also obtained similar effect.Even the contriver also finds raw material 6 in addition, the purity of 7-dihydroxyl base coumarone only has 85%, reduce with the hydrazine hydrate more than 40% and also can obtain 6 of high conversion, 7-dihydroxyl-2, the 3-Dihydrobenzofuranes, greatly reduce like this requirement to raw material, the ring-closure reaction product that is to say previous step does not need refiningly just can carry out the reduction reaction in this step, has reduced raw materials cost;
By present method obtain 6,7-dihydroxyl-2, the yield of 3-Dihydrobenzofuranes can reach more than 85%, product purity can reach more than 95%.
Under study for action, the inventor finds, after two hydroxyls of 6,7-position are carried out the alkylation protection, then carries out above-mentioned reduction reaction, and the product that reaction obtains is more easily collected than the product that hydroxyl not have to protect, and conversion rate of products is higher, less side products.The reduction yield can reach more than 90%, and the purity of reduzate is more than 98%.
Therefore, in a third aspect of the present invention, also provide a kind of 6,7-dihydroxyl-2 that prepare, the method for 3-Dihydrobenzofuranes comprises the steps:
(a) 6,7-dihydroxyl coumarone is carried out hydroxyl protection, obtain 6 of formula (I), the disubstituted coumarone of 7-;
(b) in alcoholic solvent, under alkaline condition, under the effect of reduction reagent hydrazine hydrate, with 6 of formula (I), the disubstituted coumarone of 7-reduces, and obtains 6 of formula (II), and 7-is disubstituted-2, the 3-Dihydrobenzofuranes;
(c) add aqueous acid, with 6 of the formula (II) that obtains, 7-is disubstituted-2, and the 3-Dihydrobenzofuranes carries out deprotection and obtains 6,7-dihydroxyl-2, the 3-Dihydrobenzofuranes; Reaction formula is as follows:
R in formula
1, R
2Be hydroxyl protecting group, be preferably C
1-6Alkyl or benzyl, more preferably methyl or ethyl.
In preferred embodiment, described alcoholic solvent is ethylene glycol, glycol ether, Triethylene glycol, preferred ethylene glycol.
In preferred embodiment, described alkali is mineral alkali, preferred potassium hydroxide or sodium hydroxide.
In preferred embodiment, the content of described reduction reagent hydrazine hydrate is more than 40%.
In preferred embodiment, described raw material 6, the purity of 7-dihydroxyl coumarone is more than 85%.
In preferred embodiment, 6 shown in described reduction reagent hydrazine hydrate and formula (I), the mol ratio of the disubstituted coumarone of 7-is 3～8: 1, preferred 3～4: 1.
In preferred embodiment, described aqueous acid is selected from aqueous hydrochloric acid or aqueous sulfuric acid.
In preferred embodiment, the reaction times of step (b) is 3～6 hours, and temperature of reaction is 120～180 ℃.
In preferred embodiment, described protection is undertaken by ethyl sulfate or is undertaken by the vitriol oil and methyl alcohol.
Three kinds of methods provided by the present invention are all avoided the working pressure still, have shortened the reaction times, and are easy and simple to handle, and raw material does not need to make with extra care, and greatly reduces production cost, are fit to suitability for industrialized production.
Embodiment
The present invention is further detailed explanation below in conjunction with embodiment.
Embodiment 1
Add ethylene glycol 500ml and potassium hydroxide 67.5g (1.21mol) in reaction flask, be heated to 60 ℃ of stirring and dissolving, add again 6,7-dihydroxyl coumarone 50.0g (0.3mol, purity 95%) and 100% hydrazine hydrate 45.0ml (0.93mol), slowly be heated to 120 ℃, stirring reaction 1 hour.Then steam the moisture that reaction generates, be warming up to 150 ℃, continue reaction 2 hours.TLC follows the tracks of reaction, and (developping agent: ethyl acetate: normal hexane=2: 1), reaction is finished, and is cooled to 70 ℃, and underpressure distillation goes out ethylene glycol.Add 100ml water, stir.Be cooled to 10 ℃, drip concentrated hydrochloric acid 100ml, adjust pH to 6.Add rear continuation and stirred 20 minutes, be concentrated into dried.Add the 500ml ethyl acetate in resistates, be heated to reflux, stirred 1 hour, filtered while hot, filtrate is concentrated into dried oily matter 39.6g (yield 86.6%), and HPLC detection purity is 96.3%.MS：m/z?153?(M
++H)。
Embodiment 2
Add diethylene glycol 500ml and sodium hydroxide 48.0g (1.20mol) in reaction flask, be heated to 50 ℃ of stirring and dissolving, add again 6,7-dihydroxyl coumarone 50.0g (0.3mol, purity 95%) and 85% hydrazine hydrate 68.5ml (1.20mol), slowly be heated to 130 ℃, stirring reaction 1 hour.Then steam the moisture that reaction generates, be warming up to 160 ℃, continue reaction 3 hours.TLC follows the tracks of reaction, and reaction is finished, and is cooled to 90 ℃, and underpressure distillation goes out diethylene glycol.Add 100ml water, stir.Be cooled to 10 ℃, drip concentrated hydrochloric acid 100ml, adjust pH to 6.Add rear continuation and stirred 20 minutes, be concentrated into dried.Add the 500ml ethyl acetate in resistates, be heated to reflux, stirred 1 hour, filtered while hot, filtrate is concentrated into dried oily matter 39.1g (yield 85.7%), and HPLC detection purity is 95.9%.Mass-spectrometric data is in the same manner as in Example 1.
Embodiment 3
add Triethylene glycol 60ml and potassium hydroxide 7.0g (0.13mol) in reaction flask, be heated to 60 ℃ of stirring and dissolving, add again 6,7-dihydroxyl coumarone 5.0g (0.03mol, purity 95%) and 40% hydrazine hydrate 30.0ml (0.24mol), slowly be heated to 130 ℃, stirring reaction 1 hour, then steam the moisture that reaction generates, be warming up to 180 ℃, continue reaction 5 hours, TLC follows the tracks of reaction, reaction is finished, be cooled to 100 ℃, underpressure distillation goes out Triethylene glycol, distill complete, be cooled to again 10 ℃, drip 10% sulfuric acid 60ml, adjust pH to 6.Add rear continuation and stirred 20 minutes, be concentrated into dried.Add the 100ml ethyl acetate in resistates, be heated to reflux, stirred 1 hour, filtered while hot, filtrate is concentrated into dried oily matter 3.3g (yield 72.4%), and HPLC detection purity is 91.3%.Mass-spectrometric data is in the same manner as in Example 1.
Embodiment 4
Add ethylene glycol 100ml and potassium hydroxide 13.5g (0.24mol) in reaction flask, be heated to 60 ℃ of stirring and dissolving, add again 6,7-dihydroxyl coumarone 8.5g (0.051mol, purity 85%) and 100% hydrazine hydrate 13.0ml (0.27mol), slowly be heated to 120 ℃, stirring reaction 1 hour.Then steam the moisture that reaction generates, be warming up to 150 ℃, continue reaction 2.5 hours.TLC follows the tracks of reaction, and reaction is finished, and is cooled to 80 ℃, and underpressure distillation goes out ethylene glycol.Add 30ml water, stir.Be cooled to 10 ℃, drip concentrated hydrochloric acid 20ml, adjust pH to 6.Add rear continuation and stirred 20 minutes, be concentrated into dried.Add the 80ml ethyl acetate in resistates, be heated to reflux, stirred 1 hour, filtered while hot, filtrate is concentrated into dried oily matter 6.3g (yield 81.3%), and HPLC detection purity is 95.3%.Mass-spectrometric data is in the same manner as in Example 1.
Embodiment 5
Add 6,7-dihydroxyl coumarone 10.0g (0.06mol, purity 95%), methyl alcohol 150ml and vitriol oil 2ml in reaction flask, stirring at room 16 hours.(developping agent: methyl alcohol: methylene dichloride=1: 4), reaction is finished, and adds 5% sodium bicarbonate aqueous solution accent pH extremely neutral in TLC tracking reaction, filter, boil off methyl alcohol, get light yellow oil 6,7-dimethoxy coumarone need not made with extra care and be directly used in the next step.
Add ethylene glycol 100ml, potassium hydroxide 11.5g (0.21mol) in above-mentioned oily matter, be heated to 60 ℃ of stirring and dissolving, then add 100% hydrazine hydrate 8.5ml (0.18mol), slowly be heated to 120 ℃, stirring reaction 1 hour.Then steam the moisture that reaction generates, be warming up to 150 ℃, continue reaction 2 hours.TLC follows the tracks of reaction, and reaction is finished, and is cooled to 80 ℃, and underpressure distillation goes out ethylene glycol, adds 30ml water and 100ml ethyl acetate in resistates, is heated to reflux, stirred 1 hour, and filtered while hot, filtrate is told organic layer, is concentrated into dried.
Add 100ml methyl alcohol and 10ml concentrated hydrochloric acid in above-mentioned residue, be warming up to backflow, stirring reaction 1 hour.Decompression steams methyl alcohol, is cooled to 0 ℃, continues to stir 3 hours, filters, and 60 ℃ of lower vacuum-dryings get 6,7-dihydroxyl-2,3-Dihydrobenzofuranes 7.2g (three step total recoverys 78.9%), and it is 98.6% that HPLC detects purity.Mass-spectrometric data is in the same manner as in Example 1.
Embodiment 6
Add acetone 100ml, 6 in reaction flask, 7-dihydroxyl coumarone 5.0g (0.03mol, purity 95%) and Anhydrous potassium carbonate 10.0g (0.073mol) are heated to reflux, stirring reaction 1 hour drips ethyl sulfate 8.0ml (0.061mol).Drip off and continue again reaction 3 hours, and TLC tracking reaction (developping agent: ethyl acetate: normal hexane=1: 1) cooling, filter, being concentrated into residual volume is 10ml, cooling lower dropping 20ml water, 5 ℃ of lower insulated and stirred 1 hour, filter, filter cake dry 6,7-diethoxy coumarone 6.4g.
Add ethylene glycol 50ml and potassium hydroxide 5.0g (0.09mol) in reaction flask, be heated to 60 ℃ of stirring and dissolving, then add that step reaction makes 6,7-diethoxy coumarone and 100% hydrazine hydrate 4.2ml (0.087mol), slowly be heated to 120 ℃, stirring reaction 1 hour.Then steam the moisture that reaction generates, be warming up to 150 ℃, continue reaction 2 hours.TLC follows the tracks of reaction, and reaction is finished, and is cooled to 80 ℃, and underpressure distillation goes out ethylene glycol, adds 15ml water and 60ml ethyl acetate in resistates, is heated to reflux, stirred 1 hour, and filtered while hot, filtrate is told organic layer, is concentrated into dried.
Add 50ml methyl alcohol and 5ml concentrated hydrochloric acid in above-mentioned residue, be warming up to backflow, stirring reaction 1 hour.Decompression steams methyl alcohol 400ml, is cooled to 0-5 ℃, continues to stir 1 hour, filters, and 60 ℃ of lower vacuum-dryings get 6,7-dihydroxyl-2,3-Dihydrobenzofuranes 3.7g (three step total recoverys 81.1%), and HPLC 98.1%.Mass-spectrometric data is in the same manner as in Example 1.
Claims (18)
1. one kind prepares suc as formula 6 shown in (II), and 7-is disubstituted-2, the method for 3-Dihydrobenzofuranes, and it comprises the steps:
In formula, R
1, R
2Be H, hydroxyl protecting group independently of one another,
(a) in alcoholic solvent, under alkaline condition, under the effect of reduction reagent hydrazine hydrate, will be suc as formula 6 shown in (I), the disubstituted coumarone of 7-reduces.
2. method according to claim 1, is characterized in that, described hydroxyl protecting group is C
1-6Alkyl or benzyl.
3. method according to claim 1 and 2, is characterized in that, described hydroxyl protecting group is methyl or ethyl.
4. one kind prepares 6,7-dihydroxyl-2, and the method for 3-Dihydrobenzofuranes is characterized in that, comprises the steps:
(a) in alcoholic solvent, under alkaline condition, under the effect of reduction reagent hydrazine hydrate, with raw material 6,7-dihydroxyl coumarone reduces;
(b) add the aqueous acid termination reaction, then collect from reaction solution and obtain 6,7-dihydroxyl-2,3-Dihydrobenzofuranes.
5. one kind prepares 6,7-dihydroxyl-2, and the method for 3-Dihydrobenzofuranes is characterized in that, comprises the steps:
(a) 6,7-dihydroxyl coumarone is carried out hydroxyl protection, obtain 6 of formula (I), the disubstituted coumarone of 7-;
(b) in alcoholic solvent, under alkaline condition, under the effect of reduction reagent hydrazine hydrate, with 6 of formula (I), the disubstituted coumarone of 7-reduces, and obtains 6 of formula (II), and 7-is disubstituted-2, the 3-Dihydrobenzofuranes;
(c) add aqueous acid, with 6 of the formula (II) that obtains, 7-is disubstituted-2, and the 3-Dihydrobenzofuranes carries out deprotection and obtains 6,7-dihydroxyl-2, the 3-Dihydrobenzofuranes; Reaction formula is as follows:
R in formula
1, R
2Be hydroxyl protecting group.
6. method according to claim 5, is characterized in that, described hydroxyl protecting group is C
1-6Alkyl or benzyl.
7. according to claim 5 or 6 described methods, is characterized in that, described hydroxyl protecting group is methyl or ethyl.
8. according to claim 1 or 4 or 5 described methods, is characterized in that, described alcoholic solvent is ethylene glycol, glycol ether, Triethylene glycol.
9. method according to claim 8, is characterized in that, described alcoholic solvent is ethylene glycol.
10. according to claim 1 or 4 or 5 described methods, is characterized in that, described alkali is mineral alkali.
11. method according to claim 10 is characterized in that, described mineral alkali is potassium hydroxide or sodium hydroxide.
12. according to claim 1 or 4 or 5 described methods is characterized in that, the content of described reduction reagent hydrazine hydrate is more than 40%.
13. according to claim 4 or 5 described methods is characterized in that, described raw material 6, and the purity of 7-dihydroxyl coumarone is more than 85%.
14. according to claim 1 or 4 or 5 described methods is characterized in that, 6 of described reduction reagent hydrazine hydrate and 6,7-dihydroxyl coumarone or formula (I), and the mol ratio of the disubstituted coumarone of 7-is 3～8:1.
15. method according to claim 14 is characterized in that, 6 of described reduction reagent hydrazine hydrate and 6,7-dihydroxyl coumarone or formula (I), and the mol ratio of the disubstituted coumarone of 7-is 3～4:1.
16. according to claim 4 or 5 described methods is characterized in that described aqueous acid is selected from aqueous hydrochloric acid or aqueous sulfuric acid.
17. according to claim 1 or 4 or 5 described methods is characterized in that, the reaction times of the step (b) of claim 1 and 4 step (a) and claim 5 is 3～6 hours, and temperature of reaction is 120～180 ℃.
18. method according to claim 5 is characterized in that, described protection is undertaken by ethyl sulfate or is undertaken by the vitriol oil and methyl alcohol.
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| CN2010101295098A CN102199138B (en) | 2010-03-22 | 2010-03-22 | Preparation method for 6, 7-di-substituted-2, 3 dihydrobenzofuran |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4129575A (en) * | 1976-04-12 | 1978-12-12 | Thomas C. Elder, Inc. | 8-Methoxypsoralen |
-
2010
- 2010-03-22 CN CN2010101295098A patent/CN102199138B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4129575A (en) * | 1976-04-12 | 1978-12-12 | Thomas C. Elder, Inc. | 8-Methoxypsoralen |
Non-Patent Citations (6)
| Title |
|---|
| 2-烷基-6-甲氧基-1,4-苯醌的全合成;武利强等;《有机化学》;20091231;第29卷(第3期);444-449页，特别是Scheme 4 * |
| 8-甲氧基补骨脂素的合成;张难先等;《南京大学学报(自然科学版)》;19781231(第4期);88-91，特别是89页图，实验部分三 * |
| 张难先等.8-甲氧基补骨脂素的合成.《南京大学学报(自然科学版)》.1978,(第4期),88-91页，特别是89页图，实验部分三. |
| 武利强等.2-烷基-6-甲氧基-1 4-苯醌的全合成.《有机化学》.2009 |
| 韩广甸等.黄鸣龙还原法.《有机化学》.2009,第29卷(第7期),1001-1017，特别是1001页左栏1-2段，1014页第2段. |
| 黄鸣龙还原法;韩广甸等;《有机化学》;20091231;第29卷(第7期);1001-1017，特别是1001页左栏1-2段，1014页第2段 * |
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