CN104876806A - Novel method for synthesizing bisoprolol importance intermediate - Google Patents
Novel method for synthesizing bisoprolol importance intermediate Download PDFInfo
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- CN104876806A CN104876806A CN201510270914.4A CN201510270914A CN104876806A CN 104876806 A CN104876806 A CN 104876806A CN 201510270914 A CN201510270914 A CN 201510270914A CN 104876806 A CN104876806 A CN 104876806A
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- 0 C*c(cc1)cc*1O Chemical compound C*c(cc1)cc*1O 0.000 description 2
- ISQLWWCGQXEAJG-UHFFFAOYSA-N CC(C)OCCOCc(cc1)ccc1O Chemical compound CC(C)OCCOCc(cc1)ccc1O ISQLWWCGQXEAJG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/09—Preparation of ethers by dehydration of compounds containing hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel method for synthesizing a bisoprolol importance intermediate. The novel method has the following steps: carrying out a reaction between hydroxy benzaldehyde which is taken as a raw material and acetic anhydride to obtain 4-acetoxybenzaldehyde; conducting reduction on 4-acetoxybenzaldehyde with sodium borohydride to obtain 4-acetoxyl benzyl alcohol; carrying out a reaction between 4-acetoxyl benzyl alcohol and 2-isopropoxyethanol to obtain 4-[(2-isopropoxyethanol)methyl]phenyl acetic acid, thereby avoiding side reactions such as phenolic hydroxyl etherification; under an alkaline condition, directly hydrolyzing 4-[(2-isopropoxyethanol)methyl]phenyl acetic acid without separation to recover 2-isopropoxyethanol, thereby obtaining the required intermediate, namely 4-isopropoxyethoxymethylphenol. The novel method is mild in reaction and safe to operate; impurities generated due to self-polymerization of raw materials, phenolic hydroxyl etherification and the like are reduced; the product purity and yield are relatively high; as a novel way for obtaining the bisoprolol importance intermediate, the novel method can be applied to large-scale industrialized production.
Description
Technical field
The invention belongs to medicine intermediate preparation field, be specifically related to a kind of new synthetic method of bisoprolol important intermediate.
Background technology
Bisoprolol important intermediate 4-isopropoxy ethyoxyl methyl phenol, English name 4-isopropoxyethoxymethylphenol, molecular formula: C
12h
18o
3, molecular weight: 210, it is the key intermediate of synthesis treatment stenocardia, arrhythmia and hypertension drug bisoprolol fumarate.
The synthetic method report of 4-isopropoxy ethyoxyl methyl phenol is also few, mainly contains two lines.European patent WO2007069266 discloses a kind of preparation method of 4-isopropoxy ethyoxyl methyl phenol, be specifically starting raw material by 4-hydroxy benzaldehyde, under potassium borohydride reduction, effect at catalyzer, carry out alcoholic extract hydroxyl group etherificate with 2-isopropoxide ethanol and obtain.
Reaction equation is as follows:
The shortcoming of the method is, carry out in the process of alcoholic extract hydroxyl group etherificate, raw material auto-polymerization can occur, the phenolic hydroxyl group in product and 2-isopropoxide ethanol and to side reactions such as hydroxy-benzyl alcohol generation etherificates, produces impurity, causes product yield low.Shown in patent documentation CN201210005250.5, take p-methyl phenol as raw material, through hydroxyl protection, bromo, etherificate, deprotection finally obtained product.
Reaction equation is as follows
Use a large amount of bromines in the method reaction process, there is the safety such as toxicity damage and pollution hidden trouble, and a large amount of 2-isopropoxide ethanols will be consumed.Produce a large amount of waste water in treating processes, cannot process and recycle, production cost is high and product yield is lower.
The technique of above bibliographical information has and is difficult to industrialized problem, method reaction temperature provided by the invention and, operational safety, decrease the impurity etc. because raw material auto-polymerization and phenolic hydroxyl group etherificate produce, product purity and yield higher, processing costs is low, and the acquisition for 4-isopropoxy ethyoxyl methyl phenol provides a kind of new method, and this inventive method can be applied to large-scale industrial production.
Summary of the invention
The object of this invention is to provide a kind of new synthetic method of bisoprolol important intermediate, purification procedures adopts physical method, decreases the generation of impurity, improves the yield of 4-isopropoxy ethyoxyl methyl phenol, reduce production cost.
The synthetic method of a kind of bisoprolol intermediate of the present invention, comprises the following steps:
(1) hydroxyl of diacetyl oxide protection p-Hydroxybenzaldehyde is used;
(2) with sodium borohydride reduction 4-acetoxyl group phenyl aldehyde;
(3) under the effect of catalyzer, 4-acetoxyl group benzylalcohol and 2-isopropoxide ethanol react, and after reaction terminates, obtain 4-isopropoxy ethyoxyl methyl phenol in alkaline condition direct hydrolysis, by etherificate and be hydrolyzed to one kettle way, merge into a step and carry out.Wherein:
In step (1), the mol ratio of p-Hydroxybenzaldehyde and diacetyl oxide is 1:1.2; Temperature of reaction is 130 ~ 140 DEG C; Reaction times is 3 hours.
In step (2), solvent is water, THF, methyl alcohol, ethanol, methylene dichloride, DMF, first alcohol and water; 4-acetoxyl group phenyl aldehyde and sodium borohydride material ratio are 1:(0.4 ~ 0.6); Temperature of reaction is 25 DEG C.
In step (3), the mol ratio of 4-acetoxyl group phenylcarbinol and 2-isopropoxide ethanol is 1:(6 ~ 8); Solvent is THF, methylene dichloride, chloroform, tetracol phenixin, DMSO, DMF, DMAC, 2-isopropoxide ethanol; Catalyzer is methylsulfonic acid, trifluoroacetic acid, tosic acid, the vitriol oil, concentrated hydrochloric acid, phosphoric acid; Temperature of reaction is 30 ~ 35 DEG C.
In sum, the present invention has the following advantages:
(1) generation of the side reactions such as the etherificate of phenolic hydroxyl group in raw material auto-polymerization and product is decreased;
(2) reaction conditions is gentle, and easy handling, more easily realizes suitability for industrialized production;
(3) yield is higher, and cost is lower, and the purity of the product obtained is higher.
Embodiment
Below in conjunction with embodiment, the present invention is further described.
Embodiment 1:
By 12.2g(0.1mol) p-Hydroxybenzaldehyde and the 0.3g vitriol oil join in the there-necked flask of 100ml, slowly drips 12.12g(0.12mol) acetic anhydride, reflux, after TLC detection reaction is complete, steam solvent, add 20ml water and stir, have solid to separate out, cooling crystallization, suction filtration is separated, and dry, the solid obtained is 4-acetoxyl group phenyl aldehyde 16.1g, productive rate is 98%, HPLC purity is 99.3%.
Embodiment 2:
In the there-necked flask of 100ml, add 16.1g(0.098mol) 4-acetoxyl group phenyl aldehyde and 20ml ethanol, stirring and dissolving, add 1.48g sodium borohydride in ice-water bath in batches, continue to stir, after 1h, be warming up to 25 DEG C of reactions, after TLC detection reaction is complete, steam solvent, in residue, add 30ml ethyl acetate and 10ml water, retain organic phase, continue in organic phase to add 10ml water washing, remove water layer, obtain 4-acetoxyl group benzylalcohol 15.8g by concentrated for organic phase, productive rate is 97.4%, HPLC purity is 99.5%.
Embodiment 3:
In the there-necked flask of 100ml, add 16.1g(0.098mol) 4-acetoxyl group phenyl aldehyde and 20mlTHF, stirring and dissolving, add 2.23g sodium borohydride in ice-water bath in batches, continue to stir, after 1h, be warming up to 25 DEG C of reactions, after TLC detection reaction is complete, steam solvent, in residue, add 30ml ethyl acetate and 10ml water, retain organic phase, continue in organic phase to add 10ml water washing, remove water layer, organic phase evaporate to dryness is obtained 4-acetoxyl group benzylalcohol 15.5g, productive rate is 95%, HPLC purity is 98%.
Embodiment 4:
In the there-necked flask of 100ml, add 16.1g(0.098mol) 4-acetoxyl group phenyl aldehyde and 10ml water, 1.48g sodium borohydride and 10ml methyl alcohol is added in ice-water bath, continue to stir, after 1h, be warming up to 30 DEG C of reactions, after TLC detection reaction is complete, steams solvent, in residue, add 30ml ethyl acetate and 10ml water, retain organic phase, continue in organic phase to add 10ml water washing, remove water layer, organic phase evaporate to dryness obtains 4-acetoxyl group benzylalcohol 15.7g, productive rate is 96.4%, HPLC purity is 99.0%.
Embodiment 5:
In 100ml there-necked flask, add 5.2g(0.05mol) 2-isopropoxide ethanol and the 0.1g vitriol oil, keep temperature 25 DEG C, by 8.3g(0.05mol) 4-oxyethyl group benzylalcohol is dissolved into 26g(0.25mol) mixed solution of 2-isopropoxide ethanol is slowly added drop-wise in there-necked flask.Be warming up to 35 DEG C, continue reaction, after TLC detection reaction is complete, add the sodium hydroxide solution of 24g 10% in reaction solution, continue reaction, after reaction terminates, low temperature regulates pH extremely neutral.Steam and recycling design, 30ml ethyl acetate and 10ml water is added in residue, retain organic phase, continue in organic phase to add 10ml water washing, remove water layer, in organic phase, add anhydrous magnesium sulfate drying, filter, organic phase evaporate to dryness obtains oily matter 4-isopropoxy ethyoxyl methyl phenol 9.14g, and productive rate is 87%, HPLC purity is 99.2%.
Embodiment 6:
In 100ml there-necked flask, add 5.2g(0.05mol) 2-isopropoxide ethanol, 0.1g methylsulfonic acid, keeps temperature 25 DEG C, by 8.3g(0.05mol) 4-oxyethyl group benzylalcohol is dissolved into 26g(0.25mol) mixed solution of 2-isopropoxide ethanol is slowly added drop-wise in there-necked flask.Be warming up to 35 DEG C, continue reaction, after TLC detection reaction is complete, add the sodium hydroxide solution of 24g 10% in reaction solution, continue reaction, after reaction terminates, low temperature regulates pH extremely neutral.Steam and recycling design, 30ml ethyl acetate and 10ml water is added in residue, retain organic phase, continue in organic phase to add 10ml water washing, remove water layer, in organic phase, add anhydrous magnesium sulfate drying, filter, organic phase evaporate to dryness obtains oily matter 4-isopropoxy ethyoxyl methyl phenol 8.61g, and productive rate is 82%, HPLC purity is 99.2%.
Embodiment 7:
In 100ml there-necked flask, add 5.2g(0.05mol) 2-isopropoxide ethanol, 0.1g trifluoroacetic acid, keeps temperature 25 DEG C, by 8.3g(0.05mol) 4-oxyethyl group benzylalcohol is dissolved into 36.4g(0.35mol) mixed solution of 2-isopropoxide ethanol is slowly added drop-wise in there-necked flask.Be warming up to 35 DEG C, continue reaction, after TLC detection reaction is complete, add the sodium hydroxide solution of 24g 10% in reaction solution, continue reaction, after reaction terminates, low temperature regulates pH extremely neutral.Steam and recycling design, 30ml ethyl acetate and 10ml water is added in residue, retain organic phase, continue in organic phase to add 10ml water washing, remove water layer, in organic phase, add anhydrous magnesium sulfate drying, filter, organic phase evaporate to dryness obtains oily matter 4-isopropoxy ethyoxyl methyl phenol 8.76g, and productive rate is 83.5%, HPLC purity is 99.0%.
Embodiment 8:
In 100ml there-necked flask, add 41.6g(0.40mol) 2-isopropoxide ethanol, 0.2g phosphoric acid, keeps temperature 25 DEG C, by 8.3g(0.05mol) 4-oxyethyl group benzylalcohol is added in there-necked flask, be warming up to 35 DEG C, continue reaction, after TLC detection reaction is complete, the sodium hydroxide solution of 24g 10% is added in reaction solution, continue reaction, after reaction terminates, low temperature regulates pH to neutral.Steam and recycling design, 30ml ethyl acetate and 10ml water is added in residue, retain organic phase, continue in organic phase to add 10ml water washing, remove water layer, in organic phase, add anhydrous magnesium sulfate drying, filter, organic phase evaporate to dryness obtains oily matter 4-isopropoxy ethyoxyl methyl phenol 8.31g, and productive rate is 79.1%, HPLC purity is 97.6%.
Although above-mentioned, the specific embodiment of the present invention is described; but not limiting the scope of the invention; one of ordinary skill in the art should be understood that; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various amendment or distortion that creative work can make still within protection scope of the present invention.
Claims (6)
1. a new synthetic method for bisoprolol important intermediate, is characterized in that: comprise the following steps:
(1) hydroxyl of diacetyl oxide protection p-Hydroxybenzaldehyde is used;
(2) with sodium borohydride reduction 4-acetoxyl group phenyl aldehyde;
(3) under the effect of catalyzer, 4-acetoxyl group benzylalcohol and 2-isopropoxide ethanol react, and after reaction terminates, obtain 4-isopropoxy ethyoxyl methyl phenol in alkaline condition direct hydrolysis, by etherificate and be hydrolyzed to one kettle way, merge into a step and carry out.
2. the new synthetic method of a kind of bisoprolol important intermediate according to claim 1, is characterized in that: in step (1), para hydroxybenzene aldehyde is 1:(1 ~ 3 with the mol ratio of diacetyl oxide), preferably 1:1.2; Temperature of reaction is 120 ~ 150 DEG C, preferably 130 ~ 140 DEG C; Reaction times is 2 ~ 5 hours, preferably 3 hours.
3. the new synthetic method of a kind of bisoprolol important intermediate according to claim 1, is characterized in that: in step (2), 4-acetoxyl group phenyl aldehyde and sodium borohydride material ratio are 1:(0.4 ~ 1), preferred 1:(0.4 ~ 0.6); Temperature of reaction is 25 DEG C; Solvent is water, THF, methyl alcohol, ethanol, toluene, methylene dichloride, chloroform, ethylene dichloride, DMF, first alcohol and water, particular methanol, ethanol.
4. the new synthetic method of a kind of bisoprolol important intermediate according to claim 1, is characterized in that: in step (3), 4-acetoxyl group benzylalcohol is 1:(6 ~ 10 with the mol ratio of 2-isopropoxide ethanol), preferably 1:(6 ~ 8); Temperature of reaction is 20 ~ 40 DEG C, is preferably 30 ~ 35 DEG C; Reaction times is 4 ~ 15 hours, is preferably 7 ~ 10 hours.
5. the new synthetic method of a kind of bisoprolol important intermediate according to claim 1, it is characterized in that: 4-acetoxyl group benzylalcohol and 2-isopropoxide ethanol solvent used are THF, methylene dichloride, chloroform, tetracol phenixin, DMSO, DMF, DMAC, 2-isopropoxide ethanol etc. in step (3), preferred 2-isopropoxide ethanol.
6. the new synthetic method of a kind of bisoprolol important intermediate according to claim 1, is characterized in that: in step (3), used catalyst is methylsulfonic acid, trifluoroacetic acid, tosic acid, the vitriol oil, concentrated hydrochloric acid, phosphoric acid, is preferably the vitriol oil.
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| CN201510270914.4A CN104876806A (en) | 2015-05-26 | 2015-05-26 | Novel method for synthesizing bisoprolol importance intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973761A (en) * | 2017-06-26 | 2018-05-01 | 江苏悦兴医药技术有限公司 | The synthetic method of bisoprolol fumarate's process contaminants |
| CN112441932A (en) * | 2020-12-29 | 2021-03-05 | 深圳市祥根生物科技有限公司 | Preparation method of bisoprolol fumarate impurity |
| CN112441932B (en) * | 2020-12-29 | 2024-07-12 | 深圳市祥根生物医药有限公司 | Preparation method of bisoprolol fumarate impurity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1590366A (en) * | 2002-07-12 | 2005-03-09 | 北京四环医药科技股份有限公司 | Improved method of preparing bisolol and its salt |
| WO2007069266A2 (en) * | 2005-12-12 | 2007-06-21 | Unichem Laboratories Limited | A novel process for the synthesis of bisodprolol and its intermediate |
| CN102557891A (en) * | 2012-01-10 | 2012-07-11 | 济南久创化学有限责任公司 | Preparation method for 4-isopropoxy ethyoxyl methyl phenol |
-
2015
- 2015-05-26 CN CN201510270914.4A patent/CN104876806A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1590366A (en) * | 2002-07-12 | 2005-03-09 | 北京四环医药科技股份有限公司 | Improved method of preparing bisolol and its salt |
| WO2007069266A2 (en) * | 2005-12-12 | 2007-06-21 | Unichem Laboratories Limited | A novel process for the synthesis of bisodprolol and its intermediate |
| CN102557891A (en) * | 2012-01-10 | 2012-07-11 | 济南久创化学有限责任公司 | Preparation method for 4-isopropoxy ethyoxyl methyl phenol |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973761A (en) * | 2017-06-26 | 2018-05-01 | 江苏悦兴医药技术有限公司 | The synthetic method of bisoprolol fumarate's process contaminants |
| CN112441932A (en) * | 2020-12-29 | 2021-03-05 | 深圳市祥根生物科技有限公司 | Preparation method of bisoprolol fumarate impurity |
| CN112441932B (en) * | 2020-12-29 | 2024-07-12 | 深圳市祥根生物医药有限公司 | Preparation method of bisoprolol fumarate impurity |
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Application publication date: 20150902 |