CN105016984A - Industrial preparation method of 2-(2-ethoxyphenoxy)bromic ether - Google Patents
Industrial preparation method of 2-(2-ethoxyphenoxy)bromic ether Download PDFInfo
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- CN105016984A CN105016984A CN201510380235.2A CN201510380235A CN105016984A CN 105016984 A CN105016984 A CN 105016984A CN 201510380235 A CN201510380235 A CN 201510380235A CN 105016984 A CN105016984 A CN 105016984A
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Abstract
The invention discloses an industrial preparation method of 2-(2-ethoxyphenoxy)bromic ether, which belongs to the medicine synthesis field. The method comprises the following steps: taking 2-ethoxyphenoxy and 1,2-dibromoethane as raw materials, under existence of a phase-transfer catalyst, dropping a mild dilute aqueous alkali, and performing a substitution reaction, underpressure distillation and recrystallization to obtain 2-(2-ethoxyphenoxy)bromic ether. Through practical industrial production verification, the technology has the advantages of stable quality, mild reaction condition, safe and reliable operation and no three wastes pollution, 1,2-dibromoethane can be recycled and reused, the technical reappearance is good, preparation cost is low, and the industrial preparation method is reliable.
Description
Technical field
The present invention relates to technical field of medicine synthesis, particularly the industrialized process for preparing of a kind of 2-(2-ethoxy phenoxy) bromic ether.
Background technology
Tamsulosin hydrochloride (Tamsulosin Hydrochloride) is a kind of novel Drugs against benign prostate hyperplasia, the long-acting α 1 adrenoceptor inhibitor of highly selective, by Japanese Yamanouchi pharmaceutical development success, obtains FDA approval listing in July, 1992.This medicine can suppress the contraction of prostate smooth musculature cells specifically, alleviates BPH clinical symptom rapidly, can reduce the pressure of Posterior urethral, increases urinary flow, reduces residual urine volume, on blood pressure without impact.Because it has evident in efficacy, that few side effects, recurrence rate are low feature, be widely used in the treatment of benign prostatic hyperplasia clinically, and market demand increases day by day.
2-(2-ethoxy phenoxy) bromic ether (I) is the key intermediate of synthetic drugs tamsulosin hydrochloride.At present both at home and abroad report mainly contain following two kinds of conventional preparation methods:
Method one: as document: Japanese Patent JP2000-229901A, with 2-thanatol for starting raw material, through preparing 2-(2-ethoxy phenoxy with ethylene carbonate ester condensation, sulfonation, replacement three-step reaction) bromic ether:
The method complex steps, reagent ethylene carbonate ester used and lithiumbromide expensive, three-step reaction employs three kinds of different reaction solvents respectively, for high cost large production, is unfavorable for realizing industrialization.
Method two: with 2-thanatol for raw material, carry out Williamsom ether synthesis method with glycol dibromide, single step reaction obtains 2-(2-ethoxy phenoxy) bromic ether:
As document
:j.Med.Chem.1965,8 (3), 356 ~ 357, make alkali with sodium ethylate, synthesis obtains 2-(2-ethoxy phenoxy) bromic ether.Chinese patent CN1994994A, with methyl alcohol or ethanol as solvent, sodium hydroxide makes alkali, and Tetrabutyl amonium bromide makes phase-transfer catalysis, by recrystallization, obtains product yield 63%.E. J. Med. Chem. 2014,81,89 ~ 94, then use comparatively gentle alkali salt of wormwood, the mol ratio of thanatol and ethylene dibromide is 1:4, and not with phase-transfer catalyst, aftertreatment obtains product yield 74% with column chromatography eluting.
With thanatol and 1,2-ethylene dibromide is the method for raw material, and raw material is cheap and easy to get, but problem is: existing method, cost for the separation and purification of reaction product is higher, having had a strong impact on purity and the yield of product, especially yield, is the factor must considered in industrialized production, existing method, the yield of product is general all about 70%, is the highlyest no more than 75%, and cost is higher; Adopt column chromatography, and column chromatography is difficult to carry out industrialization amplification.Therefore, when ensureing product purity and yield, existing preparation method is difficult to form reliable and stable large production technique.
Summary of the invention
The object of the invention is to: a kind of 2-(2-ethoxy phenoxy is provided) industrialized process for preparing of bromic ether, this method avoid now methodical deficiency, solve that the complicated operation, the cost that exist in existing technique are higher, product is difficult to purifying, the problems such as yield is lower.
The technical solution used in the present invention is such: the industrialized process for preparing of a kind of 2-(2-ethoxy phenoxy) bromic ether, and its concrete steps are:
(1) with 2-thanatol (II) and glycol dibromide for raw material, in the presence of a phase transfer catalyst, be added dropwise to gentle dilute alkaline soln, carry out substitution reaction;
(2), after the substitution reaction of step (1) completes, 2-(2-ethoxy phenoxy is obtained through underpressure distillation, recrystallization) bromic ether (I);
Wherein, the dilute alkaline soln of described gentleness is selected from salt of wormwood, saleratus, sodium carbonate, the one in sodium hydrogen carbonate solution that mass percentage concentration is 5 ~ 15%.
As preferred technical scheme, in step (1):
The mol ratio of 2-thanatol and glycol dibromide is 1:6 ~ 1:10.
As preferred technical scheme, in step (1):
Described phase-transfer catalyst is selected from the one in Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate; The weight proportion of phase-transfer catalyst and 2-thanatol is 1:5 ~ 1:100.
As preferred technical scheme, in step (1):
Substitution reaction temperature is 50 ~ 100 DEG C; The substitution reaction time is 6 ~ 20 hours
As preferred technical scheme, in step (2):
The recrystallization solvent adopted in described recrystallization process is selected from the one in methanol-water, alcohol-water, isopropanol-water, acetone-water, acetonitrile-water, DMF-water.
As further preferred technical scheme, in described recrystallization solvent, the mass ratio of organism and water is 1:8 ~ 1:20.
Present inventor is proved by lot of experiments, and under strong alkaline condition of the prior art, two replace supervening of by product, has had a strong impact on purity and the yield of reaction, has added step and the cost of separation and purification.Because two replace by product and target product 2-(2-ethoxy phenoxies) bromic ether structure and similar, experiment proves the dissolving properties almost indifference in all kinds of SOLVENTS, by extraction or the method for recrystallization be all with large losses product for both are separated, for the problems referred to above by cost:
(1) the present invention adopts excessive glycol dibromide, can control the generation of two replacement by products, improve positive yield, and glycol dibromide can reclaim recycled simultaneously, reduces comprehensive cost; Meanwhile, the present invention reacts in the dilute alkaline soln of gentleness, and effectively reaction produced two replace by product controls in 8%(mass percent, HPLC) within, this purge process for a rear step has laid reasonable basis, is conducive to separation and purification, improves product purity;
(2) the present invention utilizes the boiling point difference of two replacement by products and product, adopts the method for underpressure distillation, very effectively product and two can be replaced by product and separate completely, both improve product purity, and ensured product yield again;
(3) the present invention's product that underpressure distillation is obtained, form the method for mixed solvent recrystallization with a small amount of organic solvent and large water gaging, ensure that the great product of solubleness is not suffered a loss in organic solvent, ensure that yield on the one hand, also improve product purity, product purity more than 99% simultaneously.
In sum, owing to have employed technique scheme, the invention has the beneficial effects as follows: the present invention prepares 2-(2-ethoxy phenoxy) technique of bromic ether, product crystal formation is good, and proterties is stablized, and purity can reach more than 99%; The present invention prepares 2-(2-ethoxy phenoxy) technique of bromic ether, have passed through actual industrialization and produce checking, steady quality, reaction conditions is gentle, and operational safety is reliable, substantially pollute without " three wastes ", glycol dibromide is recyclable to be applied mechanically, technique favorable reproducibility, preparation cost is low, is a kind of 2-(2-ethoxy phenoxy reliably) industrialized process for preparing of bromic ether.
Embodiment
The present invention is described in detail below.
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Embodiment 1
2-(2-ethoxy phenoxy) preparation of bromic ether (I)
According to proportioning, 2-thanatol 200 Kg, 1 is added in reactor, 2-ethylene dibromide 1800 Kg, benzyltriethylammoinium chloride 4 Kg, be warming up to 60-65 DEG C, separately use a reactor, sodium bicarbonate aqueous solution 1600 Kg of preparation 15%, and instill in above-mentioned mixed solution by header tank, drip and finish, insulation reaction 10 hours.Be down to room temperature, layering, collect organic phase, underpressure distillation, collects excessive glycol dibromide 1028 Kg(-0.08 MPa, 80 ~ 90 DEG C respectively) and thick product 2-(2-ethoxy phenoxy) bromic ether 336 Kg(-0.1MPa, 130 ~ 140 DEG C); Above-mentioned thick product proceeds in reactor, adds acetonitrile 340 Kg, water 3400 Kg, be heated to 50 ~ 60 DEG C dissolve clarification after, below slow cooling to 10 DEG C.Blowing, centrifuging, dry, obtain 2-(2-ethoxy phenoxy) bromic ether straight product 305 Kg, and purity 99.1%, single contaminant < 1%(HPLC), yield 86.3%.Finished product packing is put in storage.
Embodiment 2
2-(2-ethoxy phenoxy) preparation of bromic ether (I)
According to proportioning, 2-thanatol 200 Kg, 1 is added in reactor, 2-ethylene dibromide 2170 Kg, tetrabutylammonium chloride 10 Kg, be warming up to 75-80 DEG C, separately use a reactor, preparation mass percentage concentration is aqueous sodium carbonate 2560 Kg of 12%, and instills in above-mentioned mixed solution by header tank; Drip and finish, insulation reaction 20 hours, is down to room temperature, layering, collect organic phase, underpressure distillation, collects excessive 1 respectively, 2-ethylene dibromide 1280 Kg(-0.08 MPa, 80 ~ 90 DEG C) and thick product 2-(2-ethoxy phenoxy) bromic ether 345 Kg(-0.1 MPa, 130 ~ 140 DEG C).Above-mentioned thick product proceeds in reactor, adds acetone 350 Kg, water 4200 Kg, be heated to 50 ~ 60 DEG C dissolve clarification after, below slow cooling to 10 DEG C.Blowing, centrifuging, dry, obtain 2-(2-ethoxy phenoxy) bromic ether straight product 301 Kg, and purity 99.2%, single contaminant < 1%(HPLC), yield 85.1%.Finished product packing is put in storage.
Embodiment 3
2-(2-ethoxy phenoxy) preparation of bromic ether (I)
According to proportioning, in reactor, add 2-thanatol 200 Kg, glycol dibromide 2720 Kg, 4-butyl ammonium hydrogen sulfate 2 Kg, be warming up to 95-100 DEG C, separately use a reactor, wet chemical 1850 Kg of preparation 15%, and instilled in above-mentioned mixed solution by header tank.Drip and finish, insulation reaction 6 hours.Be down to room temperature, layering, collect organic phase, underpressure distillation, collects excessive glycol dibromide 1978 Kg(-0.08 MPa, 80 ~ 90 DEG C respectively) and thick product 2-(2-ethoxy phenoxy) bromic ether 340 Kg(-0.1 MPa, 130 ~ 140 DEG C).Above-mentioned thick product proceeds in reactor, adds DMF 300 Kg, water 3600 Kg, be heated to 50 ~ 60 DEG C dissolve clarification after, below slow cooling to 10 DEG C.Blowing, centrifuging, dry, obtain 2-(2-ethoxy phenoxy) bromic ether straight product 303 Kg, and purity 99.5%, single contaminant < 1%(HPLC), yield 85.7%.Finished product packing is put in storage.
Embodiment 4
2-(2-ethoxy phenoxy) preparation of bromic ether (I)
According to proportioning, 2-thanatol 200 Kg, 1 is added in reactor, 2-ethylene dibromide 1800 Kg, Tetrabutyl amonium bromide 40 Kg, be warming up to 60-65 DEG C, separately use a reactor, potassium bicarbonate aqueous solution 1600 Kg of preparation 10%, and instill in above-mentioned mixed solution by header tank, drip and finish, insulation reaction 10 hours.Be down to room temperature, layering, collect organic phase, underpressure distillation, collects excessive glycol dibromide 1028 Kg(-0.08 MPa, 80 ~ 90 DEG C respectively) and thick product 2-(2-ethoxy phenoxy) bromic ether 336 Kg(-0.1MPa, 130 ~ 140 DEG C); Above-mentioned thick product proceeds in reactor, adds methyl alcohol 170 Kg, water 3400 Kg, be heated to 50 ~ 60 DEG C dissolve clarification after, below slow cooling to 10 DEG C.Blowing, centrifuging, dry, obtain 2-(2-ethoxy phenoxy) bromic ether straight product 302 Kg, and purity 99.1%, single contaminant < 1%(HPLC), yield 85.4%.Finished product packing is put in storage.
Embodiment 5
2-(2-ethoxy phenoxy) preparation of bromic ether (I)
According to proportioning, 2-thanatol 200 Kg, 1 is added in reactor, 2-ethylene dibromide 1800 Kg, tetrabutylammonium chloride 30 Kg, be warming up to 60-65 DEG C, separately use a reactor, sodium bicarbonate aqueous solution 3600 Kg of preparation 5%, and instill in above-mentioned mixed solution by header tank, drip and finish, insulation reaction 10 hours.Be down to room temperature, layering, collect organic phase, underpressure distillation, collects excessive glycol dibromide 1028 Kg(-0.08 MPa, 80 ~ 90 DEG C respectively) and thick product 2-(2-ethoxy phenoxy) bromic ether 336 Kg(-0.1MPa, 130 ~ 140 DEG C); Above-mentioned thick product proceeds in reactor, adds Virahol 200 Kg, water 3000 Kg, be heated to 50 ~ 60 DEG C dissolve clarification after, below slow cooling to 10 DEG C.Blowing, centrifuging, dry, obtain 2-(2-ethoxy phenoxy) bromic ether straight product 301 Kg, and purity 99.1%, single contaminant < 1%(HPLC), yield 85.1%.Finished product packing is put in storage.
Claims (6)
1. an industrialized process for preparing for 2-(2-ethoxy phenoxy) bromic ether, it is characterized in that, its concrete steps are:
(1) with 2-thanatol (II) and glycol dibromide for raw material, in the presence of a phase transfer catalyst, be added dropwise to gentle dilute alkaline soln, carry out substitution reaction;
(2), after the substitution reaction of step (1) completes, 2-(2-ethoxy phenoxy is obtained through underpressure distillation, recrystallization) bromic ether (I);
Wherein, the dilute alkaline soln of described gentleness is selected from salt of wormwood, saleratus, sodium carbonate, the one in sodium hydrogen carbonate solution that mass percentage concentration is 5 ~ 15%.
2. the industrialized process for preparing of a kind of 2-according to claim 1 (2-ethoxy phenoxy) bromic ether, is characterized in that, in step (1):
The mol ratio of 2-thanatol and glycol dibromide is 1:6 ~ 1:10.
3. the industrialized process for preparing of a kind of 2-according to claim 1 (2-ethoxy phenoxy) bromic ether, is characterized in that, in step (1):
Described phase-transfer catalyst is selected from the one in Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate; The weight proportion of phase-transfer catalyst and 2-thanatol is 1:5 ~ 1:100.
4. the industrialized process for preparing of a kind of 2-according to claim 1 (2-ethoxy phenoxy) bromic ether, is characterized in that, in step (1):
Substitution reaction temperature is 50 ~ 100 DEG C; The substitution reaction time is 6 ~ 20 hours.
5. the industrialized process for preparing of a kind of 2-according to claim 1 (2-ethoxy phenoxy) bromic ether, is characterized in that, in step (2):
The recrystallization solvent adopted in described recrystallization process adopts the mixture of organic solvent and water, is selected from the one in methanol-water, alcohol-water, isopropanol-water, acetone-water, acetonitrile-water, DMF-water.
6. the industrialized process for preparing of a kind of 2-according to claim 5 (2-ethoxy phenoxy) bromic ether, is characterized in that, the mass ratio of described organic solvent and water is 1:8 ~ 1:20.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107827722A (en) * | 2017-11-23 | 2018-03-23 | 中山奕安泰医药科技有限公司 | A kind of synthetic method of the methoxybenzaldehyde of 3 ethyoxyl 4 |
| CN113788741A (en) * | 2021-09-28 | 2021-12-14 | 大连九信精细化工有限公司 | Method for preparing 2-cyclopropyl phenol derivative |
Citations (1)
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| JP2005325026A (en) * | 2004-05-12 | 2005-11-24 | Ohara Yakuhin Kogyo Kk | Method for producing phenoxyethyl halide and its derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005325026A (en) * | 2004-05-12 | 2005-11-24 | Ohara Yakuhin Kogyo Kk | Method for producing phenoxyethyl halide and its derivative |
Non-Patent Citations (2)
| Title |
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| XIAOKE GUO ET AL.,: "Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium clannel inhibitors（part I）", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107827722A (en) * | 2017-11-23 | 2018-03-23 | 中山奕安泰医药科技有限公司 | A kind of synthetic method of the methoxybenzaldehyde of 3 ethyoxyl 4 |
| CN107827722B (en) * | 2017-11-23 | 2021-02-19 | 中山奕安泰医药科技有限公司 | Synthetic method of 3-ethoxy-4-methoxybenzaldehyde |
| CN113788741A (en) * | 2021-09-28 | 2021-12-14 | 大连九信精细化工有限公司 | Method for preparing 2-cyclopropyl phenol derivative |
| CN113788741B (en) * | 2021-09-28 | 2023-12-29 | 大连九信精细化工有限公司 | Method for preparing 2-cyclopropyl phenol derivative |
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