CN102180856B - One prepares the method for fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6- - Google Patents
One prepares the method for fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6- Download PDFInfo
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- CN102180856B CN102180856B CN201110051495.7A CN201110051495A CN102180856B CN 102180856 B CN102180856 B CN 102180856B CN 201110051495 A CN201110051495 A CN 201110051495A CN 102180856 B CN102180856 B CN 102180856B
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Abstract
The invention discloses a kind of Nebivolol Intermediates (6-fluoro-3,4-dihydro-2 H-1-benzopyran-2-ethyl formate) preparation method, the method is in alcoholic solvent or alcohol and sour mixed solvent, with nebivolol intermediate (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) for raw material, with palladium carbon (Pd/C) for catalyzer, exist at dewatering agent, under hydrogen pressure 4-4.5MPa, temperature 55-65 DEG C condition, prepare this Nebivolol Intermediates.This method initiator is easy to preparation, and productive rate is high; Simultaneous reactions post-treating method is simply efficient, liquid waste disposal burden and environmental pollution little be the simple of this Nebivolol Intermediates of preparation, the processing method of green, is suitable for scale operation.
Description
Technical field
The present invention relates to the method for the preparation Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6-) of a kind of high yield and environmental protection.
Background technology
Antihypertensive drug nebivolol hydrochloric acid (has another name called: Nebivolol, CAS:99200-09-6), it is a kind of potent third generation β1receptorblocker with high selectivity, without endogenous sympathetic activity, there is the effect reduced blood pressure with peripheral vascular resistance, and can left ventricular function be improved.As third generation beta receptor antagonist, the beta receptor antagonist of high selectivity combines with the vasorelaxation action of mediated by nitric oxide by it, has well tolerable property to hypertension and heart failure patient.By means of advantages such as its provide protection to heart, good hypotensive effect, well tolerable property and untoward reaction is few, the low good effects of dosage, nebivolol wide market, has a high potential.
Nebivolol epoxy [the fluoro-2-of 6-(oxyethane-2H)-3H, 4H-chromene, CAS:99199-90-3], be the important intermediate preparing nebivolol hydrochloric acid, the process preparing nebivolol hydrochloric acid by it is current unique industrialized operational path.The preparation of the nebivolol epoxy intermediate of high purity and high yield is the key realizing nebivolol production.The route preparing nebivolol epoxy at present mainly contains (1) halohydrin and is replaced to around-France (WO08040528Processforpreparingnebivolol), (2) tosic acid base is replaced to around-France (ChandrasekharS.andReddyM.V. for alcohol, Tetrahedron, 2000, 56, 6339-6334), (3) olefin oxidation becomes around-France (EP1803715Aprocessforpreparationofracemicnebivolol), (4) aldehyde radical is oxidized to around-France (EP145067Derivativesof2, 2 '-iminobisethanol) four kinds of methods.
Nebivolol Intermediates (6-fluoro-3,4-dihydro-2 H-1-benzopyran-2-ethyl formate) be adopt halohydrin to be replaced to the around-France initiator preparing nebivolol epoxy, obtained (US7115630Metabotropicglutamatereceptorantagonists) by esterification by Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-formic acids of 6-) and ethanol.But, its productive rate lower (79%) and initiator (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-formic acids of 6-) bad acquisition.
Therefore, research selects operational path that is efficient, green, environmental protection to have very large actual application value.
Summary of the invention
Technical problem solved by the invention is to provide preparation Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of the 6-) operational path of efficient, green a, environmental protection.
For solving above technical problem, concrete thought of the present invention is as follows, can represent with following reaction formula:
Concrete scheme is as follows:
The method is in alcoholic solvent or alcohol and sour mixed solvent, with nebivolol intermediate (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) for raw material, with palladium carbon (Pd/C) for catalyzer, exist at dewatering agent, this Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6-) is prepared under certain temperature, pressure.
Wherein said alcoholic solvent is ethanol, and the consumption (L) of ethanol is 0.36-0.67L/Kg with the pass of raw material nebivolol intermediate (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) consumption (Kg).
Wherein said alcohol is with the mixed solvent of acid, and alcoholic solvent is ethanol; Acid-soluble dose is formic acid, acetic acid, propionic acid, the vitriol oil, concentrated hydrochloric acid, phosphoric acid, perchloric acid.The volume of acid is the 1%-9% of ethanol contend amount, be wherein the best with 1%.The acid-soluble dose of Hydrogen Proton providing katalysis in reaction process, accelerates speed of reaction, Reaction time shorten.Various effect that is organic or mineral acid is substantially identical, but the increase of the consumption along with acid, side reaction also can be made to increase, reduce yield.
Wherein said catalyzer is palladium carbon (Pd/C) is catalyzer, and the amount ranges of catalyzer is 0.34-0.51 times of raw material nebivolol intermediate (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) quality.
Wherein said dewatering agent is anhydrous magnesium sulfate (MgSO4), anhydrous sodium sulphate (NaSO4).
Wherein said hydrogen pressure is preferably 4-4.5MPa.
Wherein said temperature range is preferably 55-65 DEG C.
The processing method initiator that the present invention adopts is easy to preparation, and productive rate is high; Simultaneous reactions post-treating method is simply efficient, liquid waste disposal burden and environmental pollution little.In sum, this processing method substantially increases economy, is an operational path being suitable for this Nebivolol Intermediates of scale operation.
Specific embodiment
The present invention also will be described in further detail in conjunction with the embodiments:
Below by embodiment, the present invention is specifically described; what be necessary to herein means out is that following examples are only used to further illustrate the present invention; can not be interpreted as limiting the scope of the invention, person skilled in art can make some nonessential improvement and adjustment according to foregoing invention content to the present invention.
Embodiment 1: adopt ethanol to be that Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6-) prepared by solvent
In 500ml hydriding reactor, by Nebivolol Intermediates (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) 20g (0.085mol), palladium carbon (7%Pd/C, moisture 65%) 6.8g, adds in 180ml alcohol solvent.At 4.5MPa hydrogen, under 62 DEG C of conditions, mechanic whirl-nett reaction 24 hours.By reacting liquid filtering, Recover palladium carbon, removes alcohol solvent in filtrate under reduced pressure.Distillation residuum is dissolved in methylene dichloride, is neutralized to PH=6-7 with saturated sodium bicarbonate solution.Aqueous phase with methylene dichloride back extraction once, combined dichloromethane phase.Remove to obtain methylene dichloride under reduced pressure oily matter, vacuum-drying obtained product 16.7g after 24 hours, yield 87.7%.
Embodiment 2: adopt ethanol to be that Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6-) prepared by solvent
In 1200L hydriding reactor, by Nebivolol Intermediates (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) 84.5Kg (0.085mol), palladium carbon (7%Pd/C, moisture 65%) 44Kg, adds in 800L alcohol solvent.At 4.2MPa hydrogen, under 62 DEG C of conditions, mechanic whirl-nett reaction 96 hours.By reacting liquid filtering, Recover palladium carbon, removes alcohol solvent in filtrate under reduced pressure.Distillation residuum is dissolved in methylene dichloride, is neutralized to PH=6-7 with saturated sodium bicarbonate solution.Aqueous phase with methylene dichloride back extraction once, combined dichloromethane phase.Remove to obtain methylene dichloride under reduced pressure oily matter, vacuum-drying obtained product 70Kg after 24 hours, yield 87.8%.
Embodiment 3: adopt ethanol and acetic acid mixed solvent to prepare Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6-)
In 500ml hydriding reactor, by Nebivolol Intermediates (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) 30g (0.127mol), palladium carbon (7%Pd/C, moisture 65%) 10.2g, add (ethanol 180ml, acetic acid 1.8ml) in the mixed solvent of ethanol and acetic acid.At 4.5MPa hydrogen, under 62 DEG C of conditions, mechanic whirl-nett reaction 24 hours.By reacting liquid filtering, Recover palladium carbon, removes alcohol solvent in filtrate under reduced pressure.Distillation residuum is dissolved in methylene dichloride, is neutralized to PH=6-7 with saturated sodium bicarbonate solution.Aqueous phase with methylene dichloride back extraction once, combined dichloromethane phase.Remove to obtain methylene dichloride under reduced pressure oily matter, vacuum-drying obtained product 23.6g after 24 hours, yield 83.2%.
Embodiment 4: adopt ethanol and vitriol oil mixed solvent to prepare Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6-)
In 500ml hydriding reactor, by Nebivolol Intermediates (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) 30g (0.127mol), palladium carbon (7%Pd/C, moisture 65%) 10.2g, add (ethanol 180ml, vitriol oil 16.3ml) in the mixed solvent of ethanol and the vitriol oil.At 4.5MPa hydrogen, under 62 DEG C of conditions, mechanic whirl-nett reaction 24 hours.By reacting liquid filtering, Recover palladium carbon, removes alcohol solvent in filtrate under reduced pressure.Distillation residuum is dissolved in methylene dichloride, is neutralized to PH=6-7 with saturated sodium bicarbonate solution.Aqueous phase with methylene dichloride back extraction once, combined dichloromethane phase.Remove to obtain methylene dichloride under reduced pressure oily matter, vacuum-drying obtained product 23.0g after 24 hours, yield 81.0%.
Embodiment 5: employing ethanol is solvent, and other condition prepares Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6-) for the poorest marginal condition
In 5L hydriding reactor, by Nebivolol Intermediates (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) 200g (0.85mol), palladium carbon (7%Pd/C, moisture 65%) 68g, adds in 2.5L alcohol solvent.At 4MPa hydrogen, under 55 DEG C of conditions, mechanic whirl-nett reaction 48 hours.By reacting liquid filtering, Recover palladium carbon, removes alcohol solvent in filtrate under reduced pressure.Distillation residuum is dissolved in methylene dichloride, is neutralized to PH=6-7 with saturated sodium bicarbonate solution.Aqueous phase with methylene dichloride back extraction once, combined dichloromethane phase.Remove to obtain methylene dichloride under reduced pressure oily matter, vacuum-drying obtained product 161.8g after 24 hours, yield 85.2%.
Embodiment 6: employing ethanol is solvent, other condition is that optimum marginal condition prepares Nebivolol Intermediates (fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-ethyl formates of 6-)
In 500ml hydriding reactor, by Nebivolol Intermediates (6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate) 20g (0.085mo1), palladium carbon (7%Pd/C, moisture 65%, filter after it is stirred 30min in ethanol and dewater) 6.8g, anhydrous magnesium sulfate (MgSO4) 1.5g, adds in 180ml alcohol solvent.At 4.5MPa hydrogen, under 65 DEG C of conditions, mechanic whirl-nett reaction 24 hours.By reacting liquid filtering, Recover palladium carbon, removes alcohol solvent in filtrate under reduced pressure.Distillation residuum is dissolved in methylene dichloride, is neutralized to PH=6-7 with saturated sodium bicarbonate solution.Aqueous phase with methylene dichloride back extraction once, combined dichloromethane phase.Remove to obtain methylene dichloride under reduced pressure oily matter, vacuum-drying obtained product 17.5g after 24 hours, yield 92.2%.
Claims (3)
1. a Nebivolol Intermediates 6-fluoro-3, the preparation method of 4-dihydro-4H-1-chromene-2-ethyl formate, it is characterized in that in 500ml hydriding reactor, by Nebivolol Intermediates 6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate 30g, 7% moisture 65% palladium carbon 10.2g, add in the mixed solvent of 180ml ethanol and 1.8ml acetic acid, at 4.5MPa hydrogen, under 62 DEG C of conditions, mechanic whirl-nett reaction 24 hours, by reacting liquid filtering, Recover palladium carbon, removes alcohol solvent in filtrate under reduced pressure; Distillation residuum is dissolved in methylene dichloride, pH=6-7 is neutralized to saturated sodium bicarbonate solution, aqueous phase with methylene dichloride back extraction once, combined dichloromethane phase, remove to obtain methylene dichloride under reduced pressure oily matter, vacuum-drying obtained fluoro-3, the 4-dihydro-4H-1-chromene-2-ethyl formates of product 6-after 24 hours.
2. a Nebivolol Intermediates 6-fluoro-3, the preparation method of 4-dihydro-4H-1-chromene-2-ethyl formate, it is characterized in that in 500ml hydriding reactor, by Nebivolol Intermediates 6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate 30g, 7% moisture 65% palladium carbon 10.2g, add in the mixed solvent of 180ml ethanol and the 16.3ml vitriol oil, at 4.5MPa hydrogen, under 62 DEG C of conditions, mechanic whirl-nett reaction 24 hours, by reacting liquid filtering, Recover palladium carbon, removes alcohol solvent in filtrate under reduced pressure; Distillation residuum is dissolved in methylene dichloride, pH=6-7 is neutralized to saturated sodium bicarbonate solution, aqueous phase with methylene dichloride back extraction once, combined dichloromethane phase, remove to obtain methylene dichloride under reduced pressure oily matter, vacuum-drying obtained fluoro-3, the 4-dihydro-4H-1-chromene-2-ethyl formates of product 6-after 24 hours.
3. a Nebivolol Intermediates 6-fluoro-3, the preparation method of 4-dihydro-4H-1-chromene-2-ethyl formate, it is characterized in that in 500ml hydriding reactor, by 20g Nebivolol Intermediates 6-fluorin-4-oxygen generation-4H-1-chromene-2-ethyl formate, 6.8g palladium carbon, described palladium carbon is filter dewater gained, 1.5g anhydrous magnesium sulfate MgSO after the palladium carbon of 7% moisture 65% stirs 30 minutes in ethanol
4add in 180ml alcohol solvent, at 4.5MPa hydrogen, under 65 DEG C of conditions, mechanic whirl-nett reaction 24 hours, by reacting liquid filtering, Recover palladium carbon, remove alcohol solvent in filtrate under reduced pressure, distillation residuum is dissolved in methylene dichloride, is neutralized to pH=6-7 with saturated sodium bicarbonate solution, aqueous phase with methylene dichloride back extraction once, combined dichloromethane phase, remove to obtain methylene dichloride under reduced pressure oily matter, vacuum-drying obtained fluoro-3, the 4-dihydro-4H-1-chromene-2-ethyl formates of product 6-after 24 hours.
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Effective date of registration: 20170915 Address after: 317024 Development Zone of Linhai bridge, Linhai City, Zhejiang Co-patentee after: Shanghai Aobo Biomedicine Techn Co., Ltd. Patentee after: Zhejiang Huahai Pharmaceutical Co., Ltd. Address before: 317024 Development Zone of Linhai flood bridge, Zhejiang Patentee before: Zhejiang Huahai Pharmaceutical Co., Ltd. |
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Address after: 317024 Development Zone of Linhai bridge, Linhai City, Zhejiang Patentee after: ZHEJIANG HUAHAI PHARMACEUTICAL Co.,Ltd. Patentee after: Shanghai Aobo biomedical Co.,Ltd. Address before: 317024 Development Zone of Linhai bridge, Linhai City, Zhejiang Patentee before: ZHEJIANG HUAHAI PHARMACEUTICAL Co.,Ltd. Patentee before: Shanghai Aobo Biomedical Technology Co.,Ltd. |