CN105503842A - Method for preparing nebivolol hydrochloride epoxy intermediate 6-fluoro-2-epoxy ethyl chroman - Google Patents
Method for preparing nebivolol hydrochloride epoxy intermediate 6-fluoro-2-epoxy ethyl chroman Download PDFInfo
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- CN105503842A CN105503842A CN201510990731.XA CN201510990731A CN105503842A CN 105503842 A CN105503842 A CN 105503842A CN 201510990731 A CN201510990731 A CN 201510990731A CN 105503842 A CN105503842 A CN 105503842A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a method for preparing a nebivolol hydrochloride epoxy intermediate 6-fluoro-2-epoxy ethyl chroman. The method includes the following steps that firstly, under the conditions that water, phosphate, inorganic alkali B1, zinc chloride, a hydrogen source, aldose reductase and NADPH exist, the temperature is 30-70 DEG C and the pH value is 6.0-8.0, a reduction reaction happens to 2-chloro-1-(6-fluorochromane-2-yl)-ethanon, and 2-chloro-1-(6-fluorochromane-2-yl)-alcohol is obtained; secondly, 2-chloro-1-(6-fluorochromane-2-yl)-alcohol is heated in a C1-C6 alkanol solvent and inorganic alkali B2 for a reflux reaction, an organic ester solvent is added dropwise for crystallization after the reaction ends, and 6-fluoro-2-epoxy ethyl chroman is obtained. The preparation method is mild in reaction condition, raw materials and solvents are easy to obtain, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, specifically, relate to the preparation method of a kind of nebivolol hydrochloric acid intermediate 6-fluoro-2-epoxy ethyl chroman.
Background technology
Nebivolol hydrochloric acid, developed by Johnson & Johnson company of the U.S., be used for the treatment of the medicine of essential hypertension, have the heart selectivity beta-blocker of vasorelaxation action concurrently, have the advantages such as evident in efficacy, easy administration, its chemical structural formula is as follows:
6-fluoro-2-epoxy ethyl chroman is the key intermediate in nebivolol preparation process, at present, comprises about its synthesis technique report:
European patent EP 0145067 discloses a kind of method preparing 6-fluoro-2-epoxy ethyl chroman, its with 6-fluorine chroman-2-carboxylic acid for raw material, first be reduced into corresponding alcohol, then oxidation obtains the fluoro-chroman-2-formaldehyde of 6-, then gained aldehyde is converted into epoxy compounds, and diastereomer is obtained to its fractionation, as follows:
Intermediate aldehydes needs reaction at-60 DEG C that the method is obtained, this reaction conditions is comparatively harsh, and this intermediate poor stability, directly affect the quality of subsequent step products therefrom.
US Patent No. 7960572B2 discloses an operational path,
The method reaction conditions is gentle, but has used methanesulfonic in the process preparing the chloro-1-of intermediate 2-(6-fluorine chroman-2-base) ethyl ketone, and the risk that this reagent generates genotoxicity impurity is high, is unfavorable for the control of end product quality.
US Patent No. 20110237808A1 discloses similar synthetic route, employs the bromochloromethane that toxicity is larger in preparation process, and temperature of reaction, at-80 ~-85 DEG C, is also unfavorable for suitability for industrialized production.
Chinese patent CN103833717A discloses a kind of diazotization reaction that utilizes to prepare the synthetic route of this intermediate, and the reaction conditions of this route is gentleer.But Sodium Nitrite reagent toxicity is wherein comparatively large and unsuitablely to preserve for a long time in a large number, in addition, the intermediate diazonium salt character of generation is active, and easily decompose and produce a large amount of nitrogen, suitability for industrialized production has very large potential safety hazard.
To sum up, the art still thirsts for a kind of method preparing nebivolol key intermediate newly, has not both had the reagent that the reaction conditions of chemical method harshness, toxicity are larger, dangerous high working method, also environmental protection.
Summary of the invention
The present inventor has researched and developed a kind of nebivolol key intermediate---and the preparation method of 6-fluoro-2-epoxy ethyl chroman, its reaction conditions is gentle, and raw material and reagent easily obtain, and are suitable for suitability for industrialized production.
The object of this invention is to provide the preparation method of a kind of 6-fluoro-2-epoxy ethyl chroman.
In embodiments of the invention, the invention provides the preparation method of a kind of 6-fluoro-2-epoxy ethyl chroman, comprise the steps:
(1) at water, phosphoric acid salt, mineral alkali B1, zinc chloride, hydrogen source, aldose reductase, NADPH (i.e. NADP, down together) under existent condition, temperature be 30-70 DEG C, under pH value is the condition of 6.0-8.0, the chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone generation reduction reaction, obtains the chloro-1-of 2-(6-fluorine chroman-2-base) ethanol;
(2) the chloro-1-of 2-(6-fluorine chroman-2-base) ethanol is warming up to back flow reaction in C1-C6 alkanol solvent and mineral alkali B2, reacts complete, through dripping organic ester solvent crystallization, obtains 6-fluoro-2-epoxy ethyl chroman.
In one embodiment of the present invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, comprises the steps:
(1) in reaction vessel, water, phosphoric acid salt is added, by mineral alkali B1 adjust ph to 6.0-8.0, after add zinc chloride, hydrogen source, aldose reductase, the chloro-1-of NADPH, 2-(6-fluorine chroman-2-base) ethyl ketone successively, use mineral alkali B1 adjust ph to 6.0-8.0 again, 30-70 DEG C of reaction, obtain the chloro-1-of 2-(6-fluorine chroman-2-base) ethanol;
(2) chloro-for 2-1-(6-fluorine chroman-2-base) ethanol, C1-C6 alkanol solvent, mineral alkali B2 are added reaction system, be warming up to backflow, drip organic ester solvent crystallization, obtain 6-fluoro-2-epoxy ethyl chroman.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, further, also be included in the mother liquor after step (2) crystallization and drip alkane solvents, preferably, be sherwood oil, normal hexane, hexanaphthene or methyl tertiary butyl ether, further crystallization, filter, obtain 6-fluoro-2-epoxy ethyl chroman.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, phosphoric acid salt described in step (1) is selected from sodium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydrogen phosphate, potassium primary phosphate or dipotassium hydrogen phosphate, preferably, be SODIUM PHOSPHATE, MONOBASIC and/or potassium primary phosphate.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, described in step (1), mineral alkali B1 is selected from potassium hydroxide, sodium hydroxide, sodium carbonate, salt of wormwood or ammoniacal liquor, is preferably sodium hydroxide and/or potassium hydroxide.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, described in step (1), hydrogen source is selected from formic acid or ammonium formiate, preferably, is ammonium formiate.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, in step (1), the weight ratio that water and phosphoric acid salt feed intake is 50-80:1, preferably, is 60-70:1; The weight ratio of phosphoric acid salt and the chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone is 20-80:100, preferably, and 30-65:100.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, in step (1), the mol ratio that zinc chloride and the chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone feed intake is 1:1.2-1.8, preferably, is 1:1.35-1.55.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, in step (1), the mol ratio that hydrogen source and the chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone feed intake is 1.1-1.5:1, preferably, is 1.3-1.45:1.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, in step (1), the weight ratio that aldose reductase and the chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone feed intake is 1.5-3.5:1, preferably, is 1.5-2.5:1.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, in step (1), the weight ratio that aldose reductase and NADPH feed intake is 8-15:1, preferably, is 8-12:1.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, temperature described in step (1) is 35-60 DEG C, preferably, is 50-60 DEG C.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, described in step (2), C1-C6 alkanol is selected from methyl alcohol, ethanol, propyl alcohol, propyl carbinol or the trimethyl carbinol, preferably, is methyl alcohol or ethanol.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, the mineral alkali B2 described in step (2) is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus, preferably, be sodium hydroxide and/or potassium hydroxide.
In embodiments of the invention, the preparation method of 6-provided by the invention fluoro-2-epoxy ethyl chroman, wherein, described in step (2), organic ester solvent is selected from ethyl formate, ethyl acetate or tert.-butyl acetate, preferably, is ethyl acetate.
The preparation method of nebivolol key intermediate of the present invention and 6-fluoro-2-epoxy ethyl chroman, has the advantages such as simple to operate, yield is high, product purity is high, is particularly suitable for suitability for industrialized production.
Embodiment
The present invention is further described below by specific embodiment.
Aldose reductase: purchased from Xi Bao bio tech ltd, Shanghai
NADPH: purchased from Sheng Ruitai Science and Technology Ltd. in Beijing
The chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone: be self-control, with reference to method preparation described in US Patent No. 7560575 embodiment 7.
Embodiment 1
(1) in 3L reaction flask, 32g potassium primary phosphate is added, 2kg water stirring and dissolving, with 2mol/LNaOH solution adjust ph to 7.0-7.4, add zinc chloride 40g successively again, ammonium formiate 40g, aldose reductase 200g, NADPH20g, (S) the chloro-1-of-2-(6-fluorine chroman-2-base) ethyl ketone 100g, by 2mol/L sodium hydroxide solution adjust ph to 7.0-7.4, in 55 DEG C ± 2 DEG C reactions about 12 hours, suction filtration, filter cake ethyl acetate 200ml washs, layering, water intaking uses ethyl acetate 200ml × 3 to wash mutually again, merge and organicly subtract each other pressure evaporate to dryness, obtain (S, S) the chloro-1-of-2-(6-fluorine chroman-2-base) alcohol 95 .6g, yield 94.8%, ee% > 99.5%,
(2) (the S of step (1) gained is got, S) the chloro-1-of-2-(6-fluorine chroman-2-base) ethanol 90g, ethanol 220g, sodium hydroxide 16.2g, add dry reaction bottle, be warming up to back flow reaction 4h, filter, mother liquor is evaporated under reduced pressure under <40 DEG C of condition, add ethyl acetate 300g to dissolve, drip 240g methyl tertiary butyl ether crystallization wherein, filter, dry (S, R)-6-fluoro-2-epoxy ethyl chroman 69.7g, yield 92%, HPLC purity 99.57%, ee% > 99.5%.
Embodiment 2
(1) in 3L reaction flask, 53g SODIUM PHOSPHATE, MONOBASIC is added, 4kg water stirring and dissolving, with 2mol/LNaOH solution adjust ph to 6.8-7.8, add zinc chloride 78g successively again, ammonium formiate 80g, aldose reductase 400g, NADPH42g, (S) the chloro-1-of-2-(6-fluorine chroman-2-base) ethyl ketone 100g, by 2mol/L sodium hydroxide solution adjust ph to 6.8-7.8, in 55 DEG C ± 2 DEG C reactions about 12 hours, suction filtration, filter cake ethyl acetate 400ml washs, layering, water intaking uses ethyl acetate 400ml × 3 to wash mutually again, merge and organicly subtract each other pressure evaporate to dryness, obtain (S, S) the chloro-1-of-2-(6-fluorine chroman-2-base) ethanol 93.8g, yield 93%, ee% > 99.5%,
(2) (the S of step (1) gained is got, S) the chloro-1-of-2-(6-fluorine chroman-2-base) ethanol 90g, methyl alcohol 230g, potassium hydroxide 22.7g, add dry reaction bottle, be warming up to back flow reaction 4h, filter, mother liquor is evaporated under reduced pressure under <40 DEG C of condition, add ethyl acetate 360g to dissolve, drip 240g methyl tertiary butyl ether crystallization wherein, filter, dry (S, R)-6-fluoro-2-epoxy ethyl chroman 70.1g, yield 92.5%, HPLC purity 99.65%, ee% > 99.5%.
Embodiment 3
(1) in 3L reaction flask, 60g potassium primary phosphate is added, 4kg water stirring and dissolving, with 2mol/LNaOH solution adjust ph to 6.8-7.8, add zinc chloride 78g successively again, ammonium formiate 80g, aldose reductase 400g, NADPH42g, (R) the chloro-1-of-2-(6-fluorine chroman-2-base) ethyl ketone 100g, by 2mol/L sodium hydroxide solution adjust ph to 6.0-8.0, in 55 DEG C ± 2 DEG C reaction 12-14 hour, suction filtration, filter cake ethyl acetate 400ml washs, layering, water intaking uses ethyl acetate 400ml × 3 to wash mutually again, merge and organicly subtract each other pressure evaporate to dryness, obtain (R, R) the chloro-1-of-2-(6-fluorine chroman-2-base) ethanol 92g, yield 91.2%, ee% > 99.5%,
(2) (the R of step (1) gained is got, R) the chloro-1-of-2-(6-fluorine chroman-2-base) ethanol 90g, Virahol 240g, potassium hydroxide 22.7g, add dry reaction bottle, be warming up to back flow reaction 4h, filter, mother liquor is evaporated under reduced pressure under <40 DEG C of condition, add ethyl acetate 360g to dissolve, drip 240g methyl tertiary butyl ether crystallization wherein, filter, dry (R, S)-6-fluoro-2-epoxy ethyl chroman 69.3g, yield 91.4%, HPLC purity 99.72%, ee% > 99.5%.
In embodiments of the invention, HPLC method determination and analysis method is:
Chromatographic column: CHIRALPAK, IC, 4.6 × 250mm, 5um
Moving phase: normal hexane-Virahol (95:5)
Column temperature: 30 degree
Flow velocity: 1.0ml/min
Wavelength: 210nm
Solvent: moving phase
Sample introduction concentration: 0.5mg/ml
Sample size: 20ul.
Claims (10)
1. a preparation method for nebivolol hydrochloric acid epoxy intermediate 6-fluoro-2-epoxy ethyl chroman, comprises the steps:
(1) under water, phosphoric acid salt, mineral alkali B1, zinc chloride, hydrogen source, aldose reductase, NADPH existent condition, temperature be 30-70 DEG C, under pH value is the condition of 6.0-8.0, the chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone generation reduction reaction, obtains the chloro-1-of 2-(6-fluorine chroman-2-base) ethanol;
(2) the chloro-1-of 2-(6-fluorine chroman-2-base) ethanol is warming up to back flow reaction in C1-C6 alkanol solvent and mineral alkali B2, reacts complete, through dripping organic ester solvent crystallization, obtains 6-fluoro-2-epoxy ethyl chroman.
2. the preparation method of nebivolol hydrochloric acid epoxy intermediate 6-fluoro-2-epoxy ethyl chroman, comprises the steps:
(1) in reaction vessel, water, phosphoric acid salt is added, by mineral alkali B1 adjust ph to 6.0-8.0, after add zinc chloride, hydrogen source, aldose reductase, the chloro-1-of NADPH, 2-(6-fluorine chroman-2-base) ethyl ketone successively, use mineral alkali B1 adjust ph to 6.0-8.0 again, 30-70 DEG C of reaction, obtain the chloro-1-of 2-(6-fluorine chroman-2-base) ethanol;
(2) chloro-for 2-1-(6-fluorine chroman-2-base) ethanol, C1-C6 alkanol solvent, mineral alkali B2 are added reaction system, be warming up to backflow, drip organic ester solvent crystallization, obtain 6-fluoro-2-epoxy ethyl chroman.
3. preparation method as claimed in claim 1 or 2, further, also be included in the mother liquor after step (2) crystallization and drip alkane solvents, preferably, for sherwood oil, normal hexane, hexanaphthene or methyl tertiary butyl ether, further crystallization, filters, obtains 6-fluoro-2-epoxy ethyl chroman.
4. preparation method as claimed in claim 1 or 2, wherein, described in step (1), phosphoric acid salt is selected from sodium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydrogen phosphate, potassium primary phosphate, dipotassium hydrogen phosphate, preferably, is SODIUM PHOSPHATE, MONOBASIC and/or potassium primary phosphate.
5. preparation method as claimed in claim 1 or 2, wherein, described in step (1), mineral alkali B1 is selected from potassium hydroxide, sodium hydroxide, sodium carbonate, salt of wormwood, ammoniacal liquor, is preferably sodium hydroxide and/or potassium hydroxide; Or
Described in step (2), mineral alkali B2 is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus, preferably, is sodium hydroxide and/or potassium hydroxide.
6. preparation method as claimed in claim 1 or 2, wherein, described in step (1), hydrogen source is selected from formic acid, ammonium formiate, preferably, is ammonium formiate.
7. preparation method as claimed in claim 1 or 2, wherein, in step (1), the weight ratio that water and phosphoric acid salt feed intake is 50-80:1, preferably, is 60-70:1.
8. preparation method as claimed in claim 1 or 2, wherein, in step (1), the mol ratio that zinc chloride and the chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone feed intake is 1:1.2-1.8, preferably, is 1:1.35-1.55.
9. preparation method as claimed in claim 1 or 2, wherein, in step (1), the mol ratio that hydrogen source and the chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone feed intake is 1.1-1.5:1, preferably, is 1.3-1.45:1.
10. preparation method as claimed in claim 1 or 2, wherein, the weight ratio that aldose reductase and the chloro-1-of 2-(6-fluorine chroman-2-base) ethyl ketone feed intake is 1.5-3.5:1, preferably, is 1.5-2.5:1;
Or,
The weight ratio that aldose reductase and NADPH feed intake is 8-15:1, preferably, is 8-12:1.
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Cited By (5)
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| WO2018024017A1 (en) * | 2016-08-04 | 2018-02-08 | 上海朴颐化学科技有限公司 | Preparation method for 6-fluoro-2-(epoxy-2-yl)chroman |
| CN108300743A (en) * | 2018-02-06 | 2018-07-20 | 江苏八巨药业有限公司 | The Biocatalysis method of one kind (R) -2- chloro- 1- (the fluoro- benzodihydropyran -2- bases of 6-) -1- ethyl alcohol |
| CN108314670A (en) * | 2018-02-06 | 2018-07-24 | 江苏八巨药业有限公司 | The preparation method of one kind (S) -2- chloro- 1- (the fluoro- 1- benzodihydropyrans -2- bases of 6-)-ethyl alcohol |
| CN110082451A (en) * | 2019-05-23 | 2019-08-02 | 南京趣酶生物科技有限公司 | A kind of SFC detection method of the chloro- 1- of 2- (the fluoro- chroman -2- of 6-) ethyl alcohol chirality alcohol intermediate preparation process |
| CN114150036A (en) * | 2021-12-23 | 2022-03-08 | 华东理工大学 | Continuous two-phase batch resolution process for preparing optically pure 6-fluoro-chroman-2-carboxylic acid |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018024017A1 (en) * | 2016-08-04 | 2018-02-08 | 上海朴颐化学科技有限公司 | Preparation method for 6-fluoro-2-(epoxy-2-yl)chroman |
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| CN108300743A (en) * | 2018-02-06 | 2018-07-20 | 江苏八巨药业有限公司 | The Biocatalysis method of one kind (R) -2- chloro- 1- (the fluoro- benzodihydropyran -2- bases of 6-) -1- ethyl alcohol |
| CN108314670A (en) * | 2018-02-06 | 2018-07-24 | 江苏八巨药业有限公司 | The preparation method of one kind (S) -2- chloro- 1- (the fluoro- 1- benzodihydropyrans -2- bases of 6-)-ethyl alcohol |
| CN110082451A (en) * | 2019-05-23 | 2019-08-02 | 南京趣酶生物科技有限公司 | A kind of SFC detection method of the chloro- 1- of 2- (the fluoro- chroman -2- of 6-) ethyl alcohol chirality alcohol intermediate preparation process |
| CN110082451B (en) * | 2019-05-23 | 2021-12-24 | 南京趣酶生物科技有限公司 | SFC detection method for preparation process of 2-chloro-1- (6-fluoro-chroman-2-) ethanol chiral alcohol intermediate |
| CN114150036A (en) * | 2021-12-23 | 2022-03-08 | 华东理工大学 | Continuous two-phase batch resolution process for preparing optically pure 6-fluoro-chroman-2-carboxylic acid |
| CN114150036B (en) * | 2021-12-23 | 2024-01-09 | 华东理工大学 | Continuous biphasic batch resolution process for preparing optically pure 6-fluoro-chroman-2-carboxylic acid |
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Address after: Concentrated area center area 638400 wusheng County of Guang'an city of industry of Sichuan Province Applicant after: Guang'an Kate Pharmaceutical Co., Ltd. Address before: Concentrated area center area 638400 wusheng County of Guang'an city of industry of Sichuan Province Applicant before: Guang'an Kingday Pharm & Chemical Co., Ltd. |
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Application publication date: 20160420 |