CN102190647A - Preparation method of nebivolol intermediate - Google Patents
Preparation method of nebivolol intermediate Download PDFInfo
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- CN102190647A CN102190647A CN2010101348907A CN201010134890A CN102190647A CN 102190647 A CN102190647 A CN 102190647A CN 2010101348907 A CN2010101348907 A CN 2010101348907A CN 201010134890 A CN201010134890 A CN 201010134890A CN 102190647 A CN102190647 A CN 102190647A
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Abstract
The invention provides a preparation method of a nebivolol intermediate (6-fluoro-3,4-dihydro-2H-benzopyran-2-yl)hypnone halide, which comprises the following steps: reacting a compound 6-fluoro-chroman-2-carboxylate disclosed as Formula (II) and a compound halomethane disclosed as Formula (III) under alkaline conditions in an organic solvent at low temperature, and carrying out after-treatment to obtain the (6-fluoro-3,4-dihydro-2H-benzopyran-2-yl)hypnone halide disclosed as Formula (IV). By synthesizing the (6-fluoro-3,4-dihydro-2H-benzopyran-2-yl)hypnone halide from chromancarboxylic acid by two steps, the invention has the advantages of simple technique and high yield.
Description
Technical field
The present invention relates to a kind of nebivolol intermediates preparation, be specifically related to the preparation method of a kind of Nebivolol Intermediates (6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides.
Background technology
Nebivolol hydrochloric acid (nebivolol hydrochloride), chemistry α by name, α '-[two (methylene radical) two (6-fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-methanols) of imines] hydrochloride is by U.S. Johnson﹠amp; The research and development of Johnson company, be used for the treatment of essential hypertension, commercial tablets name Nebilet first in Germany and Holland's listing in 1997, this product is the heart selectivity beta-blocker that has vasorelaxation action concurrently, and evident in efficacy, easy administration, untoward reaction are little.The nebivolol structural formula has four chiral carbon atoms, has 10 isomer, wherein (S, R, R R) has good acceptor retardation capability, and another configuration (R, S, S is not though isomer S) has pharmaceutical activity for the release of control NO effect preferably to be arranged but.Therefore, in the present streat drug, remain racemic modification.
U.S. Johnson﹠amp; Johnson company has reported that the earliest (EP0145067, US4654362), they are key intermediate with benzo tetrahydropyrans epoxy construction, through the nebivolol of polystep reaction synthesising racemation for the synthetic method of racemization nebivolol.EP0334429, US6545040 have reported that also similar synthetic method comes synthesizing optical pure (S, R, R, R) nebivolol.WO2004/041805, WO2008010022 disclose the different synthetic method of nebivolol in succession, and wherein the route of WO2008010022 will pass through intermediate (IV) and then synthesizing optical pure (S, R, R, R) nebivolol and racemization (S, R, R, R) and (R, S, S, S) nebivolol.
About synthesizing of the important intermediate formula compound (IV) in the nebivolol building-up process, patent (WO2008010022 A2) discloses several preparation methods:
Method 1. prepares beta-keto acid diester (V) earlier from chroman acid (I), and decarboxylation obtains (VI) then, and halo obtains intermediate (IV) again, altogether three steps.
Method 2. prepares beta-keto acid diester (V) earlier from chroman acid (I), and alcoholysis obtains beta-ketoester (VIII) then, and halo obtains halogenated beta-ketoester (VIII) again, and decarboxylation obtains intermediate (IV) more at last, altogether four steps.
This method exists in preparation process in needed route long (wanting for three steps at least), the reaction process and is easy to generate by product, causes the separation and purification difficulty, and shortcoming such as substep yield and total recovery be low.
Tetrahedron Letters 1997, (38), 3185 disclose this technology exists following defective 1. the mole dosage of dihalo methane and highly basic (n-Butyl Lithium) is bigger than very, be respectively 1: 4 and 1: 5, and the mol ratio of the two all only needs 1: 1.4 all 2. aftertreatment is pretty troublesome and uneconomical among the present invention, and the present invention only needs get final product with aqueous ammonium chloride solution
Chimia 1996, (50), exist step many in the synthetic method of 532 reports, need a lot of auxiliary reagents (some auxiliary reagent even also need other preparation), and there is a large amount of by products to generate, defective that productive rate is lower or the like, and route of the present invention is shorter, control easily and also the auxiliary reagent that uses seldom.
Summary of the invention
At above technological deficiency, the invention provides a kind of new preparation nebivolol intermediate (R)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides, (S)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) method of ethyl ketone halides or (±)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides.
The method of the invention comprises the steps:
A) formula (I) compound (S)-chroman acid, the acid of (R)-chroman or the acid of (±)-chroman are at acid or SOCl
2Effect is carried out esterification with alcohol respectively down, obtains formula (II) compound (S)-6-fluoro-chroman-2-acetic ester, (R)-6-fluoro-chroman-2-acetic ester or (±)-6-fluoro-chroman-2-acetic ester;
B) formula (II) compound (S)-6-fluoro-chroman-2-acetic ester, (R)-6-fluoro-chroman-2-acetic ester or (R, S)-6-fluoro-chroman-2-acetic ester, under the alkali effect, in organic solvent, react with formula (III) compound respectively, obtain formula (IV) compound (R)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides, (S)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides or (±)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides;
Wherein, R is C
1-C
4Alkyl, preferable methyl, ethyl, sec.-propyl, the tertiary butyl; X
1For Br or iodine, be preferably Br; X
2For bromine or chlorine, be preferably chlorine.
In the inventive method, alcohol is C described in the step a)
1-C
4Alkanol, be preferably methyl alcohol, ethanol, Virahol or the trimethyl carbinol.
As embodiment preferred, the temperature of reaction of esterification is-15-25 ℃ in the step a), is preferably 0 ℃; Reaction times is 0.5-5 hour, is preferably 1.5 hours.
Acid in the described step a) is for including but not limited to hydrochloric acid or sulfuric acid, and wherein, the consumption of acid is the 1%-10% of formula compound (I) quality.
In the inventive method, the organic solvent in the described step b) is toluene, dimethylbenzene, normal hexane, hexanaphthene, DMF, acetonitrile, ether, methyl tertiary butyl ether, dioxane or tetrahydrofuran (THF), or they make up arbitrarily; Preferred tetrahydrofuran (THF); The consumption of described organic solvent calculates by every 1g formula compound (II) and is generally 1～10ml, is preferably 2ml.
In the inventive method, the alkali described in the step b) is n-Butyl Lithium, diisopropylamine lithium (LDA), hexamethyl two silica-based amido lithiums (LiHDMS), sodium amide; Be preferably n-Butyl Lithium.The molar ratio of alkali described in the step b) and formula compound (II) is 1: 1～10, preferably selects 1: 1.4.
The molar ratio of (II) compound of formula described in the step b) and formula (III) compound is 1: 1～10, is preferably 1: 1.4; The temperature of reaction that step b) Chinese style (II) compound and formula (III) compound react is 0-100 ℃, is preferably-78 ℃.
The inventive method can be prepared (R)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides formula (IV) compound, (S)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides, or (±)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides.
In the inventive method, the reacted reaction product of step a) or step b) can adopt the purification process of this area routine to carry out aftertreatment.
Among the present invention as one of preferred implementation, wherein the reacted mixture of reaction products of step a) preferably adopts following method to carry out aftertreatment: i.e. formula (I) compound (S)-chroman acid, (R)-reaction mixture concentrating under reduced pressure that chroman acid or the acid of (±)-chroman and alcohol carry out after the esterification removes excessive organic solvent, transfer to after elder generation's adding 80ml ethyl acetate then and add 50ml frozen water and 10ml saturated aqueous common salt in the separating funnel again, and then with 10ml * 3 ethyl acetate extractions, merge the ester layer with 15ml * 4 saturated common salt water washings, after using anhydrous magnesium sulfate drying (spending the night) to concentrate then oily matter 41.5g.
Wherein the reacted mixture of reaction products of step b) preferably adopts following method to carry out aftertreatment: with formula (II) compound (S)-6-fluoro-chroman-2-acetic ester, (R)-6-fluoro-chroman-2-acetic ester or (±)-6-fluoro-chroman-2-acetic ester, carry out reacted reaction mixture earlier with 80ml saturated ammonium chloride solution cancellation reaction PH=7-8 with formula (III) compound halomethane, concentrating under reduced pressure is removed organic solvent then, with 40ml * 3 ethyl acetate extractions, merge the 15ml * 2 saturated common salt water washing of ester layer, anhydrous sodium sulfate drying.The filtration rear filtrate is 40 ℃ in temperature and concentrates absolutely dry, adding the 10ml dehydrated alcohol then, to put into refrigerator freezing, selectively add crystal seed (wherein enlarge do not need to add crystal seed after the charging capacity just can direct freezing crystallization) after half an hour, just there is crystal to separate out after 10 minutes, obtain crystal Deng the sufficient crystallising after-filtration
The present invention has that reactions steps is few, easy to operate, by product is few, the productive rate advantages of higher.
Embodiment
The present invention will be further described below in conjunction with concrete embodiment, but protection scope of the present invention is not limited to this.
Synthesizing of embodiment 1 (R) 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone
Take by weighing (R)-6-fluoro-3; 4-dihydro-2H-chromene-2-methyl-formiate (II) 17.3g is added in the there-necked flask of 250ml; add the bromochloromethane (III) that 14.8g heavily steams; and then add the tetrahydrofuran (THF) that 30ml handled; stir and use argon shield; measure that the 46ml n-Butyl Lithium joins in the dropping funnel of 50ml and begin slow dropping during for-78 ℃, and controlled temperature added less than-75 ℃ in about 3 hours in temperature.After dripping again temperature less than-75 ℃ of conditions under the reaction 1.5 hours.
Aftertreatment: earlier with 80ml saturated ammonium chloride solution cancellation reaction PH=7-8, THF is removed in decompression when 40 ℃ of temperature then, with 40ml * 3 ethyl acetate extractions, merges the ester layer with 15ml * 2 saturated common salt water washings, anhydrous sodium sulfate drying.Filtering rear filtrate concentrates when temperature is 40 ℃ and absolutely dryly adds the 10ml dehydrated alcohol then to put into refrigerator freezing, add crystal seed (wherein enlarge do not need to add crystal seed after the charging capacity just can direct freezing crystallization) after half an hour, just there is crystal to separate out after 10 minutes, obtain the 8.6g crystal Deng the sufficient crystallising after-filtration, the concentrated mother liquor crystallization that uses the same method again obtains the 2.6g crystal, yield 60%.
1HNMR(300MHz，CDCl
3)：δ2.15-2.40(m，2H)，2.50-2.60(dd，2H)，4.54(s，2H，)，4.55(dd，1H，CH)，6.68(d，1H)，6.70-6.72(d，2H)
Synthesizing of embodiment 2 (S) 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone
Take by weighing (S)-6-fluoro-3; 4-dihydro-2H-chromene-2-ethyl formate (II) 18.45g is added in the there-necked flask of 250ml; add the iodine methyl chloride (III) that 20.28g heavily steams; and then adding 30ml crosses the toluene of handling; stir and use argon shield; measure that 57.5ml LDA (2.0M tetrahydrofuran solution) joins in the dropping funnel of 100ml and begin slow dropping during for-78 ℃, and controlled temperature added less than-75 ℃ in about 3 hours in temperature.After dripping again temperature less than-75 ℃ of conditions under the reaction 1.5 hours.
Aftertreatment: PH=7-8 reacts with the cancellation of 80ml saturated ammonium chloride solution in elder generation, and concentrating under reduced pressure is removed toluene then, with 40ml * 3 ethyl acetate extractions, merges the 15ml * 2 saturated common salt water washing of ester layer, anhydrous sodium sulfate drying.Filtering rear filtrate is 40 ℃ in temperature and concentrates and absolutely dryly add the 10ml dehydrated alcohol then to put into refrigerator freezing, add crystal seed after half an hour, just have crystal to separate out after 10 minutes, wait the sufficient crystallising after-filtration to obtain the 8.4g crystal, the concentrated mother liquor crystallization that uses the same method again obtains the 2.5g crystal, yield 58%.
1HNMR(300MHz，CDCl
3)：δ2.15-2.40(m，2H)，2.50-2.60(dd，2H)，4.54(s，2H，)，4.55(dd，1H，CH)，6.68(d，1H)，6.70-6.72(d，2H)
Synthesizing of embodiment 3 (±) 2-bromo-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone
Take by weighing (±)-6-fluoro-3; 4-dihydro-2H-chromene-2-isopropyl formate (II) 19.6g is added in the there-necked flask of 250ml; add the methylene bromide (III) that 14.8g heavily steams; and then adding 30ml crosses the normal hexane of handling; stir and use argon shield; measure that 115ml LiHDMS (1.0M tetrahydrofuran solution) joins in the dropping funnel and begin slow dropping during for-78 ℃, and controlled temperature T＜-75 ℃ about 3 hours add in temperature.After dripping again temperature less than-75 ℃ of conditions under the reaction 1.5 hours.
Aftertreatment: PH=7-8 reacts with the cancellation of 80ml saturated ammonium chloride solution in elder generation, and concentrating under reduced pressure is removed normal hexane then, with 40ml * 3 ethyl acetate extractions, merges the 15ml * 2 saturated common salt water washing of ester layer, anhydrous sodium sulfate drying.Filter rear filtrate and concentrate absolutely dryly at 40 ℃ down, adding the 10ml dehydrated alcohol then, to put into refrigerator freezing, adds crystal seed after half an hour, just there is crystal to separate out after 10 minutes, obtain the 8.5g crystal Deng the sufficient crystallising after-filtration, the concentrated mother liquor crystallization that uses the same method again obtains the 2.2g crystal, yield 56.9%.
1HNMR(300MHz，CDCl
3)：δ2.15-2.40(m，2H)，2.50-2.60(dd，2H)，4.54(s，2H，)，4.55(dd，1H，CH)，6.68(d，1H)，6.70-6.72(d，2H)
Synthesizing of embodiment 4 (±) 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone
Take by weighing (±)-6-fluoro-3,4-dihydro-2H-chromene-2-t-butyl formate (II) 20.76g is added in the there-necked flask of 250ml, adds the methylene dichloride (III) that 19.9g heavily steams, and then adding 30ml crosses the methyl tertiary butyl ether of handling, lower the temperature to system with dry ice acetone, measure 4.5gNaNH
2Begin slow adding (making secondary solvent) in temperature for-78 ℃ the time, and controlled temperature added less than-75 ℃ in about 3 hours with tetrahydrofuran (THF).After dripping again temperature less than-75 ℃ of conditions under the reaction 1.5 hours.
Aftertreatment: PH=7-8 reacts with the cancellation of 80ml saturated ammonium chloride solution in elder generation, and concentrating under reduced pressure is removed methyl tertiary butyl ether then, with 40ml * 3 ethyl acetate extractions, merges the 15ml * 2 saturated common salt water washing of ester layer, anhydrous sodium sulfate drying.Filtering rear filtrate is 40 ℃ in temperature and concentrates down and absolutely dryly add the 10ml dehydrated alcohol then to put into refrigerator freezing, add crystal seed after half an hour, just there is crystal to separate out after 10 minutes, obtain the 8.3g crystal Deng the sufficient crystallising after-filtration, the concentrated mother liquor crystallization that uses the same method again obtains the 2.5g crystal, yield 57.4%.
1HNMR(300MHz，CDCl
3)：δ2.15-2.40(m，2H)，2.50-2.60(dd，2H)，4.54(s，2H，)，4.55(dd，1H，CH)，6.68(d，1H)，6.70-6.72(d，2H)
Embodiment 5 (±) 6-fluoro-3,4-dihydro-2H-chromene-2-methyl-formiate synthetic
Take by weighing (±)-6-fluoro-3,4-dihydro-2H-chromene-2-formic acid (I) 39.2g (0.2mol) joins in the there-necked flask of 250ml, adds 60ml methyl alcohol and stirs, fully dissolving, take by weighing then that the 1g concentrated hydrochloric acid adds and more than the backflow 5h, complete up to the TLC detection reaction.Concentrating under reduced pressure removes excessive methyl alcohol under 45 ℃ of conditions, transfer to after the adding 80ml ethyl acetate earlier and add 50ml frozen water and 10ml saturated aqueous common salt in the separating funnel again, and then with 10ml * 3 ethyl acetate extractions, merge the ester layer with 15ml * 4 saturated common salt water washings, after using anhydrous magnesium sulfate drying (spending the night) to concentrate then oily matter 41.5g.
1HNMR(300MHz，CDCl
3)：δ2.27-2.50(m，2H)，2.50-2.60(dd，2H)，3.67(s，3H)，4.52(dd，1H，CH)，6.68(d，1H)，6.70-6.72(d，2H)
Embodiment 6 (R)-6-fluoro-3,4-dihydro-2H-chromene-2-ethyl formate synthetic
Take by weighing (R)-6-fluoro-3,4-dihydro-2H-chromene-2-formic acid (I) 39.2g (0.2mol) joins in the there-necked flask of 250ml, adds 60ml ethanol and stirs, and dissolving fully places system cryosel to bathe cooling then, takes by weighing 28.6g SOCl
2Join in the dropping funnel of 50ml, connect device for absorbing tail gas, when temperature begins to drip SOCl less than-14 ℃
2, it is too fast that the control rate of addition prevents that temperature from raising, and temperature control is less than-10 ℃, and 2h adds, low temperature stirring reaction then, cryosel is bathed and is warmed up to-8 ℃ behind the 2.5h, is warmed up to 10 ℃ then and stirs 1.5h, and concentrating under reduced pressure removes excess ethanol and SOCl under 45 ℃ of conditions
2Transfer to after the adding 80ml ethyl acetate earlier and add 50ml frozen water and 10ml saturated aqueous common salt in the separating funnel again, and then with 10ml * 4 ethyl acetate extractions, merge the ester layer with 15ml * 4 saturated common salt water washings, after using anhydrous magnesium sulfate drying (spending the night) to concentrate then oily matter 44.8g.
1HNMR(300MHz，CDCl
3)：δ1.30(dd，3H)，2.27-2.50(m，2H)，2.50-2.60(dd，2H)，3.67(s，3H)，4.12(m，2H)，4.52(dd，1H，CH)，6.68(d，1H)，6.70-6.72(d，2H)
Embodiment 7 (S)-6-fluoro-3,4-dihydro-2H-chromene-2-isopropyl formate synthetic
Take by weighing (S)-6-fluoro-3,4-dihydro-2H-chromene-2-formic acid (I) 39.2g (0.2mol) joins in the there-necked flask of 250ml, adding the 60ml Virahol stirs, dissolving fully, then system is placed oil bath, taking by weighing the 0.4g vitriol oil adds, heating allows more than its backflow 5h, complete up to the TLC detection reaction, concentrating under reduced pressure removes excessive Virahol under 45 ℃ of conditions, add earlier to transfer to after the 80ml ethyl acetate to add 50ml frozen water and 10ml saturated aqueous common salt in the separating funnel again, and then with 10ml * 4 ethyl acetate extractions, merge the ester layer with 15ml * 4 saturated common salt water washings, after using anhydrous magnesium sulfate drying (spending the night) to concentrate then oily matter 47g.
1HNMR(300MHz，CDCl
3)：δ1.35(d，6H)，2.27-2.50(m，2H)，2.50-2.60(dd，2H)，3.67(s，3H)，4.31(m，H)，4.52(dd，1H，CH)，6.68(d，1H)，6.70-6.72(d，2H)。
Claims (12)
1. the preparation method of a Nebivolol Intermediates 1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides is characterized in that described method comprises the steps:
A) formula (I) compound (S)-chroman acid, the acid of (R)-chroman or the acid of (±)-chroman are at acid or SOCl
2Effect is carried out esterification with alcohol respectively down, obtains formula (II) compound (S)-6-fluoro-chroman-2-acetic ester, (R)-6-fluoro-chroman-2-acetic ester or (±)-6-fluoro-chroman-2-acetic ester;
B) formula (II) compound (S)-6-fluoro-chroman-2-acetic ester, (R)-6-fluoro-chroman-2-acetic ester or (±)-6-fluoro-chroman-2-acetic ester, under the alkali effect, in organic solvent, react with formula (III) compound halomethane respectively, obtain formula (IV) compound (R)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides, (S)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides or (±)-1-(6-fluoro-3,4-dihydro-2H-chromene-2-yl) ethyl ketone halides;
Wherein, R is C
1-C
4Alkyl, preferable methyl, ethyl, sec.-propyl, the tertiary butyl; X
1For Br or iodine, be preferably Br; X
2For bromine or chlorine, be preferably chlorine.
2. preparation method according to claim 1 is characterized in that, alcohol is C described in the step a)
1-C
4Alkanol, be preferably methyl alcohol, ethanol, Virahol or the trimethyl carbinol.
3. preparation method according to claim 2 is characterized in that, described method comprises: the temperature of reaction of esterification is-15 ℃-25 ℃ in the step a), is preferably 0 ℃; Reaction times is 0.5-5 hour, is preferably 1.5 hours.
4. preparation method according to claim 3 is characterized in that, the acid in the described step a) is hydrochloric acid or sulfuric acid, and wherein, the consumption of acid is the 1%-10% of formula compound (I) quality.
5. preparation method according to claim 4 is characterized in that, the organic solvent described in the step b) is toluene, dimethylbenzene, normal hexane, hexanaphthene, DMF, acetonitrile, ether, methyl tertiary butyl ether, dioxane or tetrahydrofuran (THF); Preferred tetrahydrofuran (THF).
6. preparation method according to claim 5 is characterized in that, the consumption of organic solvent described in the step b) is calculated as 1～10ml by every 1g formula compound (II), preferentially elects 2ml as.
7. preparation method according to claim 6 is characterized in that, the alkali described in the step b) is n-Butyl Lithium, diisopropylamine lithium, hexamethyl two silica-based amido lithiums, sodium amide; Be preferably n-Butyl Lithium.
8. preparation method according to claim 7 is characterized in that, the molar ratio of alkali described in the step b) and formula compound (II) is 1: 1～10, preferably selects 1: 1.4.
9. preparation method according to claim 8 is characterized in that, the molar ratio of (II) compound of formula described in the step b) and formula (III) compound is 1: 1～10, preferred 1: 1.4.
10. require 9 described preparation methods according to profit, it is characterized in that, described method comprises that the temperature of reaction that step b) Chinese style (II) compound and formula (III) compound react is 0 ℃～-100 ℃, is preferably-78 ℃.
11. according to the described preparation method of claim 1-10, it is characterized in that, described method steps also comprises post-processing step in a): formula (I) compound (S)-chroman acid, (R)-reaction mixture concentrating under reduced pressure that chroman acid or the acid of (±)-chroman and alcohol carry out after the esterification removes excessive organic solvent, transfer to after elder generation's adding 80ml ethyl acetate then and add 50ml frozen water and 10ml saturated aqueous common salt in the separating funnel again, and then with 10ml * 3 ethyl acetate extractions, merge the ester layer with 15ml * 4 saturated common salt water washings, after using anhydrous magnesium sulfate drying (spending the night) to concentrate then oily matter 41.5g.
12. preparation method according to claim 11, it is characterized in that, described method steps b) also comprises post-processing step in: with formula (II) compound (S)-6-fluoro-chroman-2-acetic ester, (R)-6-fluoro-chroman-2-acetic ester or (±)-6-fluoro-chroman-2-acetic ester, carry out reacted reaction mixture earlier with 80ml saturated ammonium chloride solution cancellation reaction PH=7-8 with formula (III) compound halomethane, concentrating under reduced pressure is removed organic solvent then, with 40ml * 3 ethyl acetate extractions, merge the 15ml * 2 saturated common salt water washing of ester layer, anhydrous sodium sulfate drying.Filter rear filtrate and be 40 ℃ in temperature and concentrate absolutely dryly that adding the 10ml dehydrated alcohol then, to put into refrigerator freezing, selectively adds crystal seed after half an hour, has crystal to separate out after 10 minutes, waits the sufficient crystallising after-filtration to obtain the 8.4g crystal.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104016954A (en) * | 2014-06-06 | 2014-09-03 | 常州市第四制药厂有限公司 | Method for preparing and purifying nebivolol intermediate |
| CN105198848A (en) * | 2014-06-12 | 2015-12-30 | 常州市第四制药厂有限公司 | Nebivolol intermediate crystal and preparing method thereof |
| ITUB20160227A1 (en) * | 2016-01-21 | 2017-07-21 | Menarini Int Operations Luxembourg Sa | Process for the synthesis of Nebivolol intermediates |
| CN108997297A (en) * | 2018-07-17 | 2018-12-14 | 浙江海翔药业股份有限公司 | A kind of preparation method of Nebivolol Intermediates, the intermediate for being used to prepare the Nebivolol Intermediates and preparation method thereof |
| CN109160911A (en) * | 2018-10-30 | 2019-01-08 | 雅本化学股份有限公司 | A kind of preparation method of nebivolol |
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