CN102311417B - Method for preparing benzodihydropyran compound - Google Patents

Abstract

The invention provides a method for preparing 1-(6-fluorine benzopyranyl) ethane-1,2-diol. In the preparation method, 5-fluorine-2-hydroxyacetophenone and glyceraldehyde acetonide are mainly used as raw materials, and reduction, cyclization, hydrogenation and propylidene protective group removal are carried out on a compound as shown in a formula II in the reaction. The method provided by the invention has the advantages of short whole reaction processes, mild reaction conditions, high yield, simple after-treatment such as purification and the like, and cheap and available raw materials.

Description

A kind of preparation method of chroman compounds

Technical field

The present invention relates to a kind of preparation method of medicine intermediate, particularly the preparation method of Nebivolol Intermediates chroman compounds.

Technical background

Nebivolol (Nebivolol) is a kind of medicine that hypertension is had important curative effect, and the synthesising process research of nebivolol is the field of comparison hot topic always.In the patent of disclosed all kinds of synthesis techniques, document, much adopted the key intermediate chroman compounds shown in the formula I compound to synthesize.But at formula I compound: 1-(6-fluorobenzene and pyranyl) ethane-1,2-glycol synthetic, the prior art synthetic compound of formula i generally is following four kinds of methods.

Synthesis technique one [S.Chandmsekhar, M.Venkat Reddy, Tetrahedron, 56 (2000) 6339-6344]:

(a) allybromide, K ₂CO ₃(83%); (b) (i) heating, 210 ℃ (76%), (ii) TBDMSCl, imidazoles (84%); (c) BH ₃.Me ₂S.H ₂O ₂.OH ^-(75%); (d) Dai Si-Martin's oxygenant, PPh ₃=CH-COOEt (72%); (e) (i) DIBAL (78%), (ii) the THF solution (80%) of TBAF; (f) (-)-DET, titanium isopropylate, TBHP ,-20 ℃, NaOH (65%)

Synthesis technique two [CN101553485A]:

Synthesis technique three [WO2006083779A2]:

More than three operational paths, synthesis step is many, need use poisonous and hazardous compound, and is big for environment pollution, and yield is lower.

Many in order to improve prior art synthesis technique step, shortcoming such as yield is low, it is the method for feedstock production formula I compound with 5-fluoro-2-hydroxy acetophenone and glyceraldehyde acetonide that people such as Wang Naixing [CN1978442A] have researched and developed a kind of.

The applicant repeats its experiment according to its specific embodiment.Discovery is under corresponding reaction conditions, can not obtain its described (2R)-2-[(1R)-4,4-dimethyl-3, the assorted oxygen cyclopentyl of 5-two]-6-fluorobenzene and dihydropyrane-4-ketone (compound 5a in this application) and (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone (compound 5b in this application); And partial switching takes place in the chiral centre of Glycerose in reaction process, generate four non-corresponding isomer, rather than two of describing in this application, therefore by this application disclosed method, what the post separation obtained is not some optically pure isomer, but the corresponding isomer of a pair of optics can't go out nebivolol by its follow-up prepared.And in this application, prepare compound 4a[(R by compound 5a/5b)-1-((R)-6-fluorobenzene and pyranyl) ethane-1, the 2-glycol]/4b[(S)-1-((R)-6-fluorobenzene and pyranyl) ethane-1,2-glycol], both to become to need in the reaction of methylene radical to adopt zinc amalgam be reductive agent to carbonyl reduction, zinc amalgam has than high toxicity, not only is easy to cause environmental pollution, and is not easy to industrialized production.

Summary of the invention

For solve prior art Chinese style I compound synthetic step length, severe reaction conditions, yield is low, cost is high, shortcoming such as big for environment pollution, the invention provides a kind of preparation method of new formula I compound.

One aspect of the present invention provides a kind of method of preparation I compound, and concrete steps are as follows:

1) 5-fluoro-2-hydroxy acetophenone and glyceraldehyde acetonide react formula II compound;

2) formula II compound gets the formula III compound after reduction;

3) cyclisation of formula III compound gets formula IV compound;

4) formula IV compound gets formula V compound through hydrogenation;

5) formula V compound takes off the propylidene protecting group and gets formula I compound.

When wherein glyceraldehyde acetonide was the D-glyceraldehyde acetonide, the preparation method was as follows:

When wherein glyceraldehyde acetonide was the L-glyceraldehyde acetonide, the preparation method was as follows:

The preparation method of described formula II compound is preferably 5-fluoro-2-hydroxy acetophenone and reacts with glyceraldehyde acetonide under the highly basic condition, after reacting completely, transfers pH to slightly acidic with acid, and desolventizing is carried out recrystallization and got formula II compound; Described highly basic is preferably potassium tert.-butoxide, sodium tert-butoxide, sodium hydride, LDA, more preferably potassium tert.-butoxide.

The preparation method of described formula III compound be preferably with formula II compound in the reduction reaction system, be reduced the formula III compound; Described reduction system is preferably sodium borohydride/ethanol, zinc/hydrochloric acid, zinc/acetic acid, Pd-C/H ₂, Raney Ni, lithium aluminum hydride, sodium borohydride/boron trifluoride or ether triethyl silicane/boron trifluoride diethyl etherate, more preferably sodium borohydride/ethanol.

The preparation method of described formula IV compound is preferably the formula III compound is got formula IV compound through cyclization, described reaction system is preferably trifluoroacetic anhydride/triethylamine/carbonate, trifluoroacetic anhydride/carbonate, trifluoroacetic anhydride/supercarbonate, DMF-DMA/DMF or oxalyl chloride/N, dinethylformamide/methylene dichloride; Trifluoroacetic anhydride/triethylamine/carbonate more preferably.

It is formula V compound through reduction system reducing that the preparation method of described formula I compound is preferably formula IV compound, and hydrolysis gets formula I compound under acidic conditions then; Described reduction system is preferably Pd-C/H ₂, Raney Ni, silicane reductive agent or borine, more preferably Pd-C/H ₂Described silicane reductive agent is triethyl silicane, poly-methyl polysiloxane.

The preparation method of described formula I compound also is preferably the hydrolysis of formula IV compound elder generation, is reduced to formula I compound again, or reduction and hydrolysis are carried out simultaneously.

The present invention compared with prior art, its advantage is:

1. aftertreatments such as reactions steps is short, reaction conditions is gentle, yield is high, purifying are simple.

2. each step reaction safety and environmental protection does not relate to toxicity is big, pollution is bigger solvent or reagent, and pollution-free bigger waste gas, waste liquid, waste residue produce.

3. respectively go on foot the reaction conditions gentleness, no high temperature, low temperature, high pressure and the strict water of avoiding are avoided the oxygen reaction;

4. raw materials used cheap and easy to get, main raw material 5-fluoro-2-hydroxyl-methyl phenyl ketone and D-glyceraldehyde acetonide all can directly have been bought from the market, and be cheap.

Embodiment

Following examples will be further elaborated the present invention, but be not to further restriction of the present invention.

Embodiment one

1, formula IIa compound is synthetic

1.1 (80g 0.519mol) is dissolved in the tetrahydrofuran (THF) of 1000 milliliters of dryings, 0 ℃ of cooling of ice-water bath with 5-fluoro-2-hydroxy acetophenone, add potassium tert.-butoxide (66.55g under the vigorous stirring, 0.545mol), vigorous stirring added the dichloromethane solution (w/w=0.432 of D-glyceraldehyde acetonide after 30 minutes, 234.5g, 0.779mol), 0 ℃ is stirred after 3.5 hours, drips concentrated hydrochloric acid, adjust pH value to 6, revolve the steaming desolventizing.Add ethyl acetate (1200mL) and water (500mL) in the resistates, separate organic phase, water, saturated common salt water washing, anhydrous sodium sulfate drying, be spin-dried for yellow solid, get yellow powder powder crystal (52g, 35%) with the dehydrated alcohol recrystallization.

1.2 (10g 0.065mol) is dissolved in the tetrahydrofuran (THF) of 100 milliliters of dryings, 0 ℃ of cooling of ice-water bath with 5-fluoro-2-hydroxy acetophenone, add sodium tert-butoxide (6.235g under the vigorous stirring, 0.065mol), vigorous stirring added the dichloromethane solution (w/w=0.432 of D-glyceraldehyde acetonide after 30 minutes, 29.37g, 0.098mol), 0 ℃ is stirred after 6 hours, drips concentrated hydrochloric acid, adjust pH value to 6, revolve the steaming desolventizing.Add ethyl acetate (120mL) and water (50mL) in the resistates, separate organic phase, water, saturated common salt water washing, anhydrous sodium sulfate drying, be spin-dried for yellow solid, get yellow powder powder crystal (5.52g, 30%) with the dehydrated alcohol recrystallization.

1.3 with reference to embodiment 1.2, alkali wherein is sodium hydride, reaction yield is 37%.

2, formula III a compound is synthetic

2.1 with formula IIa compound (52g, 0.183mol) be suspended in the 300mL dehydrated alcohol, (4.15g 0.110mol) is dissolved in the 200mL dehydrated alcohol, is added drop-wise in the reaction flask under 0 ℃ of cooling with sodium borohydride, 0 ℃ was stirred after 4 hours, revolve the steaming desolventizing, resistates is dissolved in the 1000mL ethyl acetate, after 5% hydrochloric acid, water and saturated common salt water washing, dry concentrate water white transparency oily thing (52.47g, 100%).

2.2 with reference to embodiment 2.1, reduction system can be sodium borohydride/ethanol, zinc/hydrochloric acid, zinc/acetic acid, Pd-C/H in the reaction ₂, Raney Ni, lithium aluminum hydride, sodium borohydride/boron trifluoride or ether triethyl silicane/boron trifluoride diethyl etherate.

Wherein reduction system is zinc/hydrochloric acid, yield 85%; Pd-C/H ₂, yield 72%; Raney Ni, yield 90%.

3, formula IVa compound is synthetic

3.1 (52.47g 0.183mol) is dissolved in 500mL acetone, adds triethylamine (255.6mL with formula III a compound, 1.83mol), 0 ℃ drip trifluoroacetic anhydride (127.4mL, 0.916mol), 0 ℃ of reaction is after about 4 hours, and stopped reaction revolves the steaming desolventizing, resistates adds the 1000mL ethyl acetate, after water, the saturated common salt water washing, dry concentrate crude product (44g, 96%), crude product can directly drop into the next step, or column chromatography is refining.

3.2 (6g 0.021mol) is dissolved in 30mL N, and dinethylformamide adds N under the room temperature, and (8.38mL 0.063mol), is warming up to 90 ℃ to the dinethylformamide dimethylacetal, and stirring is spent the night with formula III a compound.Reaction solution is cooled to room temperature, adds the 150mL ethyl acetate, after water, the saturated common salt water washing, dry concentrate the dark oil thing, rapid column chromatography (ethyl acetate/petroleum ether=1: 10) can get the optical isomer intermixture (2.1g, 40%) of formula IVa compound.

3.3 with reference to embodiment 3.2, wherein reaction system can also be trifluoroacetic anhydride/carbonate, trifluoroacetic anhydride/supercarbonate, oxalyl chloride/N, dinethylformamide/methylene dichloride, and wherein reaction system is trifluoroacetic anhydride/salt of wormwood, yield is 67%; Trifluoroacetic anhydride/sodium bicarbonate, yield are 34%.

4, formula I-SR/RR compound is synthetic

4.1 with formula IVa compound (21g, 0.084mol) be dissolved in 100mL methyl alcohol, add palladium charcoal (5%, 1g), 40 ℃ of normal pressure catalytic hydrogenations are after 1 hour, remove by filter the palladium charcoal, filtrate adds the 10mL concentrated hydrochloric acid, and stirring at room 1 hour adds the sodium bicarbonate aqueous solution neutralization, revolve the steaming desolventizing, resistates adds the 400mL ethyl acetate, after water, the saturated common salt water washing, dry concentrate light yellow solid (16.7g, 93.7%), column chromatography (ethyl acetate/petroleum ether=1: 1) can get the formula I compound of SR and RR configuration.

4.2 (77g 0.308mol) is dissolved in 500mL methyl alcohol, adds concentrated hydrochloric acid (30mL) with formula IVa compound, stirring at room one hour is revolved the steaming desolventizing, and resistates adds the 400mL ethyl acetate, after 5% sodium bicarbonate aqueous solution, water, the saturated common salt water washing, dry concentrate light yellow oil.This oily matter is dissolved in methyl alcohol (300mL), and (5%, 4g), 40 ℃ of normal pressure catalytic hydrogenations removed by filter the palladium charcoal after 1 hour, revolved the steaming desolventizing, and column chromatography (ethyl acetate/petroleum ether=1: 1) can get the formula I compound of SR and RR configuration to add the palladium charcoal.

4.3 with formula IVa compound (10g, 0.399mol) be dissolved in 50mL methyl alcohol, add concentrated hydrochloric acid (5mL), and adding palladium charcoal (5%, 0.5g), 40 ℃ of normal pressure catalytic hydrogenations are after 1 hour, remove by filter the palladium charcoal, revolve to steam and remove most of solvent, resistates adds the 40mL ethyl acetate, after 5% sodium bicarbonate aqueous solution, water, the saturated common salt water washing, dry concentrate light yellow solid.Column chromatography (ethyl acetate/petroleum ether=1: 1) can get the formula I compound of SR and RR configuration.

4.4 with reference to embodiment 4.1, its reduction system can be Raney Ni (yield 90%), silicane reductive agent (triethyl silicane, poly-methyl polysiloxane etc.), borine; Hydrolysis reaction under the acidic conditions, suitable acid can comprise: hydrochloric acid, acetic acid, trifluoroacetic acid, tosic acid etc., all acid catalyzed reaction yields are all near quantitative reaction.

1-[6-fluoro-(2R)-3,4-dihydro-2H-2-chromene]-(1R)-1

¹H?NMR(600MHz?DMSO)δ6.87(2H，m)，6.72(1H，dd，J＝0.015，0.008Hz)，4.77(1H，d，J＝0.009Hz)，4.57(1H，t，J＝0.009Hz)，3.97(H，m)，3.56(2H，m)，3.46(1H，m)，2.79(1H，m)，2.73(1H，m)，1.89(1H，m)，1.78(1H，m)；

¹³C?NMR(600MHz?DMSO)δ117.25，117.20，115.14，114.99，113.44，113.29，75.97，72.81，61.97，24.46，22.67；

${\left[a\right]}_D^{25}=-89.12\left(c1\mathrm{MeOH}\right).$

Mp：106.3-106.5℃.

1-[6-fluoro-(2S)-3,4-dihydro-2H-2-chromene]-(1R)-1

¹H?NMR(600MHz?DMSO)δ6.88(2H，m)，6.72(1H，dd，J＝0.015，0.008Hz)，4.89(1H，d，J＝0.008Hz)，4.54(1H，t，J＝0.009Hz)，3.90(H，m)，3.56(2H，m)，3.46(1H，m)，2.74(2H，m)，2.02(1H，m)，1.72(1H，m)；

¹³C?NMR(600MHz?DMSO)δ117.20，117.14，115.21，115.06，113.50，113.34，75.96，72.40，62.43，23.79，21.60；

${\left[a\right]}_D^{25}=+96.38\left(c1\mathrm{MeOH}\right).$

Mp：101.1-101.9℃.

Embodiment two

1, formula IIb compound is synthetic

(30g 0.195mol) is dissolved in the tetrahydrofuran (THF) of 300 milliliters of dryings, 0 ℃ of cooling of ice-water bath with 5-fluoro-2-hydroxy acetophenone, add potassium tert.-butoxide (23.77g under the vigorous stirring, 0.195mol), vigorous stirring added the dichloromethane solution (w/w=0.432 of L-glyceraldehyde acetonide after 30 minutes, 70.49g, 0.234mol), 0 ℃ is stirred after 3 hours, drips concentrated hydrochloric acid, adjust pH value to 6, revolve the steaming desolventizing.Add ethyl acetate (400mL) and water (300mL) in the resistates, separate organic phase, water, saturated common salt water washing, anhydrous sodium sulfate drying, be spin-dried for yellow solid, get yellow powder powder crystal (25g, 45%) with the dehydrated alcohol recrystallization.

2, formula III b compound is synthetic

With formula IIb compound (20g, 0.07mol) be suspended in the 100mL dehydrated alcohol, (1.59g 0.042mol) is dissolved in the 100mL dehydrated alcohol, is added drop-wise in the reaction flask under 0 ℃ of cooling with sodium borohydride, 0 ℃ was stirred after 4 hours, revolve the steaming desolventizing, resistates is dissolved in the 400mL ethyl acetate, after 5% hydrochloric acid, water and saturated common salt water washing, dry concentrate water white transparency oily thing (20.1g, 99.8%).

3, formula IVb compound is synthetic

(15g 0.052mol) is dissolved in 200mL acetone, adds salt of wormwood (71.9g with formula III b compound, 0.52mol), 0 ℃ drip trifluoroacetic anhydride (72.3mL, 0.52mol), be warming up to 80 ℃ subsequently and refluxed 4 hours, stopped reaction revolves the steaming desolventizing, resistates adds the 300mL ethyl acetate, after water, the saturated common salt water washing, dry concentrate crude product (9.6g, 73%), crude product can directly drop into the next step, or column chromatography is refining.

4, formula I-SS/RS compound is synthetic

With formula IVb compound (8g, 0.032mol) be dissolved in 50mL methyl alcohol, add palladium charcoal (5%, 0.8g), 40 ℃ of normal pressure catalytic hydrogenations are after 1 hour, remove by filter the palladium charcoal, filtrate adds the 5mL concentrated hydrochloric acid, and stirring at room 1 hour adds the sodium bicarbonate aqueous solution neutralization, revolve the steaming desolventizing, resistates adds the 100mL ethyl acetate, after water, the saturated common salt water washing, dry concentrate light yellow solid (6.2g, 91.4%), column chromatography (ethyl acetate/petroleum ether=1: 1) can get the formula I compound of SS and RS configuration.

1-[6-fluoro-(2S)-3,4-dihydro-2H-2-chromene]-(1S)-1

¹H?NMR(300MHz?DMSO)δ6.87(2H，m)，6.72(1H，m)，4.77(1H，d，J＝0.017Hz)，4.56(1H，m)，3.97(H，d，J＝0.035Hz)，3.54(2H，m)，3.46(1H，m)，2.78(2H，m)，1.87(1H，m)，1.78(1H，m)；

¹³C?NMR(300MHz?DMSO)δ117.39，117.28，115.31，115.02，113.62，113.31，76.09，72.94，62.09，24.56，22.78；

${\left[a\right]}_D^{25}=+92.43\left(c1\mathrm{MeOH}\right).$

Mp：106.1-106.2℃.

1-[6-fluoro-(2R)-3,4-dihydro-2H-2-chromene]-(1S)-1

¹H?NMR(300MHz?DMSO)δ6.87(2H，m)，6.72(1H，m)，4.89(1H，d，J＝0.017Hz)，4.54(1H，m)，3.90(H，m)，3.56(2H，m)，3.46(1H，m)，2.72(2H，m)，2.03(1H，m)，1.72(1H，m)；

¹³C?NMR(300MHz?DMSO)δ117.33，117.22，115.38，115.08，113.67，113.37，76.07，72.53，62.55，23.90，21.74；

${\left[a\right]}_D^{25}=-93.12\left(c1\mathrm{MeOH}\right).$

Mp：102.0-102.4℃.

Synthesizing of embodiment three nebivolols

By the nebivolol of formula I compound SRRR and RSSS configuration, can be with reference to prior art,

As patent: CN1978442A, WO2008064827A2, WO2004041805A1, US20070149612A1,

Document: S.Chandrasekhar, Tetrahedron 2000,56,6339-6334.

Yu Jing, organic chemistry, 2008,28 (3), 511-514 etc.

Claims (15)

1. the method for a preparation I compound is characterized in that

1) 5-fluoro-2-hydroxy acetophenone and glyceraldehyde acetonide react formula II compound;

2) formula II compound through reduce the formula III compound;

3) cyclisation of formula III compound gets formula IV compound;

4) formula IV compound gets formula V compound through hydrogenation;

5) formula V compound takes off the propylidene protecting group and gets formula I compound

。

2. preparation method according to claim 1 is characterized in that described glyceraldehyde acetonide is the D-glyceraldehyde acetonide.

3. preparation method according to claim 2 is characterized in that:

4. preparation method according to claim 1, it is characterized in that: described glyceraldehyde acetonide is the L-glyceraldehyde acetonide.

5. preparation method according to claim 4 is characterized in that:

。

6. according to each described preparation method among the claim 1-5, the preparation method who it is characterized in that described formula II compound: 5-fluoro-2-hydroxy acetophenone reacts with glyceraldehyde acetonide under the highly basic condition, after reacting completely, transfer pH to slightly acidic with acid, desolventizing, carry out recrystallization and get formula II compound, wherein said highly basic is potassium tert.-butoxide, sodium tert-butoxide, sodium hydride or LDA.

7. according to the preparation method described in the claim 6, it is characterized in that described highly basic is potassium tert.-butoxide.

8. according to each described preparation method among the claim 1-5, the preparation method who it is characterized in that described formula III compound: with formula II compound in the reduction reaction system, be reduced the formula III compound, wherein said reduction system is sodium borohydride/ethanol, zinc/hydrochloric acid, zinc/acetic acid, Pd-C/H ₂, Raney Ni, lithium aluminum hydride, sodium borohydride/boron trifluoride diethyl etherate or triethyl silicane/boron trifluoride diethyl etherate.

9. the preparation method described in according to Claim 8 is characterized in that described reduction system is sodium borohydride/ethanol.

10. according to each described preparation method among the claim 1-5, the preparation method who it is characterized in that described formula IV compound: the formula III compound is got formula IV compound through cyclisation, reaction system is trifluoroacetic anhydride/triethylamine, trifluoroacetic anhydride/carbonate, trifluoroacetic anhydride/supercarbonate, DMF-DMA/DMF, oxalyl chloride/N, dinethylformamide/methylene dichloride.

11. the preparation method described in the claim 10 is characterized in that described reaction system is trifluoroacetic anhydride/triethylamine.

12. according to each described preparation method among the claim 1-5, the preparation method who it is characterized in that described formula I compound: formula IV compound is formula V compound through reduction system reducing, hydrolysis gets formula I compound under acidic conditions then, and wherein said reduction system is Pd-C/H ₂, Raney Ni, silicane reductive agent or borine.

13. according to the preparation method described in the claim 12, it is characterized in that described reduction system is Pd-C/H ₂

14. according to the preparation method described in the claim 12, it is characterized in that described silicane reductive agent is triethyl silicane, poly-methyl polysiloxane.

15. according to each described preparation method among the claim 1-5, it is characterized in that the preparation method of described formula I compound: the hydrolysis of formula IV compound elder generation, be reduced to formula I compound again, or reduction and hydrolysis are carried out simultaneously.