CN101235024A - Benzodihydropyrane compounds, synthesizing method and use thereof - Google Patents
Benzodihydropyrane compounds, synthesizing method and use thereof Download PDFInfo
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Abstract
The invention relates to a chroman compound, a relative synthesis method and an application in drug preparation, wherein the compound is represented as the formula at right and is prepared from the compound 1 of the formula at right as starting material, with simple process, low cost and application for industrial production. The chroman compound can be used to prepare drugs as nebivolol hydrochloride.
Description
Technical field
The present invention relates to benzodihydropyrane compounds, synthetic method and be used to prepare the purposes of medicines such as nebivolol.
Background technology
Nebivolol (nebivolol, lobivon, nebilet, R-65824) by the development of Belgian Yang Sen company, 1997 in listing produced in USA.Its chemistry by name (RSSS) and (SRRR)-α, racemic compound [(RSSS) and (SRRR)-α of α '-imido grpup-two (methylene radical)-two [6-fluoro-2-chroman methyl alcohol], α '-(±)-[Iminobis (methylene)]-bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] bis[6-fluoro-2-chromanmethanol of or 2,2 '-(Iminodimethylene)]].Its chemical structural formula is:
Molecular formula is C
22H
25F
2NO
4, relative molecular mass is FW405.44.This medicine is a third generation beta-adrenoceptor antagonists, has height β
1Receptor-selective and slight vasorelaxation action do not have negative inotropic action when low dose of, and heart failure patient tolerate.As antihypertensive drug, the existing at present a plurality of patent reports of nebivolol are (as WO2008010022; USP20070149612A1; USP20070021623A1).People wish to develop succinct, with low cost, a suitable industrial operational path of step.
Summary of the invention
The problem to be solved in the present invention provides the new chroman compounds of a class, its preparation method and the purposes in preparation medicine such as nebivolol thereof.
The invention provides benzodihydropyrane compounds, it has following structural formula:
R in the formula
1Represent H, p-toluenesulfonyl, R
2Represent CH
2NO
2, COOH, COOR
4Or CH
2OH,
R wherein
4Represent C
1～C
4Alkyl, R
3Represent fluorine,
Representative
Or
The chroman compounds of recommending of the present invention has following structural formula:
R in the formula
1, R
2As previously mentioned.
Further the chroman compounds of recommending of the present invention has following structural formula:
R wherein
4Represent C
1～C
4Alkyl, Ts represents tosyl group.
The present invention also provides the synthetic method of above-claimed cpd, comprises the steps a) step a), b), step a)～c), step a)～d) or step a)～e):
A). compound 1 or 1 ' and Nitromethane 99Min. at the alkali that contains 5～40% weight, react down as NaOH effect and to obtain compound 2 or 2 ';
B). in organic solvent, compound 2 or 2 ' obtains compound 3 or 3 ' with acetic acid, Sodium Nitrite reaction;
C). in organic solvent, compound 3 or 3 ' and the reaction of the hydrochloric acid alcoholic solution of C1～C4 obtain compound 4 or 4 ';
D). in organic solvent, compound 4 or 4 ' reacts under the organic bases effect with Tosyl chloride and obtains compound 5 or 5 ';
E). in organic solvent, compound 5 or 5 ' obtains compound 6 or 6 ' through hydrogenation.
Described compound 1 (1 ')～6 (6 ') have following structural formula:
R in the structural formula of described compound 1 (1 ')～6 (6 ')
4As previously mentioned.
The preferred reaction conditions of synthetic method of the present invention is as follows:
In the described step a) compound 1 or 1 ' and the mol ratio of Nitromethane 99Min. be 1～100: 1, temperature of reaction is 0～50 ℃, in 0.5～5 hour reaction times, described alkali is monovalence metallic hydrogen oxygen compound, recommends NaOH;
In the described step b), the mol ratio of compound 2 or 2 ', acetic acid and Sodium Nitrite is 1: 1～100: 1～100, and temperature of reaction is 0～100 ℃, and in 1～24 hour reaction times, described organic solvent is recommended methyl-sulphoxide;
In the described step c), the mol ratio of the hydrochloric acid alcoholic solution of compound 3 or 3 ', C1～C4 is 1: 1～100, and temperature of reaction is 0～100 ℃, and the reaction times is 0.5～24 hour, described pure particular methanol or ethanol etc.;
In the described step d), the mol ratio of compound 4 or 4 ', Tosyl chloride, organic bases is 1: 1～50: 1～50, and temperature of reaction is 0～50 ℃, 1～24 hour reaction times, described organic solvent is recommended methylene dichloride, and described organic bases can be pyridine (Py), triethylamine etc.;
In the described step e), compound 5 or 5 ' and the mol ratio of sodium borohydride be 1: 1～50, temperature of reaction is 0～100 ℃, in 1～24 hour reaction times, described organic solvent is recommended tetrahydrofuran (THF).
Preferred corresponding successively respectively compound of described compound 1 (1 ')～6 (6 ') with following structural formula:
R in the structural formula of described compound 1 (1 ')～6 (6 ')
4As previously mentioned.
Described organic solvent can be dioxane, methyl-sulphoxide, acetonitrile, methylene dichloride, ether, toluene or tetrahydrofuran (THF) etc.; Described reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, lithium aluminium hydride, lithium triethylborohydride, nitrilotriacetic POTASSIUM BOROHYDRIDE or palladium-carbon; Described oxygenant is chromium trioxide, Manganse Dioxide, methyl-sulphoxide-oxalyl chloride, periodate, triphenyl carbonic acid bismuth oxide compound, platinum catalyzed oxidation or N-methylmorpholine-N-oxide compound.
Compound 1 of the present invention and 1 ' recommend to adopt following method of the present invention synthetic: obtain optically active Compound I through the reaction fractionation by Compound I I and compound III or IV in organic solvent; Optically active Compound I obtains compound V through the hydro-reduction reaction; Compound V obtains compound VI through alkylation; Compound VI obtains compound VI I through reduction reaction; Compound VI I obtains compound 1 and 1 ' through oxidizing reaction.
The structural formula of described Compound I I～VII is as follows:
Described R
3Represent fluorine.
Further be described below:
Described compound 1 obtains by five steps of following (1)～(5):
(1) splits through reaction in organic solvent by Compound I I and compound III or IV and obtain optically active Compound I, organic solvent is recommended acetone, compound (II), compound (III) or mol ratio (IV) are 1: 0: 1～10, temperature of reaction is 0～50 ℃, 0.25～5 hour reaction times, perhaps the reaction after again through recrystallization;
(2) optically active Compound I obtains compound V through the hydro-reduction reaction; Reductive agent is palladium-carbonaceous reducing agent, and the mol ratio of compound (I) and reductive agent is 1～100: 1, and temperature of reaction is 25～100 ℃/1.01 * 10
5Pa～2.02 * 10
6Pa, 1～10 hour reaction times;
(3) compound V obtains compound VI through alkylation; Alkylating reagent is the alcohol of C1～C4, and the mol ratio of compound (V) and alkylating reagent is 1: 1～100, and temperature of reaction is 0～100 ℃, 0.5～24 hour reaction times;
(4) compound VI obtains compound VI I through reduction reaction; The mol ratio of compound (VI) and reductive agent is 1: 1～100, and temperature of reaction is 0～100 ℃, and in 1～24 hour reaction times, described reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, lithium aluminium hydride, lithium triethylborohydride, nitrilotriacetic POTASSIUM BOROHYDRIDE or palladium-carbon;
(5) compound VI I obtains compound 1 through oxidizing reaction, the consumption mol ratio that compound (VI) and oxygen are former dose is 1: 1～100, temperature of reaction is 0～100 ℃, in 1～24 hour reaction times, described oxygenant is chromium trioxide, Manganse Dioxide, methyl-sulphoxide-oxalyl chloride (Swem oxygenant), periodate, triphenyl carbonic acid bismuth oxide compound, platinum catalyzed oxidation or N-methylmorpholine-N-oxide compound.
Described Compound I I recommends to adopt following method synthetic:
The reaction conditions that above-mentioned reaction scheme is recommended is as follows:
Compound 9 and MALEIC ANHYDRIDE (Maleic anhydride) and AlCl
3Mol ratio be 1: 1: 1～1: 50: 50, temperature of reaction is 0～100 ℃, the reaction times is 0.25～10 hour, used organic solvent is an ethylene dichloride.The mol ratio of compound 10 and salt of wormwood is 1: 1～50, and temperature of reaction is 0～100 ℃, and the reaction times is 0.5～10 hour, and solvent for use is a water.
Compound of the present invention can be used for preparing medicine, for example prepares nebivolol, and preferred route is as follows: wherein compound 1～6 or 1 '～6 ' preparation route can begin to prepare from compound 6 or 6 ' as previously mentioned.
The present invention adopts following steps to prepare the nebivolol medicine:
(1) compound 6 or 6 ' takes place under sodium tert-butoxide or potassium tert.-butoxide effect, and little cyclization obtains compound 7; Compound 6 or 6 ' and the mol ratio of potassium tert.-butoxide be: 1: 1～50, temperature of reaction is 0～100 ℃, the reaction times is 0.5～10 hour;
(2) compound 1 or 1 ' reacts under the alkali effect with Nitromethane 99Min. and obtains compound 2 or 2 '; Compound 2 or 2 ' nitro obtain compound 8 through reduction, compound 2 or 2 ' and the mol ratio of reductive agent be: 50: 1～1: 50, temperature of reaction was 0～100 ℃, and the reaction times is 0.5～24 hour;
(3) compound 7 reacts in organic solvent and under the effect of LiBr with compound 8 and obtains nebivolol, and the mol ratio of compound 7 and compound 8 is: 50: 1～1: 50, temperature of reaction was 0～100 ℃, and the reaction times is 0.5～24 hour;
Above-mentioned 1,1 ', 2,2 ', 3,3 ', 6 and 6 ' structural formula is as described in the claim 3; 7 and 8 structural formula of compound as:
Above-mentioned R
3Represent fluorine.
The invention provides the new chroman compounds of a class, the synthetic method of above-claimed cpd is provided and has been used for synthetic drugs such as the purposes of nebivolol or pharmaceutical intermediate, simple synthetic method of the present invention, the productive rate height, with former synthetic drugs, compare as the method for nebivolol, it is succinct to have step, with low cost, be fit to advantages such as industrial production.
Embodiment
Following examples will help further to understand the present invention, but not limit content of the present invention.
Embodiment 1
(67.8g, 0.692mol) grinding is placed on through anhydrous CaCl compound 2
2In the exsiccant 600mL ethylene dichloride, mechanical stirring adds the AlCl that grinds again
3(186.0g 1.39mol), is heated to 50 ℃, and (75.6g, 0.600mol), reflux 2h postcooling is poured in the 2L beaker that fills 360mL concentrated hydrochloric acid and 2400g ice to room temperature to add compound 1 behind the insulation 15min.Stir, when solid settlement to the bottom, the upper strata clear water is toppled over, wash back suction filtration for several times again with water, the gained solid is through petroleum ether, after the drying yellow solid compound 3,110g, productive rate are 88%.
1H?NMR(300MHz，DMSO-d
6)δ6.59(dd，1H，J＝15.2Hz，J＝2.1Hz)，6.97-7.02(m，1H)，7.33-7.40(m，1H)，7.47-7.51(m，1H)，7.85(dd，1H，J＝15.2Hz，J＝2.1Hz)。
Embodiment 2
With K
2CO
3(6.57g 47.6mmol) is dissolved in 400mL H
2Among the O, add pulverous compound 3 (10.0g, 47.6mmol), under nitrogen atmosphere, heating, temperature is controlled at about 80 ℃, TLC detects to raw material disappearance promptly stopping heating, after naturally cooling to room temperature, remove the less impurity of depolarization with ethyl acetate extraction, water layer is 1 with 1N HCl adjust pH, stirring has solid to separate out, suction filtration.Filtrate extracts the same operation in back again.With solid merge after the drying compound 47.61g, productive rate 76.1%.
1H?NMR(300MHz，DMSO-d
6)δ2.92-3.12(m，2H)，5.30(q，1H)，7.13-7.17(m，1H)，7.38-7.48(m，2H)。
Embodiment 3
(20.0g 95.2mmol) joins in the flask that fills 200mL acetone, and (10.64g 71.0mmol), has been stirred to solid and has fully separated out back, back suction filtration to treat to add behind the CL 5 with compound 4.After the solid that leaches was used acetone and recrystallizing methanol, adding 1N HCl to pH value was 1, stirs and uses ethyl acetate extraction after 15 minutes, the organic phase anhydrous Na
2SO
4Drying is removed and is desolvated after ethyl acetate and sherwood oil recrystallization get 6a (8.2g, yield: 41%); Filtrate is revolved to steam and is desolventized that the back adds that 1N HCl stirred 15 minutes so that in a small amount of Chiral Amine 5 salifies wherein are soluble in the aqueous phase, ethyl acetate extraction, organic phase anhydrous Na
2SO
4Drying is removed and is desolvated after ethyl acetate and sherwood oil recrystallization get 6b (8.6g, yield: 43%).
Embodiment 4
With compound 6a (14.6g 69.3mmol) is dissolved in the acetic acid of 400mL, adds the perchloric acid of 6.0mL, 1.46g Pd-C (10%), catalytic hydrogenation under 60 ℃, 80atm detects raw material disappearance behind about 6hr through TLC.Add 10g NaOAc and stir, filter.The filtrate decompression distillation desolventizes, and recrystallization obtains whitening compound 7, and 9.67g, yield are 75%.
1H?NMR(300MHz，DMSO-d
6)δ1.98-2.10(m，1H)，2.45-2.74(m，2H)，4.71(q，1H)，6.74-6.89(m，3H)。
Compound 6b also obtains compound 7b with identical operations hydrogenation.
(1.96g, 10mmol) with anhydrous methanol 50mL, ice-water bath is cooled to 0 ℃, drips SOCl to add substrate 7 in a 100mL round-bottomed flask
22mL.Add the water-bath of recession deicing, stirred 30 minutes, oil bath reflux 2 hours is cooled to room temperature, and steaming desolventizes the final vacuum drying and obtains colourless oil liquid.(2.02g, yield: 99%).
1H?NMR(300MHz，CDCl
3)δ1.79-2.13(m，2H)，2.56-2.80(m，2H，4.86(q，1H)，6.78-6.92(m，3H).
(0.448g 2.1mmol) places the 100mL round-bottomed flask to above-mentioned solid product, adds 20mLTHF, and ice-water bath adds NaBH after cooling off 0 ℃ in system
4(0.23g, 6mmol) and LiBrH
2O (0.66g, 6mmol).System stirring reaction 5 hours under 0 ℃ and nitrogen protection, in system, add anhydrous methanol 2mL after, be warming up to room temperature naturally, stirring reaction spends the night.Add H
2O 2.5mL cancellation reaction.Revolve and remove organic solvent, the resistates acetic acid ethyl dissolution, and use saturated NH successively
4The Cl aqueous solution, H
2O, saturated common salt water washing, anhydrous Na
2SO
4Drying is revolved to desolventize and is obtained target product 3 (0.377g, yield: 100%).
1H?NMR(300MHz，CDCl
3)δ1.80-1.96(m，2H)，2.76-2.87(m，2H)，3.72-3.86(m，2H)，4.05-4.10(m，1H)，6.74-6.78(m，3H).MS-EI：182。
Embodiment 5
0.93mL oxalyl chloride is dissolved in the anhydrous CH of 10mL
2Cl
2, being cooled to-78 ℃, temperature in anhydrous DMSO of dropping 1.2mL and the control＜-65 ℃ continues to stir 10min at-78 ℃ after adding.Drip 12a (0.91g, CH 5.0mmol) to system
2Cl
2Behind the solution 10mL, system continued stirring reaction 3 hours under this temperature, dripped the 2.5mL triethylamine then in system, was warming up to room temperature naturally, added 20mL NaHCO
3The aqueous solution, separatory after the stirring layering, the suitable CH of water
2Cl
2Extraction merges organic phase, uses 1N hydrochloric acid successively, water, saturated NaHCO
3The aqueous solution, saturated common salt water washing, anhydrous MgSO
4Dry.Cross column purification, obtain the 0.84g faint yellow solid, yield 94%.MS-EI：180。
Embodiment 6
In a 100mL round-bottomed flask, add 5mL CH
3NO
2, the 2.5mL 10%NaOH aqueous solution, 1mL CH
3OH.System stirs the CH that 30min adds 180mg (1mmol) 13 under ice-water bath
3The back 0 ℃ of following fierce stirring reaction 2 hours of OH solution (1mL) with 1N hydrochloric acid regulation system pH to 1.8, adds 10mL water and ethyl acetate in system, tell organic phase, and water continues with ethyl acetate five times.Merge organic phase, use H successively
2O, saturated NaHCO
3The aqueous solution, saturated common salt solution washing, MgSO
4Drying obtains mixture product 240mg, yield 98%.MS-EI：241。
Sometimes having polymkeric substance in the reaction system generates.Yield is corresponding can be reduced.
In a 100mL round-bottomed flask, add 10%Pd-C (48mg), 14 (240mg, 1mmol) and MeOH (20mL), normal temperature and pressure hydrogenation 24 hours.Filter, revolve and desolventize, obtain mix products 16 (193mg, yield: 90%).MS-EI：211.
Embodiment 7
In a 50mL round-bottomed flask, add 241mg 17 successively, 207mg NaNO
2, 300mg AcOH, stirred overnight at room temperature reaction behind the 2mL DMSO is warming up to 35 ℃ of reaction 3h subsequently, stops reaction, with 10% hydrochloric acid (4mL) regulation system pH to 2-3, system is joined 20mLH
2In the mixed system of O and 40mLEA, separate the back water and extract, merge organic phase and be followed successively by and use H with a small amount of EA
2O, saturated common salt solution washing, MgSO
4Drying obtains target product 18, directly carries out next step reaction.MS-ESI：(M-1)225。
Embodiment 8
In a 25mL round-bottomed flask, add to go up the step reaction product, 1O mL HCl MeOH solution, system is stirring reaction at room temperature subsequently, stops reaction behind the 3h, and system is slowly added 0 ℃ of saturated Na
2CO
3In the aqueous solution, merge organic phase with after the EA extraction three times, after the saturated common salt water washing, MgSO
4Drying obtains target product 19 behind the column purification excessively, 177mg, two step yields 70%.
1H?NMR(300MHz，CDCl
3)δ1.87-2.04(m，2H)，2.76-2.85(m，2H)，3.25(bs，1H)，3.82(s，3H)，4.21-4.27(m，1H)，4.47(bs，1H)，6.72-6.77(m，3H)。
Embodiment 9
In a 25mL round-bottomed flask, add 60mg 19, dry DCM 2Ml, dry Py 0.05mL, behind a small amount of DMAP system is cooled to 0 ℃, the DCM solution (52.4mg in 1mL) that slowly adds TsCl, reaction system is warming up to stir after the room temperature spends the night, and stops reaction and add 25mL EA in system, uses a small amount of saturated CuSO successively
4Solution, MgSO after the saturated common salt water washing
4Drying is crossed column purification, obtains marking product 20,73mg, 74%.
1H?NMR(300MHz，CDCl
3)δ1.81-1.87(m，2H)，2.35(s，3H)，2.60-2.68(m，2H)，3.62(s，3H)，4.24(q，1H)，4.96(d，J＝6.9Hz)，6.38-6.42(m，1H)，6.58-6.70(m，2H)，7.21(d，J＝8.4Hz)，7.70(d，J＝8.4Hz)。
Embodiment 10
Add 60mg 20 in a 25mL round-bottomed flask, the 10mL dry THF is cooled to system 0 ℃ subsequently, adds NaBH
440mg, after be warming up to stirring at room reaction, the 2h afterreaction stops reaction fully, obtains target product 21,40mg, 75%.
1H?NMR(300MHz，CDCl
3)δ1.72-1.80(m，2H)，2.45(s，3H)2.71-2.74(m，2H)，3.93-3.94(m，2H)，4.10-4.16(m，1H)，4.65-4.67(q，1H)，6.54-6.59(m，1H)，6.69-6.75(m，2H)，7.33(d，J＝8.4Hz)，7.81(d，J＝8.4Hz)。
Embodiment 11
In a 25mL round-bottomed flask, add 30mg 21, the 5mL dry THF, the dissolving back adds KOBu-t, stirring reaction, the 2h afterreaction is complete, adds 20mL EA in system, uses H subsequently respectively
2O, MgSO after the saturated common salt water washing
4Drying concentrates and obtains target product 22,10mg, 62%.
1HNMR(300MHz，CDCl
3)δ1.92-2.04(m，2H)，2.78-2.88(m，2H)，3.16-3.20(m，1H)，3.80-3.86(m，1H)，6.72-6.79(m，3H)。
Embodiment 12
In a 100mL round-bottomed flask, add 23,30mg, 24,20mg, THF 15mL; and LiBr, 5mg is heated to backflow under nitrogen protection, stop reaction behind the 24h, is cooled to room temperature; revolve and remove THF, the residual solid acetic acid ethyl dissolution, the saturated common salt water washing after the MgSO4 drying, is crossed column purification.Obtain 25, colorless oil solid, 25mg, yield 58%.
Claims (7)
1. benzodihydropyrane compounds is characterized in that having following structural formula:
R in the formula
1Represent H or p-toluenesulfonyl, R
2Represent CH
2NO
2, COOH, COOR
4Or CH
2OH,
R wherein
4Represent C
1～C
4Alkyl, R
3Represent fluorine,
Represent the configuration of key
Or
2. chroman compounds according to claim 1 is characterized in that having following structural formula:
R in the formula
1, R
2According to claim 1.
3. chroman compounds according to claim 1 is characterized in that having following structural formula:
R wherein
4Represent C
1～C
4Alkyl, Ts represents p-toluenesulfonyl.
4. according to the synthetic method of each described compound in the claim 1 to 3, it is characterized in that comprising the steps a), step a)～b), step a)～c), step a)～d) or step a)～e) four kinds of steps:
A). compound 1 or 1 ' reacts under the excessive monovalence metallic hydrogen oxygen compound aqueous solution effect that contains 5～40% weight with Nitromethane 99Min. and obtains compound 2 or 2 '; The mol ratio of described compound 1 or 1 ', Nitromethane 99Min. is 1～100: 1, and temperature of reaction is 0～50 ℃, 0.5～24 hour reaction times;
B). in organic solvent, compound 2 or 2 ' obtains compound 3 or 3 ' with acetic acid, Sodium Nitrite reaction; The mol ratio of compound 2 or 2 ', acetic acid and Sodium Nitrite is 1: 1～100: 1～100, and temperature of reaction is 0～100 ℃, 1～24 hour reaction times;
C). in organic solvent, compound 3 or 3 ' and the reaction of the hydrochloric acid alcoholic solution of C1～C4 obtain compound 4 or 4 '; The mol ratio of the hydrochloric acid alcoholic solution of described compound 3 or 3 ', C1～C4 is 1: 1～100, and temperature of reaction is 0～100 ℃, 0.5～24 hour reaction times;
D). in organic solvent, compound 4 or 4 ' reacts under the organic bases effect with Tosyl chloride and obtains compound 5 or 5 '; The mol ratio of described compound 4 or 4 ', Tosyl chloride, organic bases is 1: 1～50: 1～50; Temperature of reaction is 0～50 ℃, 1～24 hour reaction times;
E). in organic solvent, compound 5 or 5 ' obtains compound 6 or 6 ' through hydrogenation; Described compound 5 or 5 ' and the mol ratio of reductive agent be 1: 1～50, temperature of reaction is 0～100 ℃, 1～24 hour reaction times;
Wherein, described reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, lithium aluminium hydride, lithium triethylborohydride, nitrilotriacetic POTASSIUM BOROHYDRIDE or palladium-carbon; Described organic bases is pyridine or triethylamine;
Described compound 1 (1 ')～6 (6 ') have following structural formula:
R wherein
4According to claim 1; Ts represents tosyl group.
5. synthetic method according to claim 4 is characterized in that described compound 1 or 1 ' five steps by following (1)～(5) obtain:
(1) splits through reaction in organic solvent by Compound I I and compound III or IV and obtain optically active Compound I, compound (II), compound (III) or mol ratio (IV) are 1: 0: 1～10, temperature of reaction is 0～50 ℃, 0.25～5 hour reaction times, perhaps the reaction after again through recrystallization;
(2) optically active Compound I obtains compound V through the hydro-reduction reaction; Reductive agent is palladium-carbonaceous reducing agent, and the mol ratio of compound (I) and reductive agent is 1～100: 1, and temperature of reaction is 25～100 ℃/1.01 * 10
5Pa～2.02 * 10
6Pa, 1～10 hour reaction times;
(3) compound V obtains compound VI through alkylation; Alkylating reagent is the alcohol of C1～C4, and the mol ratio of compound (V) and alkylating reagent is 1: 1～100, and temperature of reaction is 0～100 ℃, 0.5～24 hour reaction times;
(4) compound VI obtains compound VI I through reduction reaction; The mol ratio of compound (VI) and reductive agent is 1: 1～100, and temperature of reaction is 0～100 ℃, and in 1～24 hour reaction times, described reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, lithium aluminium hydride, lithium triethylborohydride, nitrilotriacetic POTASSIUM BOROHYDRIDE or palladium-carbon;
(5) compound VI I obtains the described compound 1 or 1 ' of claim 4 through oxidizing reaction, the consumption mol ratio that compound (VI) and oxygen are former dose is 1: 1～100, temperature of reaction is 0～100 ℃, in 1～24 hour reaction times, described oxygenant is chromium trioxide, Manganse Dioxide, methyl-sulphoxide-oxalyl chloride, periodate, triphenyl carbonic acid bismuth oxide compound, platinum catalyzed oxidation or N-methylmorpholine-N-oxide compound;
The structural formula of described Compound I I～VII is as follows:
Described R
3Represent fluorine.
6. according to the purposes of each described compound in the claim 1 to 3, it is characterized in that being used to prepare the nebivolol medicine.
7. purposes according to claim 6 is characterized in that described preparation nebivolol medicine comprises the steps:
(1) compound 6 takes place under sodium tert-butoxide or potassium tert.-butoxide effect, and little cyclization obtains compound 7; The mol ratio of compound 6 and potassium tert.-butoxide is: 1: 1～50, and temperature of reaction is 0～100 ℃, the reaction times is 0.5～10 hour;
(2) compound 1 and Nitromethane 99Min. react under the alkali effect and obtain compound 2; The nitro of compound 2 obtains compound 8 through reduction, and the mol ratio of compound 2 and reductive agent is: 50: 1～1: 50, temperature of reaction was 0～100 ℃, and the reaction times is 0.5～24 hour;
(3) compound 7 reacts in organic solvent and under the effect of LiBr with compound 8 and obtains nebivolol, and the mol ratio of compound 7 and compound 8 is: 50: 1～1: 50, temperature of reaction was 0～100 ℃, and the reaction times is 0.5～24 hour;
Above-mentioned 1,1 ', 2,2 ', 3,3 ', 6 and 6 ' structural formula is as described in the claim 3; 7 and 8 structural formula of compound as:
Above-mentioned R
3Represent fluorine.
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| CN102190647A (en) * | 2010-03-12 | 2011-09-21 | 浙江海翔药业股份有限公司 | Preparation method of nebivolol intermediate |
| CN102344431A (en) * | 2010-08-05 | 2012-02-08 | 成都康弘药业集团股份有限公司 | Method for preparing nebivolol hydrochloride |
| CN102858759A (en) * | 2010-02-11 | 2013-01-02 | 马纳里尼国际运转卢森堡股份公司 | Process for the preparation of nebivolol |
| CN102875537A (en) * | 2012-09-10 | 2013-01-16 | 常州制药厂有限公司 | Novel preparation method of antithrombosis medicine |
| CN103524470A (en) * | 2013-10-15 | 2014-01-22 | 北京师范大学 | Synthesis method of 2-amino-1-(-6-fluoro-2-chromanyl)ethanol |
| CN106317006A (en) * | 2016-08-19 | 2017-01-11 | 陕西思尔生物科技有限公司 | Preparation method of 6-fluorochromane-2-formaldehyde as nebivolol intermediate |
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| CN110041294A (en) * | 2019-05-13 | 2019-07-23 | 河北科技大学 | The synthetic method and its application of the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide |
| CN111433204A (en) * | 2017-12-01 | 2020-07-17 | 拜耳制药股份公司 | Process for the preparation of (3S) -3- (4-chloro-3- { [ (2S,3R) -2- (4-chlorophenyl) -4,4, 4-trifluoro-3-methylbutyryl ] amino } phenyl) -3-cyclopropylpropionic acid and crystalline forms thereof for use as a pharmaceutically active substance |
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| CN102858759A (en) * | 2010-02-11 | 2013-01-02 | 马纳里尼国际运转卢森堡股份公司 | Process for the preparation of nebivolol |
| CN102858759B (en) * | 2010-02-11 | 2015-12-16 | 马纳里尼国际运转卢森堡股份公司 | For the preparation of the method for nebivolol |
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| CN102344431B (en) * | 2010-08-05 | 2014-03-26 | 成都康弘药业集团股份有限公司 | Method for preparing nebivolol hydrochloride |
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| CN102875537A (en) * | 2012-09-10 | 2013-01-16 | 常州制药厂有限公司 | Novel preparation method of antithrombosis medicine |
| WO2014036823A1 (en) * | 2012-09-10 | 2014-03-13 | 常州制药厂有限公司 | Novel preparation method of antithrombosis medicine |
| CN103524470A (en) * | 2013-10-15 | 2014-01-22 | 北京师范大学 | Synthesis method of 2-amino-1-(-6-fluoro-2-chromanyl)ethanol |
| CN103524470B (en) * | 2013-10-15 | 2016-04-20 | 北京师范大学 | The synthetic method of 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol |
| CN106317006A (en) * | 2016-08-19 | 2017-01-11 | 陕西思尔生物科技有限公司 | Preparation method of 6-fluorochromane-2-formaldehyde as nebivolol intermediate |
| CN111433204A (en) * | 2017-12-01 | 2020-07-17 | 拜耳制药股份公司 | Process for the preparation of (3S) -3- (4-chloro-3- { [ (2S,3R) -2- (4-chlorophenyl) -4,4, 4-trifluoro-3-methylbutyryl ] amino } phenyl) -3-cyclopropylpropionic acid and crystalline forms thereof for use as a pharmaceutically active substance |
| CN108774206A (en) * | 2018-05-25 | 2018-11-09 | 山西大学 | A kind of preparation method of the compound of the ketone of -1- containing isochroman skeleton |
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