CN1978442A - (R,R,R,S)2,2'-[imino-di(methylen)] di-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol) nebivolo chloride - Google Patents
(R,R,R,S)2,2'-[imino-di(methylen)] di-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol) nebivolo chloride Download PDFInfo
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- CN1978442A CN1978442A CN 200510125663 CN200510125663A CN1978442A CN 1978442 A CN1978442 A CN 1978442A CN 200510125663 CN200510125663 CN 200510125663 CN 200510125663 A CN200510125663 A CN 200510125663A CN 1978442 A CN1978442 A CN 1978442A
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Abstract
This invention relates to a composing method of beta 1-receptor block agent that is (R,R,R,S)2,2'-[imino-di-(methane)] double- (6-fluorine-3,4-di-H-2H-1-benzene parallel pyran-2-methanol) nye pyrrole muriate. Chira glyceraldehydes that is produced by manicol reacts with 4-fluorine hydroxybenzene to obtain (2R)-2-[(1R)-4,4-dimethyl-3,5-di-hetero- oxygen cyclopentyl ]-6-monofluoro-benzene centchroman -4-ketone; (R)-2-((R)-6-fluorine-3,4-di-H benzopyranyl)-2- hydroxyethyl -4-methyl besilate and (R)-2-((S)-6-fluorine-3,4-di-H benzopyranyl)-2-hydroxyethyl-4- methyl besilate are obtained by disoxidation and sulfonylation. At last the product is obtained by serial reaction.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, specially refer to β
1(R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be the synthetic method of your hydrochloride (hereinafter to be referred as NBL) of pyrroles how for R, R for-receptor-blocking agent.
Background technology
Of the present invention (R, R, R, how your molecular formula of hydrochloride (NBL) of pyrroles is as follows for S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3, the parallel pyrans of 4-dihydro-2H-1-benzene-2-methyl alcohol):
The report the earliest of relevant NBL appears at nineteen ninety, and it has the chroman structural unit, is one of a kind of medicine that hypertension is had important curative effect, and it is as β
1-Receptor-blocking agent is synthetic with the DL form at first.Clinical study show (R, R, R, R, S)-enantiomorph or D-R0675 have good acceptor blockage effect, can bring high blood pressure down and the rhythm of the heart, and have the effect that improves left ventricular function.To the greatest extent let it be enantiomorph (S, S, S, R) or L-R0675 do not have hypotensive activity, if but the two is share aspect hypotensive can produce good synergy.NBL, the suitability for industrialized production that is compound 1 is from chroman acid, (G.Van Lommen, M.De Bruyn and M.Schroven, J.Pharm.Belg., 1990,45) synthetic middle crucial epoxide intermediates realizes by aldehyde radical, carry out coupling by benzylamine again after two non-mapping epoxy compoundss separate by high performance liquid chromatography, and then hydrolysis obtains target compound 1.This synthetic route exists many unfavorable aspects, as the fractionation of chroman acid and separating of non-mapping epoxy compounds.Unfavorable step in synthetic, the inventor has proposed a kind of synthetic route of efficient and simple possible.
Summary of the invention
The objective of the invention is to overcome that the reactions steps that exists in the prior art is too much, operation is complicated, the conditional request harshness, product purity is low, raw material reagent costs an arm and a leg, production cost is too high, and yield is low, produces problems such as difficulty in batches, a kind of reaction conditions gentleness is provided, easy and simple to handle, synthetic route is short, and synthetic cost is low, the yield height, the NBL new synthetic method that suitable batch is produced.
The present invention relates to novel antihypertensive medicament (R, R, R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be the synthetic method of your hydrochloride of pyrroles how, and synthetic main to adopt 4-fluorophenol and natural chiral source N.F,USP MANNITOL be raw material.In reaction, with N.F,USP MANNITOL and the synthetic acetone mannitan of acetone effect, condensation product obtains the Glycerose of chirality through oxidation, Glycerose and the reaction of 4-fluorophenol obtain important intermediate (2R)-2-[(1R)-4,4-dimethyl-3, the assorted oxygen cyclopentyl of 5-two]-6-fluorobenzene and dihydropyrane-4-ketone (5a in the reaction formula), (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone (5b in the reaction formula).(5a), (5b) utilizes Clemmensen method one step reduction deprotection to obtain compound (R)-1-((R)-6-fluoro-3 respectively; 4-dihydrobenzopyrans base) ethane-1; 2-glycol (4a in the reaction formula), (S)-1-((R)-6-fluoro-3; 4-dihydrobenzopyrans base) ethane-1,2-glycol (4b in the reaction formula).(4a) and (4b) in pyridine, obtain compound (R)-2-((R)-6-fluoro-3 respectively with the p-methyl benzene sulfonic chloride reaction, 4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3a in the reaction formula), (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3b in the reaction formula).(3a) being dissolved in solvent feeds exsiccant ammonia reflux then and obtains compound (R)-2-amido-1-(((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (2 in the reaction formula), (2) obtain compound (2 in the reaction formula) with the Anhydrous potassium carbonate reflux that (3b) is dissolved in adding catalytic amount in the exsiccant methyl alcohol, 2 '-[imino-diacetic (methylene radical)] is two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) (1 in the reaction formula), (1) is dissolved in the exsiccant methylene dichloride and feeds the exsiccant hydrogen chloride gas under the room temperature and obtain final product (R, R, R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be your hydrochloride of pyrroles how.
The synthetic method of NBL of the present invention is to be the synthetic (R of raw material with the N.F,USP MANNITOL of natural chiral source and p-fluorophenol, R, R, S) 2, how the total operational path of your hydrochloride of pyrroles is as follows for 2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol):
1. Glycerose is synthetic
2. the aldehyde of compound 1 is synthetic
(1) in reactor,, joins in the acetone solvent and stir catalyzer anhydrous stannous chloride or Zinc Chloride Anhydrous, be cooled to 0～5 ℃, and then add N.F,USP MANNITOL, wherein N.F,USP MANNITOL: the mol ratio of catalyzer is 1: 1～4, room temperature reaction 3～15 hours adds the solution of potassium carbonate termination reaction; Add ether solvent subsequently, static spending the night, filter, revolve steam solid, then dissolve with dichloromethane solvent, zine ion in the water flush away product, use dried over mgso, revolve steaming except that desolvating and obtain two acetone N.F,USP MANNITOL, purifying obtains the white solid pure substance of acetone mannitan (compound 10 in the reaction formula) then;
(2) use CH
2Cl
2With 10 dissolvings of the compound in the reaction formula, at room temperature solution is joined saturated NaHCO then
3In the aqueous solution, slowly add oxygenant NaIO again
4, oxygenant NaIO wherein
4Add-on be 1～2 times of acetone mannitan material mass, the limit edged stirs, and react 1～5 hour, reacts the after-filtration that finishes; The remaining liq that obtains after the filtrate distillation is moved to underpressure distillation in the container, obtain Glycerose (compound 6 in the reaction formula);
(3) 4-fluorophenol and Acetyl Chloride 98Min. are joined in the reactor (as three-necked bottle), wherein the mol ratio of 4-fluorophenol and Acetyl Chloride 98Min. is 1: 1～3, adds catalyst A lCl
3, stirring reaction 20～40 minutes reacts 1～8 hour postcooling down to room temperature, preferred 130 ℃ at 50～160 ℃ then; Water is joined in the reaction mixture, filter and obtain filter cake, be thick product, crude product obtains 2-ethanoyl-4-fluorophenol (compound 7 in the reaction formula) behind the sherwood oil recrystallization;
(4) the 2-ethanoyl-4-fluorophenol (compound 7) and toluene or absolute ethanol solvent in the Glycerose (compound 6) in the reaction formula that step (2) is obtained, the reaction formula that step (3) obtains, preferred toluene; Add catalyzer Pyrrolidine, pyrrolidone or piperidines etc., mix solution, reacted 12～72 hours, add the HC1 of 2mol/L after reaction is finished, use CH
2Cl
2Extraction, and, use MgSO with saturated sodium-chloride salt water washing organic phase
4Dry organic phase; Organic phase is desolvated by revolving to steam to remove, the solid residue that obtains carries out column chromatography to be separated, purifying obtains (2R)-2-[(1R)-4 respectively, 4-dimethyl-3, the assorted oxygen cyclopentyl of 5-two]-6-fluorobenzene and dihydropyrane-4-ketone (the compound 5a in the reaction formula) and (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone (the compound 5b in the reaction formula); Wherein, catalyst consumption is 20%～80% of 2-ethanoyl-4-fluorophenol weight;
(5) (2R)-2-[(1R)-4 in the reaction formula that step (4) is obtained, 4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone (the compound 5a in the reaction formula), alcohol solvent, 15% hydrochloric acid solvent and zinc amalgam join in the reactor, (2R)-2-[(1R)-4 wherein, 4-dimethyl-3, the assorted oxygen cyclopentyl of 5-two]-mol ratio of 6-fluorobenzene and dihydropyrane-4-ketone and zinc amalgam is 1: 10～250, reacted 12～72 hours, and then add 12% hydrochloric acid, stir and continue reaction, after reaction is finished, question response mixture cool to room temperature after-filtration, filtrate with ethyl acetate extraction after with the washing of saturated salt solution, use Na
2SO
4Dry organic phase, organic phase is obtained thick product except that after desolvating, slightly product is purified obtains (R)-1-((S)-6-fluoro-3 respectively, 4-dihydrobenzopyrans base) ethane-1,2-glycol (the compound 4a in the reaction formula) and (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (the compound 4b in the reaction formula);
(6) (R)-1-that step (5) is obtained ((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (the compound 4a in the reaction formula) is dissolved in the exsiccant pyridine solvent, the Tosyl chloride of purifying also is dissolved in the exsiccant pyridine solvent, the two mixes stirring, wherein ((R)-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the mol ratio of 2-glycol and Tosyl chloride is 1: 1～1.5mol, 24～48 hours reaction times; In mixing solutions, add frozen water again, use extracted with diethyl ether then, with dilute hydrochloric acid and saturated NaHCO
3Solution cleans organic phase, uses MgSO
4Organic phase is carried out drying; Organic phase obtains crude product after removing and desolvating, crude product is purified to obtain (R)-2-((S)-6-fluoro-3 respectively, 4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester (the compound 3a in the reaction formula) and (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (the compound 3b in the reaction formula);
(7) (R)-2-that step (6) is obtained ((S)-6-fluoro-3,4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester (the compound 3a in the reaction formula) and exsiccant ethanol or methanol solvate join in the reactor, particular methanol, in reaction system, lead to the exsiccant ammonia then, behind the logical exsiccant ammonia reaction system is heated to 25～80 ℃ of reactions, instead with after finishing, question response system cooling back underpressure distillation is removed reaction solvent and is obtained crude product, purifying crude is obtained (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (compound 2 in the reaction formula);
(8) (R)-2-that step (6) is obtained ((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (the compound 3b in the reaction formula), (R)-2-amino-1-((S)-6-fluoro-3 that step (7) obtains, 4-dihydrobenzopyrans base) ethanol (compound 2 in the reaction formula) and exsiccant ethanol or methanol solvate join in the reactor, at catalyzer is stirring reaction in the presence of Anhydrous potassium carbonate or the sodium hydroxide, (R)-2-((R)-6-fluoro-3 wherein, 4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester with (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) the alcoholic acid mol ratio is 1: 1～1.5mol, then with the system cool to room temperature, refilter and use CH after removing reaction solvent
2Cl
2The dissolving resistates refilters that removing desolvates obtains crude product, obtain after crude product is purified (+)-[R, R, R, S]-2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydrobenzopyrans base)-2-methyl alcohol (compound 1 in the reaction formula);
(9) in reactor, (+)-[R that step (8) is obtained, R, R, S]-2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydrobenzopyrans base)-2-methyl alcohol (compound 1 in the reaction formula) is dissolved in exsiccant methyl alcohol or the methylene dichloride, preferred methylene dichloride, fed the exsiccant hydrogen chloride gas 6～18 hours under the room temperature, revolve steaming, wash with trichloromethane, filtration obtains (R, R, R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be your hydrochloride white solid of pyrroles how.
Described concentration of hydrochloric acid is 12wt%～20wt%.
Synthesis route of the present invention is brand-new, reaction conditions gentleness in the building-up process, and this technology synthesis step optical purity height, purifying short, that generate final product is easy, purification technique maturation, total recovery 10%.Compare with the method for bibliographical information, utilize cheap ammonia, both reduced the price of raw material, reduced reactions steps again, great using value arranged industrial.
Embodiment
The invention will be further described below by example.
Embodiment 1
1. two acetone N.F,USP MANNITOL is synthetic
In reactor, the 50g Zinc Chloride Anhydrous joined in the 500ml acetone stir, be cooled to 0～5 ℃, add 60g N.F,USP MANNITOL again, room temperature reaction 3～15 hours, the solution that back adding 90g salt of wormwood is dissolved in 90ml water is finished in reaction, termination reaction, adds 100ml ether, static spending the night subsequently, filter, revolve steam solid, with the zine ion in methylene dichloride dissolving, the water flush away product, use dried over mgso, revolve steaming except that desolvating and obtain two acetone N.F,USP MANNITOL, purifying obtains the white solid pure substance.
2. Glycerose contracts for (R)-2,3-sec.-propyl
Use CH
2Cl
2(300ml) (33g, 0.13mol) dissolving at room temperature joins solution saturated NaHCO then with compound two acetone N.F,USP MANNITOL
3In the aqueous solution (11.9ml).Slowly add NaIO again
4(52.8g, 0.25mol), the limit edged stirs, and react 1～5 hour, and mixing solutions reaction finishing after-filtration, the remaining liq that obtains after filtrate distilled move to underpressure distillation in the little container, obtain compound (R)-2, the 3-sec.-propyl Glycerose that contracts.
3.2-ethanoyl-4-fluorophenol
With the 4-fluorophenol (83g, 0.74mol) and Acetyl Chloride 98Min. (79ml 1.11mol) joins in the reactor, and stirring reaction is after 30 minutes, adds AlCl
3178g (1.34mol), stirring reaction 20～40 minutes.React 2 hours postcooling down to room temperature at 130 ℃ then.With H
2O (150ml) joins in the reaction mixture, filters and obtains filter cake, is thick product.Crude product obtains target product behind the sherwood oil recrystallization.
4. (2R)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone and (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone
With compound (R)-2; the 3-sec.-propyl contract Glycerose (2g, 15.3mmol), compound 2-ethanoyl-4-fluorophenol (2g, 13.0mmol); toluene (10ml), and be the mixing solutions stirring reaction 12～72 hours of the Pyrrolidine of 2-ethanoyl-4-fluorophenol weight 20%.Reaction is finished postcooling and is added 2MHCl to room temperature, and separatory with dichloromethane extraction (20 * 3) water layer, merges with the organic layer of telling previously, and with saturated sodium-chloride salt water washing (20 * 3) organic phase, uses MgSO
4Dry organic phase, with organic phase by revolve steam to remove desolvate solid, the solid residue that obtains carries out column chromatography to be separated, purifying gets product (2R)-2-[(1R)-4,4-dimethyl-3, the assorted oxygen cyclopentyl of 5-two]-6-fluorobenzene and dihydropyrane-4-ketone and (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone.
5. (R)-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-two pure and mild (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol
With (2R)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone (4g, 15.2mmol), ethanol (40ml), 15% hydrochloric acid (120ml) and zinc amalgam (90g) join in the reaction flask, reacted 12～72 hours, and then add 12% hydrochloric acid (36ml), stir and continue reaction, after reaction is finished, question response mixture cool to room temperature after-filtration, filtrate with ethyl acetate extraction after with the washing of saturated salt solution to neutral, the anhydrous sodium sulfate drying organic phase obtains heavy-gravity liquid, purified obtaining (R)-1-((S)-6-fluoro-3 with organic phase except that after desolvating, 4-dihydrobenzopyrans base) ethane-1,2-glycol white solid.
6. (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester and (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester
In reactor, add 0.5g (R)-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the 2-glycol, add the dissolving of 10ml exsiccant pyridine, stir, dropwise drip the pyridine solution of the 0.5g Tosyl chloride that contains purifying then, the two mixes stirring, 24～48 hours reaction times; Add frozen water to reaction system again, use extracted with diethyl ether, with the salt pickling of 2M, saturated aqueous common salt cleans organic phase, and anhydrous sodium sulphate is carried out drying to organic phase, filter, revolve steaming, organic phase obtain after removing and desolvating thick liquid, purified (R)-2-((S)-6-fluoro-3 that obtains respectively, the solid of 4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester and (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester.
7. (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol
((S)-6-fluoro-3, (1.5g 4.1mmol) joins in the reaction flask with 25ml exsiccant methyl alcohol 4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester, then logical exsiccant NH in reaction system with (R)-2-
3, reaction system is heated to 25～80 ℃ of reactions, instead with after finishing, question response system cooling back underpressure distillation is removed reaction solvent and is obtained crude product, and purifying crude is obtained (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol.
8. (+)-[S, R, R, R]-2,2 '-[imino-diacetic (methylene radical)] be two-(6-fluoro-3,4-dihydrobenzopyrans base)-2-methyl alcohol
In reactor, add 0.11g (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol and 0.19g (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester, use dissolve with methanol, stirring reaction in the presence of the catalyzer Anhydrous potassium carbonate then with the system cool to room temperature, refilters and uses CH after removing reaction solvent
2Cl
2The dissolving residue extracted, saturated common salt is washed to neutrality, filters, and revolves to steam except that desolvating to obtain solid, obtain after purified (+)-[R, R, R, S] white solid of-2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydrobenzopyrans base)-2-methyl alcohol.
9. (R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be the preparation of your hydrochloride of pyrroles how for R, R:
In reactor, add 0.1g (+)-[R, R, R, S]-2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydrobenzopyrans base)-and 2-methyl alcohol and exsiccant dichloromethane solution, fed the exsiccant hydrogen chloride gas under the room temperature again 6～18 hours, stir, revolve steaming,, filter and obtain (R with the trichloromethane washing, R, R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be the white solid of your hydrochloride of pyrroles how.
Embodiment 2
1. two acetone N.F,USP MANNITOL is synthetic
In reactor, the 80g Zinc Chloride Anhydrous joined in the 500ml acetone stirs,, be cooled to 0～5 ℃, add 50g N.F,USP MANNITOL again, the solution that back adding 100g salt of wormwood is dissolved in 100ml water is finished in reaction, termination reaction, adds 100ml ether, static for some time subsequently, filter, revolve steam solid, remove the zine ion in the product with methylene dichloride dissolving, washing, use dried over mgso, revolve steaming except that desolvating and obtain two acetone N.F,USP MANNITOL, purifying obtains the white solid pure substance.
2. Glycerose contracts for (R)-2,3-sec.-propyl
Use CH
2Cl
2(100ml) (11g, 0.043mol) dissolving at room temperature joins solution saturated NaHCO with compound two acetone N.F,USP MANNITOL
3In the aqueous solution (4ml), under agitation slowly add NaIO
4(17.6g, 0.083mol), the limit edged stirs, and reacts 1～5 hour, reacts the after-filtration that finishes.The remaining liq that obtains after the filtrate distillation is moved to underpressure distillation in the little container, obtain compound (R)-2, the 3-sec.-propyl Glycerose that contracts.
3.2-ethanoyl-4-fluorophenol
With the 4-fluorophenol (83g, 0.74mol) and Acetyl Chloride 98Min. (158ml 2.22mol) joins in the three-necked bottle, and stirring reaction is after 30 minutes, adds AlCl
32.0g (1.5mol), stirring reaction is 20～40 minutes.React 8 hours postcooling down to room temperature at 60 ℃ then.With H
2O (200ml) joins in the reaction mixture, filters and obtains filter cake, is thick product.Crude product obtains target product behind the sherwood oil recrystallization.
4. (2R)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone and (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone
In reactor, with compound 2-ethanoyl-4-fluorophenol (3.08g, 20.0mol), (R)-2, the 3-sec.-propyl Glycerose (3.3g that contracts, 25.2mol), absolute ethanol (20ml), and be the mixing solutions stirring reaction 12～72 hours of the pyrrolidone of 2-ethanoyl-4-fluorophenol weight 80%, stir it is dissolved fully; Reaction is finished postcooling and is added 2M HCl neutralization to room temperature, and separatory with dichloromethane extraction (20 * 3) water layer, merges with the organic layer of telling previously, and with saturated sodium-chloride salt water washing (20 * 3) organic phase, uses MgSO
4Dry organic phase, with organic phase by revolve steam to remove desolvate solid, the solid residue that obtains carries out column chromatography to be separated, purifying gets product (2R)-2-[(1R)-4,4-dimethyl-3, the assorted oxygen cyclopentyl of 5-two]-6-fluorobenzene and dihydropyrane-4-ketone and (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone.
5. (R)-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-two pure and mild (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol
With (2R)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone 2.0g, the 80g zinc amalgam, the hydrochloric acid of 88ml 15%, 48ml ethanol joins in the reaction flask, 25～40 ℃ of reactions 12～72 hours, the hydrochloric acid that adds 40ml 12% behind the stirring reaction again, stir and continue reaction, after reaction is finished, question response mixture cool to room temperature after-filtration, filtrate with ethyl acetate extraction after with the washing of saturated salt solution to neutral, the anhydrous sodium sulfate drying organic phase obtains heavy-gravity liquid, purified obtaining (R)-1-((S)-6-fluoro-3 with organic phase except that after desolvating, 4-dihydrobenzopyrans base) ethane-1,2-glycol white solid.
6. (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester and (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester
In reactor, with (R)-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, (1.0g 4.7mmol) is dissolved in exsiccant pyridine (20ml) to the 2-glycol, stirs, dropwise drip the Tosyl chloride (1.0g of purifying then, 4.8mmol) solution, the two mixes the back and stirs 24～48 hours reaction times; In mixing solutions, add frozen water again, use extracted with diethyl ether then, with dilute hydrochloric acid and saturated NaHCO
3Solution cleans organic phase, uses MgSO at last
4Organic phase is carried out drying, filter, revolve steaming.Organic phase obtains crude product after removing and desolvating, crude product is purified to obtain (R)-2-((S)-6-fluoro-3 respectively, the solid of 4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester and (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester.
7. (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol
In reactor, add (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester (1.0g, 2.7mmol), with 20ml exsiccant dissolve with methanol, stir, feed the exsiccant ammonia, reaction system is heated to 25～80 ℃ of reactions, question response system cooling back underpressure distillation is removed reaction solvent and is obtained crude product, purifying crude is obtained (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol.
8. (+)-[S, R, R, R]-2,2 '-[imino-diacetic (methylene radical)] be two-(6-fluoro-3,4-dihydrobenzopyrans base)-2-methyl alcohol
In reactor, add 0.11g (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol and 0.19g (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester, use dissolve with methanol, stirring reaction in the presence of catalyzer 10% sodium hydroxide solution then with the system cool to room temperature, refilters and uses CH after removing reaction solvent
2Cl
2The dissolving residue extracted, saturated common salt is washed to neutrality, filters, and revolves to steam except that desolvating to obtain solid, obtain after purified (+)-[R, R, R, S] white solid of-2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydrobenzopyrans base)-2-methyl alcohol.
9. (R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be the preparation of your hydrochloride of pyrroles how for R, R:
In reactor, add 0.1g (+)-[R, R, R, S]-2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydrobenzopyrans base)-2-methyl alcohol and exsiccant dichloromethane solution, feed the exsiccant hydrogen chloride gas again, stir, reacted 18 hours, revolve steaming, get solid, add the trichloromethane washing, filter (R, R, R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be the white solid of your hydrochloride of pyrroles how.
Claims (6)
1. one kind (R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be the synthetic method of your hydrochloride of pyrroles how for R, R, wherein, and the synthesizing of Glycerose:
The aldehyde of compound 1 synthesizes:
(1) in reactor, catalyzer joined in the acetone solvent stir, and then add N.F,USP MANNITOL, wherein N.F,USP MANNITOL: the mol ratio of catalyzer is 1: 1～4, and room temperature reaction adds the solution of potassium carbonate termination reaction; Add ether solvent subsequently, filter, revolve steam solid, with dichloromethane solvent dissolving, the zine ion in the water flush away product, drying, revolve and steam that removing desolvates obtains two acetone N.F,USP MANNITOL, purifying obtains the white solid pure substance of acetone mannitan then;
(2) use CH
2Cl
2Acetone mannitan dissolving with step (1) obtains at room temperature joins solution saturated NaHCO then
3In the aqueous solution, slowly add oxygenant NaIO again
4, the limit edged stirs, and reacts the after-filtration that finishes; The remaining liq that obtains after the filtrate distillation is moved to underpressure distillation in the container, obtain Glycerose;
(3) 4-fluorophenol and Acetyl Chloride 98Min. are joined in the reactor, wherein the mol ratio of 4-fluorophenol and Acetyl Chloride 98Min. is 1: 1～3, adds the catalyzer stirring reaction 20～40 minutes, reacts postcooling down to room temperature at 50～160 ℃ then; Water is joined in the reaction mixture, filter and obtain filter cake, be thick product, crude product obtains 2-ethanoyl-4-fluorophenol behind the sherwood oil recrystallization;
(4) the 2-ethanoyl-4-fluorophenol and toluene or the absolute ethanol solvent that obtain of the Glycerose that step (2) is obtained, step (3); Add catalyzer and mix solution, add HCl after reaction is finished, use CH
2Cl
2Extraction, and with saturated sodium-chloride salt water washing organic phase, dry organic phase; Organic phase is desolvated by revolving to steam to remove, the solid residue that obtains carries out column chromatography to be separated, purifying obtains (2R)-2-[(1R)-4 respectively, 4-dimethyl-3, the assorted oxygen cyclopentyl of 5-two]-6-fluorobenzene and dihydropyrane-4-ketone and (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone;
(5) (2R)-2-[(1R)-4 that step (4) is obtained, 4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone, ethanol, hydrochloric acid and zinc amalgam join in the reactor and react, (2R)-2-[(1R)-4 wherein, 4-dimethyl-3, the assorted oxygen cyclopentyl of 5-two]-mol ratio of 6-fluorobenzene and dihydropyrane-4-ketone and zinc amalgam is 1: 10～250, and then adding hydrochloric acid, stir and continue reaction, after reaction is finished, question response mixture cool to room temperature after-filtration, filtrate with ethyl acetate extraction after with the washing of saturated salt solution, dry organic phase obtains thick product with organic phase except that after desolvating, and slightly product is purified obtains (R)-1-((S)-6-fluoro-3 respectively, 4-dihydrobenzopyrans base) ethane-1,2-two pure and mild (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the 2-glycol;
(6) (R)-1-that step (5) is obtained ((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the 2-glycol is dissolved in the exsiccant pyridine solvent, the Tosyl chloride of purifying also is dissolved in the exsiccant pyridine solvent, the two mixes stirring, wherein ((R)-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the mol ratio of 2-glycol and Tosyl chloride is 1: 1～1.5mol, 24～48 hours reaction times; In mixing solutions, add frozen water again, use extracted with diethyl ether then, with dilute hydrochloric acid and saturated NaHCO
3Solution cleans organic phase, and organic phase is carried out drying; Organic phase obtains crude product after removing and desolvating, crude product is purified to obtain (R)-2-((S)-6-fluoro-3 respectively, 4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester and (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester;
(7) (R)-2-that step (6) is obtained ((S)-6-fluoro-3,4-dihydrobenzopyrans base-2-hydroxyethyl-4-toluene sulfonic acide ester and exsiccant ethanol or methanol solvate join in the reactor, in reaction system, lead to the exsiccant ammonia then, behind the logical exsiccant ammonia reaction system is heated to 25～80 ℃ of reactions, instead with after finishing, question response system cooling back underpressure distillation is removed reaction solvent and is obtained crude product, purifying crude is obtained (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol;
(8) (R)-2-that step (6) is obtained ((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester, (R)-2-amino-1-((S)-6-fluoro-3 that step (7) obtains, 4-dihydrobenzopyrans base) ethanol and exsiccant ethanol or methanol solvate join in the reactor, stirring reaction in the presence of catalyzer, (R)-2-((R)-6-fluoro-3 wherein, 4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester with (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) the alcoholic acid mol ratio is 1: 1～1.5mol, then with the system cool to room temperature, refilter and use CH after removing reaction solvent
2Cl
2The dissolving resistates refilters that removing desolvates obtains crude product, obtain after crude product is purified (+)-[R, R, R, S]-2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydrobenzopyrans base)-2-methyl alcohol;
(9) in reactor, (+)-[R, R that step (8) is obtained, R, S]-2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydrobenzopyrans base)-and the 2-dissolve with methanol is in exsiccant methyl alcohol or methylene dichloride, and feeding exsiccant hydrogen chloride gas revolves steaming under the room temperature, with the trichloromethane washing, filter and obtain (R, R, R, S) 2,2 '-[imino-diacetic (methylene radical)] two-(6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-methyl alcohol) be your hydrochloride white solid of pyrroles how.
2. according to the described method of claim 1, it is characterized in that: the oxygenant NaIO of described step (2)
4Add-on be 1～2 times of acetone mannitan material mass.
3. according to the described method of claim 1, it is characterized in that: the catalyst levels of described step (4) is 20%～80% of 2-ethanoyl-4-fluorophenol weight.
4. according to claim 1 or 3 described methods, it is characterized in that: described catalyzer is selected from a kind of in anhydrous stannous chloride, Zinc Chloride Anhydrous, Pyrrolidine, pyrrolidone, piperidines, Anhydrous potassium carbonate or the sodium hydroxide.
5 according to the described method of claim 1, it is characterized in that: the add-on of described step (4) HCl is 2mol/L.
6. according to the described method of claim 1, it is characterized in that: described concentration of hydrochloric acid is 12wt%～20wt%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510125663 CN1978442A (en) | 2005-12-02 | 2005-12-02 | (R,R,R,S)2,2'-[imino-di(methylen)] di-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol) nebivolo chloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510125663 CN1978442A (en) | 2005-12-02 | 2005-12-02 | (R,R,R,S)2,2'-[imino-di(methylen)] di-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol) nebivolo chloride |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311418A (en) * | 2010-06-29 | 2012-01-11 | 成都康弘药业集团股份有限公司 | Preparation method for benzodihydropyran compound |
| CN103193756A (en) * | 2013-04-12 | 2013-07-10 | 四川铂瑞生物医药有限公司 | Synthesis method of D-mannitol bisketal |
| CN104829584A (en) * | 2015-05-19 | 2015-08-12 | 江苏福瑞生物医药有限公司 | Synthesis method of (R)-glyceraldehyde acetonide compound |
| US10526304B2 (en) | 2015-05-19 | 2020-01-07 | Zhejiang Ausun Pharmaceutical Co., Ltd. | Nebivolol synthesis method and intermediate compound thereof |
-
2005
- 2005-12-02 CN CN 200510125663 patent/CN1978442A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311418A (en) * | 2010-06-29 | 2012-01-11 | 成都康弘药业集团股份有限公司 | Preparation method for benzodihydropyran compound |
| CN102311418B (en) * | 2010-06-29 | 2013-12-25 | 成都康弘药业集团股份有限公司 | Preparation method for benzodihydropyran compound |
| CN103193756A (en) * | 2013-04-12 | 2013-07-10 | 四川铂瑞生物医药有限公司 | Synthesis method of D-mannitol bisketal |
| CN104829584A (en) * | 2015-05-19 | 2015-08-12 | 江苏福瑞生物医药有限公司 | Synthesis method of (R)-glyceraldehyde acetonide compound |
| US10526304B2 (en) | 2015-05-19 | 2020-01-07 | Zhejiang Ausun Pharmaceutical Co., Ltd. | Nebivolol synthesis method and intermediate compound thereof |
| US11142512B2 (en) | 2015-05-19 | 2021-10-12 | Zhejiang Ausun Pharmaceutical Co., Ltd. | Nebivolol synthesis method and intermediate compound thereof |
| EP3974419A2 (en) | 2015-05-19 | 2022-03-30 | Zhejiang Ausun Pharmaceutical Co., Ltd. | Nebivolol synthesis method and intermediate compound thereof |
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