CN100387586C - Synthetic process of chiral 2-amido-1-(6-fluorine-3,4-dihydrobenzopyranyl) alCohol - Google Patents
Synthetic process of chiral 2-amido-1-(6-fluorine-3,4-dihydrobenzopyranyl) alCohol Download PDFInfo
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Abstract
The present invention belongs to the field of organic chemistry, particularly to a synthetic method for medicine intermediates (R)-2-aminyl-1-((R)-6-fluorine-3, 4-dihydro benzopyran radical) ethyl alcohol and (R)-2-aminyl-1-((S)-6-fluorine-3, 4-dihydro benzopyran radical) ethyl alcohol. The method of the present invention uses medicine intermediates (2R)-2-[(1R)-4, 4-dimethyl-3, 5-dioxo cyclopentyl]-6-fluorine centchroman-4-ketone and (2S)-2-[(1R)-4, 4 dimethyl-3, 5-dioxo cyclopentyl]-6-fluorine centchroman-4-ketone as raw materials, products obtained by using a Clemmensens method through one-step reduction and deprotection respectively react with tosyl chloride in pyridine, products which are obtained are respectively dissolved in a solvent, and then dry ammonia is led in for heating and reflux. Total yield can reach 32 percent.
Description
Technical field
The invention belongs to organic chemistry filed, specially refer to pharmaceutical intermediate (R)-2-amido-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol, (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) alcoholic acid synthetic method.
Background technology
(R)-2-amido-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol, (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol are the important intermediate of biomedical bioactive molecule.Their synthetic method has had report in " tetrahedron ".At first after reactions such as Sharpless chiral epoxy, make chipal compounds (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (as shown in the formula described 2a), (S)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (as shown in the formula described 2b), generate p-toluenesulfonic esters with the Tosyl chloride reaction then, follow and reaction of sodium azide, hydrogenation obtains compound (R)-2-amido-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (as shown in the formula described 4a), (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (as shown in the formula described 4b).This synthetic method route is long, productive rate is low, and separates to purify and utilize post to separate mostly, and the conditional request harshness during reaction reacts restive, and total recovery is low, can't produce in batches.
Summary of the invention
It is too much to the objective of the invention is to overcome the reactions steps that exists in the prior art, the operation complexity, the conditional request harshness, product purity is low, raw material reagent costs an arm and a leg, production cost is too high, yield is low, produce problems such as difficulty in batches, a kind of reaction conditions gentleness is provided, easy and simple to handle, synthetic route is short, synthetic cost is low, yield height, (R)-2-amido-1-((R)-6-fluoro-3 that suitable batch is produced, 4-dihydrobenzopyrans base) ethanol (as shown in the formula described 4a), (R)-new synthetic method of 2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (as shown in the formula described 4b).
The synthetic route of (R)-2-amido-1-provided by the invention ((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4a), (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4b) is:
(1a) described in the present invention, (1b), (2a), (2b), (3a), (3b), (4a), (4b), 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, corresponding to 1a, 1b, 2a, 2b, 3a, 3b, 4a, the 4b described in the top synthetic route, wherein, R represents dextrorotation, and the S representative is left-handed.
Chirality 2-amido-1-of the present invention (6-fluoro-3,4-dihydrobenzopyrans base) alcoholic acid synthetic method may further comprise the steps:
(1). in reaction vessel, compound 1a or 1b are mixed with freshly prepd zinc amalgam and solvent hydrochloric acid and etoh solvent, temperature of reaction is controlled at 20～60 ℃, reacted 24～72 hours, and then added solvent hydrochloric acid reflux 3～20 hours, cooling, filter, extraction, washing, dry organic phase, revolve to steam and obtain thick liquid, utilize ethyl acetate, the mixed solution recrystallization of sherwood oil or ethyl acetate and sherwood oil, obtain the white solid of 2a or 2b respectively, wherein the mol ratio of compound 1a or 1b and freshly prepd zinc amalgam is 1: 100 to 1: 150;
(2). compound 2a that step (1) is obtained or 2b are with the pyridine or the dissolving of pyrroles's solution of Tosyl chloride, stir, be cooled to-10～20 ℃, maintain the temperature at-10～20C, reacted 24～72 hours, add frozen water then, extraction, pickling, wash neutral, dry, revolve to steam and obtain solid, mixed solution recrystallization with ethyl acetate, sherwood oil or ethyl acetate and sherwood oil, obtain 3a or 3b white solid respectively, wherein the mol ratio of compound 2a or 2b and Tosyl chloride is 1: 0.9 to 1: 1.5;
(3). 3a or 3b that step (2) is obtained are dissolved in respectively in methyl alcohol or the alcohol solvent, stir, feed the exsiccant ammonia, reflux 2～24 hours, cool off, revolve steaming, dissolve with sodium hydroxide solution, extraction, washing, dry organic phase, revolve to steam and obtain solid, with ether or tetrahydrofuran (THF) recrystallization, obtain compound (R)-2-amido-1-((R)-6-fluoro-3 respectively, 4-dihydrobenzopyrans base) alcoholic acid white solid, or (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) alcoholic acid white solid.
The solvent of described step (2) is pyridine or pyrroles etc.
Described 1a is (2R)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone.
Described 1b is (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone.
Described 2a is (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the 2-glycol.
Described 2b is (S)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the 2-glycol.
Described 3a is (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester.
Described 3b is (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester.
The used acid of described pickling can be dilute hydrochloric acid etc.
The present invention adopts pharmaceutical intermediate (2R)-2-[(1R)-4; 4-dimethyl-3; 5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone (1a); (2S)-2-[(1R)-4; 4-dimethyl-3; the assorted oxygen cyclopentyl of 5-two]-6-fluorobenzene and dihydropyrane-4-ketone (1b) are raw material; utilize Clemmensens method one step reduction deprotection to obtain (R)-1-((R)-6-fluoro-3 respectively; 4-dihydrobenzopyrans base) ethane-1; 2-glycol (2a); (S)-1-((R)-6-fluoro-3; 4-dihydrobenzopyrans base) ethane-1; 2-glycol (2b); 2a and 2b obtain (R)-2-((R)-6-fluoro-3 with the Tosyl chloride reaction respectively in pyridine; 4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3a); (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3b).3a and 3b are dissolved in the solvent respectively, feed exsiccant ammonia reflux then and obtain (R)-2-amido-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4a), (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4b) obtains two kinds of solid pure substances.Of the present invention method is simple, and reaction conditions gentleness in the building-up process utilizes cheap ammonia to reduce reactions steps for raw material has reduced cost, and separation method is easy, the purification technique maturation, and total recovery can reach 32%.
Embodiment
The invention will be further described below by example.
Embodiment 1
(1). (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2a) synthetic:
In reactor, add compound 1a and freshly prepd zinc amalgam (mol ratio, 1: 120), hydrochloric acid (40ml), 48ml ethanol, stirring reaction 50 hours, and then add hydrochloric acid (20ml), reacted cooling 6 hours, filter, use ethyl acetate extraction filtrate, saturated common salt is washed to neutrality, anhydrous sodium sulfate drying filters, and revolves steaming, obtain heavy-gravity liquid (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2a).
(2). (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3a) synthetic:
In reactor, add (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2a) adds the dissolving of 10ml pyridine, stir, add then Tosyl chloride (mole this, 2a: Tosyl chloride=1: 1.0), reacted 48 hours, then, add the 10ml frozen water to reaction system, extraction, dilute hydrochloric acid is washed, the saturated common salt washing, anhydrous sodium sulfate drying filters, and revolves steaming, get thick liquid (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3a).
(3). (R)-2-amido-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4a) synthetic:
In reactor, add 1.5g (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3a), the 20ml dissolve with methanol stirs, and feeds the exsiccant ammonia, reacted 5 hours, and revolved steaming, obtain solid, with sodium hydroxide solution dissolving, extraction, washing, the Anhydrous potassium carbonate drying is filtered, and revolves steaming, obtain solid (R)-2-amido-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4a).
Embodiment 2
(1). (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2a) synthetic:
In reactor, add compound 1a, freshly prepd zinc amalgam (mol ratio, 1a: zinc amalgam=1: 1.2), 60ml hydrochloric acid, 48ml ethanol, stirring reaction 46 hours, and then add 30ml hydrochloric acid, reacted cooling 6 hours, filter, extraction filtrate, saturated common salt is washed to neutrality, anhydrous sodium sulfate drying filters, and revolves steaming, obtain heavy-gravity liquid (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2a).
(2). (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3a) synthetic:
In reactor, add (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2a) adds the dissolving of 15ml pyridine, stirs, add Tosyl chloride (mol ratio then, 2a: Tosyl chloride=1: 1.4), stirring reaction 24 hours adds the 10ml frozen water to reaction system, use extracted with diethyl ether, Diluted Acid Washing, saturated common salt washing, anhydrous sodium sulfate drying, filter, revolve steaming, get thick liquid (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3a).
(3). (R)-2-amido-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4a) synthetic:
In reactor, add 1.2g (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3a), the 20ml dissolve with methanol stirs, and feeds ammonia, reacted 6 hours, and revolved steaming and obtain solid, dissolve with sodium hydroxide solution, extraction, washing, Anhydrous potassium carbonate drying, filter, revolve steaming, obtain solid (R)-2-amido-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4a).
Embodiment 3
(1). (S)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2b) synthetic:
In reactor, add compound and freshly prepd zinc amalgam (mol ratio, 1: 110), 90ml hydrochloric acid, 48ml ethanol, stirring reaction 50 hours, and then adding dilute hydrochloric acid, reacted cooling 6 hours, filter, extraction filtrate, saturated common salt is washed to neutrality, anhydrous sodium sulfate drying filters, and revolves steaming, obtain heavy-gravity liquid (S)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the 2-glycol.
(2). (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3b) synthetic:
In reactor, add (S)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2b) adds the pyridine dissolving, stirs, add Tosyl chloride (mol ratio then, 2b: Tosyl chloride=1: 1.01), stirred 24 hours, add 10ml frozen water termination reaction to reaction system then, extraction, dilute hydrochloric acid is washed, saturated common salt washing, anhydrous sodium sulfate drying, filter, revolve steaming, get thick liquid (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester.
(3). (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4b) synthetic:
In reactor, add 1.6g (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3b) and dissolve with methanol, stir, feed ammonia, reacted 7 hours, revolve to steam and obtain solid, with sodium hydroxide solution dissolving, extraction, washing, the Anhydrous potassium carbonate drying, filter, revolve steaming, (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4b) that obtains solid.
Embodiment 4
(1) (S)-and 1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2b) synthetic:
In reactor, add compound and freshly prepd zinc amalgam (mol ratio, 1: 135), 80ml hydrochloric acid, 48ml ethanol at 25 ℃, reacted 50 hours, and then add 40ml dilute hydrochloric acid, reacted cooling 6 hours, filter, extraction filtrate, saturated common salt is washed to neutrality, anhydrous sodium sulfate drying filters, and revolves steaming, obtain heavy-gravity liquid (S)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the 2-glycol.
(2) (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3b) synthetic:
In reactor, add (S)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1,2-glycol (2b) adds the dissolving of 15ml pyridine, stirs, add Tosyl chloride (mol ratio then, 2b: Tosyl chloride=1: 1.15), stirring reaction 48 hours adds the 10ml frozen water to reaction system, use extracted with diethyl ether, dilute hydrochloric acid is washed, saturated common salt washing, anhydrous sodium sulfate drying, filter, revolve steaming, get thick liquid (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3b).
(3). (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4b) synthetic:
In reactor, add 1.8g (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester (3b), the 30ml dissolve with methanol stirs, and feeds ammonia, reacted 9 hours, steaming is revolved in cooling, obtain solid, with sodium hydroxide solution dissolving, extraction, washing, the Anhydrous potassium carbonate drying is filtered, revolve steaming, obtain solid (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) ethanol (4b).
Claims (8)
1. a chirality 2-amido-1-(6-fluoro-3,4-dihydrobenzopyrans base) alcoholic acid synthetic method, the step of described synthetic method comprises:
(1). in reaction vessel, compound 1a or 1b are mixed with freshly prepd zinc amalgam and solvent hydrochloric acid and ethanol, temperature of reaction is controlled at 20～60 ℃, and then adding solvent hydrochloric acid and reflux, cooling, filtration, extraction, washing, dry organic phase, revolve steaming, obtain thick liquid, recrystallization, obtain the white solid of 2a or 2b respectively, wherein the mol ratio of compound 1a or 1b and freshly prepd zinc amalgam is 1: 100 to 1: 150;
(2). compound 2a that step (1) is obtained or 2b are with the pyridine or the dissolving of pyrroles's solution of Tosyl chloride, stir, be cooled to-10～20 ℃, maintain the temperature at-10～20 ℃, add frozen water then, extraction, pickling, wash neutrally, dry, revolve steaming, obtain solid, recrystallization obtains 3a or 3b white solid respectively, wherein the mol ratio of compound 2a or 2b and Tosyl chloride be 1: 0.9 to 1.5;
(3). 3a or 3b that step (2) is obtained are dissolved in the solvent respectively, stir, feed the exsiccant ammonia, reflux is cooled off, is revolved steaming, dissolves with sodium hydroxide solution, extraction, washing, dry organic phase, revolve to steam and obtain solid, recrystallization obtains compound (R)-2-amido-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) alcoholic acid white solid respectively, or (R)-2-amido-1-((S)-6-fluoro-3,4-dihydrobenzopyrans base) alcoholic acid white solid;
Described 1a is (2R)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone;
Described 1b is (2S)-2-[(1R)-4,4-dimethyl-3,5-two assorted oxygen cyclopentyl]-6-fluorobenzene and dihydropyrane-4-ketone;
Described 2a is (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the 2-glycol;
Described 2b is (S)-1-((R)-6-fluoro-3,4-dihydrobenzopyrans base) ethane-1, the 2-glycol;
Described 3a is (R)-2-((R)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester;
Described 3b is (R)-2-((S)-6-fluoro-3,4-dihydrobenzopyrans base)-2-hydroxyethyl-4-toluene sulfonic acide ester.
2. method according to claim 1 is characterized in that: the compound 1a of described step (1) or 1b are 24～72 hours with the reaction times that freshly prepd zinc amalgam and solvent hydrochloric acid and ethanol mix.
3. method according to claim 1 is characterized in that: the reflux of described step (1) is 3～20 hours.
4. method according to claim 1 is characterized in that: the reaction times of described step (2) is 24～72 hours.
5. method according to claim 1 is characterized in that: described step (1) or step (2) are with ethyl acetate, sherwood oil, or the mixed solution recrystallization of ethyl acetate and sherwood oil.
6. method according to claim 1 is characterized in that: the reflux of described step (3) is 2～24 hours.
7. method according to claim 1 is characterized in that: described step (3) is with ether or tetrahydrofuran (THF) recrystallization.
8. method according to claim 1 is characterized in that: the solvent of described step (3) is methyl alcohol or ethanol.
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| BRPI0719367B8 (en) * | 2006-11-27 | 2021-05-25 | Fis Fabbrica Italiana Sintetici Spa | process for the preparation of nebivolol, its intermediates and uses |
| CN102311417B (en) * | 2010-06-29 | 2013-09-18 | 成都弘达药业有限公司 | Method for preparing benzodihydropyran compound |
| 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 |
| JP6847095B2 (en) | 2015-05-19 | 2021-03-24 | チョーチアン オウスン ファーマシューティカル カンパニー リミテッド | Nebivolol synthesis method and its intermediate compounds |
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| WO1987003584A1 (en) * | 1985-12-04 | 1987-06-18 | E.I. Du Pont De Nemours And Company | Synthesis of optically active aryloxypropanolamines and arylethanolamines |
| WO1998046586A1 (en) * | 1997-04-17 | 1998-10-22 | Astra Aktiebolag | A new process |
| WO2001092250A2 (en) * | 2000-06-02 | 2001-12-06 | Cor Therapeutics, Inc. | Synthesis of 2-acyl substituted chromanes and intermediates thereof |
| WO2002018342A2 (en) * | 2000-08-31 | 2002-03-07 | The University Of Iowa Research Foundation | Novel autoinducer molecules and uses therefor |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987003584A1 (en) * | 1985-12-04 | 1987-06-18 | E.I. Du Pont De Nemours And Company | Synthesis of optically active aryloxypropanolamines and arylethanolamines |
| WO1998046586A1 (en) * | 1997-04-17 | 1998-10-22 | Astra Aktiebolag | A new process |
| WO2001092250A2 (en) * | 2000-06-02 | 2001-12-06 | Cor Therapeutics, Inc. | Synthesis of 2-acyl substituted chromanes and intermediates thereof |
| WO2002018342A2 (en) * | 2000-08-31 | 2002-03-07 | The University Of Iowa Research Foundation | Novel autoinducer molecules and uses therefor |
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