CN1974565A - Process of racemizing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-formic acid - Google Patents
Process of racemizing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-formic acid Download PDFInfo
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- CN1974565A CN1974565A CN 200610155118 CN200610155118A CN1974565A CN 1974565 A CN1974565 A CN 1974565A CN 200610155118 CN200610155118 CN 200610155118 CN 200610155118 A CN200610155118 A CN 200610155118A CN 1974565 A CN1974565 A CN 1974565A
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Abstract
The present invention discloses process of racemizing 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-formic acid. The racemizing process includes the following steps: 1. selecting the residual mixture from racemized 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-formic acid resolving process as the material A, and at least one of (+)-(S)-6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-formic acid, (-)-(R)-6- fluoro-3, 4-dihydro-2H-1- benzopyran-2-formic acid, (2R)-6-fluoro-3, 4-dihydro -N-(dehydroabietylamino)- 2H-1-benzopyran-2-formamide, and (2S)-6-fluoro-3, 4-dihydro -N-(dehydroabietylamino) -2H-1-benzopyran -2- formamide as material B; and 2. dissolving material A and material B in solvent, adding alkali and heating reflux to obtain solution; and extracting the product directly in water or after evaporating solvent.
Description
Technical field
The present invention relates to a kind of cardiovascular agent key intermediate 6-fluoro-3, the treatment process of 4-dihydro-2H-1-chromene-2-formic acid, particularly the 6-fluoro-3, the racemization method of 4-dihydro-2H-1-chromene-2-formic acid.
Background technology
3, the structural unit of 4-dihydro-2H-1-chromene ring extensively is present in the molecular structure of many biologically actives, for example the antihypertensive drug of vitamin-E and many β1-Shou Ti antagonists.Fluorine atom has more increased its physiologically active in the introducing of phenyl ring.6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid can be used as the intermediate of multiple fluorine-containing benzopyrans compounds, occupies an important position in medicine is synthetic.Particularly importantly the 6-fluoro-3, and 4-dihydro-2H-1-chromene-2-formic acid (I) is the key intermediate as synthetic cardiovascular agent nebivolol.(S, R, R, R)-and nebivolol (nebivololol) is as novel hypotensor, has height β1Shou Ti selectivity and has slight vasorelaxation action concurrently, and heart failure patient tolerate.This compound can make through several different paths, a wherein most important and unique industrialized synthetic method is document EP 334429 reports, this method is by racemize 6-fluoro-3, ((±)-I) divides two lines finally synthetic nebivolol through being split as R to 4-dihydro-2H-1-chromene-2-formic acid behind the S enantiomorph.6-fluoro-3, the fractionation of 4-dihydro-2H-1-chromene-2-formic acid racemic modification determines the net result of this synthetic method, to racemize 6-fluoro-3, the resolution process Research Significance of 4-dihydro-2H-1-chromene-2-formic acid is great.
334429 reported method of document EP adopt racemize 6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid is raw material, generate diastereomer (2R)-6-fluoro-3 with chiral selectors dehydroabietylamine (II), 4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide (III-1) and (2S)-6-fluoro-3,4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide (III-2), separate this diastereomer fractionation of hydrolysis at last and promptly obtain 6-fluoro-3 respectively, left dextrorotatory form ((-)-(R)-I, (+)-(S)-I) of 4-dihydro-2H-1-chromene-2-formic acid.Concrete route is as follows:
In this resolution process, racemic 6-fluoro-3, the amide blend that 4-dihydro-2H-1-chromene-2-formic acid and resolution reagent generate is through obtaining a pair of diastereomer III-1 and III-2 behind the recrystallization repeatedly, and having a large amount of amide blend residues in this sepn process can't separate.In this resolution process, need at last amide hydrolysis is obtained the left and right 6-of revolving fluoro-3 respectively, 4-dihydro-2H-1-chromene-2-formic acid, hydrolyzed product need just can obtain highly purified optically active 6-fluoro-3 through recrystallization repeatedly, 4-dihydro-2H-1-chromene-2-formic acid, have the 6-fluoro-3 of unhydrolysed acid amides and optically-active in this process, 4-dihydro-2H-1-chromene-2-formic acid mixtures residue can't be separated.
Remaining mixture contains III-1, III-2, (-)-(R)-I and (+)-(the S)-I of unknown ratio in the split process, can't purify by conventional separation method more, therefore can't directly drop in the thick product of next batch and reuse, directly outwell and then cause very big waste, and cause the total recovery of this resolution process very low, cost is very high.How to address this problem, do not see relevant report as yet.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of 6-fluoro-3 that makes optically-active, the method of 4-dihydro-2H-1-chromene-2-formic acid racemization, use that this method can be reported above-mentioned document EP 334429 about racemize 6-fluoro-3, the mixture of the III-1 that contains unknown ratio, III-2, (-)-(R)-I and (+)-(the S)-I that produces in 4-dihydro-2H-1-chromene-2-formic acid split process is converted into racemize 6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid.
In order to solve the problems of the technologies described above, the invention provides a kind of 6-fluoro-3 that makes optically-active, the method for 4-dihydro-2H-1-chromene-2-formic acid racemization, carry out following steps successively:
1), select for use following substance A or substance B as raw material:
Document EP 334429 report about racemize 6-fluoro-3, (+)-(S) of the containing unknown ratio-6-fluoro-3 that produces in 4-dihydro-2H-1-chromene-2-formic acid split process, 4-dihydro-2H-1-chromene-2-formic acid, (-)-(R)-6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid, (2R)-6-fluoro-3,4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide and (2S)-6-fluoro-3, the mixture of 4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide is as substance A;
(+)-(S)-6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid, (-)-(R)-6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid, (2R)-6-fluoro-3,4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide and (2S)-6-fluoro-3, at least a in 4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide as substance B;
2), described raw material put into solvent dissolve, the mass ratio of described solvent and raw material is 1～20: 1; And add alkali as catalyzer according to the ratio that every 100mL solvent adds 1～5g alkali, behind the heating reflux reaction solution; Solvent in the evaporate to dryness solution or directly solution is poured in the water then extracts, pickling, washing, drying, evaporate to dryness, recrystallization more successively, 6-fluoro-3, the raceme of 4-dihydro-2H-1-chromene-2-formic acid.
Specifically: substance B above-mentioned steps 1) can be (+)-(S)-6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid, (-)-(R)-6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid, (2R)-6-fluoro-3,4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide, (2S)-6-fluoro-3, in 4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide any a kind, perhaps any 2 kinds mixture (these 2 kinds arbitrarily part by weight mix mutually, but all can not weight be 0), perhaps any 3 kinds mixture (these 3 kinds arbitrarily part by weight mix mutually, but all can not weight be 0), perhaps above-mentioned 4 kinds mixture (these 4 kinds arbitrarily part by weight mix mutually, but all can not weight be 0).
Improvement as the inventive method: solvent is ethanol, ethylene glycol monomethyl ether or ethylene glycol; Alkali is potassium hydroxide, sodium hydroxide or calcium hydroxide; The time of heating reflux reaction is 2～8 hours; Adopt ethyl acetate or ether as solvent in the described extraction step, adopting weight concentration in the acid pickling step is that 10% hydrochloric acid is washed till pH=2～3, adopt tap water or distilled water to be washed till pH=5～6 in the water-washing step, adopt Calcium Chloride Powder Anhydrous or anhydrous sodium sulphate to descend dry 1～2 hour at 0～30 ℃ in the drying step, adopting toluene in the re-crystallization step is solvent.
Method of the present invention has following advantage:
Method provided by the invention can be with racemize 6-fluoro-3 in the EP334429 method, the mixture of the III-1 that contains unknown ratio, the III-2, (-)-(R)-I and (+)-(the S)-I that can't be again purified by conventional separation method that produces in 4-dihydro-2H-1-chromene-2-formic acid split process is converted into racemize 6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid.Adopt the racemic modification after the inventive method transforms to connect the production that drops into next batch as raw material, can improve utilization ratio of raw materials, reduce the cost of product.Adopt the inventive method can make the racemize 6-fluoro-3 in the residue mother liquor of fractionation back in the EP334429 technology, the total yield of 4-dihydro-2H-1-chromene-2-formic acid reaches more than 80%.
Method of the present invention can also be used for III-1, III-2, (-)-(R)-I and (+)-(S)-I at least a (any a kind, any 2 kinds mixture, any 3 kinds mixture or above-mentioned 4 kinds mixture) all is converted into racemize 6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid.Realized can be after fractionation only need using 6-fluoro-3, during enantiomer of 4-dihydro-2H-1-chromene-2-formic acid, can be reused for during next splits the waste in avoiding splitting after another enantiomer racemization.
Therefore method of the present invention can directly drop into the racemic modification after transforming in the fractionation production of next batch as raw material, and this method can improve the utilization ratio of raw materials in this resolution process, reduces the cost of product.
Embodiment
Embodiment 1,
9.8g separating respectively by the EP334429 method, racemize 6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid obtain 6.3g III-1,6.8g III-2; Contain III-1, III-2, (-)-(R)-I and (+)-(the S)-I of unknown ratio in the surplus solution after the separation, this surplus solution solvent evaporated after mixing is got the 10.5g light yellow oil.Above-mentioned light yellow oil adding 100mL ethylene glycol, 2g potassium hydroxide are mixed, and stirring and refluxing 4h gets solution; Pour in the 100mL water after the solution cooling, 3 * 100mL ethyl acetate extraction, extract is washed till pH=2～3,3 * 50mL distilled water with 3 * 50mL weight concentration, 10% hydrochloric acid and is washed till pH=5～6,0～30 ℃ of drying of Calcium Chloride Powder Anhydrous, filter, remove solvent under reduced pressure, get yellow solid, use the toluene recrystallization, white crystal 3.6g, m.p.125～126 ℃, [α]
D 20=0 °, be racemize 6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid.
Embodiment 2,
Obtain 6.3g III-1 9.8g racemize 6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid separate respectively by the EP334429 method, 6.8g III-2 obtains 1.0g (-)-(R)-I and 1.1g (+)-(S)-I through hydrolysis, recrystallization purifying respectively again; Rest solution behind hydrolysis, recrystallization all contains III-1, III-2, (-)-(R)-I and (+)-(the S)-I of unknown ratio, and above-mentioned surplus solution solvent evaporated after mixing is got the 8.3g light yellow oil.Above-mentioned light yellow oil adding 50mL ethylene glycol, 2g potassium hydroxide are mixed, and stirring and refluxing 4h gets solution; Pour in the 50mL water after the solution cooling, 3 * 50mL ethyl acetate extraction, extract is washed till pH=2～3,3 * 30m tap water with 3 * 30mL, 10% hydrochloric acid and is washed till pH=5～6,0～30 ℃ of drying of anhydrous sodium sulphate, filter, remove solvent under reduced pressure, get yellow solid, use the toluene recrystallization, white crystal 2.1g, m.p.125～126 ℃, [α]
D 20=0 °.
Embodiment 3,
2.5g (+)-(S)-I adds the dissolving of 50mL ethylene glycol monomethyl ether, adds 0.5g potassium hydroxide, stirring and refluxing 6h gets solution; With the solution decompression solvent evaporated, the 50mL ethyl acetate extraction, extract is washed till pH=2～3,3 * 20mL tap water with 3 * 20mL10% hydrochloric acid and is washed till pH=5～6,0～30 ℃ of drying of anhydrous sodium sulphate, filter, boil off solvent, get white solid, use the toluene recrystallization, white crystal 2.2g, m.p.125～126 ℃, [α]
D 20=0 °.
Embodiment 4,
2.5g (+)-(S)-I adds the 50mL dissolve with ethanol, adds 0.5g potassium hydroxide, stirring and refluxing 8h gets solution; With the solution decompression solvent evaporated, the 50mL ethyl acetate extraction, extract is washed till pH=2～3,3 * 20mL distilled water with 3 * 20mL, 10% hydrochloric acid and is washed till pH=5～6,0～30 ℃ of drying of anhydrous sodium sulphate, filter, boil off solvent, get white solid, use the toluene recrystallization, white crystal 2.3g, m.p.125～126 ℃, [α]
D 20=0 °.
Embodiment 5,
2.5g (+)-(S)-I adds the dissolving of 50mL ethylene glycol monomethyl ether, adds 1.5g sodium hydroxide, stirring and refluxing 6h gets solution; With the solution decompression solvent evaporated, the 50mL ethyl acetate extraction, extract is washed till pH=2～3,3 * 20mL distilled water with 3 * 20mL10% hydrochloric acid and is washed till pH=5～6,0～30 ℃ of drying of anhydrous sodium sulphate, filter, boil off solvent, get white solid, use the toluene recrystallization, white crystal 2.1g, m.p.125～126 ℃, [α]
D 20=0 °.
Embodiment 6,
2g (+)-(S)-I mixes with 0.5g (-)-(R)-I, adds the 50mL dissolve with ethanol, adds 0.5g potassium hydroxide, and stirring and refluxing 8h gets solution; With the solution decompression solvent evaporated, the 50mL ethyl acetate extraction, extract is washed till pH=2～3,3 * 20mL distilled water with 3 * 20mL, 10% hydrochloric acid and is washed till pH=5～6,0～30 ℃ of drying of anhydrous sodium sulphate, filter, boil off solvent, get white solid, use the toluene recrystallization, white crystal 2.3g, m.p.125～126 ℃, [α]
D 20=0 °.
Embodiment 7,
2.5g (-)-(R)-I adds the 50mL dissolve with ethanol, adds 0.5g potassium hydroxide, stirring and refluxing 8h gets solution; With the solution decompression solvent evaporated, the 50mL ethyl acetate extraction, extract is washed till pH=2～3,3 * 20mL distilled water with 3 * 20mL, 10% hydrochloric acid and is washed till pH=5～6,0～30 ℃ of drying of anhydrous sodium sulphate, filter, boil off solvent, get white solid, use the toluene recrystallization, white crystal 2.3g, m.p.125～126 ℃, [α]
D 20=0 °.
Embodiment 8,
1g (-)-(R)-I mixes with 1.5g III-1, adds the dissolving of 30mL ethylene glycol, adds 1g potassium hydroxide, and stirring and refluxing 4h gets solution; Pour in the 30mL water after the solution cooling, 3 * 50mL ethyl acetate extraction, extract is washed till pH=2～3,3 * 20mL distilled water with 3 * 20mL, 10% hydrochloric acid and is washed till pH=5～6,0～30 ℃ of drying of Calcium Chloride Powder Anhydrous, filter, remove solvent under reduced pressure, get yellow solid, use the toluene recrystallization, white crystal 1.4g, m.p.125～126 ℃, [α]
D 20=0 °.
Embodiment 9,
4g III-1 mixes with 6g III-2, and adding 100mL ethylene glycol, 2g potassium hydroxide mix, and stirring and refluxing 4h gets solution; Pour in the 100mL water after the solution cooling, 2 * 100mL ethyl acetate extraction, extract is washed till pH=2～3,3 * 50m distilled water with 3 * 50mL, 10% hydrochloric acid and is washed till pH=5～6,0～30 ℃ of drying of Calcium Chloride Powder Anhydrous, filter, remove solvent under reduced pressure, get yellow solid, use the toluene recrystallization, white crystal 3.8g, m.p.125～126 ℃, [α]
D 20=0 °.
At last, it is also to be noted that what more than enumerate only is several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (7)
1, a kind of 6-fluoro-3 that makes optically-active, the method for 4-dihydro-2H-1-chromene-2-formic acid racemization is characterized in that carrying out successively following steps:
1), select for use following substance A or substance B as raw material:
Document EP 334429 report about racemize 6-fluoro-3, (+)-(S) of the containing unknown ratio-6-fluoro-3 that produces in 4-dihydro-2H-1-chromene-2-formic acid split process, 4-dihydro-2H-1-chromene-2-formic acid, (-)-(R)-6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid, (2R)-6-fluoro-3,4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide and (2S)-6-fluoro-3, the mixture of 4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide is a substance A;
(+)-(S)-6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid, (-)-(R)-6-fluoro-3,4-dihydro-2H-1-chromene-2-formic acid, (2R)-6-fluoro-3,4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide and (2S)-6-fluoro-3, at least a in 4-dihydro-N-(dehydrogenation fir amino)-2H-1-chromene-2-methane amide as substance B;
2), described raw material put into solvent dissolve, the mass ratio of described solvent and raw material is 1～20: 1; And add alkali as catalyzer according to the ratio that every 100mL solvent adds 1～5g alkali, behind the heating reflux reaction solution; Solvent in the evaporate to dryness solution or directly solution is poured in the water then extracts, pickling, washing, drying, evaporate to dryness, recrystallization more successively, 6-fluoro-3, the raceme of 4-dihydro-2H-1-chromene-2-formic acid.
2, the 6-fluoro-3 that makes optically-active according to claim 1, the method for 4-dihydro-2H-1-chromene-2-formic acid racemization is characterized in that: described solvent is ethanol, ethylene glycol monomethyl ether or ethylene glycol.
3, the 6-fluoro-3 that makes optically-active according to claim 2, the method for 4-dihydro-2H-1-chromene-2-formic acid racemization is characterized in that: described alkali is potassium hydroxide, sodium hydroxide or calcium hydroxide.
4, the 6-fluoro-3 that makes optically-active according to claim 3, the method for 4-dihydro-2H-1-chromene-2-formic acid racemization is characterized in that: the time of described heating reflux reaction is 2～8 hours.
5, the 6-fluoro-3 that makes optically-active according to claim 4, the method of 4-dihydro-2H-1-chromene-2-formic acid racemization, it is characterized in that: adopt ethyl acetate or ether in the described extraction step as solvent, adopting weight concentration in the acid pickling step is that 10% hydrochloric acid is washed till pH=2～3, adopt tap water or distilled water to be washed till pH=5～6 in the water-washing step, adopt Calcium Chloride Powder Anhydrous or anhydrous sodium sulphate to descend dry 1～2 hour at 0～30 ℃ in the drying step, adopting toluene in the re-crystallization step is solvent.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2006101551187A CN100491365C (en) | 2006-12-08 | 2006-12-08 | Process of racemizing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-formic acid |
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| CNB2006101551187A CN100491365C (en) | 2006-12-08 | 2006-12-08 | Process of racemizing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-formic acid |
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| CN100491365C CN100491365C (en) | 2009-05-27 |
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| CN102209707B (en) * | 2008-11-07 | 2014-07-09 | 优时比制药有限公司 | Novel process for the preparation of amino acid derivatives |
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| CN102209707B (en) * | 2008-11-07 | 2014-07-09 | 优时比制药有限公司 | Novel process for the preparation of amino acid derivatives |
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