CN1279035C - Method for synthesizing optical enantiomer 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate - Google Patents
Method for synthesizing optical enantiomer 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate Download PDFInfo
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- CN1279035C CN1279035C CNB2004100094927A CN200410009492A CN1279035C CN 1279035 C CN1279035 C CN 1279035C CN B2004100094927 A CNB2004100094927 A CN B2004100094927A CN 200410009492 A CN200410009492 A CN 200410009492A CN 1279035 C CN1279035 C CN 1279035C
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Abstract
The present invention belongs to the field of pharmaceutical chemistry. The present invention uses a method with two synthetic routes to respectively synthesize the object of ((+/-))-6-fluorine-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid; the ((+/-))-6-fluorine-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid and alcohol of C1 to C10 carry out esterification reaction to synthesize corresponding racemate ester; the ((+/-))-6-fluorine-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid is chemically split to prepare optically pure (R)-(-)-6-fluorine-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid and (S)-(+)-6-fluorine-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid. The synthetic method of the present invention has the advantages of easy raw material obtainment, low cost, easy operation, high optical purity of enantiomer products, and is suitable for large-scale industrialization production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, specially refer to intermediate optical purity (R)-(-)-6-fluoro-3 of β-suprarenal gland antagonist class antihypertensive drug, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3, the parallel pyrans of 4-dihydro-2H-1-benzene-2-carboxylic acid [(S)-(+)-1 in the formula] and their racemic carboxylic acid ester's synthetic method.
Background technology
Optical antipode (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3, the 4-dihydro-pyrans-2-carboxylic acid [(S)-(+)-1 in the formula] is a kind of medicine synthetic intermediate to 2H-1-benzene a pair of horses going side by side, is mainly used in the synthetic of β-suprarenal gland antagonist class antihypertensive drug.
About (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3, synthesizing of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula] and their carboxylic acid, ethyl ester, relevant report was arranged once.The method of European patent 0334429 is to be starting raw material with 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3), catalytic hydrogenation reduction by Pd-C makes racemic modification (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula], by racemic modification (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] and SOCl
2Reaction generates racemic compound (±)-6-fluoro-3, the acyl chlorides of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula].Reaction generates corresponding dehydroabietylamine acylate to this racemize acyl chlorides with (+)-dehydroabietylamine again.Recrystallization repeatedly then, and use the acid hydrolysis amide compound, split out (R)-(-)-6-fluoro-3 at last, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3, the parallel pyrans of 4-dihydro-2H-1-benzene-2-carboxylic acid [(S)-(+)-1 in the formula].Its reaction equation is as follows:
NHR
1=dehydrogenation fir amino
Racemic modification (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the synthetic method two] produces, United States Patent (USP) 4654362 is to be starting raw material with 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3), catalytic hydrogenation reduction through Pd-C makes racemic modification (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula], then to (±)-6-fluoro-3, feed in the ethanolic soln of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] and do HCl gas, backflow makes.
Enantiomorph (R)-(-)-6-fluoro-3 that European patent 0334429 is set forth, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3, the preparation method need of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula] are with pungency, SOCl that environmental pollution is bigger are arranged
2Do raw material, and used the agent that splits of more valuable chirality dehydroabietylamine.After the diastereomer amide compound that forms is split, also need under stronger acid or alkaline condition, just can discharge optically pure (R)-(-)-6-fluoro-3 to the amide compound hydrolysis, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula], (S)-(+)-and 6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula].And acid or the alkaline hydrolysis of amide compound under fiercer condition can make optically pure target compound [(±)-1 in the formula] that racemization takes place, and reduces its optical purity.United States Patent (USP) 4654362 has adopted to racemic modification (±)-6-fluoro-3, feed in the ethanolic soln of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] and do HCl gas, pass through catalytic esterification, synthetic racemic modification (±)-6-fluoro-3, the ethyl ester method of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula].This method has generated a large amount of acid waste liquids when producing HCl gas, be unfavorable for scale operation.And above-mentioned two patents are not illustrated the synthetic method of 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid yet.
Summary of the invention
It is unreasonable that one of purpose of the present invention is to overcome the synthetic method that exists in the prior art, reaction is polluted big, the fractionation cost height of enantiomorph, yield is low, product lot quantity production is difficulty, problems such as starting material can't domesticize, two reaction conditions gentlenesses are provided, easy and simple to handle, sequence of steps is reasonable, and is synthetic with low cost, (R)-(-)-6-fluoro-3 that suitability for industrialized is produced in batches, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3, the synthetic method of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula].
A further object of the present invention provides a kind of (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula], (S)-(+)-and 6-fluoro-3, the synthetic method of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula] ester.
Optical antipode 6-fluoro-3 provided by the invention, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and their racemic carboxylic acid ester's synthetic method is:
Synthetic method one:
(±)-1 (±)-1b
R
2=C
1～C
10Alkyl
Synthetic method two:
3 (±)-1 (±)-1b R
2=C
1～C
10Alkyl
Racemic modification (±)-6-fluoro-3 that is obtained with above-mentioned synthetic method one and synthetic method two, the 4-dihydro-pyrans-2-carboxylic acid [(±)-1 in the formula] is a starting raw material to 2H-1-benzene a pair of horses going side by side, can obtain (±) in the formula-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-expressed C of 2-carboxylicesters [(±)-1b in the formula]
1～C
10The carboxylicesters of alcohol; Can obtain (±) in the formula-6-fluoro-3 by 6-fluoro-4-oxo in the synthetic method two-4H-1-benzene a pair of horses going side by side pyrans-expressed compound of 2-carboxylic acid (3a in the formula), 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-expressed carboxylic acid, ethyl ester of 2-carboxylicesters [(±)-1a in the formula], as shown in the formula.
3a (±)-1a
(±)-6-fluoro-3 to above-mentioned two kinds of synthetic methods acquisition, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] compound carries out the fractionation of optical isomer, produced optical antipode (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula], (S)-(+)-and 6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula].Splitting the route method is:
Optical antipode involved in the present invention (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula], (S)-(+)-and 6-fluoro-3, the synthetic method of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula] and their racemate compound may further comprise the steps:
Synthetic method one:
(1) p-fluorophenol is dissolved in the inorganic alkaline aqueous solution, wherein the amount of the p-fluorophenol that adds in the system is the p-fluorophenol that adds 0.05～1.0mol in the alkaline aqueous solution with respect to 500～3500ml, the concentration of alkaline solution is 5wt%～30wt%, drip methyl-sulfate then in system, the consumption of methyl-sulfate adds 1～30ml when being 1.0～5.0 grams with respect to the weight of p-fluorophenol.Temperature of reaction is controlled at 15～85 ℃, and the reaction times is 1～40 hour, and obtaining product is that yield can reach more than 98% to fluoroanisole.
The alkali that reaction system is used can be sodium hydroxide, potassium hydroxide, yellow soda ash or sodium bicarbonate etc.
(2) amount to fluoroanisole that fluoroanisole is dissolved in respect to 0.1～1.0mol that step (1) is obtained is in the organic solvent of 100～900ml, add maleic anhydride, under catalyst action, carry out acylation reaction, 40～70 ℃ of temperature of reaction, the reaction times is 2～25 hours; Maleic anhydride: the mol ratio to fluoroanisole is 1～6: 1, catalyzer: the mol ratio of maleic anhydride is 2～3: 1.
In reaction system, the catalyzer of acylation reaction is selected Lewis acid for use, and organic solvent can be selected halogenated alkane such as methylene dichloride, trichloromethane, 1,2-ethylene dichloride or dithiocarbonic anhydride etc. for use.
After reaction is finished, in reaction system, add frozen water, hydrochloric acid mixed solution, and high degree of agitation.Handle step by this, the methyl that directly makes on the ehter bond to be connected is sloughed, the phenolic hydroxyl group that dissociates, thus avoided carrying out again the hydrolysis reaction step of demethylating protecting group.Demethylation protecting group and one step of acylation reaction are finished.Obtain product 4-(5-fluoro-2-hydroxyl) phenyl-4-ketone-2 at last, the 3-butylene, yield can reach more than 90%.
(3) 4-that step (2) is obtained (5-fluoro-2-hydroxyl) phenyl-4-ketone-2, the 3-butylene joins and carries out cyclization in the basic solution, the concentration of alkali can be 5wt%～30wt%, when the alkaline solution that uses during as inorganic alkali solution, the consumption of alkali is with respect to 1.0～1.5mol 4-(5-fluoro-2-hydroxyl) phenyl-4-ketone-2, during the amount of 3-butylene is 9000～13000ml, the solvent that system is used is polar solvent, temperature of reaction is at 0～65 ℃, reaction times was at 10～25 hours, obtain product 6-fluoro-2 at last, 3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 2), (yield can reach more than 92%).
The solvent that system is used is polar solvent, can use low boiling-point and polarity solvents such as ethanol, methyl alcohol, acetone, acetonitrile or water, and preferred solvent is the aqueous solution.The alkaline cyclization catalyst that uses can be sodium alkyl alcohol, sodium hydride, sodium hydroxide, potassium hydroxide or yellow soda ash etc., and preferred alkaline cyclization catalyst is a sodium hydroxide.
(4) the 6-fluoro-2 that step (3) is obtained, 3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 2) is a hydro-reduction under the 10wt%Pd-C catalysis in concentration, the consumption of Pd-C is a catalytic amount, be reflected under normal temperature and the normal pressure and both can carry out smoothly, finally make racemize (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula].
(5) (±)-6-fluoro-3 that step (4) is obtained, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid is dissolved in and carries out the chemistry fractionation in the α-Ben Yian resolving agent, forms the soda acid salt precipitation of diastereomer; The salt that separates this diastereomer obtains optical isomer (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid.
With racemize (±)-6-fluoro-3 that obtains, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] under catalyst action with C
1～C
10Alcohol carry out esterification, make (±)-6-fluoro-3 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylicesters [(±)-1b in the formula].Racemic (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and C
1～C
10The mol ratio of alcohol be 1.0～2.5: 1.3～4.0.The alcohol that esterification is used can be C
1～C
10Alkyl alcohol, as methyl alcohol, ethanol etc.The employed catalyzer of esterification can be acids, as the vitriol oil, tosic acid, Phenylsulfonic acid, assorted many super acids, dry HCl etc.Also can be organic titanate.Catalyst consumption is a catalytic amount.
Synthetic method two:
(1) p-fluorophenol is dissolved in the inorganic alkaline aqueous solution, wherein the amount of the p-fluorophenol that adds in the system is the p-fluorophenol that adds 0.05～1.0mol in the alkaline aqueous solution with respect to 500～3500ml, the concentration of alkaline solution is 5wt%～30wt%, drip methyl-sulfate then in system, the consumption of methyl-sulfate adds 1～30ml when being 1.0～5.0 grams with respect to the weight of p-fluorophenol.Temperature of reaction is controlled at 15～85 ℃, and the reaction times is 1～40 hour, and obtaining product is that yield can reach more than 98% to fluoroanisole.
(2) step (1) is obtained to be dissolved in respect to the amount to fluoroanisole 0.1～1.5mol to fluoroanisole be in the organic solvent of 50～200ml; drip acetylation reagent; under catalyst action, carry out acylation reaction; acetylation reagent: the mol ratio to fluoroanisole is 1～6: 1, catalyzer: the mol ratio to fluoroanisole is 2～3: 1.
In reaction system, the catalyzer of acylation reaction is selected Lewis acid for use, and 40～80 ℃ of temperature of reaction in 2～25 hours reaction times, obtain 5-fluoro-2-hydroxyl-methyl phenyl ketone.
The organic solvent that reaction system is used can be selected halogenated alkane such as methylene dichloride, trichloromethane, 1 for use, and 2-ethylene dichloride or dithiocarbonic anhydride etc. are preferably dithiocarbonic anhydride.Acetylation reagent can use acetic anhydride or Acetyl Chloride 98Min..
After having reacted, in reaction system, add frozen water, hydrochloric acid mixed solution, and high degree of agitation.Handle step by this, the methyl protecting group of directly sloughing ehter bond and being connected, the phenolic hydroxyl group that dissociates, thus avoided carrying out again the hydrolysis reaction step of demethylation protecting group.One step of processing of demethylating protecting group and acylate is finished.
(3) under the alkaline catalysts effect, step (2) synthetic 5-fluoro-2-hydroxyl-methyl phenyl ketone and oxalic acid diethyl ester are carried out ester condensation in organic solvent, the mol ratio of oxalic acid diethyl ester and 5-fluoro-2-hydroxyl-methyl phenyl ketone is 3.0～30: 1, the condensation intermediate is without purifying, directly under the acid catalyst effect respectively cyclization produce compound 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3), yield can reach more than 85%; Generate 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester (3a in the formula) simultaneously, yield can reach more than 86%; Temperature of reaction is 40～95 ℃, and the reaction times is 1.5～8 hours.
Alkaline catalysts that uses during ester condensation such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, n-Butyl Lithium or tert-butyl lithium etc.The preferred bases catalyzer is a sodium hydride.The solvent that uses during ester condensation, according to employed basic catalyst difference, can be with an organic solvent as, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), methyl alcohol, ethanol or acetone etc.; Also can make water make solvent; Basic catalyst: the mol ratio of 5-fluoro-2-hydroxyl-methyl phenyl ketone is 1～20: 1.
Ring-closure reaction adopts acid to make catalyzer.And control the product that ring-closure reaction generates by the ratio of controlling acid.The mixture that the acid catalyst of cyclization is selected from any two kinds of acid in sulfuric acid, concentrated hydrochloric acid, acetic acid, phosphoric acid, the polyphosphoric acid carries out catalysis.When the consumption of acid was 20～200ml usually, the consumption of ester condensation products was 1.0～5.0 grams.When with acetic acid and concentrated hydrochloric acid mixture as catalyst, acetic acid: the volume ratio of concentrated hydrochloric acid is 10～28: 1 o'clock, generates 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester (3a in the formula); Acetic acid: the volume ratio of concentrated hydrochloric acid is 1～4: 1 o'clock, generates 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3).
(4) the cyclocomplex 6-fluoro-4-oxo that step (3) is obtained-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3), or 6-fluoro-4-oxo-pyrans-2-carboxylic acid, ethyl ester (3a in the formula) is the Pd-C catalytic hydrogenation reduction reaction of 10wt% with concentration to 4H-1-benzene a pair of horses going side by side.Be reflected under normal temperature or the common pressure and both can carry out smoothly, make racemic modification (±)-6-fluoro-3 respectively, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula], and (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the formula].
By racemic modification (±)-6-fluoro-3 that 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3) reduction back generates, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula], can and C
1～C
10Alcohol carry out esterification down in catalyzer (as acid or organic titanate, consumption is a catalytic amount) effect, generate (±)-6-fluoro-3, the parallel pyrans of 4-dihydro-2H-1-benzene-2-carboxylicesters [(±)-1b in the formula]; Racemic modification (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] is 1.0～2.5: 1.5～4.5 with the mol ratio of alcohol.The alcohol that esterification is used can be C
1～C
10Alkyl alcohol, as alcohol such as methyl alcohol, ethanol.The employed catalyzer of esterification can be acids, as the vitriol oil, tosic acid, Phenylsulfonic acid, assorted many super acids or dry HCl etc.Also can be organic titanate.
(5) (±)-6-fluoro-3 that step (4) is obtained, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] is dissolved in and carries out the chemistry fractionation in the α-Ben Yian resolving agent, (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] is 1.0～2.5: 0.5～2.0 with the mol ratio of D-(+)-α-Ben Yian (MBA) or L-(-)-α-Ben Yian (MBA), forms the soda acid salt precipitation of diastereomer; The salt that separates this diastereomer, obtain optical isomer (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula], in chemical split process, select the alcohols solvent that splits for use, as methyl alcohol, ethanol, propyl alcohol, Virahol or isopropylcarbinol etc.Also can use the aqueous solution solvent that splits of alcohol.The preferred concentration of alcohol is 60～95wt%.
Two diastereomeric salts that obtain respectively behind the recrystallization, use acid to decompose, free (R)-(-)-6-fluoro-3 that discharges, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R ')-(-)-1 in the formula] and (S)-(+)-6-fluoro-3, the parallel pyrans of 4-dihydro-2H-1-benzene-2-carboxylic acid [(S)-(+)-1 in the formula].Acid can be selected hydrochloric acid or sulfuric acid for use, and its concentration is respectively 5～30wt% or 2～20wt%.
Using free optically pure (R)-(-) of acid decomposition-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3, behind 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula], MBA can recycling use.
The present invention passes through optical purity (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula], and their racemic carboxylic acid ester's is synthetic, invention has also been implemented 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3) and 6-fluoro-2, the hydro-reduction reaction of 3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 2) under 10wt%Pd-C catalysis, to resulting product (±)-6-fluoro-3, the 4-dihydro-pyrans-2-carboxylic acid [(±)-1 in the formula] is a resolving agent with optically active α-Ben Yian to 2H-1-benzene a pair of horses going side by side, carrying out chemistry splits, obtained optical isomer (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula] and (S)-(+)-6-fluoro-3, the parallel pyrans of 4-dihydro-2H-1-benzene-2-carboxylic acid [(S)-(+)-1 in the formula]; Simultaneously, use esterifying catalyst, synthesized respectively (±)-6-fluoro-3, the C of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula]
1～C
10Alcohol ester.In one's power simple synthetic method of the present invention, rationally, mild condition, pollution is little, product purity is high; Optical activity α-Ben Yian resolving agent used when particularly chemistry splits is cheap, and method for splitting is easy, has avoided the generation of racemization phenomenon in the split process, makes the enantiomeric purity height of the finished product, and suitability for industrialized is produced in batches.
Embodiment
Below by the enforcement of specific examples, the present invention is further illustrated.
Embodiment 1. is by synthetic method one preparation (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] and (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylicesters [(±)-1b in the formula]
1.1 to fluoroanisole
(25.6g 0.05mol) is dissolved among the NaOH aqueous solution 500ml of 5wt%, drips methyl-sulfate (32g with p-fluorophenol, 0.254mol), be heated to 70 ℃, stir and stop after 5 hours, after the system for the treatment of is chilled to room temperature,, collect ethyl acetate layer with ethyl acetate 20ml * 3 extractions, use anhydrous sodium sulfate drying, filter, revolve steam desolventize after, obtain lurid thick liquid, underpressure distillation, the cut of 38～40 ℃/5mmHg of collection, must be to fluoroanisole (6.2g, 98%).
1.2 4-(5-fluoro-2-hydroxyl) phenyl-4 ketone-2, the 3-butenoic acid
With maleic anhydride (4g, 0.04mol), aluminum trichloride catalyst (15g, 0.112mol), to fluoroanisole (2.5g, 0.02mol) feed intake, be dissolved among the dithiocarbonic anhydride 50ml, be heated to 60 ℃, reacted 2 hours, after having reacted, in reaction system, add frozen water, hydrochloric acid mixed solution, and high degree of agitation.Get yellow sheet crystal 4-(5-fluoro-2-hydroxyl) phenyl-4 ketone-2,3-butenoic acid (3.75g, 90%), mp178～179 ℃ (distillation).
1.3 6-fluoro-2,3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 2)
Get 4-(5-fluoro-2-hydroxyl) phenyl-4 ketone-2, (2.1g 0.01mol) is dissolved among 10% the NaOH aqueous solution 90ml 3-butenoic acid, reaction is 10 hours under 45 ℃ of temperature, transfers pH to 1.0, uses the ethyl acetate extraction product then, collect ethyl acetate layer, add anhydrous sodium sulfate drying, filter, revolve to steam and desolventize, faint yellow crude product 6-fluoro-2,3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 2), recrystallization gets product (1.93g, 92%) after the oven dry, mp163～164 ℃
(1.4 ±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula]
6-fluoro-2, and 3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 2) (21g, 0.1mol), Pd/C (2.0g), Glacial acetic acid (150ml) is positioned in the autoclave, feeds H
2, react to system and no longer inhale hydrogen.Make system put cold after, filter, revolve to steam to remove and desolvate, the black thing, use ether dissolution then, use NaHCO
3Water layer is collected in extraction (30ml * 3), uses extracted with diethyl ether (30ml * 3) after acidifying again, collects ether layer, anhydrous MgSO
4Drying is filtered, and obtains white crystal (±)-6-fluoro-3 after desolventizing, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (16.3g, 83%), mp121～123 ℃ (toluene recrystallization).
(1.5 ±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylate methyl ester [(±)-1b in the formula]
(±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (0.1mol), methyl alcohol 100ml, the tetrabutyl titanate of catalytic amount adds in the reactor, reacts to add entry after 4 hours, restir 30 minutes.Filter.Underpressure distillation again steams product behind the filtrate steaming removal solvent.Yield 86%.
(1.6 ±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the formula]
(±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (0.1mol), ethanol 150ml feeds dry HCl in the reactor, refluxes 4 hours, reacts to add entry, restir 30 minutes after finishing.Filter.Underpressure distillation again steams product behind the filtrate steaming removal solvent, gets (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the formula].Yield 88%.
Embodiment 2
1.1 to fluoroanisole
(51.2g 0.1mol) is dissolved in the Na of 5wt% with p-fluorophenol
2CO
3Among the aqueous solution 1000ml, and the dropping methyl-sulfate (64g, 0.508mol), be heated to 75 ℃, stir and stop after 5 hours, after the system for the treatment of is chilled to room temperature, with ethyl acetate 40ml * 3 extractions, collect ethyl acetate layer, use anhydrous sodium sulfate drying, filter, revolve steam desolventize after, obtain lurid thick liquid, underpressure distillation, collect the cut of 38～40 ℃/5mmHg, must be to fluoroanisole (12.4g, 98%).
1.2 4-(5-fluoro-2-hydroxyl) phenyl-4 ketone-2, the 3-butenoic acid
With maleic anhydride (8g, 0.08mol), catalyzer aluminum chloride (30g, 0.224mol), (5.0g 0.04mol) feeds intake, and is dissolved among the methylene dichloride 55ml to fluoroanisole, be heated to 60 ℃, reacted 2 hours, and after reaction is finished, in reaction system, added frozen water, hydrochloric acid mixed solution, and high degree of agitation.Get yellow sheet crystal 4-(5-fluoro-2-hydroxyl) phenyl-4 ketone-2,3-butenoic acid (7.5g, 90%), mp178～179 ℃ (distillation).
1.3 6-fluoro-2,3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 2)
Get 4-(5-fluoro-2-hydroxyl) phenyl-4 ketone-2,3-butenoic acid (4.2g, 0.02mol) be dissolved in the ethanolic soln of 100ml, and adding sodium ethylate 8.0 grams, reaction is 10 hours under 45 ℃ of temperature, transfers pH to 1.0, use the ethyl acetate extraction product then, collect ethyl acetate layer, add anhydrous sodium sulfate drying, filter, revolve to steam and desolventize, faint yellow crude product 6-fluoro-2,3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 2), recrystallization, get product (3.86g after the oven dry, 92%) mp163～164 ℃,
(1.4 ±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula]
6-fluoro-2, and 3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 2) (42g, 0.2mol), Pd/C (4.0g), Glacial acetic acid (300ml) is positioned in the autoclave, feeds H
2, react to system and no longer inhale hydrogen.Make system put cold after, filter, revolve to steam to remove and desolvate, the black thing, use ether dissolution then, use NaHCO
3Water layer is collected in extraction (60ml * 3), uses extracted with diethyl ether (60ml * 3) after acidifying again, collects ether layer, anhydrous MgSO
4Drying is filtered, and obtains white crystal (±)-6-fluoro-3 after desolventizing, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (32.6g, 83%), mp121～123 ℃ (toluene recrystallization).
(1.5 ±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylate methyl ester [(±)-1b in the formula]
(±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (0.2mol), methyl alcohol 200ml, the tetrabutyl titanate of catalytic amount adds in the reactor, reacts to add entry after 4 hours, restir 30 minutes.Filter.Underpressure distillation again steams product behind the filtrate steaming removal solvent.Yield 86%.
(1.6 ±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the formula]
(±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (0.3mol), ethanol 300ml feeds dry HCl in the reactor, refluxes 4 hours, reacts to add entry, restir 30 minutes after finishing.Filter.Underpressure distillation again steams product behind the filtrate steaming removal solvent, gets (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the formula].Yield 88%.
Embodiment 3
By synthetic method two preparation (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] and (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylicesters [(±)-1b in the formula]
1.1 to fluoroanisole
Preparation to fluoroanisole is identical with embodiment 1.
1.2 5-fluoro-2-hydroxyl-methyl phenyl ketone
To fluoroanisole (0.1mol), CS
2100ml, catalyzer aluminum chloride (0.25mol), stir down and slowly drip acetic anhydride (0.12mol), 75 ℃ of temperature of reaction are after question response finishes, in system, add an amount of hydrochloric acid and trash ice, high degree of agitation is told organic layer, water layer ethyl acetate extraction (3 * 25ml), merge organic layer and wash last organic layer Na with water
2SO
4Drying gets product 5-fluoro-2-hydroxyl-methyl phenyl ketone after desolventizing.Mp55～56℃。
1.3 (a) 5-fluoro-2-hydroxyl-methyl phenyl ketone (0.1mol), oxalic acid diethyl ester (2.5mol), sodium hydride (0.15mol) carried out ester condensation reaction 2～3 hours in 60 ℃ tetrahydrofuran (THF) 100ml.Tell organic layer, (3 * 25ml), the merging organic layer is used Na to water layer with ethyl acetate extraction
2SO
4Dry.The filtering siccative gets yellow solid thing after steaming desolventizes.Without purifying, be directly used in the next step.
(b) adding volume ratio in the yellow solid thing of above-mentioned (a) step gained is 28: 1 acetate and hydrochloride mixing acid 200ml, reacts 2～3 hours.Question response finishes, and is chilled to room temperature, has precipitation to separate out.Leach solid thing, recrystallization, 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester (3a in the formula), the solid thing (yield 86%) of white, mp122～124 ℃.
(c) adding volume ratio in the yellow solid thing of above-mentioned (a) step gained is the mixing acid 150ml of 4: 1 acetate and hydrochlorides, reacts 2～3 hours.Question response finishes, and is placed to room temperature, has precipitation to separate out.Leach solid thing, recrystallization, 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3), the solid thing (yield 85%) of white, mp120～122 ℃.
(a) 1.4 (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula]
(0.25mol), concentration is the Pd/C (5.0g) of 10wt% to 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3), and Glacial acetic acid (150ml) is positioned in the autoclave, feeds H
2, reaction is no longer inhaled hydrogen until system.Make system put cold after, filter, revolve to steam to remove and desolvate, the black thing, use ether dissolution then, use NaHCO
3Water layer is collected in extraction (30ml * 3), uses extracted with diethyl ether (30ml * 3) after acidifying again, collects ether layer, anhydrous MgSO
4Drying is filtered, and obtains white crystal (±)-6-fluoro-3 after desolventizing, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (yield 83%), recrystallization, mp120-122 ℃.
(b) (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the formula]
6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester (3a in the formula) (0.1mol), concentration is the Pd/C (2.0g) of 10wt%, Glacial acetic acid (150ml) is positioned in the autoclave, feeds H
2, react to system and no longer inhale hydrogen.Make system put cold after, filter, revolve to steam to remove and desolvate, the black thing, underpressure distillation then, light yellow thing, i.e. (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the formula] (yield 87%).
(1.5 ±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylate methyl ester [(±)-1b in the formula]
(±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (0.1mol), methyl alcohol 100ml, the tetrabutyl titanate of catalytic amount adds in the reactor, reacts to add entry after 4 hours, restir 30 minutes.Filter.Underpressure distillation again steams product behind the filtrate steaming removal solvent.Yield 86%.
1.6 chemistry splits (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula]
1.6.1 (S)-(+)-and 6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula]
(±)-6-fluoro-3, (19.6g 0.1mol), uses dissolve with methanol to 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula], adds D-(+)-α-Ben Yian (0.05mol) back and stirs cooling, white precipitate occurs, leaches precipitation, and mother liquor is put in addition.Leach behind the thing recrystallization water-solublely again, and add an amount of 10wt% concentrated hydrochloric acid, stir, the acid solution extracted with diethyl ether, combined ether layer, ether layer spends the night with anhydrous magnesium sulfate drying.Suction filtration is collected ether filtrate, revolve to steam to remove ether, Off-white solid 2.02g, i.e. S-(+)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula].Yield 20.6%, mp97-99 ℃, [α]
20 D=+14.2 ° (c=1.0, DMF).
1.6.3 (R)-(-)-and 6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula]
Mother liquor in above-mentioned (a) with the remaining α-Ben Yian of dilute hydrochloric acid flush away, is used extracted with diethyl ether, the ether layer anhydrous magnesium sulfate drying.Suction filtration is removed siccative, and filtrate is revolved inspissation and contracted, and adds methyl alcohol then and makees solvent, and cooling is stirred down and added L-(-)-α phenylethylamine (0.05mol), and precipitation is placed and spent the night.Leach precipitation, and recrystallization, water-soluble then, add an amount of 10wt% concentrated hydrochloric acid, stir the acid solution extracted with diethyl ether.Combined ether layer spends the night with anhydrous magnesium sulfate drying.Suction filtration is collected ether filtrate, revolve to steam to remove ether, gained solid recrystallization, white product, i.e. R-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula], yield 30%, mp100-101 ℃, [α]
20 D=-12.98 ° (c=1.0, DMF).
Embodiment 4
By synthetic method two preparation (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] and (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylicesters [(±)-1b in the formula]
1.1 to fluoroanisole
Preparation to fluoroanisole is identical with embodiment 1.
1.2 5-fluoro-2-hydroxyl-methyl phenyl ketone
To fluoroanisole (0.3mol), methylene dichloride 300ml, catalyzer aluminum chloride (0.75mol) stirs down slowly dripping acetyl chloride (0.34mol).After question response finishes, add an amount of hydrochloric acid and trash ice in system, high degree of agitation is told organic layer, and (3 * 75ml), the merging organic layer also washes with water water layer, last organic layer Na with ethyl acetate extraction
2SO
4Dry. get product 5-fluoro-2-hydroxyl-methyl phenyl ketone after desolventizing.Mp55～56℃。
1.3 (a) 5-fluoro-2-hydroxyl-methyl phenyl ketone (0.25mol), oxalic acid diethyl ester (6.25mol), sodium ethylate (0.375mol) carried out ester condensation reaction 2～3 hours in 78 ℃ ethanol 100ml.Tell organic layer, (3 * 62.5ml), the merging organic layer is used Na to water layer with ethyl acetate extraction
2SO
4Dry.The filtering siccative gets yellow solid thing after steaming desolventizes.Without purifying, be directly used in the next step.
(b) adding volume ratio in the yellow solid thing of above-mentioned (a) step gained is the mixing acid 500ml of 28: 1 acetate and hydrochlorides, reacts 2～3 hours.Question response finishes, and is chilled to room temperature, has precipitation to separate out.Leach solid thing, recrystallization, 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester (3a in the formula), the solid thing (yield 86%) of white, mp122～124 ℃.
(c) adding volume ratio in the yellow solid thing of above-mentioned (a) step gained is the mixing acid 375ml of 4: 1 acetate and hydrochloride, reacts 2～3 hours.Question response finishes, and is placed to room temperature, has precipitation to separate out.Leach solid thing, recrystallization, 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3), the solid thing (yield 85%) of white, mp120～122 ℃.
(a) 1.4 (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula]
(0.25mol), concentration is the Pd/C (5.0g) of 10wt% to 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid (in the formula 3), and Glacial acetic acid (150ml) is positioned in the autoclave, feeds H
2, react and no longer inhale hydrogen to system (front does not feed hydrogen?).Make system put cold after, filter, revolve to steam to remove and desolvate, the black thing, use ether dissolution then, use NaHCO
3Water layer is collected in extraction (30ml * 3), uses extracted with diethyl ether (30ml * 3) after acidifying again, collects ether layer, anhydrous MgSO
4Drying is filtered, and obtains white crystal (±)-6-fluoro-3 after desolventizing, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (yield 83%), recrystallization, mp120-122 ℃.
(b) (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the formula]
6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester (3a in the formula) (0.1mol), concentration is the Pd/C (2.0g) of 10wt%, Glacial acetic acid (150ml) is positioned in the autoclave, feeds H
2, react to system and no longer inhale hydrogen.Make system put cold after, filter, revolve to steam to remove and desolvate, the black thing, underpressure distillation then, light yellow thing, i.e. (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester [(±)-1a in the formula] (yield 87%).
(1.5 ±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylate methyl ester [(±)-1b in the formula]
(±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula] (0.25mol), methyl alcohol 250ml, the tetrabutyl titanate of catalytic amount adds in the reactor, reacts to add entry after 4 hours, restir 30 minutes.Filter.Underpressure distillation again steams product behind the filtrate steaming removal solvent.Yield 86%.
1.6 chemistry splits (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula]
1.6.1 (S)-(+)-and 6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula]
(±)-6-fluoro-3, (196g 1.0mol), with the isopropylcarbinol dissolving, adds D-(+)-α-Ben Yian (0.5mol) back and stirs cooling 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(±)-1 in the formula], white precipitate occurs, leaches precipitation, and mother liquor is put in addition.Leach behind the thing recrystallization water-solublely again, and add an amount of 5wt% concentrated hydrochloric acid, stir, the acid solution extracted with diethyl ether, combined ether layer, ether layer spends the night with anhydrous magnesium sulfate drying.Suction filtration is collected ether filtrate, revolve to steam to remove ether, Off-white solid 20.2g, i.e. S-(+)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(S)-(+)-1 in the formula].Yield 20.6%, mp97-99 ℃, [α]
20 D=+14.2 ° (c=1.0, DMF).
1.6.2 (R)-(-)-and 6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula]
Mother liquor in above-mentioned (a) with the remaining α-Ben Yian of dilute hydrochloric acid flush away, is used extracted with diethyl ether, the ether layer anhydrous magnesium sulfate drying.Suction filtration is removed siccative, and filtrate is revolved inspissation and contracted, and adds isopropylcarbinol then and makees solvent, and cooling is stirred down and added L-(-)-α phenylethylamine (0.5mol), and precipitation is placed and spent the night.Leach precipitation, and recrystallization, water-soluble then, add an amount of 5wt% concentrated hydrochloric acid, stir the acid solution extracted with diethyl ether.Combined ether layer spends the night with anhydrous magnesium sulfate drying.Suction filtration is collected ether filtrate, revolve to steam to remove ether, gained solid recrystallization, white product, i.e. R-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid [(R)-(-)-1 in the formula], yield 30%, mp100-101 ℃, [α]
20 D=-12.98 ° (c=1.0, DMF).
Claims (10)
1. optical antipode 6-fluoro-3, the synthetic method of 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, described optical antipode is (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, it is characterized in that: the synthetic method of this optical antipode may further comprise the steps:
Synthetic method one:
(1) p-fluorophenol is dissolved in the inorganic alkaline aqueous solution, drips methyl-sulfate then in system, the consumption of methyl-sulfate adds 1～30ml when being 1.0～5.0 grams with respect to the weight of p-fluorophenol, obtains product for to fluoroanisole;
(2) with step (1) obtains fluoroanisole is dissolved in the organic solvent, add maleic anhydride, under catalyst action, carry out acylation reaction; Maleic anhydride: the mol ratio to fluoroanisole is 1～6: 1;
After reaction is finished, add frozen water, hydrochloric acid mixed solution in reaction system, high degree of agitation obtains product 4-(5-fluoro-2-hydroxyl) phenyl-4-ketone-2, the 3-butylene;
(3) 4-that step (2) is obtained (5-fluoro-2-hydroxyl) phenyl-4-ketone-2, the 3-butylene joins and carries out cyclization in the basic solution, the concentration of alkali is 5wt%～30wt%, the solvent that system is used is polar solvent, obtain product 6-fluoro-2 at last, 3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid;
(4) the 6-fluoro-2 that step (3) is obtained, 3-dihydro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid hydro-reduction under palladium carbon catalyst catalysis, the consumption of palladium-carbon is a catalytic amount, gets racemize (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid;
(5) (±)-6-fluoro-3 that step (4) is obtained, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid is dissolved in and carries out the chemistry fractionation in the α-Ben Yian resolving agent, forms the soda acid salt precipitation of diastereomer; The salt that separates this diastereomer obtains optical isomer (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid;
Or
Synthetic method two:
(1) p-fluorophenol is dissolved in the inorganic alkaline aqueous solution, drips methyl-sulfate then in system, the consumption of methyl-sulfate adds 1～30ml when being 1.0～5.0 grams with respect to the weight of p-fluorophenol, obtains product for to fluoroanisole;
(2) with step (1) obtains fluoroanisole is dissolved in the organic solvent, drip acetylation reagent, carry out acylation reaction under catalyst action, acetylation reagent: the mol ratio to fluoroanisole is 1～6: 1;
After having reacted, add frozen water, hydrochloric acid mixed solution in reaction system, high degree of agitation obtains 5-fluoro-2-hydroxyl-methyl phenyl ketone;
Acetylation reagent is acetic anhydride or Acetyl Chloride 98Min.;
(3) under the alkaline catalysts effect, step (2) synthetic 5-fluoro-2-hydroxyl-methyl phenyl ketone and oxalic acid diethyl ester are carried out ester condensation in organic solvent, the mol ratio of oxalic acid diethyl ester and 5-fluoro-2-hydroxyl-methyl phenyl ketone is 3.0～30: 1, the gained condensation product under the acid catalyst effect respectively cyclization produce compound 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester;
(4) the cyclocomplex 6-fluoro-4-oxo that step (3) is obtained-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid or 6-fluoro-4-oxo-4H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester palladium carbon catalyst catalysis, make racemic modification (±)-6-fluoro-3 respectively, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid, ethyl ester;
(5) (±)-6-fluoro-3 that step (4) is obtained, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid is dissolved in and carries out the chemistry fractionation in the α-Ben Yian resolving agent, forms the soda acid salt precipitation of diastereomer; The salt that separates this diastereomer obtains optical isomer (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid.
2. method according to claim 1 is characterized in that: the step of described method one (4) racemizes (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid under catalyst action with C
1～C
10Alcohol carry out esterification, make (±)-6-fluoro-3 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylicesters; Racemize (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and C
1～C
10The mol ratio of alcohol is 1.0～2.5: 1.3～4.0.
3. method according to claim 1 is characterized in that: the step of described method two (4) racemic modifications (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid under catalyst action with C
1～C
10Alcohol carry out esterification, generate (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylicesters; Racemize (±)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and C
1～C
10The mol ratio of alcohol be 1.0～2.5: 1.5～4.5.
4. according to claim 2 or 3 described methods, it is characterized in that: described catalyzer is the vitriol oil, tosic acid, Phenylsulfonic acid, assorted many super acids, dry HCl or organic titanate.
5. method according to claim 1 is characterized in that: the alkali that the step (1) in described method one or the method two is used is sodium hydroxide, potassium hydroxide, yellow soda ash or sodium bicarbonate.
6. method according to claim 1 is characterized in that: the catalyzer of step (2) acylation reaction in described method one or the method two is a Lewis acid;
Organic solvent is methylene dichloride, trichloromethane, 1,2-ethylene dichloride or dithiocarbonic anhydride.
7. method according to claim 1 is characterized in that: the polar solvent of step (3) is ethanol, methyl alcohol, acetone, acetonitrile or water in the described method one; The alkaline cyclization catalyst that uses is sodium alkyl alcohol, sodium hydride, sodium hydroxide, potassium hydroxide or yellow soda ash.
8. method according to claim 1, it is characterized in that: the alkaline catalysts that uses during step in the described method two (3) ester condensation is sodium hydride, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, n-Butyl Lithium or tert-butyl lithium, and the consumption of alkali is a basic catalyst: the mol ratio of 5-fluoro-2-hydroxyl-methyl phenyl ketone is 1～20: 1;
The solvent that uses during ester condensation is tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), methyl alcohol, ethanol, acetone or water;
The acid catalyst of cyclization is selected from the mixture of any two kinds of acid in sulfuric acid, concentrated hydrochloric acid, acetic acid, phosphoric acid, the polyphosphoric acid, and when the consumption of acid was 20～200ml, the consumption of ester condensation products was 1.0～5.0 grams.
9. method according to claim 1 is characterized in that: the step of described method two (5) is selected methyl alcohol, ethanol, propyl alcohol, Virahol, isopropylcarbinol or their aqueous solution solvent that splits for use in chemical split process.
10. method according to claim 1, it is characterized in that: two diastereomeric salts of the step of described method two (5), be to use acid to decompose, free (R)-(-)-6-fluoro-3 that discharges, 4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzene a pair of horses going side by side pyrans-2-carboxylic acid;
Described acid is hydrochloric acid or sulfuric acid.
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| CNB2004100094927A CN1279035C (en) | 2004-08-30 | 2004-08-30 | Method for synthesizing optical enantiomer 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate |
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| CNB2004100094927A CN1279035C (en) | 2004-08-30 | 2004-08-30 | Method for synthesizing optical enantiomer 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate |
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| CN1279035C true CN1279035C (en) | 2006-10-11 |
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| US7999124B2 (en) | 2006-11-27 | 2011-08-16 | Zach System S.P.A. | Process for preparing nebivolol |
| CN101121707B (en) * | 2007-09-11 | 2010-08-25 | 四川大学 | Method for preparing 3,4-dihydro-4-oxy-2H-1-benzopyran-2-carboxylic acids compounds |
| CN101531651B (en) * | 2008-03-13 | 2011-05-04 | 四川大学 | Preparation method of optically active 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 3,4-dihydro-4-O-2H-1-benzopyran-2-carboxylic acid compounds |
| CN102408402A (en) * | 2011-12-27 | 2012-04-11 | 上海立科药物化学有限公司 | Synthesis method of (R) or (S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid |
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