CN103232491B - A kind of preparation method of cyclic phosphoric acid - Google Patents

A kind of preparation method of cyclic phosphoric acid Download PDF

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CN103232491B
CN103232491B CN201310039714.9A CN201310039714A CN103232491B CN 103232491 B CN103232491 B CN 103232491B CN 201310039714 A CN201310039714 A CN 201310039714A CN 103232491 B CN103232491 B CN 103232491B
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dimethyl
phosphoric acid
aryl
cyclic phosphoric
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CN103232491A (en
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孙凤霞
贾林茹
赵寿坡
楚静波
靳欣
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Hebei University of Science and Technology
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Abstract

The preparation method that the invention discloses a kind of cyclic phosphoric acid, it said method comprising the steps of: a isobutylaldehyde, aromatic aldehyde react generation chiral 3-aryl-3-hydroxyl-2,2-dimethyl propionic aldehyde under chiral catalyst catalytic condition; The reduction of b chiral 3-aryl-3-hydroxyl-2,2-dimethyl propionic aldehyde obtains chirality 1-aryl-2,2-dimethyl-1,3-propylene glycol; C obtains chirality 4-aryl-2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychloride when dichloromethane with phosphorus oxychloride reaction; D is hydrolyzed in the basic conditions, and acidifying generates cyclic phosphoric acid. The optical purity of the target product that this technique obtains is high, and simple to operate, less costly, yield is higher, less pollution, belongs to organic synthesis field.

Description

A kind of preparation method of cyclic phosphoric acid
Technical field
The present invention relates to organic synthesis field, the preparation method being specifically related to a kind of cyclic phosphoric acid.
Technical background
Cyclic phosphoric acid (CyclicPhosphoricAcid) and the like is that a class is novel, the highly acid resolution reagent of structural rigidity, can be effectively used for amine, aminoacid and some alkaloidal fractionations, and general structure is as follows.
Cyclic phosphoric acid structural formula
At present about the preparation of the cyclic phosphoric acid method that mainly first then synthesis DL body cycli phosphate splits again. WoltertenHoeve and HansWynberg have studied the synthesis of DL cycli phosphate; Aldol-Cannizzaro is occurred to react in ethanol by isobutylaldehyde, aromatic aldehyde and KOH; 1-aryl-2 can be obtained; 2-dimethyl-1; ammediol; after ring phosphorylated, hydrolysis obtains cycli phosphate, obtains cyclic phosphoric acid by fractionation. Its synthetic route is as follows.
The synthetic route of the cyclic phosphoric acid of Hoeve invention.
This route has an advantage simple to operate, but needs the isobutylaldehyde of at least two equivalents to participate in reaction, causes the significant wastage of isobutylaldehyde and supervenes the by-product isopropylformic acid. of equivalent. Along with the principle of energy-saving and emission-reduction and Atom economy, reduce the consumption that makes of isobutylaldehyde, reduce the generation of by-product, develop a new technique and seem extremely important.
Summary of the invention
It is an object of the invention to provide one and directly prepare high-optical-purity, simple to operate, less costly, yield is higher, the preparation method of the cyclic phosphoric acid of less pollution.
For achieving the above object, the present inventor on the basis of existing technology, has read lot of documents books and has carried out substantial amounts of research and performing creative labour, the preparation method that have developed a kind of cyclic phosphoric acid,
The present invention is achieved by below scheme:
The preparation method of a kind of cyclic phosphoric acid of the present invention comprises the following steps:
A, isobutylaldehyde and aromatic aldehyde react generation chiral 3-aryl-3-hydroxyl-2,2-dimethyl propionic aldehyde under chiral catalyst catalytic condition.
Chiral 3-aryl-3-hydroxyl-2,2-dimethyl the propionic aldehyde that b, described step a prepare obtains chirality 1-aryl-2,2-dimethyl-1,3-propylene glycol through reduction reaction;
Chirality 1-aryl-2，2-dimethyl-1，3-propanediol that c, described step b prepare, obtains chloro-5,5-dimethyl-2-oxo-1 of chirality 4-aryl-2-, 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides when dichloromethane with phosphorus oxychloride reaction;
Chloro-5,5-dimethyl-2-oxo-1 of chirality 4-aryl-2-that d, described step c prepare, 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides, it is hydrolyzed in the basic conditions, then acidifying generates cyclic phosphoric acid; Its reaction equation is:
Described alkali condition is organic base or inorganic base.
Described inorganic base is the one in sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; Described organic base is triethylamine or pyridine.
Preferably, the preparation method of described cyclic phosphoric acid, described step a is:
There is aldol reaction in isobutylaldehyde and aromatic aldehyde chiral catalyst in a solvent, generate chiral 3-aryl-3-hydroxyl-2,2-dimethyl propionic aldehyde at-30 DEG C～40 DEG C temperature;
Solvent in described step a is THF, acetonitrile, DMSO, DMF, dichloromethane, chloroform, 1,4-dioxane, methanol and H2One or more in O solvent.
The preparation method of above-mentioned cyclic phosphoric acid, in described step a, chiral catalyst is selected from (D/L)-proline, (D/L)-dried meat ammonia alcohol, one or more in (D/L) compound 1-8, and chiral catalyst structural formula is as follows:
Preferably, the preparation method of described cyclic phosphoric acid, described step a aromatic aldehyde has logical formula I:
Wherein R1、R2、R3、R4、R5Can be identical or different, represent hydrogen atom, alkyl, alkoxyl, chlorine atom, bromine atoms or atomic iodine, fluorine atom or nitro respectively; R4Can be hydrogen atom or alkyl or aromatic substituent.
Preferably, described alkyl is saturated alkyl or unsaturated alkyl, or is phenyl or substituted-phenyl or other aromatic radical; Described alkoxyl is above-mentioned alkyl and the group of oxygen atom formation.
Preferably, the mol ratio making consumption and aromatic aldehyde of described chiral catalyst is x:1,0.05 < x < 0.6.
Be commonly incorporated into when chiral catalyst is 1-(2-pyrrolidinylmethyl)-pyrrolidine Bronsted acid or Lewis acid with the use of.
Preferably, described Bronsted acid is H2SO4,CF3SO3H,p-TsOH,HNO3,CF3CO2H,CH3CO2H,H3PO4, D-(+)-10-camphorsulfonicacid or other Bronsted acids; Described Lewis acid is Sc (OTf)3,Cu(OTf)3,Zn(OTf)2,Y(OTf)3,La(OTf)3,Eu(OTf)3,Yb(OTf)3; The mol ratio making consumption and catalyst 1-(2-pyrrolidinylmethyl)-pyrrolidine of Bronsted acid or Lewis acid is x:1,0.5 < x < 2.
Preferably, the reduction reaction used in described step b can be catalytic hydrogenating reduction, it is also possible to being use reducing agent reduction, reducing agent is LiAlH4, NaBH4, KBH4 etc.Especially better with catalytic hydrogenating reduction effect.
The prominent effect that the present invention compared with prior art has:
The present invention reacts under chiral catalyst effect with isobutylaldehyde and aromatic aldehyde, generate chiral 3-aryl-3-hydroxyl-2,2-dimethyl propionic aldehyde, chirality 1-aryl-2，2-dimethyl-1，3-propanediol is obtained through reduction, again with phosphorus oxychloride generation ring-closure reaction, the chirality cyclic phosphorochloridate obtained is hydrolyzed in alkaline aqueous solution, then carries out acidifying, obtains end product cyclic phosphoric acid. The production technology of the present invention directly prepares cyclic phosphoric acid. Products therefrom optical purity is high, and reaction yield is high, and simple to operate, the link eliminating chemical resolution shortens reaction scheme, reduces reaction cost, less pollution.
Accompanying drawing explanation
Fig. 1 is DL 4-(2-chlorphenyl) liquid chromatogram of-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane;
Fig. 2 is the liquid chromatogram of (R)-(+)-4-(2-the chlorphenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of embodiment 1 gained
Fig. 3 is the liquid chromatogram of (S)-(-)-4-(2-the chlorphenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of embodiment 5 gained.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1
(R)-2-pyrrolidine formyl sulfanilamide (chiral catalyst 5; 6.15g, 0.025mol) and the mixture of isobutylaldehyde (7.2g, 0.1mol) be dissolved in the DMF of 30mL, keep under 25 DEG C of conditions stirring 15min, be added thereto to o-chlorobenzaldehyde (14.0g, 0.1mol) and continue stirring 15h. Add ammonium chloride solution washing saturated for 20ml, then use 40ml extraction into ethyl acetate 2 times. Organic over anhydrous NaSO4Dry and concentrate at reduced pressure conditions. Obtain (R)-(+)-3-(2-chlorphenyl)-3-hydroxyl-2,2-dimethyl-propionic aldehyde.
By (R)-(+)-3-(2-chlorphenyl) 3-hydroxyl-2,2-dimethyl-propionic aldehyde, ethanol, catalyst Raney nickel adds evacuation in autoclave, regulates pH8.0～10, replaces three times with nitrogen, then hydrogen exchange three times, reach 0.3MPa to Hydrogen Vapor Pressure and start reaction. Continue to be flushed with hydrogen gas when pressure is down to 0.15MPa to 0.3MPa, this operation no longer changes to pressure repeatedly, imperial pressure, nitrogen is replaced, blowing, filtering reacting liquid, reclaiming catalyst, filtrate decompression distills (R)-(+)-1-(2-chlorphenyl)-2,2-dimethyl-1, ammediol 19.93g, total recovery is 93%.
Equipped with condensing tube, thermometer there-necked flask in add 19.93g (R)-(+)-1-(2-chlorphenyl)-2,2-methyl-1,3-propanediol and 30mLCH2Cl2Solution, is stirred at room temperature and is slowly added dropwise 30mL under condition and contains POCl3The CH of (15.53g, 1.1mol)2Cl2Solution. Being warming up to reaction temperature after dropwising to reflux 4h hour, thin layer chromatography is followed the tracks of reaction and is terminated to reaction. Decompression is distilled off solvent C H2Cl2. Obtain thick liquid (R)-(+)-4-(2-chlorphenyl)-2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychloride.
To (R)-(+)-4-(2-chlorphenyl) chloro-5,5-dimethyl-2-oxo-1 of-2-, 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides drip NaOH(11.1g, 0.28mol) solution, it is heated to 90 DEG C and refluxes about 1 hour. Stirring overnight, adds enough dense HCl acidifyings, stirs some hours, is filtrated to get (R)-(+)-4-(2-chlorphenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane 18.49g.Mp224-226 DEG C, [α]D 20=+48.0°(c=2.0,CH3CH2OH), 99.99%e.e.. Fig. 1 is racemization 4-(2-chlorphenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3, the liquid chromatogram of 2-dioxaphosphorinane, Fig. 2 is above-mentioned (R)-(+)-4-(2-chlorphenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3, the liquid chromatogram of 2-dioxaphosphorinane, chromatographic condition is: mobile phase: 5% methanol+95% phosphate-buffered salt; Detection wavelength: 254nm column temperature: 25 DEG C. Flow velocity: 1.0mL/min, chromatographic column: CHIRAL-AGP.
Fig. 1 is DL 4-(2-chlorphenyl) liquid chromatogram of-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane;
Fig. 2 is the liquid chromatogram of (R)-(+)-4-(2-the chlorphenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of embodiment 1 gained.
Embodiment 2
D-dried meat ammonia alcohol (2.53g, 0.025mol) and benzaldehyde (5.3g, 0.05mol) are dissolved in the mixture of 20mlDMSO and isobutylaldehyde (3.6g, 0.05mol), keep stirring about 24h under 25 DEG C of conditions. Add ammonium chloride solution washing saturated for 20ml, then use 40ml extraction into ethyl acetate 2 times. Organic over anhydrous NaSO4Dry and concentrate at reduced pressure conditions. The L-dried meat ammonia alcohol reclaimed in water layer is applied mechanically repeatedly. Obtain (R)-(-)-3-phenyl-3-hydroxyl-2,2-dimethyl propionic aldehyde 7.65g, yield is 86%.
Addition (R) in autoclave-(-)-3-phenyl-3-hydroxyl-2,2-dimethyl-propionic aldehyde 7.65g, with Raney nickel for catalyst, methanol as solvent, in pH8.0～8.6, temperature 50 C～80 DEG C, pressure reacts when being 0.3MPa, by reacting liquid filtering after having reacted, recovery catalyst reuse, obtain (R)-(-)-1-phenyl-2,2-methyl isophthalic acid, ammediol 7.66g, yield is 99%.
Equipped with condensing tube, thermometer there-necked flask in add 7.66g (R)-(-)-1-phenyl-2,2-methyl-1,3-propanediol and 15mLCH2Cl2Solution, is stirred at room temperature and is slowly added dropwise 15mL under condition and contains 14.26g(0.046mol) POCl3CH2Cl2Solution. Being warming up to reaction temperature backflow 2h hours after dropwising, thin layer chromatography is followed the tracks of reaction and is terminated to reaction. Decompression is distilled off solvent C H2Cl2. Obtain thick liquid (R)-(-)-4-phenyl-2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychloride.
To (R)-(-) chloro-5,5-dimethyl-2-oxo-1 of-4-phenyl-2-, in 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides drip NaOH(5.0g, 0.127mol) solution, be heated to 90 DEG C reflux about 1 hour. Stirring overnight, add enough dense HCl acidifyings, stir some hours, be filtrated to get (R)-(-)-4-phenyl-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane 7.10g. Mp232～234 DEG C. 99.86%e.e.. [α]D 20=+61.5°(c=2.0,CH3CH2OH)。
Embodiment 3
(R)-1-[(2-pyrrolidine)-methyl]-nafoxidine (chiral catalyst 3; 3.45g, 0.007mol), (11.4g, 0.007mol and benzaldehyde (8.0g, 0.07mol) are dissolved in the mixture of 30mlDMSO and isobutylaldehyde (5.4g, 0.07mol) trifluoroacetic acid, keep under 25 DEG C of conditions stirring about 24h. Add the saturated Na of 20ml2HPO4Solution washing, then uses 40ml extraction into ethyl acetate 2 times. Dry, decompression distillation organic layer. The catalyst reclaimed in water layer repeats to apply mechanically. Obtain (S)-(+)-3-phenyl-3-hydroxyl-2,2-dimethyl propionic aldehyde 12.50g, yield is 93%.
Addition (S) in there-necked flask under room temperature condition-(+)-3-phenyl-3-hydroxyl-2,2-dimethyl-propionic aldehyde 12.50g, dropping 10mL contains 2.8gLiAlH4The methanol solution of (about 0.07mol), continues stirring, and thin layer chromatography is followed the tracks of reaction and terminated to reaction, and the 10% aqueous ammonium chloride solution extraction adding amount of calculation is gone out, and stirs 15min under room temperature. Decompression steam methanol, be extracted with ethyl acetate twice, merge, concentration of organic layers, obtain (S)-(+)-1-phenyl-2,2-methyl isophthalic acid, ammediol, weigh 12.03g, and yield is 95%.
Equipped with condensing tube, thermometer there-necked flask in add 12.03g (S)-(+)-1-phenyl-2,2-methyl-1,3-propanediol and 20mLCH2Cl2Solution, is stirred at room temperature and is slowly added dropwise 20mL under condition and contains POCl3The CH of (10.23g, 0.067mol)2Cl2Solution. Being warming up to reaction temperature after dropwising to reflux 2h hour, thin layer chromatography is followed the tracks of reaction and is terminated to reaction. Decompression is distilled off solvent C H2Cl2. Obtain thick liquid (S)-(+)-4-phenyl-2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychloride.
To (S)-(+) chloro-5,5-dimethyl-2-oxo-1 of-4-phenyl-2-, in 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides drip NaOH(8.0g, 0.2mol) solution, be heated to 90 DEG C reflux about 1 hour. Stirring overnight, add enough dense HCl acidifyings, stir some hours, be filtrated to get (S)-(+)-4-phenyl-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane 11.47g. Mp229～231 DEG C, 99.47%e.e., [α]D 20=+62.0°(c=2.0,CH3CH2OH)。
Embodiment 4
L-PROLINE (3.45g, 0.03mol) is dissolved in containing, in 30mlDMSO isobutylaldehyde (7.2g, 0.1mol) mixture, stirring 15min under 25 DEG C of conditions. It is added thereto to benzaldehyde (10.6g, 0.1mol) and continues stirring 20h. Add ammonium chloride solution washing saturated for 20ml, then use 40ml extraction into ethyl acetate 2 times. Organic over anhydrous NaSO4Dry and concentrate at reduced pressure conditions.
By (S)-(+)-3-phenyl-3-hydroxyl-2,2-dimethyl-propionic aldehyde, methanol, catalyst Raney nickel add evacuation in autoclave, replace three times with nitrogen, then hydrogen exchange three times, reach 0.3MPa to Hydrogen Vapor Pressure and start reaction. Continue to be flushed with hydrogen gas when pressure is down to 0.15MPa to 0.3MPa, this operation no longer changes to pressure repeatedly, imperial pressure, nitrogen is replaced, blowing, filtering reacting liquid, reclaim catalyst, filtrate decompression distill (S)-(+)-1-phenyl-2,2-methyl isophthalic acid, ammediol 16.76g, total recovery is 93%.
Equipped with condensing tube, thermometer there-necked flask in add 16.76g (S)-(+)-1-phenyl-2,2-methyl-1,3-propanediol and 30mLCH2Cl2Solution, is stirred at room temperature and is slowly added dropwise 30mL under condition and contains POCl3The CH of (15.63g, 0.1mol)2Cl2Solution. Being warming up to reaction temperature after dropwising to reflux 4h hour, thin layer chromatography is followed the tracks of reaction and is terminated to reaction. Decompression is distilled off solvent C H2Cl2. Obtain thick liquid (S)-(+)-4-phenyl-2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychloride.
To (S)-(+) chloro-5,5-dimethyl-2-oxo-1 of-4-phenyl-2-, in 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides drip NaOH(11.1g, 0.28mol) solution, be heated to 90 DEG C reflux about 1 hour. Stirring overnight, add enough dense HCl acidifyings, stir some hours, be filtrated to get (S)-(+)-4-phenyl-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane 16.44g.Mp230～232 DEG C, 99.75%e.e., [α]D 20=+61.3°(c=2.0,CH3CH2OH)。
Embodiment 5
The mixture of D-dried meat ammonia alcohol (2.53g, 0.025mol) and isobutylaldehyde (3.6g, 0.05mol) is dissolved in 20mLDMF, keeps stirring 15min under 25 DEG C of conditions, is added thereto to o-chlorobenzaldehyde (7.02g, 0.05mol) and continues stirring 17h. Add ammonium chloride solution washing saturated for 20ml, then use 40ml extraction into ethyl acetate 2 times. Organic over anhydrous NaSO4Dry and concentrate at reduced pressure conditions. The L-dried meat ammonia alcohol reclaimed in water layer is applied mechanically repeatedly. Obtain (S)-(-)-3-(2-chlorphenyl)-3-hydroxyl-2,2-dimethyl-propionic aldehyde. Weigh 9.87g, yield 93%.
Addition (S) in there-necked flask under room temperature condition-(-)-3-(2-chlorphenyl)-3-hydroxyl-2,2-dimethyl-propionic aldehyde 9.87g, dropping 10mL contains 1.75gNaBH4The methanol solution of (about 0.05mol), continues stirring, and thin layer chromatography is followed the tracks of reaction and terminated to reaction, adds appropriate water, stirs 15min under room temperature. Decompression steams methanol, separates organic layer, water layer dichloromethane extraction twice, merges, concentration of organic layers, obtains (S)-(-)-1-(2-chlorphenyl)-2，2-dimethyl-1，3-propanediol, and weigh 9.07g, and yield is 91%.
Equipped with condensing tube, thermometer there-necked flask in add 9.07g (S)-(-)-1-(2-chlorphenyl)-2,2-methyl-1,3-propanediol and 15mLCH2Cl2Solution, is stirred at room temperature and is slowly added dropwise 15mL under condition and contains POCl3The CH of (7.12g, 0.046mol)2Cl2Solution. Being warming up to reaction temperature after dropwising to reflux 4h hour, thin layer chromatography is followed the tracks of reaction and is terminated to reaction. Decompression is distilled off solvent C H2Cl2. Obtain thick liquid (S)-(-)-4-(2-chlorphenyl)-2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychloride.
To (S)-(-)-4-(2-chlorphenyl) chloro-5,5-dimethyl-2-oxo-1 of-2-, 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides drip NaOH(5.07g, 0.13mol) solution, it is heated to 90 DEG C and refluxes about 1 hour. Stirring overnight, adds enough dense HCl acidifyings, stirs some hours, is filtrated to get (S)-(-)-4-(2-chlorphenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane 8.18g. 99.61%e.e., mp223～235 DEG C, [α]D 20=+49.1°(c=2.0,CH3CH2OH). Fig. 3 is above-mentioned (S)-(-)-4-(2-chlorphenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1, the liquid chromatogram of 3,2-dioxaphosphorinanes, and chromatographic condition is: mobile phase: 5% methanol+95% phosphate-buffered salt; Detection wavelength: 254nm column temperature: 25 DEG C. Flow velocity: 1.0mL/min, chromatographic column: CHIRAL-AGP.
Fig. 3 is the liquid chromatogram of (S)-(-)-4-(2-the chlorphenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of embodiment 5 gained.
Embodiment 6
L-PROLINE (3.45g, 0.03mol) and benzaldehyde (10.6g, 0.1mol) are dissolved in the mixture of 30mlDMSO and isobutylaldehyde (7.2g, 0.1mol), keep stirring about 24h under 25 DEG C of conditions. Add ammonium chloride solution washing saturated for 20ml, then use 40ml extraction into ethyl acetate 2 times. Organic over anhydrous NaSO4Dry and concentrate at reduced pressure conditions. Reclaim L-PROLINE in water layer to repeat to apply mechanically. Obtain (S)-(+)-3-phenyl-3-hydroxyl-2,2-dimethyl propionic aldehyde 16.04g, yield is 90%.
Addition (S) in there-necked flask under room temperature condition-(+)-3-phenyl-3-hydroxyl-2,2-dimethyl-propionic aldehyde 16.04g, dropping 10mL contains 3.5gNaBH4The methanol solution of (about 0.1mol), continues stirring, and thin layer chromatography is followed the tracks of reaction and terminated to reaction, adds appropriate water, stirs 15min under room temperature.Decompression steams methanol, separates organic layer, aqueous layer with ethyl acetate extracting twice, merges, concentration of organic layers, obtain (S)-(+) 1-phenyl-2,2-methyl isophthalic acid, ammediol, weigh 15.24g, and yield is 94%.
Equipped with condensing tube, thermometer there-necked flask in add 15.24g (S)-(+)-1-phenyl-2,2-methyl-1,3-propanediol and 30mLCH2Cl2Solution, is stirred at room temperature under condition and is slowly added dropwise 30mL contains (14.26g, 0.093mol) POCl3CH2Cl2Solution. Being warming up to reaction temperature after dropwising to reflux 2h hour, thin layer chromatography is followed the tracks of reaction and is terminated to reaction. Decompression is distilled off CH2Cl2. Obtain thick liquid (S)-(+)-4-phenyl-2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychloride.
To (S)-(+) chloro-5,5-dimethyl-2-oxo-1 of-4-phenyl-2-, in 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides drip NaOH(containing 10.14g, 0.25mol) solution, be heated to 90 DEG C reflux about 1 hour. Stirring overnight, add enough dense HCl acidifyings, stir some hours, be filtrated to get (S)-(+)-4-phenyl-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane 14.33g. Mp232～233 DEG C. 99.85%e.e.. [α]D 20=+60.9°(c=2.0,CH3CH2OH)。

Claims (8)

1. the preparation method of a cyclic phosphoric acid, it is characterised in that said method comprising the steps of:
A, isobutylaldehyde and aromatic aldehyde react generation chiral 3-aryl-3-hydroxyl-2,2-dimethyl propionic aldehyde under chiral catalyst catalytic condition;
Chiral 3-aryl-3-hydroxyl-2,2-dimethyl the propionic aldehyde that b, described step a prepare obtains chirality 1-aryl-2,2-dimethyl-1,3-propylene glycol through reduction reaction;
Chirality 1-aryl-2，2-dimethyl-1，3-propanediol that c, described step b prepare, obtains chloro-5,5-dimethyl-2-oxo-1 of chirality 4-aryl-2-, 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides when dichloromethane with phosphorus oxychloride reaction;
Chloro-5,5-dimethyl-2-oxo-1 of chirality 4-aryl-2-that d, described step c prepare, 3,2-dioxaphosphorinane phosphoryl chloride phosphorus oxychlorides, hydrolysis in the basic conditions, acidifying generate cyclic phosphoric acid; Described alkali condition is organic base or inorganic base;
Described inorganic base is the one in sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; Described organic base is triethylamine or pyridine;
Described step a aromatic aldehyde has logical formula I:
Wherein R1、R2、R3、R4、R5It is identical or different, represents hydrogen atom, alkyl, alkoxyl, chlorine atom, bromine atoms or atomic iodine, fluorine atom or nitro respectively.
2. the preparation method of cyclic phosphoric acid according to claim 1, it is characterised in that described step a is:
There is aldol reaction in isobutylaldehyde and aromatic aldehyde chiral catalyst in a solvent, generate chiral 3-aryl-3-hydroxyl-2,2-dimethyl propionic aldehyde at-30 DEG C～40 DEG C temperature;
Solvent in described step a is THF, acetonitrile, DMSO, DMF, dichloromethane, chloroform, 1,4-dioxane, methanol and H2One or more in O solvent.
3. the preparation method of cyclic phosphoric acid according to claim 2, it is characterized in that in described step a, chiral catalyst is selected from (D/L)-proline, (D/L)-dried meat ammonia alcohol, (D/L) one or more in compound 1-8, chiral catalyst structural formula is as follows:
4. the preparation method of cyclic phosphoric acid according to claim 1, it is characterised in that described alkyl is saturated alkyl or unsaturated alkyl, or be phenyl or substituted-phenyl;Described alkoxyl is alkyl and the group of oxygen atom formation.
5. the preparation method of cyclic phosphoric acid according to claim 1, it is characterised in that the mol ratio making consumption and aromatic aldehyde of chiral catalyst is x:1,0.05 < x < 0.6.
6. the preparation method of cyclic phosphoric acid according to claim 3, it is characterised in that when chiral catalyst is 1-(2-pyrrolidinylmethyl)-pyrrolidine add Bronsted acid or Lewis acid with the use of.
7. the preparation method of cyclic phosphoric acid according to claim 6, it is characterised in that described Bronsted acid is H2SO4,CF3SO3H,p-TsOH,HNO3,CF3CO2H,CH3CO2H,H3PO4, D-(+)-camphorsulfonic acid; Described Lewis acid is Sc (OTf)3,Cu(OTf)3,Zn(OTf)2,Y(OTf)3,La(OTf)3,Eu(OTf)3,Yb(OTf)3; The mol ratio making consumption and 1-(2-pyrrolidinylmethyl)-pyrrolidine of Bronsted acid or Lewis acid is x:1,0.5 < x < 2.
8. the preparation method of cyclic phosphoric acid according to claim 1, it is characterised in that the reduction reaction described in described step b is catalytic hydrogenating reduction, or use reducing agent reduction, described reducing agent is LiAlH4、NaBH4Or KBH4In one.
CN201310039714.9A 2013-02-01 2013-02-01 A kind of preparation method of cyclic phosphoric acid Expired - Fee Related CN103232491B (en)

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EP0180276A1 (en) * 1984-10-24 1986-05-07 Stamicarbon B.V. Dioxaphosphorinanes, their preparation and use for resolving optically active compounds

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