CN102850394A - Preparation method of PPOH - Google Patents
Preparation method of PPOH Download PDFInfo
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- CN102850394A CN102850394A CN2012103813442A CN201210381344A CN102850394A CN 102850394 A CN102850394 A CN 102850394A CN 2012103813442 A CN2012103813442 A CN 2012103813442A CN 201210381344 A CN201210381344 A CN 201210381344A CN 102850394 A CN102850394 A CN 102850394A
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- butyl ester
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Abstract
The invention provides a preparation method of PPOH, comprising the following steps of: by taking phosphorus trichloride and propargyl alcohol as initial raw materials and using a method for introducing gas which is not reacted with a system into a reaction system, taking away generated hydrogen chloride by gas flow, simply treating, reacting with tert butyl alcohol, heating and rearranging and catalytically hydrogenating to obtain the PPOH di-tert-butyl ester to obtain the PPOH in case of acid catalysis. The method provided by the invention is a concise and high-efficiency synthetic route. The method is reasonable to design, high in safety, high in operability and high in yield.
Description
Technical field
The present invention relates to the preparation method of the synthetic key intermediate of a kind of Broad spectrum antibiotics phosphonomycin, particularly a kind of preparation method along the propylene phosphonic acids.
Background technology
Suitable propylene phosphonic acids (
Cis-Propenylphosphonic acid), abbreviation CPPA, molecular formula is C
3H
7PO
3, be the important intermediate of synthetic Broad spectrum antibiotics phosphonomycin.
Synthetic method along the propylene phosphonic acids, that the people such as Christensen are at Scientific Magazine [Science the earliest, 1969,166 (1), 123-125] the middle method of reporting, use the reaction of Grignard reagent 1-proyl magnesium bromide and two tert.-butoxy phosphoryl chlorides, obtain 1-proyl phosphonic acids di-n-butyl, then methyl alcohol is made solvent, uses the hydrogenation of Lindlar catalyst to obtain along propylene phosphonic acids di-n-butyl, then takes off normal-butyl with the form of butylene under the concentrated hydrochloric acid condition and obtains along the propylene phosphonic acids.
Glamkowski is at 1968 application GB1237232 (1971) and J. Org. Chem., 1970,35 (10), reported another synthetic method among the 3510-3512, under the condition of ice bath, the trimethyl carbinol and phosphorus trichloride reaction, triethylamine is done acid binding agent, benzene is made solvent, and nucleophilic substitution occurs, and obtains chloro phosphorous acid di tert butyl carbonate, then react with propiolic alcohol, obtain two tert.-butoxies phosphorous acid-2-propynyl ester, then add thermal rearrangement and obtain the propadiene phosphonic acid di-tert-butyl ester, then, benzene is made solvent, 5% Pd/C is as catalyzer, and catalytic hydrogenation obtains along the propylene phosphonic acid di-tert-butyl ester, obtains cis-propene phosphoric acid after using at last concentrated hydrochloric acid catalysis to take off the tertiary butyl with the form of iso-butylene.Patent documentation US3597451 (1971) and US3849482 (1974) have also mentioned the method preparation along the propylene phosphonic acids, are used for the synthetic of different phosphonate derivatives.
Take the propadiene phosphonic acids as raw material, the catalytic hydrogenation preparation has a lot of bibliographical informations along the method for propylene phosphonic acids.The Zhengzhou University people from Soviet Union such as ships at [chemical science and technology, 2005,13 (5), 34-38] in reported, use pickling process, a series of active ingredients, the different catalyzer of massfraction have been prepared, different carriers to Kaolinite Preparation of Catalyst is studied, and has compared palladium and these two kinds of different activities components of ruthenium, the activity of the catalyzer of preparation, the best catalyzer of catalytic activity of report is 5% Pd/C, and the catalyzed reaction transformation efficiency is 50.45%.
The people from Soviet Union such as ships also at [Zhengzhou University's journal (Edition), 2006,38 (2), 87-100] in, preparation method to catalyzer 5%Pd/C is studied, some influence factors in the catalyst preparation process are investigated, drawn the best preparation method of catalyzer, and it is characterized.The catalyst reaction of preparation, peak rate of conversion is 52.58%.
Among the patent documentation US3733356 (1973) of Merck company, two kinds of synthetic methods that prepare along the propylene phosphonic acids have been reported.First method is to use propiolic alcohol and phosphorus trichloride reaction, and phosphorus trichloride is not only done reactant but also do reaction solvent, and reaction is heated to 74 oC, and fast as far as possible adds propiolic alcohol below the phosphorus trichloride liquid level, then be warming up to backflow.Three as a child afterreaction was complete, had finished nucleophilic substitution and rearrangement reaction, obtained propadiene two phosphonyl chlorides and 2-propargyl alcoholate propadiene phosphonyl chloride.Then underpressure distillation obtains propadiene two phosphonyl chloride sterlings, and next step uses benzene to do solvent, 5%Pd/C catalytic hydrogenation, obtains along propylene two phosphonyl chlorides, and under 0-10 oC condition, hydrolysis obtains along the propylene phosphonic acids at last.
Patent documentation US3733356 (1973), another method is that propadiene two phosphoryl chloride sterlings are hydrolyzed, obtain propadiene phosphoric acid, then change into sodium salt with sodium hydroxide, add thermal isomerization and obtain 1-propine phosphonic acids disodium salt, then water is made solvent, is used the Pd/C catalytic hydrogenation, obtains along propylene phosphonic acids disodium salt, uses at last the method for ion-exchange to obtain along the propylene phosphonic acids.
The shortcomings such as prior art preparation is along propylene phosphonic acids method, mostly deposits the cis-propene phosphoric acid purity that obtains low, and impurity is many.
Summary of the invention
Technical problem to be solved by this invention is for the deficiencies in the prior art, provides a kind of method more reasonable, succinct efficient preparation method along the propylene phosphonic acids.
Technical problem to be solved by this invention is to realize by following technical scheme.The present invention is a kind of preparation method along the propylene phosphonic acids, is characterized in, its step is as follows:
(1) preparation of propadiene phosphonic acid di-tert-butyl ester;
Under condition of ice bath, in three mouthfuls of reaction vessels, the adding volume ratio is the phosphorus trichloride of 13.85～13.95:20～40 and the mixture of non-polar solvent, then dripping volume ratio is the propiolic alcohol of 2.60～3.20:70～90 and the mixture of non-polar solvent, and the volume ratio of phosphorus trichloride and propiolic alcohol is 13.85～13.95:2.60～3.20; Toward system, pass into argon gas, nitrogen or argon gas from three mouthfuls of reaction vessel one ends, at the other end of three mouthfuls of reaction vessels as the air outlet, absorb with waste lye, the mixture of propiolic alcohol and non-polar solvent dropwises, the TLC detection reaction finishes, revolve steaming, obtain the mixture of dichloro-phosphorous acid-2-propynyl ester, chloro phosphorous acid two-2-propynyl ester and tricresyl phosphite-2-propynyl ester;
Under the condition of ice bath, the mixture that obtains more than adding in the reaction vessel, add non-polar solvent, drip triethylamine, then drip the trimethyl carbinol, the weightmeasurement ratio of said mixture, non-polar solvent, triethylamine, the trimethyl carbinol is 7.5～8.0g:70～90 ml:14～15ml:7.0～8.0 g; Dropwise, stirring at room 20～40 minutes is heated to backflow to system again, after the end that refluxes system is spin-dried for, and adds an amount of toluene, suction filtration, and then with toluene filter wash cake, obtain the propadiene phosphonic acid di-tert-butyl ester after filtrate is concentrated;
(2) preparation of suitable propylene phosphonic acid di-tert-butyl ester;
Propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene that step (1) is made add in the hydriding reactor, and the weightmeasurement ratio of propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene is 9.50～11.00 g:0.50～1.20g:150～300ml; Hydrogen pressure 1.8～2.2MPa, catalytic hydrogenation is complete to TLC monitoring raw material reaction, uses to be lined with diatomaceous sand core funnel suction filtration, after mother liquor is concentrated, obtains along the propylene phosphonic acid di-tert-butyl ester; Described catalyzer is selected from 5%Pd/C, 10%Pd/C or Lindlar catalyzer;
(3) preparation of suitable propylene phosphonic acids;
The suitable propylene phosphonic acid di-tert-butyl ester that step (2) is obtained adds in the reaction vessel, add toluene, then add concentrated hydrochloric acid or suitable propylene phosphonic acids, weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and concentrated hydrochloric acid is 9.7～9.9 g:70～90 ml:0.4～0.6 ml, and perhaps the weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and suitable propylene phosphonic acids is 9.2～9.6 g:40～60ml:0.1～0.3 ml; After the reflux 3 hours, TLC monitoring reacts completely, revolve steam remove toluene after, obtain finished product along the propylene phosphonic acids.
In above-described preparation method's along the propylene phosphonic acids the step (1), the volume ratio of phosphorus trichloride and non-polar solvent be preferably 13.90:30 mixture; The volume ratio of propiolic alcohol and non-polar solvent is preferably 3.02:80; The volume ratio of phosphorus trichloride and propiolic alcohol is preferably 13.90:3.02; The weightmeasurement ratio of the mixture of dichloro-phosphorous acid-2-propynyl ester, chloro phosphorous acid two-2-propynyl ester and tricresyl phosphite-2-propynyl ester, non-polar solvent, triethylamine, the trimethyl carbinol is preferably 7.84g:80 ml:14.62ml:7.44g.
In the preparation method's of above-described suitable propylene phosphonic acids the step (2), the weightmeasurement ratio of propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene is preferably 10.65 g:0.50～1.00g:200ml; Hydrogen pressure 2.0MPa.
In the preparation method's of above-described suitable propylene phosphonic acids the step (3), weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and concentrated hydrochloric acid is preferably 9.8 g:80 ml:0.5 ml, and perhaps the weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and suitable propylene phosphonic acids is preferably 9.4 g:50ml:0.2 ml; After the reflux 3 hours, TLC monitoring reacts completely, revolve steam remove toluene after, obtain finished product along the propylene phosphonic acids.
Above-described described non-polar solvent is disclosed any non-polar solvent in the prior art along among the preparation method of propylene phosphonic acids, preferred methylene dichloride or chloroform.
The synthetic route of the inventive method is as follows:
The first step reaction of the present invention, there are two by products to generate, be respectively tricresyl phosphite-2-propynyl ester and chloro phosphorous acid two-2-propynyl ester, continue and trimethyl carbinol reaction, then add thermal rearrangement, catalytic hydrogenation, the latter two can both be converted into catalytic hydrogenation along the propylene phosphonic acid ester, and are last, and the two can both be converted into along the propylene phosphonic acids under acidic conditions.
Compared with prior art, the inventive method discloses a succinct efficiently synthetic route.It is take phosphorus trichloride and propiolic alcohol as starting raw material, use passes into not the method with the gas of system reaction in the reaction system, take away the hydrogenchloride of generation with air-flow, react with the trimethyl carbinol after the simple process, reheating rearrangement, catalytic hydrogenation obtains obtaining under acid catalysis at last along the propylene phosphonic acids along the propylene phosphonic acid di-tert-butyl ester.The method is reasonable in design, and is safe, workable, and yield is high.
Embodiment
Below in conjunction with embodiment technical solution of the present invention is described in further detail, so that those skilled in the art further understand the present invention, and does not consist of Copyright law of the present invention.Below use high pressure lipuid chromatography (HPLC) (HPLC) to carry out assay in each experiment, use magnetic nuclear resonance method to carry out molecular structure and identify, use tlc (TLC) monitoring reaction progress.
Embodiment 1, a kind of preparation method along the propylene phosphonic acids, and its step is as follows:
(1) preparation of propadiene phosphonic acid di-tert-butyl ester;
Under condition of ice bath, in three mouthfuls of reaction vessels, adding volume ratio is the phosphorus trichloride of 13.85:20 and the mixture of non-polar solvent, and then dripping volume ratio is the propiolic alcohol of 2.60:70 and the mixture of non-polar solvent, and the volume ratio of phosphorus trichloride and propiolic alcohol is 13.85:2.60; Toward system, pass into argon gas, nitrogen or argon gas from three mouthfuls of reaction vessel one ends, at the other end of three mouthfuls of reaction vessels as the air outlet, absorb with waste lye, the mixture of propiolic alcohol and non-polar solvent dropwises, the TLC detection reaction finishes, revolve steaming, obtain the mixture of dichloro-phosphorous acid-2-propynyl ester, chloro phosphorous acid two-2-propynyl ester and tricresyl phosphite-2-propynyl ester;
Under the condition of ice bath, the mixture that obtains more than adding in the reaction vessel adds non-polar solvent, drips triethylamine, then drip the trimethyl carbinol, the weightmeasurement ratio of said mixture, non-polar solvent, triethylamine, the trimethyl carbinol is 7.5g:70ml:14ml:7.0 g; Dropwise, stirring at room 20 minutes is heated to backflow to system again, after the end that refluxes system is spin-dried for, and adds an amount of toluene, suction filtration, and then with toluene filter wash cake, obtain the propadiene phosphonic acid di-tert-butyl ester after filtrate is concentrated;
(2) preparation of suitable propylene phosphonic acid di-tert-butyl ester;
Propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene that step (1) is made add in the hydriding reactor, and the weightmeasurement ratio of propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene is 9.50g:0.50g:150ml; Hydrogen pressure 1.8MPa, catalytic hydrogenation is complete to TLC monitoring raw material reaction, uses to be lined with diatomaceous sand core funnel suction filtration, after mother liquor is concentrated, obtains along the propylene phosphonic acid di-tert-butyl ester; Described catalyzer is selected from 5%Pd/C, 10%Pd/C or Lindlar catalyzer;
(3) preparation of suitable propylene phosphonic acids;
The suitable propylene phosphonic acid di-tert-butyl ester that step (2) is obtained adds in the reaction vessel, add toluene, then add concentrated hydrochloric acid or suitable propylene phosphonic acids, weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and concentrated hydrochloric acid is 9.7 g:70 ml:0.4 ml, and perhaps the weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and suitable propylene phosphonic acids is 9.2 g:40ml:0.1 ml; After the reflux 3 hours, TLC monitoring reacts completely, revolve steam remove toluene after, obtain finished product along the propylene phosphonic acids.
Embodiment 2, a kind of preparation method along the propylene phosphonic acids, and its step is as follows:
(1) preparation of propadiene phosphonic acid di-tert-butyl ester;
Under condition of ice bath, in three mouthfuls of reaction vessels, adding volume ratio is the phosphorus trichloride of 13.95:40 and the mixture of non-polar solvent, and then dripping volume ratio is the propiolic alcohol of 3.20:90 and the mixture of non-polar solvent, and the volume ratio of phosphorus trichloride and propiolic alcohol is 13.95:3.20; Toward system, pass into argon gas, nitrogen or argon gas from three mouthfuls of reaction vessel one ends, at the other end of three mouthfuls of reaction vessels as the air outlet, absorb with waste lye, the mixture of propiolic alcohol and non-polar solvent dropwises, the TLC detection reaction finishes, revolve steaming, obtain the mixture of dichloro-phosphorous acid-2-propynyl ester, chloro phosphorous acid two-2-propynyl ester and tricresyl phosphite-2-propynyl ester;
Under the condition of ice bath, the mixture that obtains more than adding in the reaction vessel adds non-polar solvent, drips triethylamine, then drip the trimethyl carbinol, the weightmeasurement ratio of said mixture, non-polar solvent, triethylamine, the trimethyl carbinol is 8.0g:90 ml:15ml:8.0 g; Dropwise, stirring at room 40 minutes is heated to backflow to system again, after the end that refluxes system is spin-dried for, and adds an amount of toluene, suction filtration, and then with toluene filter wash cake, obtain the propadiene phosphonic acid di-tert-butyl ester after filtrate is concentrated;
(2) preparation of suitable propylene phosphonic acid di-tert-butyl ester;
Propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene that step (1) is made add in the hydriding reactor, and the weightmeasurement ratio of propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene is 11.00 g:1.20g:300ml; Hydrogen pressure 2.2MPa, catalytic hydrogenation is complete to TLC monitoring raw material reaction, uses to be lined with diatomaceous sand core funnel suction filtration, after mother liquor is concentrated, obtains along the propylene phosphonic acid di-tert-butyl ester; Described catalyzer is selected from 5%Pd/C, 10%Pd/C or Lindlar catalyzer;
(3) preparation of suitable propylene phosphonic acids;
The suitable propylene phosphonic acid di-tert-butyl ester that step (2) is obtained adds in the reaction vessel, add toluene, then add concentrated hydrochloric acid or suitable propylene phosphonic acids, weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and concentrated hydrochloric acid is 9.9 g:90 ml:0.6 ml, and perhaps the weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and suitable propylene phosphonic acids is 9.6 g:60ml:0.3 ml; After the reflux 3 hours, TLC monitoring reacts completely, revolve steam remove toluene after, obtain finished product along the propylene phosphonic acids.
Embodiment 3, a kind of preparation method along the propylene phosphonic acids, and its step is as follows:
(1) preparation of propadiene phosphonic acid di-tert-butyl ester;
Under condition of ice bath, in three mouthfuls of reaction vessels, adding volume ratio is the phosphorus trichloride of 13.90:30 and the mixture of non-polar solvent, and then dripping volume ratio is the propiolic alcohol of 2.90:80 and the mixture of non-polar solvent, and the volume ratio of phosphorus trichloride and propiolic alcohol is 13.90:2.90; Toward system, pass into argon gas, nitrogen or argon gas from three mouthfuls of reaction vessel one ends, at the other end of three mouthfuls of reaction vessels as the air outlet, absorb with waste lye, the mixture of propiolic alcohol and non-polar solvent dropwises, the TLC detection reaction finishes, revolve steaming, obtain the mixture of dichloro-phosphorous acid-2-propynyl ester, chloro phosphorous acid two-2-propynyl ester and tricresyl phosphite-2-propynyl ester;
Under the condition of ice bath, the mixture that obtains more than adding in the reaction vessel adds non-polar solvent, drips triethylamine, then drip the trimethyl carbinol, the weightmeasurement ratio of said mixture, non-polar solvent, triethylamine, the trimethyl carbinol is 7.8g:80 ml:14.5ml:7.5g; Dropwise, stirring at room 30 minutes is heated to backflow to system again, after the end that refluxes system is spin-dried for, and adds an amount of toluene, suction filtration, and then with toluene filter wash cake, obtain the propadiene phosphonic acid di-tert-butyl ester after filtrate is concentrated;
(2) preparation of suitable propylene phosphonic acid di-tert-butyl ester;
Propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene that step (1) is made add in the hydriding reactor, and the weightmeasurement ratio of propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene is 10.50 g:0.8g:200ml; Hydrogen pressure 2.0MPa, catalytic hydrogenation is complete to TLC monitoring raw material reaction, uses to be lined with diatomaceous sand core funnel suction filtration, after mother liquor is concentrated, obtains along the propylene phosphonic acid di-tert-butyl ester; Described catalyzer is selected from 5%Pd/C, 10%Pd/C or Lindlar catalyzer;
(3) preparation of suitable propylene phosphonic acids;
The suitable propylene phosphonic acid di-tert-butyl ester that step (2) is obtained adds in the reaction vessel, add toluene, then add concentrated hydrochloric acid or suitable propylene phosphonic acids, weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and concentrated hydrochloric acid is 9.8 g:80 ml:0.5 ml, and perhaps the weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and suitable propylene phosphonic acids is 9.4 g:50ml:0.2 ml; After the reflux 3 hours, TLC monitoring reacts completely, revolve steam remove toluene after, obtain finished product along the propylene phosphonic acids.
Embodiment 4, a kind of preparation method's preparation experiment one along the propylene phosphonic acids, and its step is as follows:
(1) preparation of propadiene phosphonic acid di-tert-butyl ester
Under the condition of ice bath, in the 250 ml there-necked flasks, add phosphorus trichloride (13.90 ml, 159.31 mmol) with 30 ml methylene dichloride, then drip propiolic alcohol (3.02 ml, 51.88 mmol) and the mixture of 80 ml methylene dichloride, logical argon gas from there-necked flask one end toward system, absorbs with waste lye as the air outlet at the other end of there-necked flask, after 1 hour, the mixture of propiolic alcohol and methylene dichloride dropwises, and the TLC detection reaction finishes, and revolves steaming, obtaining the oil of 7.84 g yellow, is dichloro-phosphorous acid-2-propynyl ester, the mixture of chloro phosphorous acid two-2-propynyl ester and tricresyl phosphite-2-propynyl ester.
Under the condition of ice bath, in 250 ml round-bottomed flasks, add the oil of 7.84 g yellow obtained in the previous step, add methylene dichloride 80 ml, drip triethylamine (14.62ml, 104.89 mmol), drip in the process of triethylamine, the yellow of system is deepened, and change is sticky, white cigarette is arranged in the round-bottomed flask, then drip the trimethyl carbinol (7.44 g, 100.38 mmol), what system became in the process of dropping is more sticky, dropwise stirring at room half an hour after half an hour.System is heated to backflow, after two hours, system is spin-dried for, add toluene 100 ml, suction filtration, and then with toluene filter wash cake (3 * 100 ml), obtain the oil of 10.65 g yellow after filtrate concentrates.
The nuclear-magnetism of propadiene phosphonic acid di-tert-butyl ester:
1H-NMR (400 MHz, CDCl
3) δ: 1.50 (s, 18H), 4.92 (t,
J=6.9 Hz, 2H) 5.33 (t,
J=6.9 Hz, 1H).
(2) preparation of suitable propylene phosphonic acid di-tert-butyl ester
Propadiene phosphonic acid di-tert-butyl ester 10.65 g, 5% palladium carbon (0.55 g) and 200 ml toluene are added in the hydriding reactor, hydrogen pressure 2MPa, catalytic hydrogenation, react after 2 hours, TLC monitoring raw material reaction is complete, use is lined with diatomaceous sand core funnel suction filtration, after mother liquor is concentrated, obtains the oil of 9.8 g yellow.
Nuclear-magnetism along the propylene phosphonic acid di-tert-butyl ester:
1H-NMR (400 MHz, CDCl
3) δ: 1.60 (s, 18H), 1.98-2.03 (m, 3H), 5.52-5.63 (m, 1H), 6.21-6.35 (m, 1H).
(3) preparation of suitable propylene phosphonic acids
In the 250 ml round-bottomed flasks, add suitable propylene phosphonic acid di-tert-butyl ester (9.8 g, 41.83 mmol) obtained in the previous step, add 80 ml toluene, then add concentrated hydrochloric acid 0.5 ml, reflux is after 3 hours, and TLC monitors, react completely, revolve steam remove toluene after, obtain the oil of 4.9 g yellow.High pressure liquid phase analysis, 99%, five step of purity reaction yield 77% (in propiolic alcohol).
Nuclear-magnetism along the propylene phosphonic acids:
1H-NMR (400 MHz, DMSO-d
6) δ: 1.91-1.93 (m, 3H), 5.56-5.62 (m, 1H), 6.20-6.36 (m, 1H), 7.35 (s, 1H).
Liquid-phase condition: chromatographic column, Baseline C
18Reverse-phase chromatographic column, 250 * 4.6 mm, 5 μ m; Moving phase is methyl alcohol and 5% phosphate aqueous solution (2: 98); Detect wavelength, 206 nm; Flow velocity, 1 ml/min.
Embodiment 5, a kind of preparation method's preparation experiment two along the propylene phosphonic acids, and its step is as follows:
(1) preparation of propadiene phosphonic acid di-tert-butyl ester
Under the condition of ice bath, in the 250 ml there-necked flasks, add phosphorus trichloride (27.8 ml, 318.62 mmol) with 70 ml methylene dichloride, then drip propiolic alcohol (5.4 ml, 92.76 mmol) and the mixture of 100 ml methylene dichloride, logical argon gas from there-necked flask one end toward system, the other end of there-necked flask absorbs with waste lye as the air outlet, after 1 hour, the mixture of propiolic alcohol and methylene dichloride dropwises, and the TLC detection reaction finishes, and revolves steaming, obtaining the oil of 14.5 g yellow, is dichloro-phosphorous acid-2-propynyl ester, the mixture of chloro phosphorous acid two-2-propynyl ester and tricresyl phosphite-2-propynyl ester.
Under the condition of ice bath, in 250 ml round-bottomed flasks, add the oil of 14.5 g yellow obtained in the previous step, add methylene dichloride 100 ml, drip triethylamine (32.16ml, 230.76 mmol), drip in the process of triethylamine, the yellow of system is deepened, and change is sticky, white cigarette is arranged in the round-bottomed flask, then drip the trimethyl carbinol (15.62 g, 210.8 mmol), what system became in the process of dropping is more sticky, dropwise stirring at room half an hour after half an hour.System is heated to backflow, after two hours, system is spin-dried for, add toluene 150 ml, suction filtration, and then with toluene filter wash cake (3 * 150 ml), obtain the oil of 19.3 g yellow after filtrate concentrates.
(2) preparation of suitable propylene phosphonic acid di-tert-butyl ester
Propadiene phosphonic acid di-tert-butyl ester 19.3 g, 5% palladium carbon (1.0 g) and 300 ml toluene, add in the hydriding reactor, hydrogen pressure 2MPa, catalytic hydrogenation, react after 3 hours, TLC monitoring raw material reaction is complete, uses to be lined with diatomaceous sand core funnel suction filtration, after mother liquor is concentrated, obtain the oil of 18.8 g yellow.
(3) preparation of suitable propylene phosphonic acids
In the 250 ml round-bottomed flasks, add suitable propylene phosphonic acid di-tert-butyl ester 18.8 g obtained in the previous step, add 100 ml toluene, then add along propylene phosphonic acids 0.2 g, reflux is after 4 hours, and TLC monitors, react completely, revolve steam remove toluene after, obtain the oil of 9.2 g yellow.High pressure liquid phase analysis, 99%, five step of purity reaction yield 81% (in propiolic alcohol).
Claims (5)
1. the preparation method along the propylene phosphonic acids is characterized in that, its step is as follows:
(1) preparation of propadiene phosphonic acid di-tert-butyl ester;
Under condition of ice bath, in three mouthfuls of reaction vessels, the adding volume ratio is the phosphorus trichloride of 13.85～13.95:20～40 and the mixture of non-polar solvent, then dripping volume ratio is the propiolic alcohol of 2.60～3.20:70～90 and the mixture of non-polar solvent, and the volume ratio of phosphorus trichloride and propiolic alcohol is 13.85～13.95:2.60～3.20; Toward system, pass into argon gas, nitrogen or argon gas from three mouthfuls of reaction vessel one ends, at the other end of three mouthfuls of reaction vessels as the air outlet, absorb with waste lye, the mixture of propiolic alcohol and non-polar solvent dropwises, the TLC detection reaction finishes, revolve steaming, obtain the mixture of dichloro-phosphorous acid-2-propynyl ester, chloro phosphorous acid two-2-propynyl ester and tricresyl phosphite-2-propynyl ester;
Under the condition of ice bath, the mixture that obtains more than adding in the reaction vessel, add non-polar solvent, drip triethylamine, then drip the trimethyl carbinol, the weightmeasurement ratio of said mixture, non-polar solvent, triethylamine, the trimethyl carbinol is 7.5～8.0g:70～90 ml:14～15ml:7.0～8.0 g; Dropwise, stirring at room 20～40 minutes is heated to backflow to system again, after the end that refluxes system is spin-dried for, and adds an amount of toluene, suction filtration, and then with toluene filter wash cake, obtain the propadiene phosphonic acid di-tert-butyl ester after filtrate is concentrated;
(2) preparation of suitable propylene phosphonic acid di-tert-butyl ester;
Propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene that step (1) is made add in the hydriding reactor, and the weightmeasurement ratio of propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene is 9.50～11.00 g:0.50～1.20g:150～300ml; Hydrogen pressure 1.8～2.2MPa, catalytic hydrogenation is complete to TLC monitoring raw material reaction, uses to be lined with diatomaceous sand core funnel suction filtration, after mother liquor is concentrated, obtains along the propylene phosphonic acid di-tert-butyl ester; Described catalyzer is selected from 5%Pd/C, 10%Pd/C or Lindlar catalyzer;
(3) preparation of suitable propylene phosphonic acids;
The suitable propylene phosphonic acid di-tert-butyl ester that step (2) is obtained adds in the reaction vessel, add toluene, then add concentrated hydrochloric acid or suitable propylene phosphonic acids, weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and concentrated hydrochloric acid is 9.7～9.9 g:70～90 ml:0.4～0.6 ml, and perhaps the weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and suitable propylene phosphonic acids is 9.2～9.6 g:40～60ml:0.1～0.3 ml; After the reflux 3 hours, TLC monitoring reacts completely, revolve steam remove toluene after, obtain finished product along the propylene phosphonic acids.
2. the preparation method along the propylene phosphonic acids according to claim 1 is characterized in that, in step (1), the volume ratio of phosphorus trichloride and non-polar solvent be 13.90:30 mixture; The volume ratio of propiolic alcohol and non-polar solvent is 3.02:80; The volume ratio of phosphorus trichloride and propiolic alcohol is 13.90:3.02; The weightmeasurement ratio of the mixture of dichloro-phosphorous acid-2-propynyl ester, chloro phosphorous acid two-2-propynyl ester and tricresyl phosphite-2-propynyl ester, non-polar solvent, triethylamine, the trimethyl carbinol is 7.84g:80 ml:14.62ml:7.44g.
3. the preparation method along the propylene phosphonic acids according to claim 1 is characterized in that, in step (2), the weightmeasurement ratio of propadiene phosphonic acid di-tert-butyl ester, catalyzer and toluene is 10.65 g:0.50～1.00g:200ml; Hydrogen pressure 2.0MPa.
4. the preparation method along the propylene phosphonic acids according to claim 1, it is characterized in that, in step (3), weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and concentrated hydrochloric acid is 9.8 g:80 ml:0.5 ml, and perhaps the weightmeasurement ratio along propylene phosphonic acid di-tert-butyl ester, toluene and suitable propylene phosphonic acids is 9.4 g:50ml:0.2 ml; After the reflux 3 hours, TLC monitoring reacts completely, revolve steam remove toluene after, obtain finished product along the propylene phosphonic acids.
5. any one described preparation method along the propylene phosphonic acids is characterized in that according to claim 1-4, and described non-polar solvent is methylene dichloride or chloroform.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108558940A (en) * | 2018-06-01 | 2018-09-21 | 徐州诺克非医药科技有限公司 | A kind of synthetic method of intermediate allene phosphonic acids |
| CN108840885A (en) * | 2018-05-28 | 2018-11-20 | 徐州诺克非医药科技有限公司 | A kind of synthetic method of intermediate propylene phosphonic acid |
| CN110511243A (en) * | 2019-09-11 | 2019-11-29 | 武汉工程大学 | It is catalyzed the method that allene phosphoric acid prepares cis-propene phosphoric acid in water using core-shell catalyst |
| CN110887925A (en) * | 2019-12-03 | 2020-03-17 | 上海峰林生物科技有限公司 | High performance liquid chromatography method for determining fosfomycin sodium impurities |
| CN112375098A (en) * | 2020-12-07 | 2021-02-19 | 商河探荣新技术开发中心 | Application of carbonate-borane catalyst in preparation of antibiotic intermediate |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108840885A (en) * | 2018-05-28 | 2018-11-20 | 徐州诺克非医药科技有限公司 | A kind of synthetic method of intermediate propylene phosphonic acid |
| CN108558940A (en) * | 2018-06-01 | 2018-09-21 | 徐州诺克非医药科技有限公司 | A kind of synthetic method of intermediate allene phosphonic acids |
| CN110511243A (en) * | 2019-09-11 | 2019-11-29 | 武汉工程大学 | It is catalyzed the method that allene phosphoric acid prepares cis-propene phosphoric acid in water using core-shell catalyst |
| CN110511243B (en) * | 2019-09-11 | 2021-12-24 | 武汉工程大学 | Method for preparing cis-propenyl phosphoric acid by catalyzing allene phosphoric acid in water by using core-shell type catalyst |
| CN110887925A (en) * | 2019-12-03 | 2020-03-17 | 上海峰林生物科技有限公司 | High performance liquid chromatography method for determining fosfomycin sodium impurities |
| CN112375098A (en) * | 2020-12-07 | 2021-02-19 | 商河探荣新技术开发中心 | Application of carbonate-borane catalyst in preparation of antibiotic intermediate |
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