CN101638420A - Synthesis method of phosphorus acetylenic bond - Google Patents
Synthesis method of phosphorus acetylenic bond Download PDFInfo
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- CN101638420A CN101638420A CN200910110907A CN200910110907A CN101638420A CN 101638420 A CN101638420 A CN 101638420A CN 200910110907 A CN200910110907 A CN 200910110907A CN 200910110907 A CN200910110907 A CN 200910110907A CN 101638420 A CN101638420 A CN 101638420A
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- phosphorus
- synthetic method
- acetylenic bond
- hydrogen
- acetylenic
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Abstract
The invention relates to a synthesis method of a phosphorus acetylenic bond, which belongs to a method for synthesizing the phosphorus acetylenic bond. The invention provides a synthesis method of thephosphorus acetylenic bond, which has easily-obtained materials, high output and simple operation and is more suitable for large-scale production. The method comprises the following steps: taking terminal alkynes of hydrogen-phosphate ester or hydrogen-phosphorous acid ester as raw materials, taking copper (I, II) salts as catalyst, taking alkali as acid bonding agent, and reacting in organic solvents to generate the phosphorus acetylenic bond.
Description
Technical field
The present invention relates to the method for a kind of synthetic phosphorus alkynes (P-C ≡ C) key, especially relate to a kind of use hydrogen phosphorous acid ester or hydrogen phosphinate, Terminal Acetylenes is a raw material, copper (I, II) salt is as catalyzer, and alkali is as acid binding agent, and the method for phosphorus acetylenic bond is synthesized in reaction in organic solvent.
Background technology
The synthetic method of phosphorus acetylenic bond adopts alkynes grignard reagent (Grignard reagent) and organolithium reagent synthesis method in early days.Just drop into research as far back as Petrov laboratory in 1962, and having set up one, to utilize the grignard reagent of alkynes and the method that phosphorus reagent synthesizes 1-alkynes phosphinate be one of early stage widely used classical way.Chattha experimental group in 1967 and Aguiar experimental group in 1971 are improved this traditional method.This method is until still be widely used in organic synthesis now, yet the end-group alkyne that contains carbonyl, halogen or the reactive hydrogen except that alkynes hydrogen can't synthesize with this method owing to self-interaction, and this method productive rate is not high, and bibliographical information only is 51%～70%.Because traditional grignard reagent (Grignard reagent) synthesis method productive rate is not high, Rachel Dizere and Philippe Savignac have developed with (EtO)
2P (O) CCl
3Synthetic method for substrate.Having synthesized R with this method is the compound of aryl and heterocyclic aryl, reaction yield 87%～96%.Yet this reactive applications scope is very limited, and reaction substrate is difficult synthetic, and synthesis step is more, and temperature of reaction is lower, the difficult control of reaction conditions.
People such as Kose are the synthesis method of substrate with alkynyl iodobenzene sulfonate, and the Midura experimental group utilizes the phosphono selenium compound to synthesize 1-alkynes phosphinate, and this method reaction yield higher (81%～95%) is applicable to that the bi-ester of phosphite of fatty alkynes is synthetic; The shortcoming of this method maximum is that reaction substrate is difficult synthetic, so the scope of application is narrow, should not promote.
Hayes group utilizes the end ene compound of dibromo to synthesize the alkynes phosphonate compound of ucleosides, for ucleosides anti HIV-1 virus drug research provides new research direction.But the synthetic comparatively difficulty of the two bromo end alkene of this method, and cost an arm and a leg, still also need to improve.
Except above-mentioned widely used synthetic method and improving one's methods, 1-alkynes phosphinate synthetic also has following interesting synthesis method: people such as Marchesin are that substrate synthesizes with 5-An Ji oxazole, because substrate is difficult synthetic and range of application is seriously restricted; People such as Abe synthesize with microwave reaction, productive rate less than 50%, and reaction effect is not good enough.Therefore, need the method that a kind of raw material is cheap and easy to get, productive rate is high, simple to operate, can be more suitable for the needs of scale operation like this.
Summary of the invention
The object of the present invention is to provide that a kind of raw material is cheap and easy to get, productive rate is high, the synthetic method of simple to operate, the phosphorus acetylenic bond that is more suitable for scale operation.
Technical scheme of the present invention is at hydrogen phosphorous acid ester or hydrogen phosphinate, and Terminal Acetylenes is a raw material, and copper (I, II) salt is as catalyzer, and alkali is as acid binding agent, and reaction generates phosphorus acetylenic bond in organic solvent.
Synthetic route of the present invention is:
In the formula, X is O, S or Se etc.; R
1, R
2And R
3Be organic side chain arbitrarily independently.
Concrete steps of the present invention are:
In container, add mantoquita, organic solvent, hydrogen phosphorous acid ester or hydrogen phosphinate, Terminal Acetylenes and alkali successively, reaction down refluxes, after reaction finishes, removal of solvent under reduced pressure, obtain yellow viscous liquid, in polarity is sherwood oil: carry out column chromatographic isolation and purification under the eluent condition of ethyl acetate=5: 1～1: 2, promptly get product.
Described mantoquita is cuprous salt or cupric salt, and described mantoquita is preferably CuI, CuBr, CuCl, CuCl
2, CuSO
45H
2O, Cu (OAc)
2H
2O, Cu (OTf)
2Deng in a kind of, the preferred cupric salt of described mantoquita; The molar ratio of mantoquita consumption is 0～1 equivalent, and the molar ratio of mantoquita consumption is preferably 0.1 equivalent.
Described hydrogen phosphorous acid ester or hydrogen phosphinate can be R
1R
2POH, R
1R
2PSH, R
1R
2PSeH etc., R
1, R
2, R
3Be organic side chain arbitrarily independently.
Described Terminal Acetylenes can be acetylene, phenylacetylene or organic side chain terminal alkyne compound arbitrarily; In molar ratio, the reaction raw materials Terminal Acetylenes: hydrogen phosphorous acid ester or hydrogen phosphinate are 1: (0～2), preferred reaction raw material Terminal Acetylenes: hydrogen phosphorous acid ester or hydrogen phosphinate are 1: 1.
Described alkali is organic bases or mineral alkali, and organic bases is preferably triethylamine, diisopropylethylamine or diethylamine etc., and mineral alkali is preferably carbonate, supercarbonate or the oxyhydroxide etc. of basic metal and alkaline-earth metal, the preferred diethylamine of described alkali.
Described organic solvent is organic solvent arbitrarily, organic solvent is preferably methylene dichloride, ethyl acetate, toluene, dioxane, acetonitrile, methyl-sulphoxide (DMSO), N, a kind of in dinethylformamide (DMF), acetone, N-methylmorpholine, the N-Methyl pyrrolidone etc., preferred acetone or dipole solvent etc.
Compare with the synthetic method of existing phosphorus acetylenic bond, the present invention has following outstanding advantage and technique effect:
1. can be widely applied to various hydrogen phosphorous acid esters or hydrogen phosphinate;
2. can be widely applied to various Terminal Acetylenes, comprise that groups such as containing hydroxyl, carbonyl, ester group, itrile group, halogen is all unaffected;
Catalyzer be monovalence or cupric salt all can, catalyzer is cheap, obtains easily (industrial goods);
4. (step finishes) simple to operate do not need very low temperature or ultrahigh-temperature;
5. many kinds of organic solvents all can efficiently be finished reaction.
It will be understood to those of skill in the art that; the present invention not only is suitable for forming phosphorus alkynes arbitrarily; and be suitable for containing other reactive functionality Terminal Acetylenes and contain the hydrogen phosphorous acid ester or the hydrogen phosphinate of other reactive functionality; simultaneously those skilled in the art also will appreciate that, a lot of protecting groups can be used for and are suitable for this situation.
Embodiment
Below will describe invention in more detail, and its purpose only is to illustrate the present invention, rather than limits it with embodiment.
Embodiment 1: add the CuI of 100mg successively in the round-bottomed flask of 25mL, the CH of 15mL
3CN, the diisopropoxy phosphorous acid ester of 5mmol, the phenylacetylene of 6mmol, and the diethylamine of 80mg, the reaction 24h that makes it to reflux down, after reaction finished, removal of solvent under reduced pressure obtained being the thick product of yellow viscous liquid.In polarity is sherwood oil: carry out column chromatographic isolation and purification under the eluent condition of ethyl acetate=5: 1, promptly get product, productive rate 20%.
Embodiment 2: add the CuBr of 100mg successively in the round-bottomed flask of 25mL, the DMSO of 10mL, the isopropoxy of 5mmol-D4T-phosphorous acid ester, the propargyl alcohol of 6mmol, and the K of 130mg
2CO
3Make it at 45 ℃ of following reaction 30h, be transferred to separating funnel after naturally cooling to room temperature, reaction solution adds 40mL CH
2Cl
2, use 2*10mL H
2O washes, and discards water layer, and organic phase is used the HCl of 20mL 0.1mol/L, the H of 10mL more respectively
2O, the saturated nacl aqueous solution washing of 10mL, concentrating under reduced pressure is removed methylene dichloride, obtains brown viscous liquid.In polarity is sherwood oil: carry out column chromatographic isolation and purification under the eluent condition of ethyl acetate=1: 2, promptly get product, productive rate 50%.
Embodiment 3: add the CuCl of 100mg successively in the round-bottomed flask of 25mL, the DMF of 10mL, the isopropyl phenyl seleno phosphorous acid ester of 5mmol, the diethyl propargyl amine of 6mmol.Be transferred to separating funnel after making it at room temperature to react 25h, reaction solution adds 40mL CH
2Cl
2, use 2*10mL H
2O washes, and re-uses the saturated nacl aqueous solution washing of 10mL, and concentrating under reduced pressure is removed methylene dichloride, obtains yellow viscous liquid.In polarity is sherwood oil: carry out column chromatographic isolation and purification under the eluent condition of ethyl acetate=1: 1, promptly get product, productive rate 88%.
Embodiment 4: the Cu (OAc) that adds 100mg in the round-bottomed flask of 25mL successively
2H
2O, the acetone of 10mL, the diisopropoxy thiophosphite of 5mmol, the N-propargyl of 6mmol is to methyl benzenesulfonamide.Make it at 0 ℃ of following reaction 50h, rise to the room temperature concentrating under reduced pressure naturally after, obtain yellow paste solid.In polarity is sherwood oil: carry out column chromatographic isolation and purification under the eluent condition of ethyl acetate=3: 1, promptly get product, productive rate 86%.
Embodiment 5: the CuSO that adds 100mg in the round-bottomed flask of 25mL successively
45H
2O, the ethyl acetate of 25mL, the diisopropoxy phosphorous acid ester of 5mmol, 9-ethynyl-9-fluorenol of 6mmol.Make it to reflux down and react 44h, concentrating under reduced pressure is removed ethyl acetate, obtains the paste solid.In polarity is sherwood oil: carry out column chromatographic isolation and purification under the eluent condition of ethyl acetate=2: 1, promptly get product, productive rate 89%.
Claims (10)
1. the synthetic method of phosphorus acetylenic bond is characterized in that its synthetic route is:
In the formula, X is O, S or Se etc.; R
1, R
2And R
3Be organic side chain arbitrarily independently.
2. the synthetic method of phosphorus acetylenic bond as claimed in claim 1 is characterized in that its concrete steps are:
In container, add mantoquita, organic solvent, hydrogen phosphorous acid ester or hydrogen phosphinate, Terminal Acetylenes and alkali successively, reaction down refluxes, after reaction finishes, removal of solvent under reduced pressure, obtain yellow viscous liquid, in polarity is sherwood oil: carry out column chromatographic isolation and purification under the eluent condition of ethyl acetate=5: 1～1: 2, promptly get product.
3. the synthetic method of phosphorus acetylenic bond as claimed in claim 1 is characterized in that described mantoquita is cuprous salt or cupric salt.
4. as the synthetic method of claim 1 or 3 described phosphorus acetylenic bonds, it is characterized in that described mantoquita is CuI, CuBr, CuCl, CuCl
2, CuSO
45H
2O, Cu (OAc)
2H
2O, Cu (OTf)
2In a kind of; The molar ratio of described mantoquita consumption is 0～1 equivalent.
5. the synthetic method of phosphorus acetylenic bond as claimed in claim 1 is characterized in that described hydrogen phosphorous acid ester or hydrogen phosphinate are R
1R
2POH, R
1R
2PSH, R
1R
2PSeH, R
1, R
2, R
3Be organic side chain arbitrarily independently.
6. the synthetic method of phosphorus acetylenic bond as claimed in claim 1 is characterized in that described Terminal Acetylenes is acetylene, phenylacetylene or organic side chain terminal alkyne compound arbitrarily.
7. the synthetic method of phosphorus acetylenic bond as claimed in claim 1 is characterized in that in molar ratio, the reaction raw materials Terminal Acetylenes: hydrogen phosphorous acid ester or hydrogen phosphinate are 1: 0～2.
8. the synthetic method of phosphorus acetylenic bond as claimed in claim 1, it is characterized in that described alkali is organic bases or mineral alkali, organic bases is triethylamine, diisopropylethylamine or diethylamine, and mineral alkali is carbonate, supercarbonate or the oxyhydroxide of basic metal and alkaline-earth metal.
9. the synthetic method of phosphorus acetylenic bond as claimed in claim 1 is characterized in that described organic solvent is organic solvent arbitrarily.
10. as the synthetic method of claim 1 or 9 described phosphorus acetylenic bonds, it is characterized in that organic solvent is methylene dichloride, ethyl acetate, toluene, dioxane, acetonitrile, methyl-sulphoxide, N, a kind of in dinethylformamide, acetone, N-methylmorpholine, the N-Methyl pyrrolidone.
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|---|---|---|---|
| CN2009101109072A CN101638420B (en) | 2009-01-14 | 2009-01-14 | Synthesis method of phosphorus acetylenic bond |
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| CN2009101109072A CN101638420B (en) | 2009-01-14 | 2009-01-14 | Synthesis method of phosphorus acetylenic bond |
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| Publication Number | Publication Date |
|---|---|
| CN101638420A true CN101638420A (en) | 2010-02-03 |
| CN101638420B CN101638420B (en) | 2012-01-11 |
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|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061504A (en) * | 2015-09-16 | 2015-11-18 | 湖南大学 | Preparation method of P-alkynyl phosphate compound |
-
2009
- 2009-01-14 CN CN2009101109072A patent/CN101638420B/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061504A (en) * | 2015-09-16 | 2015-11-18 | 湖南大学 | Preparation method of P-alkynyl phosphate compound |
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| CN101638420B (en) | 2012-01-11 |
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