CN101544668A - Method for preparing 2,4-di-double-bond 15-carbon phosphonate - Google Patents
Method for preparing 2,4-di-double-bond 15-carbon phosphonate Download PDFInfo
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- CN101544668A CN101544668A CN200910097232A CN200910097232A CN101544668A CN 101544668 A CN101544668 A CN 101544668A CN 200910097232 A CN200910097232 A CN 200910097232A CN 200910097232 A CN200910097232 A CN 200910097232A CN 101544668 A CN101544668 A CN 101544668A
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Abstract
The invention discloses a method for preparing a vitamin A intermediate 2,4-di-double-bond 15-carbon phosphonate. The prior methods use beta-ionone as a raw material and have long synthetic routes which are often more than three steps. The method n uses the beta-ionone as the raw material to perform condensation reaction with ethylene tetraethyl diphosphonate to obtain the target compound 2,4-di-double-bond 15-carbon diethyl phosphonate. The method uses the beta-ionone as the raw material to generate the target product 2,4-di-double-bond 15-carbon phosphonate only through one-step reaction, and has simple process route and great industrial value.
Description
Technical field
The present invention relates to a kind of V
AThe important intermediate 3-methyl-5-of carboxylicesters (2,6,6-trimethylammonium-1-tetrahydrobenzene-1-yl)-2, the synthetic method of 4-pentadienyl diethyl phosphonate.
Background technology
Vitamin A (V
A) and derivative be class staple product, wherein a V
ARamification of carboxylic esters such as V
AAcetic ester, cetylate etc. are widely used in medicine, foodstuff additive and the fodder additives; The product of each major company is all with V in the world
ACarboxylicesters is main, and 3-methyl-5-(2,6,6-trimethylammonium-1-tetrahydrobenzene-1-yl)-2,4-pentadienyl diethyl phosphonate (hereinafter to be referred as 2,4-di-double-bond 15-carbon phosphonate) are to be the C of feature with Wittig-Horner reaction
15+ C
5Route synthesizes V
AThe key intermediate of alkyl acid esters (R wherein
1Be alkyl), therefore the study on the synthesis to 2,4-di-double-bond 15-carbon phosphonate has important significance for theories and using value.
The preparation of 2,4-di-double-bond 15-carbon phosphonate and application are paid attention to by people gradually.Its topmost preparation method is reset by the 15-carbon phosphonate of the 15-carbon phosphonate of 1,3 two pairs of key or 1,4 two pairs of key to obtain, and is as follows:
And the 15-carbon phosphonate of the two pairs of keys in position, 1,3 (or 1,4) is got through the Wittig-Horner reaction by corresponding 14 carbon aldehyde (the two keys of two or three-digit) and gem-diphosphonate; The two key 14 carbon aldehyde of 2 in intermediate be by alpha, beta-lonone and methyl chloroacetate in the presence of alkaline condensing agent, synthesize through the Darzens condensation reaction, as follows:
2 two key 14 carbon aldehyde of alpha, beta-lonone
3 two key 14 carbon aldehyde of intermediate are to make terminal epoxides earlier by alpha, beta-lonone and methyl sulfonium father-in-law salt in the presence of alkali, are obtained by magnesium bromide catalysis open loop again; And 14 carbon aldehyde of these 3 two keys can reset under base catalysis and be 2 pairs of more stable key 14 carbon aldehyde, and are as follows:
Alpha, beta-lonone methyl sulfonium father-in-law salt terminal epoxides
14 carbon aldehyde of 2 two keys of 14 carbon aldehyde of 3 two keys
At last, 14 carbon aldehyde (the two keys of two or three-digit) obtain corresponding 15-carbon phosphonate with gem-diphosphonate through the Wittig-Horner reaction:
15-carbon phosphonate can also be made by following method:
This method requires low-temp reaction, and yield not high (78.4%).
Also having one in addition is the synthetic route of raw material with the alpha, beta-lonone, as follows:
Alpha, beta-lonone Ge Shi product
1,2,4-three double-bond 15-carbon phosphonates 2, the 15-carbon phosphonate of two pairs of keys of 4-
In this route, the grignard reagent reaction of alpha, beta-lonone elder generation and vinylchlorid obtains the 15 carbon tertiary alcohols, this alcohol again with the chloro phosphonous acid diethyl ester react 1,2,4-three double-bond 15-carbon phosphonates, get 2 with Lin Dele catalyzer selective reduction terminal double link then, the 15-carbon phosphonate of two pairs of keys of 4-, the selective reduction of final step has big difficulty.
Above-mentioned several method is a raw material with the alpha, beta-lonone all, and synthetic route is long, usually all more than three steps.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, and provides a kind of simple and direct reaction scheme to prepare 2, the 4-di-double-bond 15-carbon phosphonate.
For this reason, the present invention adopts following technical scheme: 2, and the preparation method of the 15-carbon phosphonate of two pairs of keys of 4-, with the alpha, beta-lonone is that raw material and second ethyl diphosphonic acid carry out condensation reaction, obtain target compound 2, two pairs of keys of 4-, 15 carbon diethyl phosphonates, synthetic route is as follows:
Described reaction raw materials alpha, beta-lonone is large Industrial products, and the second ethyl diphosphonic acid can be by Arbuzov (A Erbucaifu) method by ethylene dibromide and phosphonous acid triethyl prepared in reaction.
Above-mentioned preparation method, condensation reaction is carried out in the presence of alkali, the mole dosage of alkali be second ethyl diphosphonic acid mole dosage 0.7-1.3 doubly, be preferably and wait mole, so that reaction is abundant as far as possible.
Above-mentioned preparation method adds reaction raw materials second ethyl diphosphonic acid earlier, adds described alkali then, adds the reaction raw materials alpha, beta-lonone at last, and described alkali and alpha, beta-lonone adopt the dropping mode to add, and help controlling better reaction like this.
Above-mentioned preparation method, described alkali is an alkali metal salt or the lithium alkylide of alcohols, to adopt highly basic such as sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium for well, other highly basic there is no particular restriction.
Above-mentioned preparation method, the temperature of condensation reaction are between-50 ℃ to 0 ℃.
Above-mentioned preparation method, condensation reaction is carried out in the presence of organic solvent, described organic solvent is ether solvent or dipolar aprotic solvent, described ether solvent is ether, tetrahydrofuran (THF) or glycol dimethyl ether, and dipolar aprotic solvent is dimethyl formamide, dimethyl sulfoxide (DMSO) or 6-methyl phosphonic triamide.
The present invention is that raw material only needs single step reaction can generate target product 2 with the alpha, beta-lonone, the 4-di-double-bond 15-carbon phosphonate, and operational path is simple and direct, has industrial value.
The invention will be further described below in conjunction with embodiment.
Embodiment
Analytical instrument of using among the embodiment and equipment: gas chromatography mass spectrometry, MS5973N-GC6890N (U.S. Agilent company); Nuclear magnetic resonance analyser, AVANCE DMX II I 400M (mark in the TMS, Bruker company); Infrared spectrometer, NICOLET 360FT-IR; Gas-chromatography, the beautiful 7890F in sky, Shanghai.
Embodiment 1: the preparation of second ethyl diphosphonic acid
In being furnished with the 1000ml there-necked flask of thermometer and reflux condensing tube; Add 188g (1mol) ethylene dibromide and 516g (3mol) phosphonous acid triethyl, calorified 150-160 ℃ of back flow reaction 4 hours, gas phase is followed the tracks of reaction and is carried out.Cool to 80 ℃ afterwards, the water pump decompression steams unreacted raw material; Residue is a crude product, with the oil pump rectification under vacuum get product 214.5g (about 120-125 ℃/1mmHg), gas phase analysis shows that product content is 98.5%, yield 71%.
Structure verification:
1HNMR(δ，ppm，CDCl
3)：1.33(t，J＝7.2Hz，12H，-CH
3)，1.97-1.99(m，4H，-CH
2-PO(OEt)
2)，4.06-4.179(m，8H，PO(O-CH
2-)
2)
13CNMR(δ，ppm，CDCl
3)：61.96(O-CH
2-)，19.16(-CH
2-P)，16.45(-CH
3)GC-MS(m/e)：302，275，257，229，201，173，165(100％)，155，137，109
Embodiment 2:2, the preparation of 4-di-double-bond 15-carbon phosphonate
In the 500ml three-necked bottle; add 30.2g second ethyl diphosphonic acid (0.1mol) and 100ml glycol dimethyl ether; nitrogen protection; stirring is cooled to-35 ℃ with cryostat; keep this temperature to criticize and add 11.2 gram potassium tert.-butoxides (0.1mol); added in about 10 minutes, and stirred after 10 minutes, be added dropwise to the solution (0.1mol) that 19.2 gram alpha, beta-lonones are dissolved in the 100ml ether again.Add half an hour approximately, and then stir half an hour, thin layer is followed the tracks of the raw material (developping agent: ethyl acetate: sherwood oil=1:3) that disappears substantially, break away from cryostat, add 100ml toluene and 100ml water, stir half an hour, temperature is raised to 12 ℃ automatically during this time, layering, water layer merges organic layer with the extraction of 100ml toluene, wash with 50ml, collect 140-160 ℃/1mmHg cut with the oil pump distillation behind the organic layer water pump decompression and solvent recovery, get product 17.3g (gas phase content 90.5%), yield 46.1%.
1HNMR (δ, ppm, CDCl3): 1.01 (s, 6H, C (CH
3)
2); 1.32 (t, J=7.0Hz, 6H, PO (OCH
2-CH
3)
2); 1.45-1.47 (m, 2H, C-CH on the ring
2); 1.59-1.63 (m, 2H, middle CH on the ring
2); 1.68 (s, 3H, C=C-CH on the ring
3); 1.83 (d, J=3.5Hz, 3H, CH
3-C (3)); 2.00 (t, J=6.2Hz, 2H, C=C-CH on the ring
2-); 2.73 (dd, J=22.9Hz, 8.0Hz, 2H ,-CH
2-P); 4.06-4.14 (m, 4H, PO (O-CH
2-) 2); (5.43 d, J=3.0Hz, 1H, H-C (2)); (6.06 s, 2H, H-C (4), H-C (5));
GC-MS(m/e)：340，325(100％)，289，219，202，187，146，119，105，91，69
Embodiment 3:2, the preparation of 4-di-double-bond 15-carbon phosphonate
In the 500ml three-necked bottle, add 30.2g second ethyl diphosphonic acid (0.1mol) and 100ml tetrahydrofuran (THF), stirring is cooled to-45 ℃ with cryostat, keep this temperature to be added dropwise to the butyllithium hexane solution 10ml (0.1mol) of 10mol/L with syringe, added in about 10 minutes, stir after 10 minutes, be added dropwise to the solution (0.1mol) that 19.2 gram alpha, beta-lonones are dissolved in the 100ml tetrahydrofuran (THF) again.Add half an hour approximately, and then stir half an hour, thin layer is followed the tracks of the raw material (developping agent: ethyl acetate: sherwood oil=1:3) that disappears substantially, add 100ml toluene and 100ml water, stir half an hour, during temperature be raised to 15 ℃ automatically, layering, water layer extracts with 100ml toluene, merge organic layer,, collect 140-160 ℃/1mmHg cut with the oil pump distillation behind the organic layer water pump decompression and solvent recovery with the 50ml washing, get product 18.4g (gas phase content 92%), yield 49.8%.
Embodiment 4:2, the preparation of 4-di-double-bond 15-carbon phosphonate
In the 500ml three-necked bottle, add 30.2g second ethyl diphosphonic acid (0.1mol) and 100ml dimethyl formamide, stirring is cooled to-15 ℃ with cryostat, keep this temperature to be added dropwise to sodium ethylate 12.5 grams (0.1mol) of content 55%, added in about 10 minutes, stir after 10 minutes, be added dropwise to the solution that 19.2 gram alpha, beta-lonones (0.1mol) are dissolved in the 100ml dimethyl formamide again.Add half an hour approximately, and then stir half an hour, thin layer is followed the tracks of the raw material (developping agent: ethyl acetate: sherwood oil=1:3) that disappears substantially, add 100ml toluene and 100ml water, stir half an hour, during temperature be raised to 5 ℃ automatically, layering, water layer extracts with 100ml toluene, merge organic layer,, collect 140-160 ℃/1mmHg cut with the oil pump distillation behind the organic layer water pump decompression and solvent recovery with the 50ml washing, get product 10.4g (gas phase content 91%), yield 27.8%.
Embodiment 5:2, the preparation of 4-di-double-bond 15-carbon phosphonate
Other charge ratio and reaction process are with embodiment 4, and just reaction solvent replaces dimethyl formamide with dimethyl sulfoxide (DMSO), get product 9.9g (gas phase content 91%), yield 26.5% at last.
Embodiment 6:2, the preparation of 4-di-double-bond 15-carbon phosphonate
Other charge ratio and reaction process are with embodiment 3, and just reaction solvent replaces tetrahydrofuran (THF) with 6-methyl phosphonic triamide, get product 16.9g (gas phase content 88%), yield 43.7% at last.
Embodiment 7:2, the preparation of 4-di-double-bond 15-carbon phosphonate
Other charge ratio and reaction process just replace potassium tert.-butoxide with sodium tert-butoxide with embodiment 2, get product 17.1g (gas phase content 89%), yield 44.7% at last.
The above only is preferred embodiment of the present invention, is not technical scheme of the present invention is done any pro forma restriction.Every foundation technical spirit of the present invention all falls within the scope of protection of the present invention any simple modification, equivalent variations and modification that above embodiment did.
Claims (8)
1,2, the preparation method of 4-di-double-bond 15-carbon phosphonate, its step is as follows: be raw material with the alpha, beta-lonone, itself and second ethyl diphosphonic acid carry out condensation reaction, obtain target compound 3-methyl-5-(2,6,6-trimethylammonium-1-tetrahydrobenzene-1-yl)-2,4-pentadienyl diethyl phosphonate.
2, preparation method according to claim 1 is characterized in that described condensation reaction carries out in the presence of alkali, the mole dosage of alkali be second ethyl diphosphonic acid mole dosage 0.7-1.3 doubly.
3, preparation method according to claim 2 is characterized in that adding reaction raw materials second ethyl diphosphonic acid earlier, adds described alkali then, adds the reaction raw materials alpha, beta-lonone at last, and described alkali and alpha, beta-lonone adopt the dropping mode to add.
4,, it is characterized in that described alkali is an alkali metal salt or the lithium alkylide of alcohols according to claim 2 or 3 described preparation methods.
5, preparation method according to claim 4 is characterized in that described alkali is sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide or butyllithium.
6, according to claim 1,2 or 3 described preparation methods, the temperature that it is characterized in that condensation reaction is between-50 ℃ to 0 ℃.
7, according to claim 1,2 or 3 described preparation methods, it is characterized in that condensation reaction carries out in the presence of organic solvent, described organic solvent is ether solvent or dipolar aprotic solvent.
8, preparation method according to claim 7 is characterized in that described ether solvent is ether, tetrahydrofuran (THF) or glycol dimethyl ether, and dipolar aprotic solvent is dimethyl formamide, dimethyl sulfoxide (DMSO) or 6-methyl phosphonic triamide.
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| CN2009100972322A CN101544668B (en) | 2009-03-30 | 2009-03-30 | Method for preparing 3-methyl-5-(2,6,6-trimethyl-1- cyclohexene-1-yl)2,4-Pentadienyl-diethyl phosphonate |
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Cited By (5)
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| CN101792374A (en) * | 2010-04-06 | 2010-08-04 | 绍兴文理学院 | 1-methoxyl-2,6,10-trimethyl-1,3,5,9-undecene tetraene and preparation method and application thereof |
| CN101824051A (en) * | 2010-03-09 | 2010-09-08 | 浙江医药股份有限公司新昌制药厂 | Lycopene intermediate 1,3,6,10-4-pentadienyl phosphonate as well as preparation method and application thereof |
| CN102180774A (en) * | 2011-04-02 | 2011-09-14 | 绍兴文理学院 | Preparation method of C-14 enol ether |
| CN102190565A (en) * | 2010-03-04 | 2011-09-21 | 绍兴文理学院 | Method for preparing intermediate of vitamin A, namely tetradecanal |
| CN102140117B (en) * | 2010-02-02 | 2012-10-17 | 绍兴文理学院 | 1, 4, 6, 10-tetra-double bond pentadec-carbon phosphonate, preparation method thereof and method for preparing lycopene |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4916250A (en) * | 1988-10-31 | 1990-04-10 | Loyola University Of Chicago | Phosphonate reagent compositions |
| CN1172910C (en) * | 2001-01-05 | 2004-10-27 | 浙江医药股份有限公司新昌制药厂 | Process for preparing VA derivative |
| CN101318975A (en) * | 2008-07-18 | 2008-12-10 | 广州智特奇生物科技有限公司 | Method for preparing 3-methyl-5-(2,6,6-trimethyl-1-cyclohexene-1-base)-2, 4-pentadiene-dialkyl phosphoric ester |
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2009
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| CN102140117B (en) * | 2010-02-02 | 2012-10-17 | 绍兴文理学院 | 1, 4, 6, 10-tetra-double bond pentadec-carbon phosphonate, preparation method thereof and method for preparing lycopene |
| CN102190565A (en) * | 2010-03-04 | 2011-09-21 | 绍兴文理学院 | Method for preparing intermediate of vitamin A, namely tetradecanal |
| CN102190565B (en) * | 2010-03-04 | 2013-07-03 | 绍兴文理学院 | Method for preparing intermediate of vitamin A, namely tetradecanal |
| CN101824051A (en) * | 2010-03-09 | 2010-09-08 | 浙江医药股份有限公司新昌制药厂 | Lycopene intermediate 1,3,6,10-4-pentadienyl phosphonate as well as preparation method and application thereof |
| CN101824051B (en) * | 2010-03-09 | 2012-07-18 | 浙江医药股份有限公司新昌制药厂 | Lycopene intermediate 1,3,6,10-4-pentadienyl phosphonate as well as preparation method and application thereof |
| CN101792374A (en) * | 2010-04-06 | 2010-08-04 | 绍兴文理学院 | 1-methoxyl-2,6,10-trimethyl-1,3,5,9-undecene tetraene and preparation method and application thereof |
| CN101792374B (en) * | 2010-04-06 | 2012-11-28 | 绍兴文理学院 | 1-methoxyl-2,6,10-trimethyl-1,3,5,9-undecene tetraene and preparation method and application thereof |
| CN102180774A (en) * | 2011-04-02 | 2011-09-14 | 绍兴文理学院 | Preparation method of C-14 enol ether |
| CN102180774B (en) * | 2011-04-02 | 2013-06-12 | 绍兴文理学院 | Preparation method of C-14 enol ether |
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