CN104945433B - Method for preparing cyclopropyl phosphonate - Google Patents
Method for preparing cyclopropyl phosphonate Download PDFInfo
- Publication number
- CN104945433B CN104945433B CN201510353069.7A CN201510353069A CN104945433B CN 104945433 B CN104945433 B CN 104945433B CN 201510353069 A CN201510353069 A CN 201510353069A CN 104945433 B CN104945433 B CN 104945433B
- Authority
- CN
- China
- Prior art keywords
- phosphonate ester
- reaction
- cyclopropyl phosphonate
- phenyl
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- QGOOVYDNNMBCPD-UHFFFAOYSA-N C1(CC1)OP(O)=O Chemical compound C1(CC1)OP(O)=O QGOOVYDNNMBCPD-UHFFFAOYSA-N 0.000 title abstract 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 123
- 150000002576 ketones Chemical class 0.000 claims abstract description 24
- 239000003513 alkali Substances 0.000 claims abstract description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 cyclopropyl phosphonate ester Chemical class 0.000 claims description 107
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 90
- 239000000047 product Substances 0.000 claims description 68
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 56
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 50
- 238000004440 column chromatography Methods 0.000 claims description 28
- 229910052786 argon Inorganic materials 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 10
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 5
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- LRTZIJCDXOAKRC-UHFFFAOYSA-N cyclopropylphosphane Chemical compound PC1CC1 LRTZIJCDXOAKRC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 239000000706 filtrate Substances 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 238000003541 multi-stage reaction Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 238000004458 analytical method Methods 0.000 description 34
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 238000010828 elution Methods 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 150000001335 aliphatic alkanes Chemical class 0.000 description 24
- 230000018044 dehydration Effects 0.000 description 24
- 238000006297 dehydration reaction Methods 0.000 description 24
- 239000003208 petroleum Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229960001866 silicon dioxide Drugs 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 230000005311 nuclear magnetism Effects 0.000 description 21
- 238000001035 drying Methods 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 18
- 235000005513 chalcones Nutrition 0.000 description 18
- 230000003287 optical effect Effects 0.000 description 18
- 235000010290 biphenyl Nutrition 0.000 description 17
- 239000004305 biphenyl Substances 0.000 description 17
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 15
- 239000007788 liquid Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012805 post-processing Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- UGGKZBXVAYVPJB-UHFFFAOYSA-N 2-(oxo-lambda5-phosphanylidyne)acetonitrile Chemical compound P(=O)#CC#N UGGKZBXVAYVPJB-UHFFFAOYSA-N 0.000 description 1
- LNYTUARMNSFFBE-UHFFFAOYSA-N 4-(diethylazaniumyl)benzoate Chemical compound CCN(CC)C1=CC=C(C(O)=O)C=C1 LNYTUARMNSFFBE-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000035220 Dyserythropoietic Congenital Anemia Diseases 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- FBWJHGIUUCOZRM-UHFFFAOYSA-N cyclopropylphosphonic acid Chemical class OP(O)(=O)C1CC1 FBWJHGIUUCOZRM-UHFFFAOYSA-N 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000002903 organophosphorus compounds Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical class [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The invention discloses a method for preparing cyclopropyl phosphonate. More specifically, n-butyllithium is adopted to promote the reaction of diethyl phosphate and alpha, beta-unsaturated ketone, and a one-pot method is adopted to synthesize the cyclopropyl phosphonate. Compared with the prior art, the method for preparing the cyclopropyl phosphonate has the advantages that reaction materials are easy to get, conditions are mild, and the yield of target products is high and can maximumly reach 95 percent; one-step operation can complete multi-step reaction, and the reaction efficiency is high; the amount of used alkali is relatively small, aftertreatment of the reaction is easy, and pruduct purification is facilitated; the stereoselectivity of the prepared cyclopropyl phosphonate is good, and the de value is larger than 99 percent; and universality is achieved for multiple substitutive alpha, beta-unsaturated ketone.
Description
Technical field
The invention belongs to the preparing technical field of organic phosphorus compound, and in particular to a kind of cyclopropyl phosphonate ester preparation side
Method.
Background technology
The synthesis of cyclopropanes compound is always one of focus of organic chemistry research field.Cyclopropyl phosphonic acids ester structure
Unit is found in many natural products and drug molecule for having good biological active, in addition cyclopropyl phosphonate ester compound
And the key intermediate of synthesis Multiple Pesticides and drug molecule.
In prior art, the method for synthesizing cyclopropyl phosphonate ester mainly includes following three kinds：
Synthesized by [2+1] annulation.As at room temperature, by phosphoryl acetonitrile under the effect of 4 equivalent alkali with α, β-two
Halogenated alkane reaction 20-380 hours are obtained polysubstituted cyclopropanes compound, and yield is 1 ~ 55%；Or with Ru (II)-
Pheox catalyzed alkenes or acrylate and dizaomethyl phosphonate reaction, obtain trans cyclopropyl phosphonate ester, and yield is 33-
93%, although the reactiondeValue is very high, but diazonium compound used has potential danger because unstable, explosive
（I. L. Odinets, et al. Heteroatom Chem. 2006, 17, 13; S. Iwasa,et al. Org.
Lett. 2014, 16, 3012）.
Synthesized by 1,3- elimination reactions.As promoted γ-Bromopropyl phosphonate ester to send out with 2 equivalent potassium tert-butoxides at room temperature
Raw 1,3- is eliminated, and prepares cyclopropyl phosphonate ester with 81% yield, but the product of the reaction is without stereo selectivity（Y.
Segall, et al. Synth. Commun. 2008, 38, 848）.
Synthesized by cyclopropyl Grignard reagent.Such as Jankowski is anti-with chlorine p diethylaminobenzoic acid base ester with cyclopropyl Grignard reagent
Cyclopropyl phosphonate ester should be prepared, yield is 51%（WO 2007/087068 A2）.
Above method can generate cyclopropyl phosphonate ester, but most or need multistep to complete, or need to be obtained in advance complicated former
Material, or the highly basic of noble metal catalyst or excess need to be used, it is particularly with optically active cyclopropyl phosphonate ester is prepared, required
Condition it is frequently more harsh, such as need to use chiral raw material, cryogenic conditions, or need add chiral ligand coordinate, etc..In view of
The good biological activity that cyclopropyl phosphonate ester has, finds in a mild condition and synthesizes this kind of efficiently, highly-solid selectively
The method of compound is necessary.
The content of the invention
It is an object of the invention to provide a kind of method for preparing cyclopropyl phosphonate ester, by diethyl phosphite in the presence of alkali
With α, one pot of change reaction of alpha, beta-unsaturated ketone, develop a kind of conjunction that source is simple, high activity, high selectivity, safety, universality are good
The method of cyclization propyl phosphonous acid ester.
To achieve the above object of the invention, the technical solution used in the present invention is：
A kind of method for preparing cyclopropyl phosphonate ester, it is characterised in that comprise the following steps：Under the conditions of anhydrous and oxygen-free,
With diethyl phosphite and α, alpha, beta-unsaturated ketone is reactant, with alkali as accelerator, at 60～85 DEG C, in organic solvent instead
Answer and prepare within 1～8 hour product cyclopropyl phosphonate ester；
The alpha, beta-unsaturated ketone chemical structure of general formula is：, wherein, Ar1It is selected from：Phenyl, to fluorine
Phenyl, rubigan, p-bromophenyl, p-trifluoromethyl phenyl, to cyano-phenyl, p-methylphenyl, an aminomethyl phenyl, 2- thiophene
One kind in base, Ar2It is selected from：Phenyl, p-fluorophenyl, rubigan, p-bromophenyl, p-trifluoromethyl phenyl, p-methylphenyl,
One kind in m-methoxyphenyl, 2- thienyls.
In above-mentioned technical proposal, the alkali is n-BuLi, lithium ethoxide, the one kind in sodium hydride, preferably n-BuLi,
Under similarity condition, n-BuLi can more efficiently promote the reaction of formation of cyclopropyl phosphonate ester.
In above-mentioned technical proposal, course of reaction includes：Under the conditions of anhydrous and oxygen-free, by n-BuLi, diethyl phosphite,
α, alpha, beta-unsaturated ketone and solvent are sequentially added in reactor, are mixed, stirring reaction 1～8 hour at 60～85 DEG C, terminate anti-
Should, extracted, used desiccant dryness extract, filter, removal of solvent under reduced pressure, most after Jing rapid column chromatographies obtain cyclopropyl phosphine
Acid esters.
In above-mentioned technical proposal, reaction dissolvent can be acetonitrile, toluene, glycol dimethyl ether and toluene/hempa
Acyl triamine, acetonitrile/HMPA mixed solvent, preferably acetonitrile.
It is in above-mentioned technical proposal, described to be preferably in inert argon atmosphere under the conditions of anhydrous and oxygen-free.
In above-mentioned technical proposal, the consumption of the n-BuLi is α, 1～1.2 times of the molal quantity of alpha, beta-unsaturated ketone, excellent
Elect 1.05 times as, the consumption of n-BuLi is slightly in excess in α, it is complete that alpha, beta-unsaturated ketone is conducive to reacting, but n-BuLi
Consumption crosses conference to be increased reaction cost and affects the post processing of reaction system.
In above-mentioned technical proposal, the consumption of the diethyl phosphite is α, the 2.5～3.5 of the molal quantity of alpha, beta-unsaturated ketone
Times, preferably 3 times.
In above-mentioned technical proposal, the reaction temperature is preferably 80 DEG C；Temperature is too low to easily cause reaction not exclusively, and 80 DEG C are
The boiling point of acetonitrile solvent, that is, react the effect in the acetonitrile of backflow best.
In above-mentioned technical proposal, the response time is 1～8 hour.Work as Ar1Or Ar2For phenyl or electron deficiency aryl when, reaction
Time is preferably 1 hour；Work as Ar1Or Ar2For electron rich aryl when, the response time be 5 hours.
In the present invention, electron deficiency aryl be p-fluorophenyl, rubigan, p-bromophenyl, p-trifluoromethyl phenyl, to cyano group
Phenyl, an aminomethyl phenyl；Electron rich aryl is p-methylphenyl, 2- thienyls.
In above-mentioned technical proposal, terminating reaction, extraction, with desiccant dryness extract, filtration, removal of solvent under reduced pressure, most
The operations such as cyclopropyl phosphonate ester are obtained by rapid column chromatography and belongs to prior art in itself, it is extractant used in which, dry
Drying prescription, eluant are also prior art, and those skilled in the art can select suitable reagent according to the property of final product, excellent
In the technical scheme of choosing, terminating reaction adopts water, and extractant is ethyl acetate, and desiccant is anhydrous sodium sulfate, and rapid column chromatography is adopted
With gradient elution, eluant is ethyl acetate/petroleum ether system（Volume ratio is 1: 2～1: 7）.
Above-mentioned technical proposal can be expressed as follows：
Due to the utilization of above-mentioned technical proposal, the present invention has following advantages compared with prior art:
1. the present invention promotes diethyl phosphite and alpha, beta-unsaturated ketone to carry out one pot of change of reaction using n-BuLi first
Method synthesizes cyclopropyl phosphonate ester, and the raw material of reaction is easy to get, mild condition, and activity is high, easy to operate, the high income of target product, most
It is high by reachable 95%.
2. synthetic route single stepping disclosed by the invention completes multistep reaction, and reaction efficiency is high, and reaction condition simply may be used
Control, post processing are simple, and overcoming prior art needs many more manipulations, complicated post processing prepare the defect of product.
3. method disclosed by the invention is relatively fewer using the amount of alkali, is α, and the 1～1.2 of the molal quantity of alpha, beta-unsaturated ketone
Times, preferably 1.05 times, far below the consumption of prior art alkali, the post processing of reaction is simple, is conducive to the purification of product；Gained
The stereo selectivity of cyclopropyl phosphonate ester is good,d eValue>99%, the high income of product reaches as high as 95%；Achieve unexpected
Technique effect.
4. to various substituted α, alpha, beta-unsaturated ketone has universality to method disclosed by the invention, particularly with preparing light
The cyclopropyl phosphonate ester of activity is learned, the preparation condition of the present invention is simple, is coordinated without using chiral raw material or addition chiral ligand,
Optically active cyclopropyl phosphonate ester in high yield is successfully prepared, prior art is overcome and is prepared optically active cyclopropyl phosphonic acids
The high defect of ester complicated condition, ingredient requirement, is conducive to the commercial Application of cyclopropyl phosphonate ester.
Specific embodiment
With reference to embodiment, the invention will be further described：
Embodiment one：The synthesis of diphenyl chalcone
1-Phenylethanone. is sequentially added in 250 mL round-bottomed flasks（5.8 mL, 50 mmol）, benzaldehyde（5.1 mL, 50
mmol）, sodium hydrate aqueous solution（2.53 g sodium hydroxide, 25 mL distilled water）With 95% ethanol（30 mL）.24 are stirred under room temperature
After hour, system has a large amount of faint yellow solids to separate out.Sucking filtration, a small amount of absolute ethanol washing of filter cake, then tied with dehydrated alcohol again
It is brilliant.Gained faint yellow solid is product, and yield is 95%.
1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 16.0
Hz, 1H), 7.65–7.62 (m, 2H), 7.56–7.55 (m, 2H), 7.50–7.47 (m, 2H), 7.41–7.40
(m, 3H).
The synthesis of other diaryl chalcones refers to the preparation method of embodiment one.
Embodiment two：N-BuLi promotes diethyl phosphite and diphenyl chalcone that cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.99 mL, 1.2 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, diphenyl chalcone（0.208 g, 1.0 mmol）And solvent acetonitrile（2 mL）, at 80 DEG C, stirring reaction is after 1 hour
Water terminating reaction, ethyl acetate is added to extract three times, extract anhydrous sodium sulfate drying is filtered, removal of solvent under reduced pressure, finally
Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system, and volume ratio is 1: 2～1: 7）Obtain
Yellow solid is respective rings propyl phosphonous acid ester, and yield is 93%,deValue>99%, product optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.12–7.05 (m, 8H), 6.76–6.74 (m, 2H), 4.13–
3.96 (m, 4H), 3.05–2.96 (m, 1H), 2.10–2.02 (m, 1H), 1.74–1.68 (m, 1H), 1.32–
1.22 (m, 6H)。
Embodiment three：N-BuLi promotes diethyl phosphite and diphenyl chalcone that cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.99 mL, 1.2 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, diphenyl chalcone（0.208 g, 1.0 mmol）And acetonitrile/HMPA mixed solvent（2 mL, volume
Than for 5: 1）, at 80 DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, the anhydrous sulfur of extract
Sour sodium is dried, and filters, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant be ethyl acetate/
Petroleum ether system, volume ratio are 1: 2～1: 7）Obtain yellow solid and be respective rings propyl phosphonous acid ester, yield is 89%,d eValue
>99%, product optical activity is good.The nuclear magnetic data of product is with embodiment two.
Example IV：N-BuLi promotes diethyl phosphite and diphenyl chalcone that cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.83 mL, 1.0 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.455mL, 3.5
mmol）, diphenyl chalcone（0.208 g, 1.0 mmol）And solvent acetonitrile（2 mL）, stirring reaction 1.5 hours at 80 DEG C
Water terminating reaction, ethyl acetate is added to extract afterwards three times, extract anhydrous sodium sulfate drying is filtered, removal of solvent under reduced pressure, most
By silicagel column rapid column chromatography（Gradient elution, eluant are ethyl acetate/petroleum ether system, and volume ratio is 1: 2～1: 7）
Respective rings propyl phosphonous acid ester is to yellow solid, yield is 88%,d eValue>99%, product optical activity is good.The nuclear-magnetism of product
Data consistent with Example two.
Embodiment five：N-BuLi promotes diethyl phosphite and diphenyl chalcone that cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, diphenyl chalcone（0.208 g, 1.0 mmol）And solvent acetonitrile（2 mL）, at 80 DEG C, stirring reaction is after 1 hour
Water terminating reaction, ethyl acetate is added to extract three times, extract anhydrous sodium sulfate drying is filtered, removal of solvent under reduced pressure, finally
Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system, and volume ratio is 1: 2～1: 7）Obtain
Yellow solid is respective rings propyl phosphonous acid ester, and yield is 93%,d eValue>99%, product optical activity is good.The nuclear-magnetism number of product
According to same embodiment two.
Embodiment six：N-BuLi promotes diethyl phosphite and diphenyl chalcone that cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.99 mL, 1.2 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.325mL, 2.5
mmol）, diphenyl chalcone（0.208 g, 1.0 mmol）And toluene/HMPA mixed solvent（2 mL, volume
Than for 5: 1）, at 85 DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 5 hours, the anhydrous sulfur of extract
Sour sodium is dried, and filters, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant be ethyl acetate/
Petroleum ether system, volume ratio are 1: 2～1: 7）Obtain yellow solid and be respective rings propyl phosphonous acid ester, yield is 80%,d eValue
>99%, product optical activity is good.The nuclear magnetic data of product is with embodiment two.
Embodiment seven：Lithium ethoxide promotes diethyl phosphite and diphenyl chalcone that cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, lithium ethoxide is added in reaction bulb under argon protection（0.06
G, 1.2 mmol）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0 mmol）, diphenyl chalcone（0.208
G, 1.0 mmol）And toluene/HMPA mixed solvent（2 mL, volume ratio are 5: 1）, stirring reaction 8 at 80 DEG C
Water terminating reaction, ethyl acetate is added to extract after hour three times, extract anhydrous sodium sulfate drying is filtered, is removed under reduced pressure molten
Agent, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system, and volume ratio is 1: 2～1
∶7）Obtain yellow solid and be respective rings propyl phosphonous acid ester, yield is 84%,d eValue>99%, product optical activity is good.Product
Nuclear magnetic data with embodiment two.
Embodiment eight：N-BuLi promotes diethyl phosphite and diphenyl chalcone that cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.99 mL, 1.2 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.32 mL, 2.5
mmol）, diphenyl chalcone（0.208 g, 1.0 mmol）And solvent acetonitrile（2 mL）, at 80 DEG C, stirring reaction is after 2 hours
Water terminating reaction, ethyl acetate is added to extract three times, extract anhydrous sodium sulfate drying is filtered, removal of solvent under reduced pressure, finally
Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system, and volume ratio is 1: 2～1: 7）Obtain
Yellow solid is respective rings propyl phosphonous acid ester, and yield is 84%,d eValue>99%, product optical activity is good.The nuclear-magnetism number of product
According to same embodiment two.
Embodiment nine：N-BuLi promotes diethyl phosphite and diphenyl chalcone that cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.99 mL, 1.2 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, diphenyl chalcone（0.208 g, 1.0 mmol）And solvent acetonitrile（2 mL）, at 60 DEG C, stirring reaction is after 8 hours
Water terminating reaction, ethyl acetate is added to extract three times, extract anhydrous sodium sulfate drying is filtered, removal of solvent under reduced pressure, finally
Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system, and volume ratio is 1: 2～1: 7）Obtain
Yellow solid is respective rings propyl phosphonous acid ester, and yield is 82%,d eValue>99%, product optical activity is good.The nuclear-magnetism number of product
According to same embodiment two.
Embodiment ten：N-BuLi promotes diethyl phosphite and 1- phenyl -3- p-fluorophenyl -2- propylene -1- reactive ketones
Synthesis cyclopropyl phosphonate ester
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- phenyl -3- p-fluorophenyl -2- propylene -1- ketone（0.226 g, 1.0 mmol）And solvent acetonitrile（2 mL）, 80 DEG C
Lower stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying is filtered,
Removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant be ethyl acetate/petroleum ether system, volume
Than for 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 94%,d eValue>99%, product light
Learn activity good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.08–7.01(m, 5H), 6.81–6.73 (m, 4H), 4.14–
3.97 (m, 4H), 3.04–2.96 (m, 1H), 2.09–2.01 (m, 1H), 1.71–1.65 (m, 1H), 1.29–
1.22 (m, 6H)。
Embodiment 11：N-BuLi promotes diethyl phosphite and 1- phenyl -3- rubigan -2- propylene -1- ketone anti-
Cyclopropyl phosphonate ester should be synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- phenyl -3- rubigan -2- propylene -1- ketone（0.243 g, 1.0 mmol）And solvent acetonitrile（2 mL）, 80 DEG C
Lower stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying is filtered,
Removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant be ethyl acetate/petroleum ether system, volume
Than for 1: 2～1: 7）Obtain yellow solid and be respective rings propyl phosphonous acid ester, yield is 95%,d eValue>99%, product optics is lived
Property is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.08–6.74 (m, 9H), 4.16–3.96 (m, 4H), 3.05–
2.97 (m, 1H), 2.08–2.00 (m, 1H), 1.71–1.63 (m, 1H), 1.30–1.22 (m, 6H)。
Embodiment 12：N-BuLi promotes diethyl phosphite and 1- phenyl -3- p-bromophenyl -2- propylene -1- ketone anti-
Cyclopropyl phosphonate ester should be synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- phenyl -3- p-bromophenyl -2- propylene -1- ketone（0.287 g, 1.0 mmol）And solvent acetonitrile（2 mL）, 80 DEG C
Lower stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying is filtered,
Removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant be ethyl acetate/petroleum ether system, volume
Than for 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 94%,d eValue>99%, product light
Learn activity good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.27–7.23 (m, 2H), 7.09–7.08 (m, 3H), 6.94–
6.92 (m, 2H), 6.77–6.75 (m, 2H), 4.14–3.97 (m, 4H), 3.05–2.97 (m, 1H), 2.09–
2.01 (m, 1H), 1.70–1.64 (m, 1H), 1.30–1.24 (m, 6H)。
Embodiment 13：N-BuLi promote diethyl phosphite and 1- phenyl -3- p-trifluoromethyl phenyl -2- propylene -
1- reactive ketones synthesize cyclopropyl phosphonate ester
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- phenyl -3- p-trifluoromethyl phenyl -2- propylene -1- ketone（0.276 g, 1.0 mmol）And solvent acetonitrile（2
mL）, at 80 DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, and extract is dry with anhydrous sodium sulfate
It is dry, filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether
System, volume ratio are 1: 2～1: 7）Obtain yellow solid and be respective rings propyl phosphonous acid ester, yield is 85%,d eValue>99%,
Product optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.38–7.36 (m, 2H), 7.18–7.17 (m, 2H), 7.10–
7.05 (m, 3H), 6.76–6.72 (m, 2H), 4.18–3.99 (m, 4H), 3.10–3.02 (m, 1H), 2.13–
2.04 (m, 1H), 1.76–1.70 (m, 1H), 1.31–1.24 (m, 6H)。
Embodiment 14：N-BuLi promotes diethyl phosphite and 1- phenyl -3- to cyano-phenyl -2- propylene -1- ketone
Cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- phenyl -3- are to cyano-phenyl -2- propylene -1- ketone（0.233 g, 1.0 mmol）And solvent acetonitrile（2 mL）, 80
At DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying, mistake
Filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system,
Volume ratio is 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 90%,d eValue>99%, produce
Thing optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.41–7.39 (m, 2H), 7.19–7.08 (m, 5H), 6.75–
6.73 (m, 2H), 4.18–4.00 (m, 4H), 3.11–3.03 (m, 1H), 2.13–2.06 (m, 1H), 1.78–
1.72 (m, 1H), 1.31–1.24 (m, 6H)。
Embodiment 15：N-BuLi promotes diethyl phosphite and 1- phenyl -3- p-methylphenyl -2- propylene -1- ketone
Cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- phenyl -3- p-methylphenyl -2- propylene -1- ketone（0.222 g, 1.0 mmol）And solvent acetonitrile（1 mL）, 80
At DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 5 hours, extract anhydrous sodium sulfate drying, mistake
Filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system,
Volume ratio is 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 86%,d eValue>99%, produce
Thing optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.13–7.06 (m, 5H), 6.68–6.60 (m, 4H), 4.13–
3.97 (m, 4H), 3.70 (s, 3H), 3.00–2.92 (m, 1H), 2.07–1.99 (m, 1H), 1.66–1.60
(m, 1H), 1.30–1.22 (m, 6H)。
Embodiment 16：N-BuLi promotes aminomethyl phenyl -2- propylene -1- ketone between diethyl phosphite and 1- phenyl -3-
Cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, aminomethyl phenyl -2- propylene -1- ketone between 1- phenyl -3-（0.222 g, 1.0 mmol）And solvent acetonitrile（2 mL）, 80
At DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying, mistake
Filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system,
Volume ratio is 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 92%,d eValue>99%, produce
Thing optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 6.99–6.65 (m, 9H), 4.05–3.89 (m, 4H), 2.94–
2.86 (m, 1H), 2.09 (s, 3H), 1.99–1.91 (m, 1H), 1.63–1.56 (m, 1H), 1.21–1.14
(m, 6H)。
Embodiment 17：N-BuLi promotes diethyl phosphite and 1- phenyl -3- (2- thienyls) -2- propylene -1- ketone
Cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- phenyl -3- (2- thienyls) -2- propylene -1- ketone（0.214 g, 1.0 mmol）And solvent acetonitrile（1 mL）, 80
At DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 6 hours, extract anhydrous sodium sulfate drying, mistake
Filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system,
Volume ratio is 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 84%,d eValue>99%, produce
Thing optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.14–7.10 (m, 3H), 7.04–7.03 (m, 1H), 6.93–
6.88 (m, 2H), 6.76–6.69 (m, 2H), 4.21–4.00 (m, 4H), 3.01–3.03 (m, 1H), 2.16–
2.08 (m, 1H), 1.90–1.85 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1
Hz, 3H)。
Embodiment 18：N-BuLi promotes diethyl phosphite and 1- p-fluorophenyl -3- phenyl -2- propylene -1- ketone anti-
Cyclopropyl phosphonate ester should be synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- p-fluorophenyl -3- phenyl -2- propylene -1- ketone（0.226 g, 1.0 mmol）And solvent acetonitrile（2 mL）, 80 DEG C
Lower stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying is filtered,
Removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant be ethyl acetate/petroleum ether system, volume
Than for 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 85%,d eValue>99%, product light
Learn activity good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.12–7.06 (m, 5H), 6.76–6.68 (m, 4H), 4.12–
3.95 (m, 4H), 3.02–2.94 (m, 1H), 2.10–2.03 (m, 1H), 1.69–1.63 (m, 1H), 1.29–
1.22 (m, 6H)。
Embodiment 19：N-BuLi promotes diethyl phosphite and 1- rubigan -3- phenyl -2- propylene -1- ketone anti-
Cyclopropyl phosphonate ester should be synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- rubigan -3- phenyl -2- propylene -1- ketone（0.243 g, 1.0 mmol）And solvent acetonitrile（2 mL）, 80 DEG C
Lower stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying is filtered,
Removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant be ethyl acetate/petroleum ether system, volume
Than for 1: 2～1: 7）Obtain white solid and be respective rings propyl phosphonous acid ester, yield is 86%,d eValue>99%, product optics is lived
Property is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.15–7.12 (m, 3H), 7.07–7.02 (m, 4H), 6.67–
6.65 (m, 2H), 4.13–3.87 (m, 4H), 3.00–2.92 (m, 1H), 2.20–2.03 (m, 1H), 1.69–
1.64 (m, 1H), 1.29–1.23 (m, 6H)。
Embodiment 20：N-BuLi promotes diethyl phosphite and 1- rubigan -3- rubigan -2- propylene -1-
Reactive ketone synthesizes cyclopropyl phosphonate ester
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- rubigan -3- rubigan -2- propylene -1- ketone（0.277 g, 1.0 mmol）And solvent acetonitrile（2 mL）,
At 80 DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying,
Filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether body
System, volume ratio are 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 90%,d eValue>
99%, product optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.12–6.98 (m, 6H), 6.69–6.67 (m, 2H), 4.14–
3.97 (m, 4H), 3.01–2.93 (m, 1H), 2.10–2.02 (m, 1H), 1.66–1.60(m, 1H), 1.29–
1.23(m, 6H)。
Embodiment 21：N-BuLi promotes diethyl phosphite and 1- p-bromophenyl -3- phenyl -2- propylene -1- ketone
Cyclopropyl phosphonate ester is synthesized
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- p-bromophenyl -3- phenyl -2- propylene -1- ketone（0.287 g, 1.0 mmol）And solvent acetonitrile（2 mL）, 80 DEG C
Lower stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying is filtered,
Removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant be ethyl acetate/petroleum ether system, volume
Than for 1: 2～1: 7）Obtain white solid and be respective rings propyl phosphonous acid ester, yield is 81%,d eValue>99%, product optics is lived
Property is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.19–7.11 (m, 5H), 7.06–7.05 (m, 2H), 6.61–
6.59 (m, 2H), 4.15–3.95 (m, 4H), 2.98–2.90 (m, 1H), 2.10–2.02 (m, 1H), 1.68–
1.61 (m, 1H), 1.29–1.22 (m, 6H)。
Embodiment 22：N-BuLi promotes diethyl phosphite and 1- p-trifluoromethyl phenyl -3- phenyl -2- third
Alkene -1- reactive ketones synthesize cyclopropyl phosphonate ester
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- p-trifluoromethyl phenyl -3- phenyl -2- propylene -1- ketone（0.276 g, 1.0 mmol）And solvent acetonitrile（2
mL）, at 80 DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, and extract is dry with anhydrous sodium sulfate
It is dry, filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether
System, volume ratio are 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 92%,d eValue>
99%, product optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.31–7.29 (m, 2H), 7.14–7.06 (m, 5H), 6.84–
6.82 (m, 2H), 4.15–3.97 (m, 4H), 3.08–3.00 (m, 1H), 2.17–2.09 (m, 1H), 1.78–
1.69 (m, 1H), 1.29–1.23 (m, 6H)。
Embodiment 23：N-BuLi promotes diethyl phosphite and 1- p-methylphenyl -3- phenyl -2- propylene -1-
Reactive ketone synthesizes cyclopropyl phosphonate ester
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- p-methylphenyl -3- phenyl -2- propylene -1- ketone（0.222 g, 1.0 mmol）And solvent acetonitrile（1 mL）, 80
At DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 5 hours, extract anhydrous sodium sulfate drying, mistake
Filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether system,
Volume ratio is 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 87%,d eValue>99%, produce
Thing optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.11–7.06 (m, 5H), 6.86–6.84 (m, 2H), 6.63–
6.61 (m, 2H), 4.14–3.94 (m, 4H), 3.01–2.93 (m, 1H), 2.18 (s, 3H), 2.07–1.99
(m, 1H), 1.69–1.63 (m, 1H), 1.26–1.20 (m, 6H)。
Embodiment 24：N-BuLi promote diethyl phosphite and 1- m-methoxyphenyl -3- phenyl -2- propylene -
1- reactive ketones synthesize cyclopropyl phosphonate ester
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- m-methoxyphenyl -3- phenyl -2- propylene -1- ketone（0.238 g, 1.0 mmol）And solvent acetonitrile（2 mL）,
At 80 DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 1 hour, extract anhydrous sodium sulfate drying,
Filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/petroleum ether body
System, volume ratio are 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 91%,d eValue>
99%, product optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.10 (s, 5H), 6.97–6.93 (m, 1H), 6.59–6.56
(m, 1H), 6.41–6.39 (m, 1H), 6.18 (s, 1H), 4.12–3.96 (m, 4H), 3.49 (s, 3H),
3.01–2.93 (m, 1H), 2.09–2.01 (m, 1H), 1.70–1.64 (m, 1H), 1.28–1.20 (m, 6H)。
Embodiment 25：N-BuLi promotes diethyl phosphite and 1- (2- thienyls) -3- phenyl -2- propylene -1-
Reactive ketone synthesizes cyclopropyl phosphonate ester
In the reaction bulb processed through dehydration and deoxidation, add in reaction bulb under argon protectionn- BuLi oneself
Alkane solution（0.87 mL, 1.05 mmol, 1.21 M）, diethyl phosphite is subsequently slowly added to successively（0.39 mL, 3.0
mmol）, 1- (2- thienyls) p-methylphenyl -3- phenyl -2- propylene -1- ketone（0.214 g, 1.0 mmol）And solvent acetonitrile
（1 mL）, at 80 DEG C, stirring reaction adds water terminating reaction, ethyl acetate to extract three times after 5 hours, extract anhydrous slufuric acid
Sodium be dried, filter, removal of solvent under reduced pressure, most after Jing silicagel column rapid column chromatographies（Gradient elution, eluant are ethyl acetate/stone
Oily ether system, volume ratio are 1: 2～1: 7）Obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, yield is 81%,d e
Value>99%, product optical activity is good.
The Theoretical molecular formula of obtained product and main nuclear-magnetism test data are as follows, by analysis, actual to synthesize
Product is consistent with theory analysis.
1H NMR (400 MHz, CDCl3) δ 7.20–7.15 (m, 5H), 6.96–6.94 (m, 1H), 6.73–
6.71 (m, 1H), 6.44 (d, J = 3.5 Hz, 1H), 4.15–3.94 (m, 4H), 3.23–3.15 (m, 1H),
2.18–2.11 (m, 1H), 1.65–1.59 (m, 1H), 1.31–1.22 (m, 6H)。
Claims (10)
1. a kind of method for preparing cyclopropyl phosphonate ester, it is characterised in that comprise the following steps：In the reactor, in anhydrous nothing
Under the conditions of oxygen, with diethyl phosphite and α, alpha, beta-unsaturated ketone is reactant, with alkali as accelerator, at 60～85 DEG C, is being had
Reaction in machine solvent prepares product cyclopropyl phosphonate ester for 1～8 hour；
According to molar ratio computing, alkali: diethyl phosphite: α, alpha, beta-unsaturated ketone are (1.0～1.2): (2.5～3.5): 1；
The alpha, beta-unsaturated ketone chemical structure of general formula is：, wherein, Ar1It is selected from：Phenyl, to fluorobenzene
Base, rubigan, p-bromophenyl, p-trifluoromethyl phenyl, to cyano-phenyl, p-methylphenyl, an aminomethyl phenyl, 2- thienyls
In one kind, Ar2It is selected from：Phenyl, p-fluorophenyl, rubigan, p-bromophenyl, p-trifluoromethyl phenyl, p-methylphenyl,
One kind in methoxyphenyl, 2- thienyls；
The alkali is n-BuLi, lithium ethoxide, the one kind in sodium hydride；
The chemical structure of general formula of the cyclopropyl phosphonate ester is：
。
2. the method for preparing cyclopropyl phosphonate ester according to claim 1, it is characterised in that：The alkali is n-BuLi.
3. the method for preparing cyclopropyl phosphonate ester according to claim 1, it is characterised in that：The anhydrous and oxygen-free condition is argon
Gas atmospheric condition.
4. the preparation method of cyclopropyl phosphonate ester according to claim 1, it is characterised in that：According to molar ratio computing, alkali: phosphorous
Diethyl phthalate: alpha, beta-unsaturated ketone is 1.05: 3.0: 1.
5. the method for preparing cyclopropyl phosphonate ester according to claim 1, it is characterised in that：The organic solvent be toluene/
HMPA mixed solvent, acetonitrile/HMPA mixed solvent, acetonitrile, toluene or glycol dimethyl ether.
6. the method for preparing cyclopropyl phosphonate ester according to claim 5, it is characterised in that：The organic solvent is acetonitrile.
7. the method for preparing cyclopropyl phosphonate ester according to claim 1, it is characterised in that：Work as Ar1Or Ar2For phenyl or scarce
During electron-rich aryl, the response time is 1 hour；Work as Ar1Or Ar2For electron rich aryl when, the response time be 5 hours.
8. the method for preparing cyclopropyl phosphonate ester according to claim 1, it is characterised in that：The reaction temperature is 80 DEG C.
9. the method for preparing cyclopropyl phosphonate ester according to claim 1, it is characterised in that：By alkali, diethyl phosphite, α,
Alpha, beta-unsaturated ketone, organic solvent are sequentially added in reactor.
10. the method for preparing cyclopropyl phosphonate ester according to claim 1, it is characterised in that：After reaction terminates, extractive reaction
Liquid, after extract desiccant dryness filter, the solvent in filtrate is removed under reduced pressure, most after Jing rapid column chromatographies obtain cyclopropyl phosphine
Acid esters.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510353069.7A CN104945433B (en) | 2015-06-24 | 2015-06-24 | Method for preparing cyclopropyl phosphonate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510353069.7A CN104945433B (en) | 2015-06-24 | 2015-06-24 | Method for preparing cyclopropyl phosphonate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104945433A CN104945433A (en) | 2015-09-30 |
| CN104945433B true CN104945433B (en) | 2017-03-22 |
Family
ID=54160549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510353069.7A Active CN104945433B (en) | 2015-06-24 | 2015-06-24 | Method for preparing cyclopropyl phosphonate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104945433B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108516992B (en) * | 2018-03-29 | 2020-02-07 | 宁波工程学院 | Method for photocatalytic synthesis of 1-aryl cyclopropyl phosphonate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7385064B1 (en) * | 2005-11-30 | 2008-06-10 | The Research Foundation Of State University Of New York | Catalysts for use in enantioselective synthesis |
| MX2008008642A (en) * | 2006-01-13 | 2008-09-12 | Pharmacyclics Inc | Inhibitors of tyrosine kinases and uses thereof. |
-
2015
- 2015-06-24 CN CN201510353069.7A patent/CN104945433B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104945433A (en) | 2015-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Burk et al. | New chiral phospholanes; synthesis, characterization, and use in asymmetric hydrogenation reactions | |
| CN105153229B (en) | A kind of chiral tridentate PNN parts and its application in asymmetric hydrogenation | |
| EP1451133B1 (en) | P-chiral phospholanes and phosphocyclic compounds and their use in asymmetric catalytic reactions | |
| US8097738B2 (en) | Ruthenium (II) catalysts for use in stereoselective cyclopropanations | |
| JP2007528893A (en) | C1-symmetric bisphosphine ligands and their use in the asymmetric synthesis of pregabalin | |
| EP0770085A1 (en) | Heteroaromatic diphosphines as chiral ligands | |
| CN104402718B (en) | A kind of chiral allyl ester type compound and preparation method thereof | |
| CN104277072B (en) | A kind of preparation method of (E)-2-aryl vinyl phosphate derivatives | |
| CN104945433B (en) | Method for preparing cyclopropyl phosphonate | |
| JP6054108B2 (en) | Process for producing optically active 2,3-dihydrofarnesal | |
| JP4427109B2 (en) | Phosphorane and diphosphorane, metal complexes thereof, use thereof and method of asymmetric hydrogenation | |
| CN105294401A (en) | Preparation method of crizotinib intermediate (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol | |
| JP2972887B1 (en) | Asymmetric synthesis using optically active bisphosphinomethanes and their rhodium or copper complexes | |
| CN107973820B (en) | A kind of application of ionic iron (II) complex | |
| CN109970560B (en) | Preparation method of tri-substituted 1, 3-diene compound | |
| CN102746335B (en) | Preparation method of chiral phosphine oxide | |
| CN114907404A (en) | 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolylphosphine ligand and preparation method and application thereof | |
| CN101328190B (en) | Chiral N, P ligand, preparation and application thereof | |
| CN105669743A (en) | Method for preparing phosphinic acid ester/phosphorous acid ester/phosphoric acid ester from P(O)-OH compound and aryl boronic acid | |
| CN104945434A (en) | (2-disubstituted phosphino-phenyl)-1-alkyl-indol-phosphine ligand and synthetic method and application thereof | |
| JP2009235067A (en) | Axially asymmetric phosphorus compound and method for producing the same | |
| CN102464681A (en) | Chiral bidentate phosphite ligand, and preparation method and uses thereof | |
| JP2008169201A (en) | Novel optically biaryl phosphorus compound and method for producing the same | |
| Murakata et al. | The first organocatalyst-mediated enantioselective substitution of racemic iodoalkanes under radical conditions | |
| CN102838633B (en) | Method for preparing gamma-oxophosphonate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170809 Address after: Suzhou City, Jiangsu province 215137 Xiangcheng District Ji Road No. 8 Patentee after: Soochow University Address before: Zhangjiagang mayor Jingyang Road Suzhou City, Jiangsu province 215600 No. 10 Patentee before: Zhangjiagang Institute of Industrial Technologies Soochow University |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191219 Address after: 710018 unit 1, building 1, Wangjing international building, Fengcheng 6th Road, Xi'an Economic and Technological Development Zone, Shaanxi Province Patentee after: Shaanxi one intellectual property operation Co., Ltd. Address before: Suzhou City, Jiangsu province 215137 Xiangcheng District Ji Road No. 8 Patentee before: Soochow University |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200623 Address after: 215500 No.13, Caotang Road, Changshu, Suzhou, Jiangsu Province Patentee after: Changshu intellectual property operation center Co.,Ltd. Address before: 710018 unit 1, building 1, Wangjing international building, Fengcheng 6th Road, Xi'an Economic and Technological Development Zone, Shaanxi Province Patentee before: SHAANXI ZHUANYI INTELLECTUAL PROPERTY OPERATION Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 215500 5th floor, building 4, 68 Lianfeng Road, Changfu street, Changshu City, Suzhou City, Jiangsu Province Patentee after: Changshu intellectual property operation center Co.,Ltd. Address before: No.13 caodang Road, Changshu City, Suzhou City, Jiangsu Province Patentee before: Changshu intellectual property operation center Co.,Ltd. |