CN104945433A - Method for preparing cyclopropyl phosphonate - Google Patents
Method for preparing cyclopropyl phosphonate Download PDFInfo
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- CN104945433A CN104945433A CN201510353069.7A CN201510353069A CN104945433A CN 104945433 A CN104945433 A CN 104945433A CN 201510353069 A CN201510353069 A CN 201510353069A CN 104945433 A CN104945433 A CN 104945433A
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- acid ester
- phosphonic acid
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- phenyl
- cyclopropyl
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- 238000000034 method Methods 0.000 title claims abstract description 59
- 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 124
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 68
- 150000002576 ketones Chemical class 0.000 claims abstract description 33
- 239000003513 alkali Substances 0.000 claims abstract description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 90
- 239000000047 product Substances 0.000 claims description 73
- FBWJHGIUUCOZRM-UHFFFAOYSA-N cyclopropylphosphonic acid Chemical compound OP(O)(=O)C1CC1 FBWJHGIUUCOZRM-UHFFFAOYSA-N 0.000 claims description 58
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 57
- 238000000605 extraction Methods 0.000 claims description 54
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 50
- -1 p-trifluoromethyl phenyl Chemical group 0.000 claims description 43
- 239000007788 liquid Substances 0.000 claims description 39
- 238000004440 column chromatography Methods 0.000 claims description 28
- 229910052786 argon Inorganic materials 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 7
- 125000003118 aryl group Chemical group 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
- 238000002360 preparation method Methods 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
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- 125000004799 bromophenyl group Chemical group 0.000 claims description 5
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 3
- 230000007812 deficiency Effects 0.000 claims description 3
- 239000002274 desiccant 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
- 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
- 239000000126 substance Substances 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 230000006837 decompression Effects 0.000 claims 1
- 239000000706 filtrate Substances 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000003541 multi-stage reaction Methods 0.000 abstract 1
- 238000000746 purification Methods 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 34
- 230000015572 biosynthetic process Effects 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 239000003480 eluent Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 238000010828 elution Methods 0.000 description 25
- 239000003208 petroleum Substances 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
- 230000018044 dehydration Effects 0.000 description 24
- 238000006297 dehydration reaction Methods 0.000 description 24
- 238000001035 drying Methods 0.000 description 24
- 230000003287 optical effect Effects 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
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 17
- 235000010290 biphenyl Nutrition 0.000 description 17
- 230000005311 nuclear magnetism Effects 0.000 description 17
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 230000000694 effects Effects 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
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003446 ligand Substances 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
- CXOIECRVHUDBSA-UHFFFAOYSA-N 3-bromopropylphosphonic acid Chemical compound OP(O)(=O)CCCBr CXOIECRVHUDBSA-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 239000012300 argon atmosphere Substances 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
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 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
- 229960004756 ethanol Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002156 mixing Methods 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
- 239000000575 pesticide Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000967 suction filtration Methods 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, be specifically related to a kind of cyclopropyl phosphonic acid ester preparation method.
Background technology
The synthesis of cyclopropanes compound is one of focus of organic chemistry research field always.Cyclopropyl phosphonate building block is found in the natural product and drug molecule a lot with good biological activity, and cyclopropyl phosphonate ester compound is also the key intermediate of synthesis Multiple Pesticides and drug molecule in addition.
In prior art, the method for the synthesis of cyclopropyl phosphonic acid ester mainly comprises following three kinds:
Synthesized by [2+1] annulation.As at room temperature, phosphoryl acetonitrile can be obtained polysubstituted cyclopropanes compound with α, β-saturated dihalide hydrocarbon reaction 20-380 hour under 4 equivalent alkali effects, and yield is 1 ~ 55%; Or with Ru (II)-Pheox catalyzed alkene or acrylate and dizaomethyl phosphonate reaction, obtain trans cyclopropyl phosphonic acid ester, yield is 33-93%, although this reaction
debe worth very high, but diazonium compound used have potential danger (I. L. Odinets, et al. Heteroatom Chem. 2006,17,13 because of unstable, explosive; S. Iwasa, et al. Org. Lett. 2014,16,3012).
Synthesized by 1,3-eliminative reaction.As at room temperature promoted that γ-Bromopropyl phosphonic acid ester 1,3-occurs and eliminates with 2 equivalent potassium tert.-butoxides, the yield with 81% prepares cyclopropyl phosphonic acid ester, but the product of this reaction is without stereoselectivity (Y. Segall, et al. Synth. Commun. 2008,38,848).
Synthesized by cyclopropyl Grignard reagent.Prepare cyclopropyl phosphonic acid ester as Jankowski reacts with cyclopropyl Grignard reagent and chlorine di(2-ethylhexyl)phosphate ethyl ester, yield is 51%(WO 2007/087068 A2).
Above method can generate cyclopropyl phosphonic acid ester, but it is most or need multistep to complete, or complicated raw material need be obtained in advance, maybe need to use noble metal catalyst or excessive highly basic, especially for the optically active cyclopropyl phosphonic acid ester of preparation, required condition is often more harsh, as used chiral raw material, cold condition, or need to add chiral ligand cooperation, etc.In view of the good biological activity that cyclopropyl phosphonic acid ester has, method that is efficient, this compounds of highly-solid selectively ground synthesis in a mild condition of finding is necessary.
Summary of the invention
The object of this invention is to provide a kind of method preparing cyclopropyl phosphonic acid ester, lower diethyl phosphite and α is there is by alkali, change reaction for one pot of alpha, beta-unsaturated ketone, develop a kind of method of the synthesis cyclopropyl phosphonic acid ester simple, high reactivity, highly selective, safety, universality are good of originating.
To achieve the above object of the invention, the technical solution used in the present invention is:
A kind of method preparing cyclopropyl phosphonic acid ester, it is characterized in that, comprise the following steps: under anhydrous and oxygen-free condition, with diethyl phosphite and α, alpha, beta-unsaturated ketone is reactant, take alkali as promotor, at 60 ~ 85 DEG C, react in organic solvent and within 1 ~ 8 hour, prepare product cyclopropyl phosphonic acid ester;
Described alpha, beta-unsaturated ketone chemical structure of general formula is:
, wherein, Ar
1be selected from: phenyl, to fluorophenyl, rubigan, to bromophenyl, p-trifluoromethyl phenyl, to the one in cyano-phenyl, p-methylphenyl, an aminomethyl phenyl, 2-thienyl, Ar
2be selected from: phenyl, to fluorophenyl, rubigan, to the one in bromophenyl, p-trifluoromethyl phenyl, p-methylphenyl, m-methoxyphenyl, 2-thienyl.
In technique scheme, described alkali is the one in n-Butyl Lithium, lithium ethoxide, sodium hydride, and be preferably n-Butyl Lithium, under similarity condition, n-Butyl Lithium more efficiently can promote the formation reaction of cyclopropyl phosphonic acid ester.
In technique scheme, reaction process comprises: under anhydrous and oxygen-free condition, n-Butyl Lithium, diethyl phosphite, alpha, beta-unsaturated ketone and solvent is added successively in reactor, mixing, stirring reaction 1 ~ 8 hour at 60 ~ 85 DEG C, termination reaction, extracts, use desiccant dryness extraction liquid, filter, removal of solvent under reduced pressure, obtains cyclopropyl phosphonic acid ester finally by rapid column chromatography.
In technique scheme, reaction solvent can be acetonitrile, toluene, glycol dimethyl ether and toluene/HMPA, acetonitrile/HMPA mixed solvent, is preferably acetonitrile.
In technique scheme, described under anhydrous and oxygen-free condition be preferably in inert argon atmosphere.
In technique scheme, the consumption of described n-Butyl Lithium is α, 1 ~ 1.2 times of the mole number of alpha, beta-unsaturated ketone, be preferably 1.05 times, the consumption of n-Butyl Lithium is slightly in excess in α, alpha, beta-unsaturated ketone is conducive to the complete of reaction, but the consumption of n-Butyl Lithium is crossed conference increase reaction cost and affected the aftertreatment of reaction system.
In technique scheme, the consumption of described diethyl phosphite is 2.5 ~ 3.5 times of the mole number of alpha, beta-unsaturated ketone, is preferably 3 times.
In technique scheme, described temperature of reaction is preferably 80 DEG C; Temperature is too low easily causes reaction not exclusively, and 80 DEG C is the boiling point of acetonitrile solvent, and it is best namely to react effect in the acetonitrile of backflow.
In technique scheme, the reaction times is 1 ~ 8 hour.Work as Ar
1or Ar
2during for phenyl or electron deficiency aryl, the reaction times is preferably 1 hour; Work as Ar
1or Ar
2during for electron rich aryl, the reaction times is 5 hours.
In the present invention, electron deficiency aryl be to fluorophenyl, rubigan, to bromophenyl, p-trifluoromethyl phenyl, to cyano-phenyl, an aminomethyl phenyl; Electron rich aryl is p-methylphenyl, 2-thienyl.
In technique scheme, termination reaction, extraction, use desiccant dryness extraction liquid, filter, removal of solvent under reduced pressure, obtain the operations such as cyclopropyl phosphonic acid ester itself finally by rapid column chromatography and all belong to prior art, wherein used extraction agent, siccative, eluent is also prior art, those skilled in the art can select suitable reagent according to the character of final product, in preferred technical scheme, termination reaction adopts water, extraction agent is ethyl acetate, siccative is anhydrous sodium sulphate, rapid column chromatography adopts gradient elution, eluent is ethyl acetate/petroleum ether system (volume ratio is 1: 2 ~ 1: 7).
Technique scheme can be expressed as follows:
Due to the utilization of technique scheme, the present invention compared with prior art has following advantages:
1. the present invention uses n-Butyl Lithium promotion diethyl phosphite and alpha, beta-unsaturated ketone to carry out reaction one pot of change method synthesis cyclopropyl phosphonic acid ester first, and the raw material of reaction is easy to get, mild condition, and active high, easy to operate, the yield of target product is high, reaches as high as 95%.
2. synthetic route single stepping disclosed by the invention completes polystep reaction, and reaction efficiency is high, and reaction conditions is simply controlled, and aftertreatment is simple, overcomes the defect that prior art needs many more manipulations, complicated aftertreatment could prepare product.
3. method disclosed by the invention uses the amount of alkali relatively less, is 1 ~ 1.2 times of the mole number of alpha, beta-unsaturated ketone, is preferably 1.05 times, and far below the consumption of prior art alkali, the aftertreatment of reaction is simple, is conducive to the purifying of product; The stereoselectivity of gained cyclopropyl phosphonic acid ester is good,
devalue >99%, the yield of product is high, reaches as high as 95%; Achieve beyond thought technique effect.
4. method disclosed by the invention is to the α of multiple replacement, alpha, beta-unsaturated ketone has universality, especially for the optically active cyclopropyl phosphonic acid ester of preparation, preparation condition of the present invention is simple, coordinate without the need to using chiral raw material or adding chiral ligand, optically active cyclopropyl phosphonic acid ester of high yield is prepared in success, overcomes prior art and prepares optically active cyclopropyl phosphonic acid ester complicated condition, defect that ingredient requirement is high, be conducive to the industrial application of cyclopropyl phosphonic acid ester.
Embodiment
Below in conjunction with embodiment, the invention will be further described:
Embodiment one: the synthesis of phenylbenzene cinnamophenone
Methyl phenyl ketone (5.8 mL, 50 mmol), phenyl aldehyde (5.1 mL, 50 mmol), aqueous sodium hydroxide solution (2.53 g sodium hydroxide, 25 mL distilled water) and 95% ethanol (30 mL) is added successively in 250 mL round-bottomed flasks.Stirred at ambient temperature is after 24 hours, and system has a large amount of faint yellow solid to separate out.Suction filtration, a small amount of absolute ethanol washing of filter cake, then use dehydrated alcohol recrystallization.Gained faint yellow solid is product, and yield is 95%.
1H NMR (400 MHz, CDCl
3):
δ8.03 (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 cinnamophenone can the preparation method of reference example one.
Embodiment two: n-Butyl Lithium promotes diethyl phosphite and phenylbenzene cinnamophenone Reactive Synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.99 mL of-BuLi, 1.2 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), phenylbenzene cinnamophenone (0.208 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 93%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.12–7.05 (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-Butyl Lithium promotes diethyl phosphite and phenylbenzene cinnamophenone Reactive Synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.99 mL of-BuLi, 1.2 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), phenylbenzene cinnamophenone (0.208 g, 1.0 mmol) and acetonitrile/HMPA mixed solvent (2 mL, volume ratio is 5: 1), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 89%,
devalue >99%, product optical activity is good.The nuclear magnetic data of product is with embodiment two.
Embodiment four: n-Butyl Lithium promotes diethyl phosphite and phenylbenzene cinnamophenone Reactive Synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.83 mL of-BuLi, 1.0 mmol, 1.21 M), slowly add diethyl phosphite (0.455mL successively subsequently, 3.5 mmol), phenylbenzene cinnamophenone (0.208 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1.5 hours, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 88%,
devalue >99%, product optical activity is good.The nuclear magnetic data of product is with embodiment two.
Embodiment five: n-Butyl Lithium promotes diethyl phosphite and phenylbenzene cinnamophenone Reactive Synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), phenylbenzene cinnamophenone (0.208 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 93%,
devalue >99%, product optical activity is good.The nuclear magnetic data of product is with embodiment two.
Embodiment six: n-Butyl Lithium promotes diethyl phosphite and phenylbenzene cinnamophenone Reactive Synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.99 mL of-BuLi, 1.2 mmol, 1.21 M), slowly add diethyl phosphite (0.325mL successively subsequently, 2.5 mmol), phenylbenzene cinnamophenone (0.208 g, 1.0 mmol) and toluene/HMPA mixed solvent (2 mL, volume ratio is 5: 1), at 85 DEG C, stirring reaction added water termination reaction after 5 hours, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 80%,
devalue >99%, product optical activity is good.The nuclear magnetic data of product is with embodiment two.
Embodiment seven: lithium ethoxide promotes diethyl phosphite and phenylbenzene cinnamophenone Reactive Synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, in reaction flask, lithium ethoxide (0.06 g is added under argon shield, 1.2 mmol), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), phenylbenzene cinnamophenone (0.208 g, 1.0 mmol) and toluene/HMPA mixed solvent (2 mL, volume ratio is 5: 1), at 80 DEG C, stirring reaction added water termination reaction after 8 hours, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 84%,
devalue >99%, product optical activity is good.The nuclear magnetic data of product is with embodiment two.
Embodiment eight: n-Butyl Lithium promotes diethyl phosphite and phenylbenzene cinnamophenone Reactive Synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.99 mL of-BuLi, 1.2 mmol, 1.21 M), slowly add diethyl phosphite (0.32 mL successively subsequently, 2.5 mmol), phenylbenzene cinnamophenone (0.208 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 2 hours, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 84%,
devalue >99%, product optical activity is good.The nuclear magnetic data of product is with embodiment two.
Embodiment nine: n-Butyl Lithium promotes diethyl phosphite and phenylbenzene cinnamophenone Reactive Synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.99 mL of-BuLi, 1.2 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), phenylbenzene cinnamophenone (0.208 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 60 DEG C, stirring reaction added water termination reaction after 8 hours, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 82%,
devalue >99%, product optical activity is good.The nuclear magnetic data of product is with embodiment two.
Embodiment ten: n-Butyl Lithium promotes that diethyl phosphite and 1-phenyl-3-are to fluorophenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-phenyl-3-is to fluorophenyl-2-propylene-1-ketone (0.226 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 94%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.08–7.01(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-Butyl Lithium promotes diethyl phosphite and 1-phenyl-3-rubigan-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-phenyl-3-rubigan-2-propylene-1-ketone (0.243 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 95%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.08–6.74 (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-Butyl Lithium promotes that diethyl phosphite and 1-phenyl-3-are to bromophenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-phenyl-3-is to bromophenyl-2-propylene-1-ketone (0.287 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 94%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.27–7.23 (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-Butyl Lithium promotes diethyl phosphite and 1-phenyl-3-p-trifluoromethyl phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 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 added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow solid and be respective rings propyl phosphonous acid ester, productive rate is 85%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.38–7.36 (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-Butyl Lithium promotes that diethyl phosphite and 1-phenyl-3-are to cyano-phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-phenyl-3-is to cyano-phenyl-2-propylene-1-ketone (0.233 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 90%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.41–7.39 (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-Butyl Lithium promotes diethyl phosphite and 1-phenyl-3-p-methylphenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-phenyl-3-p-methylphenyl-2-propylene-1-ketone (0.222 g, 1.0 mmol) and solvent acetonitrile (1 mL), at 80 DEG C, stirring reaction added water termination reaction after 5 hours, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 86%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.13–7.06 (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-Butyl Lithium promotes aminomethyl phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester between diethyl phosphite and 1-phenyl-3-
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), aminomethyl phenyl-2-propylene-1-ketone (0.222 g between 1-phenyl-3-, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 92%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ6.99–6.65 (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-Butyl Lithium promotes diethyl phosphite and 1-phenyl-3-(2-thienyl)-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-phenyl-3-(2-thienyl)-2-propylene-1-ketone (0.214 g, 1.0 mmol) and solvent acetonitrile (1 mL), at 80 DEG C, stirring reaction added water termination reaction after 6 hours, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 84%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.14–7.10 (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-Butyl Lithium promotes that diethyl phosphite and 1-are to fluorophenyl-3-phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-is to fluorophenyl-3-phenyl-2-propylene-1-ketone (0.226 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 85%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.12–7.06 (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-Butyl Lithium promotes diethyl phosphite and 1-rubigan-3-phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-rubigan-3-phenyl-2-propylene-1-ketone (0.243 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain white solid and be respective rings propyl phosphonous acid ester, productive rate is 86%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.15–7.12 (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-Butyl Lithium promotes diethyl phosphite and 1-rubigan-3-rubigan-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 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 added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 90%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.12–6.98 (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-Butyl Lithium promotes that diethyl phosphite and 1-are to bromophenyl-3-phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-is to bromophenyl-3-phenyl-2-propylene-1-ketone (0.287 g, 1.0 mmol) and solvent acetonitrile (2 mL), at 80 DEG C, stirring reaction added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain white solid and be respective rings propyl phosphonous acid ester, productive rate is 81%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.19–7.11 (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-Butyl Lithium promotes diethyl phosphite and 1-p-trifluoromethyl phenyl-3-phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 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 added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 92%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.31–7.29 (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-Butyl Lithium promotes diethyl phosphite and 1-p-methylphenyl-3-phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-p-methylphenyl-3-phenyl-2-propylene-1-ketone (0.222 g, 1.0 mmol) and solvent acetonitrile (1 mL), at 80 DEG C, stirring reaction added water termination reaction after 5 hours, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 87%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.11–7.06 (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-Butyl Lithium promotes diethyl phosphite and 1-m-methoxyphenyl-3-phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 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 added water termination reaction after 1 hour, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 91%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3)
δ7.10 (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-Butyl Lithium promotes diethyl phosphite and 1-(2-thienyl)-3-phenyl-2-propylene-1-reactive ketone synthesis cyclopropyl phosphonic acid ester
In the reaction flask through dehydration and deoxidation process, add in reaction flask under argon shield
nhexane solution (0.87 mL of-BuLi, 1.05 mmol, 1.21 M), slowly add diethyl phosphite (0.39 mL successively subsequently, 3.0 mmol), 1-(2-thienyl) 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 added water termination reaction after 5 hours, extraction into ethyl acetate three times, extraction liquid anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, finally by silicagel column rapid column chromatography (gradient elution, eluent is ethyl acetate/petroleum ether system, volume ratio is 1: 2 ~ 1: 7) obtain yellow oily liquid and be respective rings propyl phosphonous acid ester, productive rate is 81%,
devalue >99%, product optical activity is good.
Theoretical molecular formula and the main nuclear-magnetism test data of obtained product are as follows, and known by analyzing, actual synthetic product is consistent with theoretical analysis.
1H NMR (400 MHz, CDCl
3) 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. prepare the method for cyclopropyl phosphonic acid ester for one kind, it is characterized in that, comprise the following steps: in the reactor, under anhydrous and oxygen-free condition, with diethyl phosphite and alpha, beta-unsaturated ketone for reactant, take alkali as promotor, at 60 ~ 85 DEG C, react in organic solvent and within 1 ~ 8 hour, prepare product cyclopropyl phosphonic acid ester;
According to molar ratio computing, alkali: diethyl phosphite: alpha, beta-unsaturated ketone is (1.0 ~ 1.2): (2.5 ~ 3.5): 1;
Described alpha, beta-unsaturated ketone chemical structure of general formula is:
, wherein, Ar
1be selected from: phenyl, to fluorophenyl, rubigan, to bromophenyl, p-trifluoromethyl phenyl, to the one in cyano-phenyl, p-methylphenyl, an aminomethyl phenyl, 2-thienyl, Ar
2be selected from: phenyl, to fluorophenyl, rubigan, to the one in bromophenyl, p-trifluoromethyl phenyl, p-methylphenyl, m-methoxyphenyl, 2-thienyl;
Described alkali is the one in n-Butyl Lithium, lithium ethoxide, sodium hydride.
2. prepare the method for cyclopropyl phosphonic acid ester according to claim 1, it is characterized in that: described alkali is n-Butyl Lithium.
3. prepare the method for cyclopropyl phosphonic acid ester according to claim 1, it is characterized in that: described anhydrous and oxygen-free condition is argon gas atmosphere condition.
4. the preparation method of cyclopropyl phosphonic acid ester according to claim 1, is characterized in that: according to molar ratio computing, alkali: diethyl phosphite: alpha, beta-unsaturated ketone is 1.05: 3.0: 1.
5. prepare the method for cyclopropyl phosphonic acid ester according to claim 1, it is characterized in that: described organic solvent is toluene/HMPA mixed solvent, acetonitrile/HMPA mixed solvent, acetonitrile, toluene or glycol dimethyl ether.
6. prepare the method for cyclopropyl phosphonic acid ester according to claim 5, it is characterized in that: described organic solvent is acetonitrile.
7. prepare the method for cyclopropyl phosphonic acid ester according to claim 1, it is characterized in that: work as Ar
1or Ar
2during for phenyl or electron deficiency aryl, the reaction times is 1 hour; Work as Ar
1or Ar
2during for electron rich aryl, the reaction times is 5 hours.
8. prepare the method for cyclopropyl phosphonic acid ester according to claim 1, it is characterized in that: described temperature of reaction is 80 DEG C.
9. prepare the method for cyclopropyl phosphonic acid ester according to claim 1, it is characterized in that: alkali, diethyl phosphite, alpha, beta-unsaturated ketone, organic solvent are added in reactor successively.
10. prepare the method for cyclopropyl phosphonic acid ester according to claim 1, it is characterized in that: after reaction terminates, extractive reaction liquid, filters after extraction liquid desiccant dryness, the solvent in decompression removing filtrate, obtains cyclopropyl phosphonic acid ester finally by rapid column chromatography.
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| CN108516992A (en) * | 2018-03-29 | 2018-09-11 | 宁波工程学院 | Photocatalytic synthesis at 1- aryl cyclopropyl phosphonate esters method |
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| US7385064B1 (en) * | 2005-11-30 | 2008-06-10 | The Research Foundation Of State University Of New York | Catalysts for use in enantioselective synthesis |
| CN101421269A (en) * | 2006-01-13 | 2009-04-29 | 环状药物公司 | Inhibitors of tyrosine kinases and uses thereof |
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| US7385064B1 (en) * | 2005-11-30 | 2008-06-10 | The Research Foundation Of State University Of New York | Catalysts for use in enantioselective synthesis |
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| CN108516992A (en) * | 2018-03-29 | 2018-09-11 | 宁波工程学院 | Photocatalytic synthesis at 1- aryl cyclopropyl phosphonate esters method |
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