CN105061504A - Preparation method of P-alkynyl phosphate compound - Google Patents
Preparation method of P-alkynyl phosphate compound Download PDFInfo
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- CN105061504A CN105061504A CN201510589162.8A CN201510589162A CN105061504A CN 105061504 A CN105061504 A CN 105061504A CN 201510589162 A CN201510589162 A CN 201510589162A CN 105061504 A CN105061504 A CN 105061504A
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Abstract
The invention discloses a preparation method of a P-alkynyl phosphate compound. The preparation method comprises the following steps: sequentially adding lithium hexamethyl disilazane (LiHMDS), diethyl chlorophosphate (ClP(O)(OEt)2) and the LiHMDS into a water-free solution of P-acetyl phosphate as shown in a general formula 2 in an atmosphere of protective gas to obtain the P-alkynyl phosphate compound as shown in a general formula 1. The preparation method of the P-alkynyl phosphate compound has the advantages that (1) a substrate can be conveniently prepared from cheap raw materials without various expensive aryne reagents; (2) the universality is high, and the preparation of benzimidazole ynamine derivatives containing various substituent compositions is easily realized; (3) the operation is simple and convenient, and an intermediate does not need to be separated; (4) a target compound is easy to separate and purify, and the yield is higher.
Description
Technical field
The present invention relates to alkynyl phosphate compounds, particularly relate to the preparation method of alkynyl phosphate compounds.
Background technology
The preparation method of traditional P-alkynyl phosphate compounds comprises the hydrolyzable Ph of employing
2p (O) Cl, Ph
2p (O) Li, Ph
2the preparation of P (O) Mg acetylide, the employing bromo-1-alkene of palladium chtalyst 1,1-bis-and the H cross-coupling of phosphite or the H oxidative coupling of copper catalysis terminal olefin and phosphonic acid ester.But above-mentioned several synthetic method major parts are only applicable to a small amount of substrate and substrate is expensive is not suitable for extensive synthesis.Thus need to provide a kind of preparation method being suitable for the P-alkynyl phosphate compounds that versatility is good, substrate price is low.
Summary of the invention
Based on this, provide a kind of preparation method of P-alkynyl phosphate compounds.
A preparation method for P-alkynyl phosphate compounds, comprises the following steps:
Under the atmosphere of shielding gas, by lithium hexamethyldisilazide LiHMDS, diethyl chloro-phosphate ClP (O) (OEt)
2join successively in the anhydrous solvent of the P-acyl ethyl phosphonic acid ester shown in general formula 2 with lithium hexamethyldisilazide and react, obtain the P-alkynyl phosphate compounds shown in general formula 1;
Wherein, the temperature when adding LiHMDS reaction controls at-10 ~-78 DEG C; Add ClP (O) (OEt)
2after, react at system is warming up to 10 ~ 30 DEG C, R
1and R
2independently be selected from for carbonatoms be 1 ~ 10 alkyl and alkyl substituents or carbonatoms be 6 ~ 12 aryl and aryl substituent.
Further, add LiHMDS reaction in first time to add ClP (O) (OEt) after 20 ~ 40 minutes
2; Adding ClP (O) (OEt)
2react second time after 20 ~ 40 minutes and add LiHMDS, the reaction times that second time adds LiHMDS is 1 ~ 3 hour.
Further, P-acyl ethyl phosphonic acid ester is 1:0.8 ~ 1.2 with the mol ratio of the LiHMDS added for the first time.
Further, P-acyl ethyl phosphonic acid ester and ClP (O) (OEt)
2mol ratio be 1.0 ~ 1.4.
Further, P-acyl ethyl phosphonic acid ester is 1:1.0 ~ 3.0 with the mol ratio of the LiHMDS added for the second time.
Further, R
2during for ethyl, R
1for phenyl, 4-p-methoxy-phenyl, 2,5-Dimethoxyphenyl, 4-aminomethyl phenyl, 2-aminomethyl phenyl, 3,4-3,5-dimethylphenyl, 4-iodophenyl, 4-bromophenyl, 4-chloro-phenyl-, 4-fluorophenyl, 2-naphthyl, 6-methoxyl group-2-naphthyl, xenyl, 2-furyl, 2-thienyl, styryl or the sub-p-methoxy-phenyl of 3,4-bis-; R
1during for phenyl, R
2for methyl, ethyl, sec.-propyl, normal-butyl.
Further, anhydrous solvent is tetrahydrofuran (THF) or ether.
Further, add after LiHMDS react in second time, also comprise and add saturated ammonium chloride solution quencher reaction, extraction, washing, dry, separation obtains P-alkynyl phosphate compounds.
Further, be separated into silica gel column chromatography and be separated, leacheate is sherwood oil and ethyl acetate volume ratio is the mixed solution of 5:1.
Further, shielding gas is nitrogen.
The preparation method of above-mentioned P-alkynyl phosphate compounds, provides a kind of substrate 2, LiHMDS of P-acyl ethyl phosphonic acid ester and substrate 2 and acts on and form enol negative ion; Then ClP (O) (OEt)
2the intermediate 3 formed containing a good leaving group is reacted with enol negative ion; Finally under LiHMDS effect, eliminate a part diethyl phosphoric acid [HOP (O) (OEt)
2] form P-alkynyl phosphate compounds.Substrate can obtain conveniently by cheap raw material, does not need to use expensive various aryne reagent; Preparation method (1) substrate of above-mentioned P-alkynyl phosphate compounds can obtain conveniently by cheap raw material, does not need to use expensive various aryne reagent; (2) versatility is good, is easy to the preparation of the benzoglyoxaline ynamine derivative realized containing various different substituents combination; (3) easy and simple to handle, do not need to be separated intermediate; (4) target compound is easily separated and purify, and productive rate is higher.
Accompanying drawing explanation
Fig. 1 is the nucleus magnetic resonance of compound 1a
1h spectrogram;
Fig. 2 is the nucleus magnetic resonance of compound 1a
13c spectrogram;
Fig. 3 is the nucleus magnetic resonance of compound 1a
31p spectrogram;
Fig. 4 is the nucleus magnetic resonance of compound 1b
1h spectrogram;
Fig. 5 is the nucleus magnetic resonance of compound 1b
13c spectrogram;
Fig. 6 is the nucleus magnetic resonance of compound 1b
31p spectrogram.
Embodiment
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, are described in detail the specific embodiment of the present invention below in conjunction with accompanying drawing.Set forth a lot of detail in the following description so that fully understand the present invention.But the present invention can be much different from alternate manner described here to implement, those skilled in the art can when without prejudice to doing similar improvement when intension of the present invention, therefore the present invention is by the restriction of following public concrete enforcement.
A preparation method for P-alkynyl phosphate compounds, comprises the following steps:
Under the atmosphere of shielding gas, by lithium hexamethyldisilazide LiHMDS, diethyl chloro-phosphate ClP (O) (OEt)
2join successively in the anhydrous solution of the P-acyl ethyl phosphonic acid ester shown in general formula 2 with lithium hexamethyldisilazide and react, obtain the P-alkynyl phosphate compounds shown in general formula 1;
Wherein, the temperature when adding LiHMDS reaction controls at-10 ~-78 DEG C; Add ClP (O) (OEt)
2after, react at system is warming up to 10 ~ 30 DEG C, R
1and R
2independently be selected from for carbonatoms be 1 ~ 10 alkyl and alkyl substituents, carbonatoms be 6 ~ 12 aryl and aryl substituent.
The present invention proposes the One-step Synthesis method of the P-alkynyl phosphate compounds 1 based on P-acyl ethyl phosphonic acid ester substrate 2.Successively by lithium hexamethyldisilazide (LiHMDS), diethyl chloro-phosphate [ClP (O) (OEt)
2] and LiHMDS join and to have reacted in the anhydrous solution of substrate 2.Temperature when adding LiHMDS reaction controls at-10 ~-78 DEG C; If temperature can cause the decomposition of substrate 2 higher than-10 DEG C, thus yield reduces, and temperature is lower than-78 DEG C, and cost is higher on the one hand, and the speed of reaction is lower on the other hand.Add ClP (O) (OEt)
2after, react at system is warming up to 10 ~ 30 DEG C, temperature is too low, and phosphineization is insufficient, has impact to next step elimination; Temperature is too high, and side reaction can be made to increase.The alkyne thioether compounds of various difference replacement can be obtained by the present invention.
Method of the present invention can be expressed as follows with reaction formula:
An important and key innovation of the present invention is, provide P-acyl ethyl phosphonic acid ester substrate 2, the α-hydrogen of its carbonyl is very active, easily lose under highly basic effect, form carbanion, structure tautomeric with enol negative ion formation, for follow-up building-up reactions provides favourable reactive group plinth.
The preparation method of P-alkynyl phosphate compounds of the present invention is one pot reaction, and a point three phases carries out, and the mechanism related to is as follows: i) first LiHMDS and substrate 2 act on and form enol negative ion; Ii) then ClP (O) (OEt)
2the intermediate 3 formed containing good leavings group is reacted with enol negative ion; Iii) finally under LiHMDS effect, a part diethyl phosphoric acid [HOP (O) (OEt) is eliminated
2] form P-alkynyl phosphoric acid ester 1.As follows:
The substrate 2 used in the present invention can obtain by the following method: be first obtained by reacting alpha-brominated alkyl ethyl ketone by alkyl ethyl ketone and cupric bromide, then alpha-brominated alkyl ethyl ketone is carried out nucleophilic substitution reaction with alkyl phosphite (in alkyl phosphite, the carbon atom number of alkyl is 1 ~ 10, as trimethyl phosphite, triethyl-phosphite etc.) respectively and obtain substrate 2.Alkyl in alpha-brominated alkyl ethyl ketone is the different alkyl replaced, and the carbon atom number of aryl is 4 ~ 15.
The preparation method of above-mentioned P-alkynyl phosphate compounds, provides a kind of substrate 2, LiHMDS of P-acyl ethyl phosphonic acid ester and substrate 2 and acts on and form enol negative ion; Then ClP (O) (OEt)
2the intermediate 3 formed containing a good leaving group is reacted with enol negative ion; Finally under LiHMDS effect, eliminate a part diethyl phosphoric acid [HOP (O) (OEt)
2] form P-alkynyl phosphate compounds.Substrate can obtain conveniently by cheap raw material, does not need to use expensive various aryne reagent; Preparation method (1) substrate of above-mentioned P-alkynyl phosphate compounds can obtain conveniently by cheap raw material, does not need to use expensive various aryne reagent; (2) versatility is good, is easy to the preparation of the benzoglyoxaline ynamine derivative realized containing various different substituents combination; (3) easy and simple to handle, do not need to be separated intermediate; (4) target compound is easily separated and purify, and productive rate is higher.
Further, add LiHMDS reaction in first time to add ClP (O) (OEt) after 20 ~ 40 minutes
2; Adding ClP (O) (OEt)
2react second time after 20 ~ 40 minutes and add LiHMDS, the reaction times that second time adds LiHMDS is 1 ~ 3 hour.If the reaction times is too short, react insufficient; Overlong time, side reaction increases.
Further, P-acyl ethyl phosphonic acid ester is 1:0.8 ~ 1.2 with the mol ratio of the LiHMDS added for the first time.Equivalent is too low, reacts insufficient, causes starting material left; Equivalent is excessive, and the decomposition of substrate or side reaction can be caused to increase.
Further, P-acyl ethyl phosphonic acid ester and ClP (O) (OEt)
2mol ratio be 1.0 ~ 1.4.Equivalent is too low, reacts insufficient, causes starting material left; Equivalent is excessive, and the decomposition of substrate or side reaction can be caused to increase.
Further, P-acyl ethyl phosphonic acid ester is 1:1.0 ~ 3.0 with the mol ratio of the LiHMDS added for the second time.Equivalent is too low, reacts insufficient, causes starting material left; Equivalent is excessive, and the decomposition of substrate or side reaction can be caused to increase.
Further, R
2during for ethyl, R
1for phenyl, 4-p-methoxy-phenyl, 2,5-Dimethoxyphenyl, 4-aminomethyl phenyl, 2-aminomethyl phenyl, 3,4-3,5-dimethylphenyl, 4-iodophenyl, 4-bromophenyl, 4-chloro-phenyl-, 4-fluorophenyl, 2-naphthyl, 6-methoxyl group-2-naphthyl, xenyl, 2-furyl, 2-thienyl, styryl or the sub-p-methoxy-phenyl of 3,4-bis-; R
1during for phenyl, R
2for methyl, ethyl, sec.-propyl, normal-butyl.
Further, anhydrous solvent is tetrahydrofuran (THF) or ether.
Further, add after LiHMDS react in second time, also comprise and add saturated ammonium chloride solution quencher reaction, extraction, washing, dry, separation obtains P-alkynyl phosphate compounds.
Further, be separated into silica gel column chromatography and be separated, leacheate is sherwood oil and ethyl acetate volume ratio is the mixed solution of 5:1.
Further, shielding gas is nitrogen.
It is below specific embodiment.
Embodiment 1
R
1＝Ph；R
2＝CH
2CH
3
Under room temperature, alpha-brominated methyl phenyl ketone (498mg is added in reaction flask, 2.5mmol) then in reaction system, slowly add triethyl-phosphite (415mg with toluene (15ml), 2.5mmol), after adding, TLC follows the tracks of reaction, about 6h reacts complete, 100mL water is added in reaction solution, with dichloromethane extraction (30mL × 3), organic phase saturated common salt water washing, anhydrous sodium sulfate drying, pressure reducing and steaming solvent after filtering, resistates is separated [V (sherwood oil): V (CH by silica gel column chromatography
2cl
2)=1:1] obtain substrate 2a499mg, productive rate 78%.
2a colorless oil
1HNMR(400MHz,CDCl
3)δ＝8.00(d,J＝7.3Hz,2H),7.58(t,J＝7.4Hz,1H),7.47(t,J＝7.7Hz,2H),4.13(p,J＝7.2Hz,4H),3.63(d,J＝22.7Hz,2H),1.27(t,J＝7.1Hz,6H)(ppm).
MS(EI)m/z＝256.1(M
+,7).
Embodiment 2
1a chemical structural formula is as follows:
Under-78 DEG C of nitrogen protections, LiHMDS (concentration is the tetrahydrofuran solution 1.8mL of 1.0mol/L) is added drop-wise in tetrahydrofuran (THF) (15mL) solution of substrate 2a (460mg, 1.8mmol), stirs 30 minutes.By ClP (O) (OEt)
2(0.3mL, 2.2mmol) is added dropwise in above-mentioned reaction system liquid.After dropwising, remove refrigerating unit, naturally rise to 25 DEG C and continue stirring 30 minutes.Again reaction is cooled to-78 DEG C, then in above-mentioned reaction system, drips LiHMDS (concentration is the tetrahydrofuran solution 5.4mL of 1.0mol/L), and continue stirring 1 hour at this temperature.React with saturated ammonium chloride solution quencher, reaction mixture is injected water, be extracted with ethyl acetate (30mL × 3), organic phase saturated common salt water washing, anhydrous sodium sulfate drying, removes solvent under reduced pressure after filtration, resistates is separated by silica gel column chromatography, leacheate is [V (sherwood oil): V (ethyl acetate)=5:1], obtains 1a198mg, productive rate 83%.
1a colorless oil, gets and carries out magnetic resonance detection and mass spectrometric detection in right amount.
Nucleus magnetic resonance
1h composes as shown in Figure 1:
1hNMR (400MHz, CDCl
3) δ=7.55 (d, J=7.1Hz, 2H), 7.45 (t, J=7.5Hz, 1H), 7.36 (t, J=7.4Hz, 2H), 4.26 – 4.18 (m, 4H), 1.40 (t, J=7.0Hz, 6H) (ppm).
Nucleus magnetic resonance
13c composes as shown in Figure 2:
13cNMR (100MHz, CDCl
3) δ=132.8,132.7,130.8,128.7,119.7,119.6,99.4,98.9,80.0,77.0,63.4,63.3,16.3,16.2 (ppm).
Nucleus magnetic resonance
31p composes as shown in Figure 3:
31pNMR (160MHz, CDCl
3) δ=-5.92 (ppm).
IR(neat):ν＝3058,2986,2934,2908,2187,1489,1444,1390,1265,1163,1024,974,857,760,690,650(cm
-1).
MS(EI):m/z＝238.1(M
+,16).
Embodiment 3
1b chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-4-methyl acetophenone for substrate 2b (R prepared by raw material
1=4-CH
3c
6h
4; R
2=CH
2cH
3), productive rate 72%.
2b colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.84(d,J＝8.3Hz,2H),7.20(d,J＝7.8Hz,2H),4.11–4.00(m,4H),3.53(d,J＝22.7Hz,2H),2.34(s,3H),1.21(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝270.1(M
+,6).
Prepare product 1b
Compare difference with embodiment 2 to be: substrate 2b is dissolved in ether, at-70 DEG C, first time adds LiHMDS, and the stirring reaction time is 20 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 10 DEG C and stirs 20 minutes.Be cooled to-60 DEG C, second time adds the stirring 1.5 hours of LiHMDS.Wherein, 2b: LiHMDS:ClP (O) (OEt) that first time adds
2the mol ratio of the LiHMDS that second time adds is=1:0.8:1:1.All the other are with embodiment 2.Substrate is 2b (R
1=4-CH
3c
6h
4; R
2=CH
2cH
3), product is 1b, and productive rate is 84%.
1b colorless oil
Nucleus magnetic resonance
1h composes as shown in Figure 4:
1hNMR (400MHz, CDCl
3) δ=7.44 (d, J=8.1Hz, 2H), 7.16 (d, J=8.0Hz, 2H), 4.25 – 4.16 (m, 4H), 2.37 (s, 3H), 1.39 (t, J=7.1Hz, 6H) (ppm).
Nucleus magnetic resonance
13c composes as shown in Figure 5:
13cNMR (100MHz, CDCl
3) δ=141.5,132.7,132.7,129.4,116.5,116.5,100.1,99.5,79.3,76.3,63.3,63.3,21.8,16.3,16.2 (ppm).
Nucleus magnetic resonance
31p composes as shown in Figure 6:
31pNMR (160MHz, CDCl
3) δ=-4.59 (ppm).
IR(neat):ν＝2985,2934,2905,2184,1508,1266,1158,1023,973,863,815,788,739,608(cm
-1).
MS(EI):m/z＝252.1(M
+,46).
Embodiment 4
1c chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-2-methyl acetophenone for substrate 2c (R prepared by raw material
1=2-CH
3c
6h
4; R
2=CH
2cH
3), productive rate 70%.
2c colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.70(d,J＝7.7Hz,1H),7.33(t,J＝7.5Hz,1H),7.21(dd,J＝16.9,7.7Hz,2H),4.06(p,J＝7.2Hz,4H),3.54(d,J＝22.5Hz,2H),2.46(s,3H),1.21(t,J＝7.1Hz,6H)(ppm).
MS(EI)m/z＝270.1(M
+,40).
Prepare product 1c
Compare difference with embodiment 2 to be: substrate 2c is dissolved in ether, at-60 DEG C, first time adds LiHMDS, and the stirring reaction time is 10 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 15 DEG C and stirs 25 minutes.Be cooled to-78 DEG C, second time adds the stirring 1.5 hours of LiHMDS, and leacheate is [V (sherwood oil): V (ethyl acetate)=5:1].Wherein, 2c: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:1:1:1.All the other are with embodiment 2.Substrate is 2c (R
1=2-CH
3c
6h
4; R
2=CH
2cH
3), product is 1c, productive rate 88%.
1c pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.50(d,J＝7.6Hz,1H),7.32(t,J＝7.5Hz,1H),7.22(d,J＝7.6Hz,1H),7.17(t,J＝7.6Hz,1H),4.26–4.17(m,4H),2.46(s,3H),1.39(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝141.92,141.90,133.19,133.16,130.8,129.9,125.9,119.5,119.4,104.2,98.7,98.2,83.5,80.5,63.4,63.3,20.6,16.3,16.2(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.87(ppm).
IR(neat):ν＝2985,2938,2911,2182,1480,1453,1388,1265,1161,1024,974,868,785,762,647(cm
-1).
MS(EI):m/z＝252.1(M
+,45).
Embodiment 5
1d chemical structural formula is as follows:
Step is with embodiment 1.Be that substrate 2d (R prepared by raw material with triethyl-phosphite and α-bromo-3,4-dimethyl acetophenones
1=3,4-(CH
3)
2c
6h
3; R
2=CH
2cH
3), productive rate 75%.
2d colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.76(s,1H),7.72(d,J＝7.9Hz,1H),7.21(d,J＝7.9Hz,1H),4.16–4.07(m,4H),3.59(d,J＝22.7Hz,2H),2.30(s,6H),1.27(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝284.1(M
+,11).
Prepare product 1d
Compare difference with embodiment 2 to be: substrate 2d is dissolved in ether, at-50 DEG C, first time adds LiHMDS, and the stirring reaction time is 25 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 20 DEG C and stirs 30 minutes.Be cooled to-50 DEG C, second time adds the stirring 1.5 hours of LiHMDS, and leacheate is [V (sherwood oil): V (ethyl acetate)=4:1].Wherein, 2d: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:0.9:1.1:1.5.All the other are with embodiment 2.Substrate is 2d (R
1=3,4-(CH
3)
2c
6h
3; R
2=CH
2cH
3), product is 1d, productive rate 94%.
1d colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.32(s,1H),7.29(d,J＝7.8Hz,1H),7.11(d,J＝7.8Hz,1H),4.24–4.16(m,4H),2.26(s,3H),2.23(s,3H),1.38(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝140.3,137.2,133.63,133.60,130.3,130.25,129.9,116.7,116.7,100.4,99.8,78.9,75.9,63.3,63.25,20.1,19.6,16.24,16.17(ppm).
31PNMR(160MHz,CDCl
3)δ＝-4.48(ppm).
IR(neat):ν＝2985,2938,2905,2177,1450,1451,1393,1268,1164,1024,972,803,624(cm
-1).
MS(EI):m/z＝266.1(M
+,21).
Embodiment 6
1e chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-4-methoxyacetophenone for substrate 2e (R prepared by raw material
1=4-CH
3oC
6h
4; R
2=CH
2cH
3), productive rate 70%.
2e colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.96(d,J＝8.9Hz,2H),6.91(d,J＝8.9Hz,2H),4.10(p,J＝7.3Hz,4H),3.84(s,3H),3.54(d,J＝22.7Hz,2H),1.25(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝286(M
+,12).
Prepare product 1e
Compare difference with embodiment 2 to be: substrate 2d is dissolved in ether, at-50 DEG C, first time adds LiHMDS, and the stirring reaction time is 25 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 20 DEG C and stirs 30 minutes.Be cooled to-50 DEG C, second time adds the stirring 1.5 hours of LiHMDS, and leacheate is [V (sherwood oil): V (ethyl acetate)=4:1].Wherein, 2d: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:1.1:1.2:1.8.All the other are with embodiment 2.
Substrate is 2e (R
1=4-CH
3oC
6h
4; R
2=CH
2cH
3), product is 1e, productive rate 82%.
1e colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.47(d,J＝8.7Hz,2H),6.85(d,J＝8.9Hz,2H),4.23–4.13(m,4H),3.80(s,3H),1.37(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝161.5,134.50,134.48,114.3,111.4,111.3,100.2,99.6,78.7,75.7,63.23,63.17,55.5,16.23,16.16(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.43(ppm).
IR(neat):ν＝2982,2938,2905,2182,1603,1509,1295,1257,1172,1024,973,866,837,787(cm
-1).
MS(EI):m/z＝268(M
+,19).
Embodiment 7
1f chemical structural formula is as follows:
Step is with embodiment 1.Be that substrate 2f (R prepared by raw material with triethyl-phosphite and α-bromo-2,5-dimethoxy-acetophenones
1=2,5-(CH
3o)
2c
6h
3; R
2=CH
2cH
3), productive rate 70%.
2f pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.22(d,J＝3.2Hz,1H),7.00(dd,J＝9.0,3.2Hz,1H),6.86(d,J＝9.0Hz,1H),4.10–4.01(m,4H),3.84(s,3H),3.79(d,J＝21.8Hz,2H),3.73(s,3H),1.21(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝316(M
+,40).
Prepare product 1f
Compare difference with embodiment 2 to be: at-40 DEG C, first time adds LiHMDS, and the stirring reaction time is 30 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 22 DEG C and stirs 35 minutes.Be cooled to-50 DEG C, second time adds the stirring 2 hours of LiHMDS, and leacheate is [V (sherwood oil): V (ethyl acetate)=4.5:1].Wherein, 2f: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:1.2:1.2:2.0.All the other are with embodiment 2.Substrate is 2f (R
1=2,5-(CH
3o)
2c
6h
3; R
2=CH
2cH
3), product is 1f, productive rate 81%.
1f colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.00(d,J＝3.1Hz,1H),6.95(dd,J＝9.1,3.1Hz,1H),6.81(d,J＝9.1Hz,1H),4.27–4.18(m,4H),3.81(s,3H),3.75(s,3H),1.39(t,J＝7.1Hz,6H).
13CNMR(100MHz,CDCl
3)δ＝156.23,156.21,153.1,118.9,118.48,118.5,112.3,109.3,109.2,96.6,96.1,83.5,80.6,63.4,63.3,56.4,56.0,16.24,16.17(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.78(ppm).
IR(neat):ν＝2985,2938,2905,2837,2181,1501,1463,1267,1234,1166,1024,962,804,724,662,611(cm
-1).
MS(EI):m/z＝298(M
+,77).
Embodiment 8
1g chemical structural formula is as follows:
Step is with embodiment 1.Be that substrate 2g (R prepared by raw material with triethyl-phosphite and α-bromo-3,4-dioxymethylene methyl phenyl ketones
1=3,4-(OCH
2o) C
6h
3; R
2=CH
2cH
3), productive rate 76%.
2g colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.61(dd,J＝8.2,1.4Hz,1H),7.45(d,J＝1.4Hz,1H),6.84(d,J＝8.2Hz,1H),6.03(s,2H),4.12(p,J＝7.2Hz,4H),3.53(d,J＝22.7Hz,2H),1.27(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝300.1(M
+,16).
Prepare product 1g
Compare difference with embodiment 2 to be: at-30 DEG C, first time adds LiHMDS, and the stirring reaction time is 33 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 24 DEG C and stirs 36 minutes.Be cooled to-40 DEG C, second time adds the stirring 2.2 hours of LiHMDS, and leacheate is [V (sherwood oil): V (ethyl acetate)=4.5:1].Wherein, 2g: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:1.2:1.3:2.2.All the other are with embodiment 2.Substrate is 2g (R
1=3,4-(OCH
2o) C
6h
3; R
2=CH
2cH
3), product is 1g, productive rate 84%.
1g colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.10(d,J＝8.0Hz,1H),6.95(s,1H),6.77(d,J＝8.1Hz,1H),5.99(s,2H),4.23–4.15(m,4H),1.37(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝150.1,147.7,128.43,128.41,112.61,112.55,112.18,112.16,108.8,101.9,99.8,99.3,78.4,75.4,63.32,63.27,16.24,16.17(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.70(ppm).
IR(neat):ν＝2986,2907,2179,1604,1505,1489,1443,1339,1253,1207,1131,1101,1029,974,822,754,664,593(cm
-1).
MS(EI):m/z＝282.1(M
+,39).
Embodiment 9
1h chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-4-fluoro acetophenone for substrate 2h (R prepared by raw material
1=4-FC
6h
4; R
2=CH
2cH
3), productive rate 75%.
2h pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝8.11–7.99(m,2H),7.13(t,J＝8.4Hz,2H),4.12(p,J＝7.2Hz,4H),3.58(d,J＝22.8Hz,2H),1.27(t,J＝7.0Hz,6H)(ppm).
MS(EI):m/z＝274.2(M
+,7).
Prepare product 1h
Compare difference with embodiment 2 to be: substrate 2h is dissolved in ether, at-20 DEG C, first time adds LiHMDS, and the stirring reaction time is 35 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 25 DEG C and stirs 38 minutes.Be cooled to-10 DEG C, second time adds the stirring 2.4 hours of LiHMDS, and leacheate is [V (sherwood oil): V (ethyl acetate)=4.7:1].Wherein, 2h: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:1.2:1.4:2.4.All the other are with embodiment 2.Substrate is 2h (R
1=4-FC
6h
4; R
2=CH
2cH
3), product is 1h, productive rate 85%.
1h pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.54(dd,J＝8.6,5.4Hz,2H),7.05(t,J＝8.6Hz,2H),4.25–4.15(m,4H),1.38(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝165.2,162.7,135.04,135.01,134.95,134.93,116.3,116.1,115.84,115.80,115.78,115.74,98.3,97.7,79.9,77.0,63.4,63.3,16.24,16.18(ppm).
31PNMR(160MHz,CDCl
3)δ＝-6.18(ppm).
IR(neat):ν＝2985,2935,2905,2189,1599,1508,1267,1236,1160,1024,975,867,843,800,742(cm
-1).
MS(EI):m/z＝256.1(M
+,10).
Embodiment 10
1i chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-4-chloro-acetophenone for substrate 2i (R prepared by raw material
1=4-ClC
6h
4; R
2=CH
2cH
3), productive rate 75%.
2i colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.91(d,J＝8.7Hz,2H),7.39(d,J＝8.7Hz,2H),4.13–4.02(m,4H),3.55(d,J＝22.8Hz,2H),1.23(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝290.1(M
+,8).
Prepare product 1i
Compare difference with embodiment 2 to be: substrate 2i is dissolved in ether, at-25 DEG C, first time adds LiHMDS, and the stirring reaction time is 37 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 25 DEG C and stirs 40 minutes.Be cooled to-20 DEG C, second time adds the stirring 2.6 hours of LiHMDS.Wherein, 2i: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:1.2:1.4:2.6.All the other are with embodiment 2.Substrate is 2i (R
1=4-ClC
6h
4; R
2=CH
2cH
3), product is 1i, productive rate 88%.
1i colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.47(d,J＝8.3Hz,2H),7.33(d,J＝8.3Hz,2H),4.25–4.15(m,4H),1.38(t,J＝7.0Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝137.2,133.92,133.89,130.9,129.1,118.1,118.0,98.0,97.4,81.0,78.0,63.44,63.38,16.24,16.17(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.31(ppm).
IR(neat):ν＝2986,2935,2908,2189,1587,1488,1393,1267,1092,1022,975,858,832,762,701(cm
-1).
MS(EI):m/z＝272.1(M
+,17).
Embodiment 11
1j chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-4-bromoacetophenone for substrate 2j (R prepared by raw material
1=4-BrC
6h
4; R
2=CH
2cH
3), productive rate 73%.
2j pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.85(d,J＝8.5Hz,2H),7.59(d,J＝8.5Hz,2H),4.15–4.05(m,4H),3.57(d,J＝22.8Hz,2H),1.26(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝334.1(M
+,12).
Prepare product 1j
Compare difference with embodiment 2 to be: substrate 2j is dissolved in ether, at-10 DEG C, first time adds LiHMDS, and the stirring reaction time is 40 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 30 DEG C and stirs 40 minutes.Be cooled to-78 DEG C, second time adds the stirring 3 hours of LiHMDS.Wherein, 2j: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:1.2:1.4:2.8.All the other are with embodiment 2.All the other are with embodiment 2.Substrate is 2j (R
1=4-BrC
6h
4; R
2=CH
2cH
3), product is 1j, productive rate 81%.
1j pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.50(d,J＝8.5Hz,2H),7.40(d,J＝8.4Hz,2H),4.25–4.16(m,4H),1.39(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝134.05,134.02,132.1,125.6,118.61,118.56,98.0,97.5,81.2,78.2,63.47,63.42,16.27,16.20(ppm).
31PNMR(160MHz,CDCl
3)δ＝-6.39(ppm).
IR(neat):ν＝2985,2938,2905,2187,1483,1391,1265,1164,1025,976,857,823,761,680(cm
-1).
MS(EI):m/z＝316.1(M
+,16).
Embodiment 12
1k chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-4-Iodoacetophenone for substrate 2k (R prepared by raw material
1=4-IC
6h
4; R
2=CH
2cH
3), productive rate 70%.
2k pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.82(d,J＝8.5Hz,2H),7.69(d,J＝8.5Hz,2H),4.15–4.06(m,4H),3.56(d,J＝22.8Hz,2H),1.26(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝382.1(M
+,17).
Prepare product 1k
Compare difference with embodiment 2 to be: substrate 2k is dissolved in ether, at-10 DEG C, first time adds LiHMDS, and the stirring reaction time is 38 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 28 DEG C and stirs 40 minutes.Be cooled to-70 DEG C, second time adds the stirring 2 hours of LiHMDS.Wherein, 2k: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:1.2:1.4:3.All the other are with embodiment 2.Substrate is 2k (R
1=4-IC
6h
4; R
2=CH
2cH
3), product is 1k, productive rate 78%.
1k pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.70(dd,J＝10.1,8.4Hz,2H),7.24(dd,J＝11.3,5.9Hz,2H),4.23–4.13(m,4H),1.37(m,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝138.1,138.0,133.92,133.90,130.8,119.1,119.0,98.2,97.7,81.4,78.4,63.48,63.42,16.28,16.21(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.30(ppm).
IR(neat):ν＝2984,2938,2902,2187,1479,1392,1263,1024,975,856,820,760,668(cm
-1).
MS(EI):m/z＝364.0(M
+,27).
Embodiment 13
1l chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-4-phenyl acetophenone for substrate 2l (R prepared by raw material
1=4-Biphenyl, i.e. 4-xenyl; R
2=CH
2cH
3), productive rate 69%.
2l colorless oil
1HNMR(400MHz,CDCl
3)δ＝8.07(d,J＝8.4Hz,2H),7.68(d,J＝8.4Hz,2H),7.61(d,J＝7.3Hz,2H),7.45(t,J＝7.4Hz,2H),7.38(t,J＝7.3Hz,1H),4.20–4.06(m,4H),3.64(d,J＝22.7Hz,2H),1.28(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝332.2(M
+,20).
Prepare product 1l
Compare difference with embodiment 2 to be: at-10 DEG C, first time adds LiHMDS, and the stirring reaction time is 40 minutes.Dropwise ClP (O) (OEt)
2system temperature rises to 30 DEG C and stirs 40 minutes.Be cooled to-78 DEG C, second time adds the stirring 1 hour of LiHMDS.Wherein, 2l: LiHMDS:ClP (O) (OEt) that first time adds
2: the mol ratio of the LiHMDS that second time adds is=1:1.0:1.4:3.All the other are with embodiment 2.Substrate is 2l (R
1=4-Biphenyl; R
2=CH
2cH
3), product is 1l, productive rate 88%.
1l colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.64–7.55(m,6H),7.44(t,J＝7.5Hz,2H),7.37(t,J＝7.3Hz,1H),4.28–4.19(m,4H),1.41(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝143.5,139.7,133.2,133.1,129.0,128.3,127.3,127.2,118.3,118.2,99.4,99.0,80.5,77.4,63.36,63.31,16.25,16.18(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.93(ppm).
IR(neat):ν＝3036,2982,2938,2908,2184,1485,1265,1023,974,861,765,695,635(cm
-1).
MS(EI):m/z＝314.2(M
+,38).
Embodiment 14
1m chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-2-acetonaphthone for substrate 2m (R prepared by raw material
1=2-Naphthyl, i.e. 2-naphthyl; R
2=CH
2cH
3), productive rate 72%.
2m pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝8.54(s,1H),8.04(d,J＝8.6Hz,1H),7.96(d,J＝8.1Hz,1H),7.86(t,J＝8.4Hz,2H),7.57(dt,J＝15.0,6.9Hz,2H),4.19–4.06(m,4H),3.74(d,J＝22.7Hz,2H),1.26(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝306.1(M
+,26).
Prepare product 1m
Step is with embodiment 2.Substrate is 2m (R
1=Naphthalene-2-yl; R
2=CH
2cH
3), product is 1m, productive rate 87%.
1m colorless oil
1HNMR(400MHz,CDCl
3)δ＝8.10(s,1H),7.84–7.78(m,3H),7.56–7.49(m,3H),4.29–4.21(m,4H),1.41(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝133.89,133.86,133.85,132.54,128.5,128.1,128.0,127.94,127.92,127.89,127.1,116.73,116.67,99.8,99.3,80.0,77.1,63.38,63.32,16.25,16.18(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.94(ppm).
IR(neat):ν＝3057,2985,2932,2908,2185,1266,1159,1024,964,905,861,792,750,632,592(cm
-1).
MS(EI):m/z＝288.1(M
+,34).
Embodiment 15
1n chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-6-methoxyl group-2-acetonaphthone for substrate 2n (R prepared by raw material
1=6-MeO-2-naphthyl, i.e. 6-methoxyl group-2-naphthyl; R
2=CH
2cH
3), productive rate 74%.
2n colorless oil
1HNMR(400MHz,CDCl
3)δ＝8.39(d,J＝1.1Hz,1H),7.95(dd,J＝8.7,1.8Hz,1H),7.79(d,J＝9.0Hz,1H),7.68(d,J＝8.7Hz,1H),7.12(dd,J＝8.9,2.5Hz,1H),7.07(d,J＝2.4Hz,1H),4.14–4.00(m,4H),3.86(s,3H),3.65(d,J＝22.7Hz,2H),1.20(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝336.1(M
+,27).
Prepare product 1n
Step is with embodiment 2.Substrate is 2n (R
1=6-MeO-naphthalene-2-yl; R
2=CH
2cH
3), product is 1n, productive rate 89%.
1n colorless oil
1HNMR(400MHz,CDCl
3)δ＝8.02(s,1H),7.68(dd,J＝8.5,5.1Hz,2H),7.49(d,J＝8.5Hz,1H),7.16(d,J＝9.0Hz,1H),7.09(s,1H),4.29–4.19(m,4H),3.90(s,3H),1.41(t,J＝7.0Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝159.4,135.5,133.7,133.6,129.7,128.7,128.6,128.0,127.2,120.1,114.2,114.1,105.9,100.5,99.9,79.4,76.4,63.34,63.29,55.5,16.26,16.19(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.65(ppm).
IR(neat):ν＝2985,2935,2905,2179,1625,1480,1391,1263,1262,1162,1024,970,941,784,703,638(cm
-1).
MS(EI):m/z＝318.1(M
+,61).
Embodiment 16
1o chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-2-furans ethyl ketone for substrate 2o (R prepared by raw material
1=2-furyl, i.e. 2-furyl; R
2=CH
2cH
3), productive rate 69%.
2o pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.57(d,J＝1.5Hz,1H),7.24(d,J＝3.6Hz,1H),6.51(dd,J＝3.6,1.7Hz,1H),4.13–4.03(m,4H),3.43(d,J＝22.6Hz,2H),1.22(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝246.1(M
+,25).
Prepare product 1o
Step is with embodiment 2.Substrate is 2o (R
1=furan-2-yl; R
2=CH
2cH
3), product is 1o, productive rate 86%.
1o pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.45(d,J＝0.8Hz,1H),6.85(d,J＝3.5Hz,1H),6.42(dd,J＝3.4,1.7Hz,1H),4.23–4.14(m,4H),1.36(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝145.9,134.6,134.5,120.24,120.2,111.4,88.9,88.3,85.1,82.2,63.59,63.54,16.2,16.1(ppm).
31PNMR(160MHz,CDCl
3)δ＝-6.79(ppm).
IR(neat):ν＝3122,2987,2938,2908,2183,1471,1391,1267,1215,1162,1024,977,944,811,757(cm
-1).
MS(EI):m/z＝228.1(M
+,19).
Embodiment 17
1p chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-2-thiophene ethyl ketone for substrate 2p (R prepared by raw material
1=2-thienyl, i.e. 2-thiophene phenyl; R
2=CH
2cH
3), productive rate 70%.
2p pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.78(dd,J＝3.8,0.8Hz,1H),7.65(dd,J＝4.9,0.8Hz,1H),7.10(dd,J＝4.8,4.0Hz,1H),4.10(qd,J＝7.5,0.9Hz,4H),3.50(d,J＝22.5Hz,2H),1.24(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝252.1(M
+,12).
Prepare product 1p
Step is with embodiment 2.Substrate is 2p (R
1=2-thienyl, i.e. 2-thiophene phenyl; ; R
2=CH
2cH
3), product is 1p, productive rate 87%.
1p pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.42(d,J＝5.2Hz,2H),7.01(t,J＝4.3Hz,1H),4.19(m,4H),1.37(t,J＝7.0Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝136.07,136.04,130.7,127.5,119.33,119.27,92.8,92.3,84.0,81.0,63.44,63.38,16.23,16.16(ppm).
31PNMR(160MHz,CDCl
3)δ＝-6.27(ppm).
IR(neat):ν＝3077,2986,2938,2908,2174,1263,1174,1023,976,852,801,715,638(cm
-1).
MS(EI):m/z＝244.1(M
+,13).
Embodiment 18
1q chemical structural formula is as follows:
Step is with embodiment 1.With triethyl-phosphite and α-bromo-styryl ethyl ketone for substrate 2q (R prepared by raw material
1=(E)-styrenic, i.e. styryl; R
2=CH
2cH
3), productive rate 68%.
2q colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.62(d,J＝16.1Hz,1H),7.55(dd,J＝6.5,3.0Hz,2H),7.38(dd,J＝5.1,1.8Hz,3H),6.87(d,J＝16.1Hz,1H),4.20–4.09(m,4H),3.30(d,J＝22.7Hz,2H),1.31(t,J＝7.1Hz,6H)(ppm).
MS(EI):m/z＝282.1(M
+,13).
Prepare product 1q
Step is with embodiment 2.Substrate is 2q (R
1=(E)-styrenic; R
2=CH
2cH
3), product is 1q, productive rate 75%.
1q colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.43–7.38(m,2H),7.38–7.33(m,3H),7.22(d,J＝16.4Hz,1H),6.18(dd,J＝16.4,3.7Hz,1H),4.24–4.15(m,4H),1.39(t,J＝7.1Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝147.47,147.43,135.0,130.18,129.04,126.97,104.68,104.61,99.12,98.59,81.56,78.56,63.31,63.25,16.29,16.22(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.96(ppm).
IR(neat):ν＝3033,2986,2935,2908,2208,2152,1607,1447,1391,1262,1163,1101,1024,972,799,756,689,591(cm
-1).
MS(EI):m/z＝264(M
+,18).
Embodiment 19
1r chemical structural formula is as follows:
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone and trimethyl phosphite for substrate 2r (R prepared by raw material
1=Ph; R
2=CH
3), productive rate 75%.
2r pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝8.00–7.92(m,2H),7.59–7.52(m,1H),7.48–7.40(m,2H),3.77–3.70(m,7H),3.61(dd,J＝22.6,3.4Hz,2H)(ppm).
MS(EI):m/z＝228.1(M
+,17).
Prepare product 1r
Step is with embodiment 2.Substrate is 2r (R
1=Ph; R
2=CH
3), product is 1r, productive rate 81%.
1r pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.54(d,J＝7.5Hz,2H),7.44(t,J＝7.4Hz,1H),7.35(t,J＝7.6Hz,2H),3.83(d,J＝12.3Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝132.76,132.73,130.94,128.66,119.3,119.28,100.28,99.75,78.41,75.41,53.53,53.47(ppm).
31PNMR(160MHz,CDCl
3)δ＝-2.77(ppm).
IR(neat):ν＝3063,3000,2956,2852,2187,1492,1450,1271,1179,1033,861,840,765,689,647(cm
-1).
MS(EI):m/z＝210(M
+,22).
Embodiment 20
1s chemical structural formula is as follows:
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone for preparing substrate 2s (R with triisopropyl phosphite raw material
1=Ph; R
2=i-Pr, i.e. sec.-propyl), productive rate 72%.
2s pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝8.00(d,J＝8.2Hz,2H),7.57(dd,J＝10.8,3.9Hz,1H),7.45(t,J＝7.7Hz,2H),4.71(dq,J＝12.6,6.5Hz,2H),3.58(d,J＝22.9Hz,2H),1.26(dd,J＝6.2,3.0Hz,13H)(ppm).
MS(EI):m/z＝284.2(M
+,3).
Prepare product 1s
Step is with embodiment 2.Substrate is 2s (R
1=Ph; R
2=i-Pr), product is 1s, productive rate 93%.
1s pale yellow oil
1HNMR(400MHz,CDCl
3)δ＝7.51(d,J＝7.5Hz,2H),7.40(t,J＝7.4Hz,1H),7.33(t,J＝7.5Hz,2H),4.84–4.71(m,2H),1.37(d,J＝6.1Hz,12H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝132.53,132.5,130.57,128.59,119.87,119.81,81.37,78.40,72.40,72.35,23.96,23.92,23.69,23.64(ppm).
31PNMR(160MHz,CDCl
3)δ＝-8.60(ppm).
IR(neat):ν＝3063,3000,2956,2852,2187,1492,1450,1271,1179,1033,861,840,765,689,647(cm
-1).
MS(EI):m/z＝266(M
+,3).
Embodiment 21
1t chemical structural formula is as follows:
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone and tributyl phosphate for substrate 2t (R prepared by raw material
1=Ph; R
2=n-Bu), productive rate 71%.
2t colorless oil
1HNMR(400MHz,CDCl
3)δ＝8.03–7.90(m,2H),7.60–7.48(m,1H),7.43(t,J＝7.2Hz,2H),4.01(q,J＝6.7Hz,4H),3.59(dd,J＝22.8,1.7Hz,2H),1.59–1.50(m,4H),1.33–1.22(m,4H),0.84(td,J＝7.3,1.7Hz,6H)(ppm).
MS(EI):m/z＝313(M
+,0.5).
Prepare product 1t
Step is with embodiment 2.Substrate is 2t (R
1=Ph; R
2=n-Bu), product is 1d, productive rate 80%.
1t colorless oil
1HNMR(400MHz,CDCl
3)δ＝7.53(d,J＝7.1Hz,2H),7.42(t,J＝7.5Hz,1H),7.34(t,J＝7.4Hz,2H),4.13(dd,J＝14.2,6.7Hz,4H),1.74–1.65(m,4H),1.48–1.38(m,4H),0.92(t,J＝7.4Hz,6H)(ppm).
13CNMR(100MHz,CDCl
3)δ＝132.66,132.63,130.72,128.6,119.67,119.61,99.36,98.84,79.86,76.89,66.99,66.93,32.28,32.20,18.75,13.61(ppm).
31PNMR(160MHz,CDCl
3)δ＝-5.60(ppm).
IR(neat):ν＝2961,2935,2869,2187,1465,1271,1066,1025,992,900,858,761,695,653(cm
-1).
MS(EI):m/z＝294(M
+,1.5).
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (10)
1. a preparation method for P-alkynyl phosphate compounds, is characterized in that, comprises the following steps:
Under the atmosphere of shielding gas, by lithium hexamethyldisilazide LiHMDS, diethyl chloro-phosphate ClP (O) (OEt)
2join successively in the anhydrous solvent of the P-acyl ethyl phosphonic acid ester shown in general formula 2 with lithium hexamethyldisilazide and react, obtain the P-alkynyl phosphate compounds shown in general formula 1;
Wherein, the temperature when adding LiHMDS reaction controls at-10 ~-78 DEG C; Add ClP (O) (OEt)
2after, react at system is warming up to 10 ~ 30 DEG C, R
1and R
2independently be selected from for carbonatoms be 1 ~ 10 alkyl and alkyl substituents, carbonatoms be 6 ~ 12 aryl and aryl substituent.
2. the preparation method of P-alkynyl phosphate compounds according to claim 1, is characterized in that, adds LiHMDS reaction add ClP (O) (OEt) after 20 ~ 40 minutes in first time
2; Adding ClP (O) (OEt)
2react second time after 20 ~ 40 minutes and add LiHMDS, the reaction times that second time adds LiHMDS is 1 ~ 3 hour.
3. the preparation method of P-alkynyl phosphate compounds according to claim 1, is characterized in that, described P-acyl ethyl phosphonic acid ester is 1:0.8 ~ 1.2 with the mol ratio of the LiHMDS that first time adds.
4. the preparation method of P-alkynyl phosphate compounds according to claim 1, is characterized in that, described P-acyl ethyl phosphonic acid ester and described ClP (O) (OEt)
2mol ratio be 1.0 ~ 1.4.
5. the preparation method of P-alkynyl phosphate compounds according to claim 1, is characterized in that, described P-acyl ethyl phosphonic acid ester is 1:1.0 ~ 3.0 with the mol ratio of the LiHMDS that second time adds.
6. the preparation method of P-alkynyl phosphate compounds according to claim 1, is characterized in that, R
2during for ethyl, R
1for phenyl, 4-p-methoxy-phenyl, 2,5-Dimethoxyphenyl, 4-aminomethyl phenyl, 2-aminomethyl phenyl, 3,4-3,5-dimethylphenyl, 4-iodophenyl, 4-bromophenyl, 4-chloro-phenyl-, 4-fluorophenyl, 2-naphthyl, 6-methoxyl group-2-naphthyl, xenyl, 2-furyl, 2-thienyl, styryl or the sub-p-methoxy-phenyl of 3,4-bis-; R
1during for phenyl, R
2for methyl, ethyl, sec.-propyl, normal-butyl.
7. the preparation method of P-alkynyl phosphate compounds according to claim 1, is characterized in that, described anhydrous solvent is tetrahydrofuran (THF) or ether.
8. the preparation method of P-alkynyl phosphate compounds according to claim 1, is characterized in that, adds after LiHMDS reacted in second time, also comprise and add saturated ammonium chloride solution quencher reaction, extraction, washing, drying, is separated and obtains P-alkynyl phosphate compounds.
9. the preparation method of P-alkynyl phosphate compounds according to claim 8, is characterized in that, described in be separated into silica gel column chromatography be separated, leacheate is sherwood oil and ethyl acetate volume ratio is the mixed solution of 5:1.
10. the preparation method of the P-alkynyl phosphate compounds according to any one of claim 1 ~ 9, described shielding gas is nitrogen.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180725A (en) * | 2018-09-21 | 2019-01-11 | 大连理工大学 | A kind of preparation method of novel alkynyl phosphate |
| CN109320503A (en) * | 2018-12-10 | 2019-02-12 | 怀化学院 | Benzimidazole alkynes aminated compounds without metal one-pot synthesis method |
| CN109438510A (en) * | 2018-12-07 | 2019-03-08 | 怀化学院 | The synthetic method of P- alkynyl phosphate compounds |
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| CN1058021A (en) * | 1990-07-04 | 1992-01-22 | 默里尔多药物公司 | The 9-purinyl phosphonic acid derivatives |
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| JP2010248183A (en) * | 2009-03-26 | 2010-11-04 | Takeda Chem Ind Ltd | Heterocyclic compound |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180725A (en) * | 2018-09-21 | 2019-01-11 | 大连理工大学 | A kind of preparation method of novel alkynyl phosphate |
| CN109180725B (en) * | 2018-09-21 | 2020-08-14 | 大连理工大学 | Preparation method of alkynyl phosphate |
| CN109438510A (en) * | 2018-12-07 | 2019-03-08 | 怀化学院 | The synthetic method of P- alkynyl phosphate compounds |
| CN109438510B (en) * | 2018-12-07 | 2020-12-01 | 怀化学院 | Synthesis method of P-alkynyl phosphate compound |
| CN109320503A (en) * | 2018-12-10 | 2019-02-12 | 怀化学院 | Benzimidazole alkynes aminated compounds without metal one-pot synthesis method |
| CN109320503B (en) * | 2018-12-10 | 2022-07-01 | 怀化学院 | Metal-free one-pot synthesis method of benzimidazole alkynylamine compounds |
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