CN101591355A - A kind of chiral phosphonate and synthetic method thereof - Google Patents
A kind of chiral phosphonate and synthetic method thereof Download PDFInfo
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- CN101591355A CN101591355A CNA2009101171904A CN200910117190A CN101591355A CN 101591355 A CN101591355 A CN 101591355A CN A2009101171904 A CNA2009101171904 A CN A2009101171904A CN 200910117190 A CN200910117190 A CN 200910117190A CN 101591355 A CN101591355 A CN 101591355A
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- oxazolinyl
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Abstract
A kind of chiral phosphonate is a phenylbenzene phosphonic acids-2-[(4S)-4,5-dihydro-4-R-2-oxazolinyl] phenol ester, following chemical formula is arranged, R is selected from-CH in the formula
2CH (CH
3)
2Or-CH (CH
3)
2Or-ph or-CH
2Ph.The synthetic method of this compound be at first by 2-cyanophenol and L-amino alcohol at anhydrous and oxygen-free and catalyzer ZnCl
2When existing in chlorobenzene solvent back flow reaction 24 hours preparation intermediate, then intermediate and diphenyl phosphonyl chloride under the anhydrous and oxygen-free condition in toluene and triethylamine mixed solvent 24 hours synthetic target products of back flow reaction.This compound shows good catalytic activity and high enantioselectivity as chiral ligand and organometallics formation title complex in the amygdalic acid asymmetric synthesis.
Description
One, technical field
The present invention relates to a kind of chipal compounds and preparation method thereof, specifically a kind of phosphonic acid ester and synthetic method thereof that contains the chiral oxazoline base.
Two, background technology
The title complex of chiral oxazoline and metal (shows the active and high enantioselectivity of good asymmetry catalysis, thereby is subjected to paying close attention to widely at Didls-Alder in the many reactions such as diene cycloaddition reaction, Michael (Mi Xieer) condensation reaction, Friedel-Crafts (Fu Ruide-carat Buddhist now) condensation reaction, Aldol (alcohol aldehyde) condensation reaction of Di Lesi-Ai Erte).
The applicant is engaged in the development of asymmetric compound for a long time, and patent of invention, ZL200610096004.X, CN101016311A, CN101099936A, 200810020198.4, CN101279954A, 200810022278.3,200910116614.5 have been applied for successively.
Three, summary of the invention
The present invention is intended to provide a kind of efficient chiral catalyst for the asymmetric synthesis field particularly prepares the chiral drug compound, technical problem to be solved be select and the synthesis of chiral part with the preparation composition catalyst.
The alleged chiral phosphine compound of the present invention is that chemical name is a phenylbenzene phosphonic acids-2-[(4S)-4,5-dihydro-4-R-2-oxazolinyl] phenol ester, following chemical structural formula is arranged:
R is selected from-CH in the formula
2CH (CH
3)
2(1 ', 1 '-dimethyl ethyl) or-CH (CH
3)
2(1 '-methylethyl) or-Ph (phenyl) or-CH
2Ph (benzyl).
This compound can form title complex with organometallics and show good catalytic activity and high enantioselectivity in the amygdalic acid asymmetric synthesis as chiral ligand.
The synthetic method of this chiral phosphine compound was two steps, the first step is with 2-4-hydroxy-benzonitrile (2-cyanophenol) and L-amino alcohol prepared in reaction intermediate 2-[(4S)-4,5-dihydro-4-R-2-oxazolinyl] phenol, above-mentioned intermediate of second step and diphenyl phosphonyl chloride are [(Ph)
2POCl] synthetic target product, flow process schematically as follows:
Described L-amino alcohol is selected from L-leucinol or L-valerian ammonia alcohol or L-benzene glycinol or L-phenylalaninol.Closed-loop shaped oxazoline base when above-mentioned each L-amino alcohol reacts with the 2-cyanophenol respectively, the R base that it carries is followed successively by-CH
2CH (CH
3)
2,-CH (CH
3)
2,-Ph and-CH
2Ph.
The synthetic method of this chiral phosphine compound is first synthetic target product behind the preparation intermediate, comprises reaction, separation and purifying, the reaction that it is characterized in that preparing intermediate by 2-cyanophenol and L-amino alcohol under the anhydrous and oxygen-free condition and the anhydrous ZnCl of catalyzer
2When existing in chlorobenzene solvent back flow reaction 24 hours, separate then, purifying, i.e. reaction is sloughed chlorobenzene after finishing, chloroform extraction is used in the back that is dissolved in water, and uses column chromatography purification behind the extraction phase precipitation; The reaction of synthetic target product be prepared intermediate with diphenyl phosphonyl chloride under the anhydrous and oxygen-free condition in toluene and triethylamine mixed solvent back flow reaction 24 hours, separate then, purifying, i.e. slough solvent after the reaction end, use column chromatography purification.
Four, description of drawings
Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 8, Figure 11, Figure 14 are respectively intermediate 1a, 1b, 1c, 1d and compound 2a, 2b, 2c, 2d
1HNMR figure.
Fig. 6, Fig. 9, Figure 12, Figure 15, be compound 2a, 2b, 2c, 2d respectively
13CNMR figure.
Fig. 7, Figure 10, Figure 13, Figure 16, be compound 2a, 2b, 2c, 2d respectively
31PNMR figure
Five, embodiment
(1) preparation of intermediate 1a～1d
1, intermediate 1a 2-[(4S)-4,5-dihydro-4-(1 ', 1 '-dimethyl ethyl)-the 2-oxazolinyl] preparation of phenol:
In the 100mL two-mouth bottle, under the anhydrous and oxygen-free condition, add anhydrous ZnCl
260mg (0.37mmol), the 40mL chlorobenzene, 2-cyanophenol 1.0g (5.6mmol), L-leucinol 3g, temperature rising reflux reaction 24h, stopped reaction, decompression is desolvated to remove, and residuum is dissolved in water, and uses CHCl
3(30mL * 2) extraction, the organic phase anhydrous sodium sulfate drying, rotation removes and desolvates, and thick product with sherwood oil/methylene dichloride (4: 1) column chromatography, is got colourless oil liquid 0.85g, productive rate 44%; [a]
5 D=-48.67 ° of (c=0.54, CHCl
3):
1HNMR (500MHz, CDCl
3, 27 ℃), and δ (ppm)=12.30 (s, 1H), 7.63～7.65 (d, J=8Hz, 1H), 7.36 (t, J=0.5Hz, 1H), 7.00～7.02 (d, J=8Hz, 1H), 6.86 (t, J=0Hz, 1H), 4.47 (t, J=0.5Hz, 1H), 4.37～4.3 (m, 1H), 3.93 (t, J=0.5Hz, 1H), 1.84～1.87 (m, 1H), 1.61～1.66 (m, 1H), 0.98～1.00 (m, J=11,6H).
2, intermediate 1b 2-[(4S)-4,5-dihydro-4-(1 '-methylethyl)-2-oxazolinyl] preparation of phenol:
Get 2-cyanophenol 1.0g (5.6mmol), L-valerian ammonia alcohol 3g, the preparation method is with example 1.Productive rate 56%.[a]
5 D＝-28.6°(c＝0.64，CHCl
3)：
1H?NMR(500MHz，CDCl
3，27℃)，δ(ppm)＝12.38(s，1H)，7.66～7.68(dd，J＝2.5，2.5Hz，1H)，7.38(t，1H)，7.06～7.03(d，J＝14Hz，1H)，6.89(t，1H)，4.39～4.42(m，1H)，4.12～4.13(m，2H)，1.78～1.82(m，1H)，0.96～1.06(dd，J＝11，11.5Hz，1H).
3, intermediate 1c 2-[(4S)-4,5-dihydro-4-(phenyl)-2-oxazolinyl] preparation of phenol:
Get 2-cyanophenol 1.0g, L-benzene glycinol 3g, reactions steps is with example 1, productive rate 55%; [a]
5 D=-23.4 ° of (c=0.35, CHCl
3):
1HNMR(500MHz，CDCl
3，27℃)，δ(ppm)＝12.36(s，1H)，7.87～7.88(d，J＝2.5Hz，1H)，7.34～7.49(m，6H)，7.17～7.20(d，J＝14Hz，1H)，7.00(t，1H)，5.44～5.50(m，1H)，4.78(t，J＝2Hz，1H)，4.26(t，1H).
4, intermediate 1d 2-[(4S)-4,5-dihydro-4-(benzyl)-2-oxazolinyl] preparation of phenol:
Get 2-cyanophenol 1.0g, L-phenylalaninol 3g, reactions steps is with example 1, productive rate 60%; [a]
5 D=-3.07 ° of (c=1.13, CHCl
3):
1HNMR(500MHz，CDCl
3，27℃)，δ(ppm)＝12.22(s，1H)，7.64(d，J＝8Hz，1H)，7.25～7.41(m，6H)，7.04～7.06(d，J＝8Hz，1H)，6.89(t，1H)，4.61～4.64(m，1H)，4.39(t，J＝0.5Hz，1H)，3.10～3.14(q，1H)，2.81～2.85(q，1H).
(2) compound 2a～2d's is synthetic
5, compound 2a phenylbenzene phosphonic acids-2-[(4S)-4,5-dihydro-4-(1 ', 1 '-dimethyl ethyl)-the 2-oxazolinyl] phenol ester synthetic:
In the 100mL two-mouth bottle, under the anhydrous and oxygen-free condition, add 40mL toluene, 2-[(4S)-4,5-dihydro-4-(1 ', 1 '-dimethyl ethyl)-the 2-oxazolinyl] phenol (intermediate 1a) 2g (9.17mmol), triethylamine 20mL, phenylbenzene phosphono 1.0mL (6.96mmol) is with the mixture heating up 24h that refluxes, stopped reaction, decompression is desolvated to remove, thick product with sherwood oil/methylene dichloride (1: 9) column chromatography, is got weak yellow liquid 1.16g, productive rate 40%; [a]
5 D=-17.68 ° of (c=0.27, CHCl
3):
1HNMR(500MHz，CDCl
3，27℃)，δ(ppm)＝8.04～8.07(m，3H)，7.74～7.76(d，J＝8Hz，1H)，7.74(d，J＝8Hz，1H)，7.66(d，J＝8.5Hz，1H)，7.40～7.42(m，5H)，7.26～7.29(m，1H)，7.08(t，J＝0.5Hz，1H)，4.38～4.46(m，2H)，3.90(t，1H)，1.86～1.89(m，1H)，1.73～1.76(m，1H)，1.39～1.42(m，1H)，0.96～1.02(dd，J＝6.5Hz，6.5Hz，6H)，
13CNMR(125MHz，CDCl
3，27℃)160.98，149.95(x2)，132.34(x2)，132.12(x2)，131.25(x2)，128.46(x2)，128.34(x2)，124.16(x2)，121.64(x2)，120.18(x2)，56.63，45.79，39.72，25.22，22.45，22.32.
13PNMR：25.413，IR(KBr)：2970，2917，2849，2251，1679，1612，1588，1462，1440，1390，11313，1273，1221，1124，1063，1031，789，733，691，649，621，592，570，528；HRMS(EI)：m/z(％)：calcd?for?C
25H
26NO
3P：419.1650；found：419.1659.
6, compound 2b phenylbenzene phosphonic acids-2-[(4S)-4,5-dihydro-4-(1 '-methylethyl)-2-oxazolinyl] phenol ester synthetic:
Intermediate 2-[(4S)-4,5-dihydro-4-(1 '-methylethyl)-2-oxazolinyl] synthetic method of phenol (intermediate 1b) and diphenyl phosphonyl chloride is with example 5.
Weak yellow liquid, productive rate 38%; [a]
5 D=-20.27 ° of (c=0.28, CHCl
3):
1HNMR(500MHz，CDCl
3，27℃)δ(ppm)＝7.60～7.68(m，5H)，7.24～7.36(m，7H)，6.99(J＝8.5，1H)，6.84((t，1H)，4.28～4.43(m，1H)，4.08～4.14(m，2H)，1.76～1.82(m，1H)，0.92～1.00(dd，J＝7Hz，6.5Hz，6H).
13CNMR(125MHz，CDCl
3，27℃)165.16，160.05(x2)，133.32(x2)，131.37(x2)，131.27(x2)，128.28(x2)，128.14(x2)，128.05(x2)，118.62(x2)，116.78(x2)，71.62，69.94，33.10，18.78，18.66，
13PNMR(300MHz，CDCl
3，27℃)δ(ppm)＝23.18.IR(KBr)：3057，2959，2926，2872，1676，1644，1618，1583，1555，1492，1464，1438，1364，1438，1364，1309，1260，1233，1201，1155，1094，1069，1035，999，959，911，859，830，800，755，728；HRMS(EI)：m/z(％)：calcd?forC
24H
24NO
3P：405.1494；found：405.1502.
7, compound 2c phenylbenzene phosphonic acids-2-[(4S)-4,5-dihydro-4-(phenyl)-2-oxazolinyl] phenol ester synthetic:
Intermediate 2-[(4S)-4,5-dihydro-4-(phenyl)-2-oxazolinyl] synthetic method of phenol (intermediate 1c) and diphenyl phosphonyl chloride is with example 5.
Weak yellow liquid, productive rate 42%; [a]
5 D=19.38 ° of (c=0.05, CHCl
3):
1HNMR(500MHz，CDCl
3，27℃)δ(ppm)＝8.00～8.07(m，3H)，7.88(d，J＝7.5Hz，1H)，7.72(d，J＝8.5Hz，2H)，7.10～7.46(m，12H)，4.28(m，1H)，5.46(t，J＝1.5Hz，1H)，4.74～4.77(m，1H)，4.25(t，J＝0.5Hz，1H).
13CNMR(125MHz，CDCl
3，27℃)166.41，160.20，141.68，133.71，131.36，131.25，128.94，128.29，128.16(x2)，127.96(x2)，126.57，118.78，116.96，74.12，68.95.
13PNMR(300MHz，CDCl
3，27℃)，δ(ppm)＝25.56.IR(KBr)：3064，3033，2956，2924，2854，2250，1684，1643，1612，1590，1537，1495，1479，1461，1440，1378，1304，1274，1249，1221，1138，1156，1126，1070，1030，909，793，754，734，698，648，626，557，527.；HRMS(EI)：m/z(％)：calcd?forC
27H
23NO
3P：440.1416；found：440.1385.
8, compound 2d phenylbenzene phosphonic acids-2-[(4S)-4,5-dihydro-4-(benzyl)-2-oxazolinyl] phenol ester synthetic:
Intermediate 2-[(4S)-4,5-dihydro-4-(benzyl)-2-oxazolinyl] synthetic method of phenol (intermediate 1d) and diphenyl phosphonyl chloride is with example 5.
Weak yellow liquid, productive rate 45%; [a]
5 D=14.04 ° of (c=0.14, CHCl
3):
1HNMR(500MHz，CDCl
3，27℃)δ(ppm)＝7.61～7.70(m，5H)，7.23～7.38(m，11H)，7.00(d，J＝8Hz，1H)，6.86(t，J＝0.5Hz，2H)，4.60～4.64(m，1H)，4.39(t，J＝0.5Hz，1H)，4.14(t，J＝0.5Hz，2H)，3.09～3.13(m，1H)，2.79～2.84(m，.1H)，
13CNMR(125MHz，CDCl
3，27℃)165.55，160.01(x2)，137.64(x2)，133.48(x2)，131.34(x2)，131.24(x2)，129.30(x2)，128.72(x2)，128.27(x2)，128.11()x2)，126.78(x2)，118.70(x2)，116.84(x2)，71.28，66.82，42.00.
13PNMR(300MHz，CDCl
3，27℃)，δ(ppm)＝23.205.IR(KBr)：3061，3028，2955，2924，2854，1642，1617，1492，1438，1367，1311，1259，1234，1156，1129，1067，960，756，727，698.HRMS(EI)：m/z(％)：calcd?forC
28H
24NO
3P：453.1494；found：454.1522
Claims (2)
1, a kind of chiral phosphonate is characterized in that name is called diphenylphosphine acid-2-[(4S)-4,5-dihydro-4-R-2-oxazolinyl] phenol ester, following chemical structural formula is arranged:
R is selected from-CH in the formula
2CH (CH
3)
2Or-CH (CH
3)
2Or-ph or-CH
2Ph.
2, a kind of synthetic method by the described chiral phosphonate of claim 1 is to synthesize target product behind the preparation intermediate earlier, comprise reaction, separation and purifying, it is characterized in that: preparation intermediate 2-[(4S)-4,5-dihydro-4-R-2-oxazolinyl] reaction of phenol be by 2-cyanophenol and L-amino alcohol under the anhydrous and oxygen-free condition and the anhydrous ZnCl of catalyzer
2Refluxed 24 hours in chlorobenzene solvent when existing, described L-amino alcohol is selected from L-leucinol or L-valerian ammonia alcohol or L-benzene glycinol or L-phenylalaninol; The reaction of synthetic target product be above-mentioned intermediate and diphenyl phosphonyl chloride under the anhydrous and oxygen-free condition in toluene and triethylamine mixed solvent back flow reaction 24 hours.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101962391A (en) * | 2010-03-17 | 2011-02-02 | 合肥工业大学 | Chiral phosphorus compound |
| CN102127111A (en) * | 2010-11-30 | 2011-07-20 | 罗梅 | Chiral phosphonate compound |
| CN102351898A (en) * | 2011-08-29 | 2012-02-15 | 罗梅 | Synthesis method of diphenyl phosphonic acid |
| CN103965243A (en) * | 2014-06-02 | 2014-08-06 | 罗梅 | Chiral phosphonate crystal compound and use |
| CN105524092A (en) * | 2016-02-22 | 2016-04-27 | 合肥祥晨化工有限公司 | Synthesis method of chiral zinc complex crystal |
-
2009
- 2009-07-01 CN CNA2009101171904A patent/CN101591355A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101962391A (en) * | 2010-03-17 | 2011-02-02 | 合肥工业大学 | Chiral phosphorus compound |
| CN101962391B (en) * | 2010-03-17 | 2012-09-26 | 合肥工业大学 | Chiral phosphorus compound |
| CN102127111A (en) * | 2010-11-30 | 2011-07-20 | 罗梅 | Chiral phosphonate compound |
| CN102127111B (en) * | 2010-11-30 | 2013-01-09 | 罗梅 | Chiral phosphonate compound |
| CN102351898A (en) * | 2011-08-29 | 2012-02-15 | 罗梅 | Synthesis method of diphenyl phosphonic acid |
| CN103965243A (en) * | 2014-06-02 | 2014-08-06 | 罗梅 | Chiral phosphonate crystal compound and use |
| CN105524092A (en) * | 2016-02-22 | 2016-04-27 | 合肥祥晨化工有限公司 | Synthesis method of chiral zinc complex crystal |
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