CN100395270C - Linear polystyrene supported (4S)-5,5-disubstituted oxazolidin one and its preparation method and uses - Google Patents
Linear polystyrene supported (4S)-5,5-disubstituted oxazolidin one and its preparation method and uses Download PDFInfo
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Abstract
The present invention relates to a linear polystyrene supporting carrier (4S)-5, 5-disubstituted oxazolidine 1 and 2, and the structure is disclosed in the specification. The present invention comprises that nature L-tyrosine is used; esterification, amination and Grignard addition, ring closing, aether forming and polymerizing are carried out to obtain the compound. The following compound of the present invention can be used as a chiral assisting reagent; homogeneous phase synthesis reaction is carried out in a process of inducing the asymmetric reaction; the reaction is quick; the in-line inspection is convenient; the chirality assisting reagent is difficult to open a ring when relieved moreover, the present invention has the advantages of low cost and easy obtainment of reacting raw materials and the reagent, feasible routes, simple treatment after the reaction and good yield.
Description
Technical field
The present invention relates to a kind of linear polystyrene-supported (4S)-5,5-two Qu Dai oxazolidinones and its production and use.
Background technology
Since Merrifield propping up with insoluble polymer first in 1963 carry synthetic polypeptide since, particularly in recent years along with the needs of a large amount of screening of medicaments, the solid phase organic synthesis has obtained very big development.The solid phase organic synthesis has lot of advantages with synthetic the comparing of the liquid phase of classics, demonstrates very strong vitality and magnetism, shows: be convenient to sharp separation in (1) reaction process and purify, simplify the separation and purification target product; (2) can improve reaction yield by the consumption that increases the liquid phase reaction thing, excessive reactant can be removed by washing after reaction is finished in the liquid phase; (3) be convenient to realize sequencing, automated operation, accelerate building-up process, raise the efficiency; (4) substrate that contains the substrate of different substituents or similar by replacing makes up mutually with different reactant, realizes that combinatorial chemistry is synthetic, can synthesize multiple compound simultaneously.
Along with further investigation to solid phase synthesis process, it is found that solid phase synthesis exist inhomogeneous reaction, long reaction time, productive rate not high, be not easy to carry out deficiencies such as online detection with ordinary method.Through exploratory development, find to utilize soluble polymer carrier (as linear polystyrene) to carry out that the liquid phase combination is synthetic not only to have the advantage of solid phase synthesis, also have concurrently classical liquid reactive homogeneous reaction, reaction fast, be convenient to advantage such as online detection.Therefore soluble polymer is widely used, and substitutes soluble polymkeric substance gradually and prop up and carry a synthetic a large amount of micromolecular compound storehouse, has improved the efficient of drug screening further.
Utilizing chiral auxiliary reagent to carry out asymmetric synthesis is one of the most ripe, most widely used method of development in the asymmetric synthesis, its action principle is at first will have to induce asymmetric reaction after the chiral auxiliary reagent of chirality and achirality material link up by the chemical bond key, utilize its sterically hindered inducing to produce new chiral centre, again chiral auxiliary reagent is escaped at last and obtain chiral product.Chiral oxazolidinone is one of most widely used chiral auxiliary reagent, in order to reduce loaded down with trivial details post-processing step and to reclaim and reuse expensive De oxazolidone, in view of solid phase is propped up a year synthetic plurality of advantages, the researchist is loaded in it and has induced multiple asymmetric reaction on insoluble polymer, has realized the recycling use of chiral oxazolidinone.
During unsubstituted, product is escaped the Shi oxazolidone from chiral auxiliary reagent the open loop side reaction takes place easily on the problem Shi ， oxazolidone ring, cause the product productive rate low, the chiral auxiliary reagent structure is suffered partial destruction etc.In order to overcome above-mentioned deficiency, there are two substituent 5 No. 5 of Cai Yong oxazolidone of the present invention, 5-phenylbenzene and 5, the 5-dimethyl replaces the De oxazolidone, the shortcoming of easy open loop when freeing to overcome said structure Jian Dan De oxazolidone, and with 5,5-Er replacement De oxazolidone props up and is loaded on the soluble polymer, make linear polystyrene-supportedly 5,5-Er replaces the De oxazolidone.
Summary of the invention
Problem to be solved by this invention provide can as chiral auxiliary reagent in inducing asymmetric reaction, carry out homogeneous phase building-up reactions, reaction fast, be convenient to be not easy when online detection and chiral auxiliary reagent are freed polystyrene-supported 5 of open loop, promptly linear polystyrene-supported (4S)-5 of 5-two Qu Dai oxazolidinones, 5-Er methyl oxazolidinone 1 and linear polystyrene-supported (4S)-5,5-diphenyl-oxazole alkane ketone 2 and its production and use, raw material of the present invention and reagent are cheap and easy to get, route is feasible, post-reaction treatment is simple.
Technical scheme provided by the invention is, linear polystyrene-supported (4S)-5, and 5-two Qu Dai oxazolidinones, its structure is as follows:
Compound 1 is linear polystyrene-supported (4S)-5, and 5-Er methyl oxazolidinone, compound 2 are linear polystyrene-supported (4S)-5,5-diphenyl-oxazole alkane ketone, and 1 and 2 molecular weight Mw is 10000～14000, m: n=1: 1-1: 3.
The present invention also provides above-mentioned linear polystyrene-supported (4S)-5, the preparation method of 5-two Qu Dai oxazolidinones:
1. linear polystyrene-supported (4S)-5, the preparation of 5-Er methyl oxazolidinone 1:
(1) in methyl alcohol, under the effect of thionyl chloride, compound 3 and methyl alcohol generation esterification get compound 4, and temperature of reaction is 20 ℃～70 ℃, and the reaction times is 12～72h, and the mol ratio of above-claimed cpd is a compound 3: thionyl chloride=1: 1～3;
(2) in organic solvent, under the effect of triethylamine, compound 4 and the reaction of heavy carbonic di tert butyl carbonate obtain compound 5, and temperature of reaction is 20 ℃～40 ℃, reaction times is 12～48h, and the mol ratio of above-claimed cpd is a compound 4: triethylamine: heavy carbonic di tert butyl carbonate=1: 1～5: 1～1.5;
(3) in organic solvent, compound 5 and the reaction of methyl iodide Grignard reagent obtain compound 6, and temperature of reaction is 20 ℃～40 ℃, and the reaction times is 12～48h, and the mol ratio of above-claimed cpd is a compound 5: methyl iodide Grignard reagent=1: 5～10;
(4) in organic solvent, ring closure reaction takes place and obtains compound 7 in compound 6 under the effect of sodium hydroxide, and temperature of reaction is 50 ℃～70 ℃, and the reaction times is 8～24h;
(5) in organic solvent, compound 7 under the effect of the crown ether of salt of wormwood and catalytic amount and to chloromethylation vinylbenzene react compound 8, temperature of reaction is 20 ℃～80 ℃, reaction times is 8～72h, and the mol ratio of above-claimed cpd is a compound 7: salt of wormwood: to chloromethylation vinylbenzene=1: 1～5: 1～2;
(6) in organic solvent, the copolymerization under action of evocating of compound 8 and vinylbenzene obtains linear polystyrene-supported (4S)-5,5-Er methyl oxazolidinone 1, temperature of reaction is 60 ℃～80 ℃, reaction times is 12～72h, the mol ratio of above-claimed cpd is a compound 8: vinylbenzene=1: 1～3, and described initiator is a Diisopropyl azodicarboxylate;
Above-claimed cpd 3,4,5,6,7,8 has following structural formula:
Above-mentioned reaction process is represented by following reaction formula:
2. linear polystyrene-supported (4S)-5, the preparation of 5-diphenyl-oxazole alkane ketone 2:
(1) in organic solvent, compound 4 and bromobenzene Grignard reagent reacting generating compound 9, temperature of reaction is 20 ℃～40 ℃, and the reaction times is 12～48h, and the mol ratio of above-claimed cpd is a compound 4: bromobenzene Grignard reagent=1: 6～10;
(2) in organic solvent, under the effect of salt of wormwood, compound 9 and Vinyl chloroformate react compound 10, temperature of reaction is 20 ℃～40 ℃, reaction times is 12～48h, and the mol ratio of above-claimed cpd is a compound 9: salt of wormwood: Vinyl chloroformate=1: 1～5: 1～1.5;
(3) under the effect of the salt of wormwood of catalytic amount, compound 10 pressure that reduces pressure closes ring less than the 20mm mercury column and generates compound 11, and temperature of reaction is 100 ℃～150 ℃, and the reaction times is 4～12h;
(4) in organic solvent, compound 11 under the effect of the crown ether of salt of wormwood and catalytic amount and to chloromethylation vinylbenzene react compound 12, temperature of reaction is 20 ℃～80 ℃, reaction times is 8～72h, and the mol ratio of above-claimed cpd is a compound 11: salt of wormwood: to chloromethylation vinylbenzene=1: 1～5: 1～2;
(5) in organic solvent, the copolymerization under the initiator effect of compound 12 and vinylbenzene obtains linear polystyrene-supported (4S)-5,5-diphenyl-oxazole alkane ketone 2, temperature of reaction is 60 ℃～80 ℃, reaction times is 12～72h, the mol ratio of above-claimed cpd is a compound 12: vinylbenzene=1: 1～3, and described initiator is a Diisopropyl azodicarboxylate;
Above-claimed cpd 9,10,11,12 has following structural formula:
Above-mentioned reaction process is represented by following reaction formula:
The present invention proposes two kinds of linear polystyrene-supported (4S)-5, there are two substituent 5 No. 5 of 5-two Qu Dai oxazolidinones and preparation method thereof Cai Yong oxazolidone, 5-phenylbenzene and 5, the 5-dimethyl replaces the De oxazolidone, and with 5,5-Er replacement De oxazolidone props up and is loaded on the soluble polymer, can be used as chiral auxiliary reagent and in inducing asymmetric reaction, carry out the homogeneous phase building-up reactions, reaction is fast, be convenient to be difficult for open loop when online detection and chiral auxiliary reagent are freed, and reaction raw materials of the present invention and reagent are cheap and easy to get, route is feasible, post-reaction treatment is simple, productive rate is better.
Embodiment
To help to understand the present invention by following examples, but not limit content of the present invention.
Embodiment 1
With SOCl
2(12mL, 0.17mol) be added in the methyl alcohol (120mL), temperature keeps-10 ℃ and lasting 20 minutes, and adding L-tyrosine (25.0g, 0.14mol), 20 ℃ of reaction 72h, remove methyl alcohol, resistates is used the anhydrous diethyl ether recrystallization after being dissolved in hot methyl alcohol, filters and washs with ether, vacuum-drying gets white solid and is L-tyrosine methyl ester hydrochloride (31.1g, 96.2%).M.p.187-189 ℃ (lit.190-191 ℃); [α]
D 20=+69.8 (c 1.06, pyridine) [lit[α]
D 20=+70.9 (c 1.1, pyridine)]; IR:3350,3213,1743,1596,1515,1445,843cm
-1 1HNMR:7.06 (2H, d, ArH), 6.80 (2H, d, ArH), 4.28 (1H, m, CH), 3.74 (3H, s, CH
3), 3.16 (1H, m, CH
2), 3.08 (1H, m, CH
2);
13CNMR:170.3,155.4,131.0 (2C), 125.6,116.1 (2C), 54.4,53.7,34.9.
Embodiment 2
With SOCl
2(36mL, 0.51mol) be added in the methyl alcohol (120mL), temperature keeps-10 ℃ and lasting 20 minutes, and adding L-tyrosine (25.0g, 0.14mol), 70 ℃ of reaction 12h, remove methyl alcohol, resistates is used the anhydrous diethyl ether recrystallization after being dissolved in hot methyl alcohol, filters and washs with ether, vacuum-drying gets white solid and is L-tyrosine methyl ester hydrochloride (29.4g, 90%).M.p.187-189 ℃ (lit.190-191 ℃); [α]
D 20=+69.8 (c 1.06, pyridine) [lit.[α]
D 20=+70.9 (c 1.1, pyridine)]; IR:3350,3213,1743,1596,1515,1445,843cm
-1 1HNMR:7.06 (2H, d, ArH), 6.80 (2H, d, ArH), 4.28 (1H, m, CH), 3.74 (3H, s, CH
3), 3.16 (1H, m, CH
2), 3.08 (1H, m, CH
2);
13CNMR:170.3,155.4,131.0 (2C), 125.6,116.1 (2C), 54.4,53.7,34.9.
Embodiment 3
(10g 0.043mol) is dissolved in 1, among the mixing solutions 100mL of 4-dioxane and water (1: 1 with the L-tyrosine methyl ester hydrochloride, v/v), 0 ℃ add down triethylamine (10mL, 0.07mol), heavy carbonic di tert butyl carbonate (7.3g, 0.042mol), 20 ℃ are stirred 48h, water and ethyl acetate dilution, tell organic phase, water ethyl acetate extraction (20mL * 3), after organic phase merges, anhydrous magnesium sulfate drying.Remove and obtain clear crystal after the ethyl acetate and be (2S)-2-(N-tertbutyloxycarbonyl) amino-3-(4 '-hydroxy phenyl)-methyl propionate (10.3g, 81%).m.p.104-105℃，[α]
D 20＝+20.4(c?0.72，THF)；IR：3365，2978，1740，1689，1516，828；
1HNMR：6.96(2H，d，ArH)，6.72(2H，d，ArH)，5.03(1H，m，OH)，4.54(1H，m，CH)，3.71(3H，s，OCH
3)，3.01(1H，m，CH
2)，2.98(1H，m，CH
2)，1.42(9H，s，CH
3)；
13CNMR：173.1，155.8，155.6，130.8(2C)，127.9，115.9(2C)，80.7，55.0，52.7，38.0，28.7(3C)；MS：m/z＝319.9(M+Na
+)。
Embodiment 4
(10g 0.043mol) is dissolved in 1, among the mixing solutions 100mL of 4-dioxane and water (1: 1) with the L-tyrosine methyl ester hydrochloride, 0 ℃ adds triethylamine (30mL down, 0.21mol), adding heavy carbonic di tert butyl carbonate (11g, 0.063mol), 40 ℃ are stirred 12h, organic phase is told in water and ethyl acetate dilution, water ethyl acetate extraction (20mL * 3), after organic phase merges, anhydrous magnesium sulfate drying.Remove and obtain clear crystal after the ethyl acetate and be (2S)-2-(N-tertbutyloxycarbonyl) amino-3-(4 '-hydroxy phenyl)-methyl propionate (10.2g, 80.2%).m.p.104-105℃，[α]
D 20＝+20.4(c?0.72，THF)；IR：3365，2978，1740，1689，1516，828；
1HNMR：6.96(2H，d，ArH)，6.72(2H，d，ArH)，5.03(1H，m，OH)，4.54(1H，m，CH)，3.71(3H，s，OCH
3)，3.01(1H，m，CH
2)，2.98(1H，m，CH
2)，1.42(9H，s，CH
3)；
13CNMR：173.1，155.8，155.6，130.8(2C)，127.9，115.9(2C)，80.7，55.0，52.7，38.0，28.7(3C)；MS：m/z＝319.9(M+Na
+)。
Embodiment 5
(7.2g, 0.3mol), (14mL, 0.225mol) and the mixing solutions of anhydrous diethyl ether (150mL), 0.5h then refluxes to add methyl iodide to add magnesium chips in three-necked bottle.(20 ℃ are stirred 48h down for 13.3g, anhydrous ether solution 0.045mol) (100mL) to add (2S)-2-(N-tertbutyloxycarbonyl) amino-3-(4 '-hydroxy phenyl)-methyl propionate.Regulate pH to neutral with ammonia chloride water solution, tell ether layer, water extracted with diethyl ether (30mL * 3), merge organic phase and use anhydrous magnesium sulfate drying, remove and desolvate, and usefulness alcohol-water-ethyl acetate (2: 3: 2, v/v/v) recrystallization obtains clear crystal and is (2S)-2-(N-tertbutyloxycarbonyl) amino-3-(4 '-hydroxy phenyl)-1,1-dimethyl propyl alcohol (6.4g, 47.5%).m.p.155.6-156.3℃，[α]
D 20＝-39.4(c?0.91，THF)；IR：3355，2976，1686，1516，1247，1169，828；
1HNMR：7.05(2H，d，ArH)，6.70(2H，d，ArH)，5.67(1H，m，OH)，3.65(1H，m，CH)，3.05(1H，m，CH
2)，2.52(1H，m，CH
2)，1.20-1.18(15H，t，CH
3)；
13CNMR：155.7，155.6，130.8，129.2(2C)，115.8(2C)，80.4，72.4，68.2，37.4，28.8(3C)，26.7，21.2；MS：m/z＝318.1(M+Na
+)。
Embodiment 6
(12g, 0.5mol), (28mL, 0.45mol) and the mixing solutions of anhydrous diethyl ether (150mL), 0.5h then refluxes to add methyl iodide to add magnesium chips in three-necked bottle.(40 ℃ are stirred 12h down for 13.3g, anhydrous ether solution 0.045mol) (100mL) to add (2S)-2-(N-tertbutyloxycarbonyl) amino-3-(4 '-hydroxy phenyl)-methyl propionate.Regulate pH to neutral with the dilute hydrochloric acid hydrolysis and with the aqueous solution of ammonia chloride, tell ether layer, water extracted with diethyl ether (30mL * 3), merge organic phase and use anhydrous magnesium sulfate drying, remove and desolvate, and usefulness alcohol-water-ethyl acetate (2: 3: 2, v/v/v) recrystallization obtains clear crystal and is (2S)-2-(N-tertbutyloxycarbonyl) amino-3-(4 '-hydroxy phenyl)-1,1-dimethyl propyl alcohol (7.8g, 58%).m.p.155.6-156.3℃，[α]
D 20＝-39.4(c?0.91，THF)；IR：3355，2976，1686，1516，1247，1169，828；
1HNMR：7.05(2H，d，Ar)，6.70(2H，d，Ar)，5.67(1H，m，OH)，3.65(1H，m，CH)，3.05(1H，m，CH
2)，2.52(1H，m，CH
2)，1.20-1.18(15H，t，CH
3)；
13CNMR：155.7，155.6，130.8，129.2(2C)，115.8(2C)，80.4，72.4，68.2，37.4，28.8(3C)，26.7，21.2；MS：m/z＝318.1(M+Na
+)。
Embodiment 7
With (2S)-2-(N-tertbutyloxycarbonyl) amino-3-(4 '-hydroxy phenyl)-1,1-dimethyl propyl alcohol (5g, 0.017mol) join sodium hydroxide (4.8g, 0.12mol) methyl alcohol (75mL) solution in, remove methyl alcohol behind 50 ℃ of reaction 24h, tell organic phase after water (20mL) and ethyl acetate (30mL) dilution, water ethyl acetate extraction (30mL * 3).Merge organic phase and use anhydrous magnesium sulfate drying, be (4S)-4-(4 '-hydroxybenzyl)-5,5-two methyl oxazolidinones (2.8g, 75.6%) except that obtaining light yellow solid after desolvating.m.p.138.2-139.3℃，[α]
D 20＝-121.8(c?0.08，THF)；IR：3290，1729，1515，1235；
1HNMR：7.00(2H，d，ArH)，6.70(2H，d，ArH)，3.75(1H，m，CH)，2.73(1H，m，CH
2)，2.62(1H，m，CH
2)，1.34(6H，d，CH
3)；
13CNMR：160.0，156.3，130.2(2C)，128.3，115.6(2C)，84.1，63.5，36.1，26.9，21.1；MS：m/z＝244.0(M+Na
+)。
Embodiment 8
With (2S)-2-(N-tertbutyloxycarbonyl) amino-3-(4 '-hydroxy phenyl)-1,1-dimethyl propyl alcohol (5g, 0.017mol) join sodium hydroxide (4.8g, 0.12mol) methyl alcohol (75mL) solution in, remove methyl alcohol behind 70 ℃ of reaction 12h, tell organic phase after water (20mL) and ethyl acetate (30mL) dilution, water ethyl acetate extraction (30mL * 3).Merge organic phase and use anhydrous magnesium sulfate drying, be (4S)-4-(4 '-hydroxybenzyl)-5,5-two methyl oxazolidinones (3g, 81%) except that obtaining light yellow solid after desolvating.m.p.138.2-139.3℃，[α]
D 20＝-121.8(c?008，THF)；IR：3290，1729，1515，1235；
1HNMR：7.00(2H，d，ArH)，6.70(2H，d，ArH)，3.75(1H，m，CH)，2.73(1H，m，CH
2)，2.62(1H，m，CH
2)，1.34(6H，d，CH
3)；
13CNMR：160.0，156.3，130.2(2C)，128.3，115.6(2C)，84.1，63.5，36.1，26.9，21.1；MS：m/z＝244.0(M+Na
+)。
Embodiment 9
Get (4S)-4-(4 '-hydroxybenzyl)-5, (3.3g 0.015mol) is dissolved among the DMF (20mL) 5-Er methyl oxazolidinone, adding to chloromethylation vinylbenzene (2mL, 0.018mol), Anhydrous potassium carbonate (2g, 0.015mol), catalytic amount crown ether, 20 ℃ of reaction 72h.Decompression removes that water (15mL) and methylene dichloride (30mL) dilute behind the DMF.Tell organic phase, water dichloromethane extraction (30mL * 3), anhydrous magnesium sulfate drying, remove desolvate pale yellow powder, with ethanol-ethyl acetate-water (1: 2: 1, v/v/v) recrystallization obtains clear crystal and is (4S)-4-(4 '-(4 "-vinyl) benzyloxy) benzyl)-5,5-Er methyl oxazolidinone (2.8g, 56%).m.p.146.0-147.2℃，[α]
D 20＝-53.65(c?0.5783，THF)；IR(NaCl，cm
-1)：3412，1781，2982，2899，1512，1290，999，918，828；
1HNMR：7.44(2H，d?ArH)，7.39(2H，d，ArH)，7.09(2H，d?ArH)，6.93(2H，d，ArH)，6.75(1H，dd，＝CH)，5.78(1H，d，＝CH
2)，5.27(1H，d，＝CH
2)，5.04(2H，s，O-CH
2)，4.93(1H，s，NH)，3.62(1H，d，CH)，2.78(1H，d，CH
2)，2.63(1H，d，CH
2)，1.47-1.44(6H，d，CH
3)；
13CNMR：158.4，158.2，137.8，136.8(2C)，130.3(2C)，129.5，128.1(2C)，126.8(2C)，115.9(2C)，114.6，83.6，70.2，63.6，36.6，27.9，22.3；MS：m/z＝337.9(M
+)。
Embodiment 10
Get (4S)-4-(4 '-hydroxybenzyl)-5, (3.3g 0.015mol) is dissolved among the DMF (20mL) 5-Er methyl oxazolidinone, adding to chloromethylation vinylbenzene (4mL, 0.036mol), Anhydrous potassium carbonate (10g, 0.075mol), catalytic amount crown ether, 80 ℃ of reaction 12h.Decompression removes that water (15mL) and methylene dichloride (30mL) dilute behind the DMF.Tell organic phase, water dichloromethane extraction (30mL * 3), anhydrous magnesium sulfate drying, remove desolvate pale yellow powder, with ethanol-ethyl acetate-water (1: 2: 1, v/v/v) recrystallization obtains clear crystal and is (4S)-4-(4 '-(4 "-vinyl) benzyloxy) benzyl)-5,5-Er methyl oxazolidinone (2.57g, 51.4%).m.p.146.0-147.2℃，[α]
D 20＝-53.65(c?0.5783，THF)；IR(NaCl，cm
-1)：3412，1781，2982，2899，1512，1290，999，918，828；
1HNMR：7.44(2H，d?ArH)，7.39(2H，d，ArH)，7.09(2H，d?ArH)，6.93(2H，d，ArH)，6.75(1H，dd，＝CH)，5.78(1H，d，＝CH
2)，5.27(1H，d，＝CH
2)，5.04(2H，s，O-CH
2)，4.93(1H，s，NH)，3.62(1H，d，CH)，2.78(1H，d，CH
2)，2.63(1H，d，CH
2)，1.47-1.44(6H，d，CH
3)；
13CNMR：158.4，158.2，137.8，136.8(2C)，130.3(2C)，129.5，128.1(2C)，126.8(2C)，115.9(2C)，114.6，83.6，70.2，63.6，36.6，27.9，22.3；MS：m/z＝337.9(M
+)。
Embodiment 11
Get (4S)-4-(4 '-(4 "-vinyl) benzyloxy) benzyl)-5,5-Er methyl oxazolidinone (1g 00029mol) is dissolved among the THF, add successively vinylbenzene (0.33mL, 0.0029mol), AIBN (0.0033g, 0.02mmol).60 ℃ of reaction 12h.Post reaction mixture is added drop-wise in the ice methyl alcohol, filters and with after the ice methanol wash, and the dry polymkeric substance line style that must white powder be is polystyrene-supported 5,5-two methyl oxazolidinones (1.1g, 84%).IR：3280，3058，3026，2924，2853，1752，1511，1242，999，822，761，701cm
-1；
1HNMR：7.25-6.45(m)，4.90(2H，s，OCH
2)，3.62(1H，s，CH)，2.75(1H，s，CH
2)，2.60(1H，s，CH
2)，1.81-1.25(m)；
13CNMR：158.4，145.5，130.4，129.5，128.1，126.2，115.8，83.6，70.5，63.5，40.8，36.6，28.0，22.4；Elementary?analysis?calcd：C，78.88％；H，7.08％；N，3.17％；found：C，79.4％；H，7.08％；N，3.11％.
Embodiment 12
Get (4S)-4-(4 '-(4 "-vinyl) benzyloxy) benzyl)-5,5-Er methyl oxazolidinone (1g 0.0029mol) is dissolved among the THF, add successively vinylbenzene (1mL, 0.0087mol), AIBN (0.0033g, 0.02mmol).80 ℃ of reaction 72h.Post reaction mixture is added drop-wise in the ice methyl alcohol, filters and with after the ice methanol wash, and the dry polymkeric substance line style that must white powder be is polystyrene-supported 5,5-two methyl oxazolidinones (1.69g, 89%).IR：3280，3058，3026，2924，2853，1752，1511，1242，999，822，761，701cm
-1；
1HNMR：7.25-6.45(m)，4.90(2H，s，OCH
2)，3.62(1H，s，CH)，2.75(1H，s，CH
2)，2.60(1H，s，CH
2)，1.81-1.25(m)；
13CNMR：158.4，145.5，130.4，129.5，128.1，126.2，115.8，83.6，70.5，63.5，40.8，36.6，28.0，22.4；Elementary?analysis?calcd：C，83.17％；H，7.29％；N，2.16％；found：C，83.44％；H，7.31％；N，2.09％.
Embodiment 13
(3.4g 0.14mol), adds bromobenzene (14.3mL to add the exsiccant magnesium chips in three-necked flask, 0.135mol) THF (130mL) solution, the 1h that refluxes then promptly gets Grignard reagent, ice bath adds down exsiccant L-L-Tyrosine methyl ester (6.3g, 0.027mol), 20 ℃ of reaction 48h.Reaction finishes and is adjusted to pH=7 with the dilute hydrochloric acid hydrolysis and with ammoniacal liquor after the back adds frozen water.Water merges organic phase and uses anhydrous MgSO with ethyl acetate extraction (50mL * 3)
4Drying, the decompression desolvate yellow solid, get white crystal (2S)-2-amino-3-(4 '-hydroxy phenyl)-1 with re-crystallizing in ethyl acetate, 1-phenylbenzene propyl alcohol (5.1g, 59%).m.p.214-216℃(lit.215-217℃)；[α]
D 25＝-90.8(c?0.1884，THF)[lit.[α]
D 20＝-92.3(c?0.377，THF)]；IR：3352，1595，1515，1448，824，767，704cm
-1；
1HNMR：7.60-7.18(10H，m，ArH)，7.12(2H，m，ArH)，6.70(2H，m，ArH)4.22(1H，dd，CH)，2.77(1H，dd?CH
2)，1.85(1H，dd，CH
2)；
13CNMR：149.0，145.4(2C)，131.7，130.6(2C)，128.7(2C)，128.1(2C)，127.5(4C)，127.2(2C)，115.6(2C)，88.6，70.5，39.6；MS：m/z＝342.5(M+Na
+)。
Embodiment 14
(7.2g 0.3mol), adds bromobenzene (28.6mL to add the exsiccant magnesium chips in three-necked flask, 0.27mol) THF (130mL) solution, the 1h that refluxes then promptly gets Grignard reagent, ice bath adds down exsiccant L-L-Tyrosine methyl ester (6.3g, 0.027mol), 40 ℃ of reaction 12h.Reaction finishes and is adjusted to pH=7 with the dilute hydrochloric acid hydrolysis and with ammoniacal liquor after the back adds frozen water.Water merges organic phase and uses anhydrous MgSO with ethyl acetate extraction (50mL * 3)
4Drying, the decompression desolvate yellow solid, get white crystal (2S)-2-amino-3-(4 '-hydroxy phenyl)-1 with re-crystallizing in ethyl acetate, 1-phenylbenzene propyl alcohol (5.7g, 67%).m.p.214-216℃(lit.215-217℃)；[α]
D 25＝-90.8(c?0.1884，THF)[lit.[α]
D 20＝-92.3(c?0.377，THF)]；IR：3352，1595，1515，1448，824，767，704cm
-1；
1HNMR：7.60-7.18(10H，m，ArH)，7.12(2H，m，ArH)，6.70(2H，m，ArH)4.22(1H，dd，CH)，2.77(1H，dd?CH
2)，1.85(1H，dd，CH
2)；
13CNMR：149.0，145.4(2C)，131.7，130.6(2C)，128.7(2C)，128.1(2C)，127.5(4C)，127.2(2C)，115.6(2C)，88.6，70.5，39.6；MS：m/z＝342.5(M+Na
+)。
Embodiment 15
With (2S)-2-amino-3-(4 '-hydroxy phenyl)-1, (3.03g 0.01mol) is dissolved in the deionized water (20mL) 1-phenylbenzene propyl alcohol, adds K respectively
2CO
3(1.38g, 0.01mol) and methylene dichloride (50mL) stirring at room 10 minutes, (1.14mL 0.1mol), stirs and adds Na after 10 minutes to add Vinyl chloroformate
2CO
3Saturated solution (10mL), 20 ℃ are stirred 48h.The water organic phase is separated, and water merges organic phase, anhydrous MgSO with dichloromethane extraction (50mL * 3)
4Drying is filtered, decompression desolvate brown oil (2S)-2-(N-ethoxycarbonyl) amino-3-(4 '-hydroxy phenyl)-1,1-phenylbenzene propyl alcohol (2.8g, 71.6%).IR：3409，1759，1693，1597，1516，1448，824，737，703cm
-1；
1HNMR：δ8.15(1H，s，NH)，7.71(2H，d，ArH)，7.67(2H，d，ArH)，7.34(2H，m，ArH)，7.22(2H，m，ArH)，7.12(2H，m，ArH)，6.96(2H，d，ArH)，6.69(2H，d，ArH)，4.85(1H，m，CH)，3.78(2H，dd，COOCH
2)，2.81(1H，m，CH
2)，2.61(1H，m，CH
2)，0.94(3H，m，CH
3)
13CNMR：157.4，155.2，145.5，145.2，130.7(2C)，130.2，129.0(4C)，128.7(2C)，127.6，127.4，126.1，126.0，115.8(2C)，81.6，616，59.4，36.1，14.8；MS：m/z＝414.7(M+Na
+)。
Embodiment 16
With (2S)-2-amino-3-(4 '-hydroxy phenyl)-1, (3.03g 0.01mol) is dissolved in the deionized water (20mL) 1-phenylbenzene propyl alcohol, adds K respectively
2CO
3(6.9g, 0.05mol) and methylene dichloride (50mL) stirring at room 10 minutes, (1.71mL 0.15mol), stirs and adds Na after 10 minutes to add Vinyl chloroformate
2CO
3Saturated solution (10mL), 40 ℃ are stirred 12h.The water organic phase is separated, and water merges organic phase, anhydrous MgSO with dichloromethane extraction (50mL * 3)
4Drying is filtered, decompression desolvate brown oil (2S)-2-(N-ethoxycarbonyl) amino-3-(4 '-hydroxy phenyl)-1,1-phenylbenzene propyl alcohol (2.7g, 69.1%).IR：3409，1759，1693，1597，1516，1448，824，737，703cm
-1；
1HNMR：δ8.15(1H，s，NH)，7.71(2H，d，ArH)，7.67(2H，d，ArH)，7.34(2H，m，ArH)，7.22(2H，m，ArH)，7.12(2H，m，ArH)，6.96(2H，d，ArH)，6.69(2H，d，ArH)，4.85(1H，m，CH)，3.78(2H，dd，COOCH
2)，2.81(1H，m，CH
2)，2.61(1H，m，CH
2)，0.94(3H，m，CH
3)
13CNMR：157.4，155.2，145.5，145.2，130.7(2C)，130.2，129.0(4C)，128.7(2C)，127.6，127.4，126.1，126.0，115.8(2C)，81.6，61.6，59.4，36.1，14.8；MS：m/z＝414.7(M+Na
+)。
Embodiment 17
At (2S)-2-(N-ethoxycarbonyl) amino-3-(4 '-hydroxybenzyl)-1,1-phenylbenzene propyl alcohol (1.96g, 5mmol) the middle catalytic amount K that adds
2CO
3(0.014g 0.1mmol), is warming up to 100 ℃, and the 20mm mercury column that reduces pressure reaction 4h gets the beige solid, gets (4S)-4-(4 '-hydroxybenzyl)-5 with recrystallizing methanol, 5-diphenyl-oxazole alkane ketone (1.17g, 68.2%).m.p.220.1-220.6℃；[α]
D 25＝-5.99(c1.2604，THF)；IR：3405，1746，1596，1515，1448，823，735，700cm
-1；
1HNMR：δ8.26(1H，s，NH)770(2H，d，ArH)，7.46-7.30(8H，m，ArH)，7.01(2H，d，ArH)，6.72(2H，d，ArH)，4.85(1H，dd，CH)，2.61(1H，dd，CH
2)，2.17(1H，dd，CH
2)；
13CNMR：157.5，156.8，144.5，140.9，131.1(2C)，129.2(2C)，128.9(2C)，128.8，128.6(2C)，128.4，127.1，126.8(2C)，116.2(2C)，89.1，62.2，39.5；MS：m/z＝368.6(M+Na
+)。
Embodiment 18
At (2S)-2-(N-ethoxycarbonyl) amino-3-(4 '-hydroxybenzyl)-1,1-phenylbenzene propyl alcohol (1.96g, 5mmol) the middle catalytic amount K that adds
2CO
3(0.014g 0.1mmol), is warming up to 150 ℃, and the 20mm mercury column that reduces pressure reaction 12h gets the beige solid, gets (4S)-4-(4 '-hydroxybenzyl)-5 with recrystallizing methanol, 5-diphenyl-oxazole alkane ketone (1.21g, 70.1%).m.p.220.1-220.6℃；[α]
D 25＝-5.99(c1.2604，THF)；IR：3405，1746，1596，1515，1448，823，735，700cm
-1；
1HNMR：δ8.26(1H，s，NH)7.70(2H，d，ArH)，7.46-7.30(8H，m，ArH)，7.01(2H，d，ArH)，6.72(2H，d，ArH)，4.85(1H，dd，CH)，2.61(1H，dd，CH
2)，2.17(1H，dd，CH
2)；
13CNMR：157.5，156.8，144.5，140.9，131.1(2C)，129.2(2C)，128.9(2C)，128.8，128.6(2C)，128.4，127.1，126.8(2C)，116.2(2C)，89.1，62.2，39.5；MS：m/z＝368.6(M+Na
+)。
Embodiment 19
Get (4S)-4-(4 '-hydroxybenzyl)-5,5-diphenyl-oxazole alkane ketone (2.4g, 0.01085mol), be dissolved among the DMF (20mL), adding is to chloromethylation vinylbenzene (1.46ml, 0.01mol), add Anhydrous potassium carbonate (1.5g, 0.011mol), the 18-that adds catalytic amount is preced with-6 ethers, and suction filtration is removed salt of wormwood behind 20 ℃ of reaction 72h, decompression gets yellow powder after removing DMF, water and methylene dichloride dilution, water merges organic phase, anhydrous magnesium sulfate drying with dichloromethane extraction (30mL * 3) back, rotary evaporation gets oily matter, column chromatography separate white powder (4S)-4-(4 '-(4 "-vinyl benzyloxy base) benzyl)-5,5-diphenyl-oxazole alkane ketone (1.55g, 31%).m.p.167.9-168.4℃；IR：3095，3030，2922，1759，1610，1583，1510，1387，1242，1177，997，820，760，700cm
-1；
1HNMR：δ7.54(2H，m，Ar)，7.42-7.29(12H，m，Ar)，7.02(2H，d，Ar)，690(2H，d，Ar)，6.70(1H，dd，＝CH)，5.75(1H，d，＝CH
2)，5.25(1H，d，＝CH
2)，5.02(2H，s，OCH
2)，4.61(1H，dd，CH
2)，2.53(1H，dd，CH)，2.12(1H，dd，CH)；
13CNMR：158.3，157.8，142.7，139.6，137.7，136.8，136.7，130.4，129.4(4C)，129.1(2C)，128.9，128.7，128.4，128.1，126.8(2C)，126.7(2C)，126.5(2C)，115.8(2C)，114.6，89.4，70.2，62.2，39.3；MS?m/z＝484.2(M+Na
+)。
Embodiment 20
Get (4S)-4-(4 '-hydroxybenzyl)-5,5-diphenyl-oxazole alkane ketone (2.4g, 0.01085mol), be dissolved among the DMF (20mL), adding is to chloromethylation vinylbenzene (2.92ml, 0.02mol), add Anhydrous potassium carbonate (7.5g, 0.055mol), the 18-that adds catalytic amount is preced with-6 ethers, and suction filtration is removed salt of wormwood behind 80 ℃ of reaction 8h, decompression gets yellow powder after removing DMF, water and methylene dichloride dilution, water merges organic phase, anhydrous magnesium sulfate drying with dichloromethane extraction (30mL * 3) back, rotary evaporation gets oily matter, column chromatography separate white powder (4S)-4-(4 '-(4 "-vinyl benzyloxy base) benzyl)-5,5-diphenyl-oxazole alkane ketone (1.23g, 24.6%).m.p.167.9-168.4℃；IR：3095，3030，2922，1759，1610，1583，1510，1387，1242，1177，997，820，760，700cm
-1；
1HNMR：δ7.54(2H，m，Ar)，7.42-7.29(12H，m，Ar)，7.02(2H，d，Ar)，6.90(2H，d，Ar)，6.70(1H，dd，＝CH)，5.75(1H，d，＝CH
2)，5.25(1H，d，＝CH
2)，5.02(2H，s，OCH
2)，4.61(1H，dd，CH
2)，2.53(1H，dd，CH)，2.12(1H，dd，CH)；
13CNMR：158.3，157.8，142.7，139.6，137.7，136.8，136.7，130.4，129.4(4C)，129.1(2C)，128.9，128.7，128.4，128.1，126.8(2C)，126.7(2C)，126.5(2C)，115.8(2C)，114.6，89.4，70.2，62.2，39.3；MS：m/z＝484.2(M+Na
+)。
Embodiment 21
Get (4S)-4-(4 '-(4 "-vinyl benzyloxy base) benzyl)-5; 5-diphenyl-oxazole alkane ketone (0.5g; 0.0011mol) be dissolved in and add vinylbenzene (0.125mL; 0.0011mol), (0.002g; 1%mol) is warmed up to 60 ℃ of afterreaction 12h to AIBN under the nitrogen protection behind the THF (4mL) successively.Post reaction mixture is with being added drop-wise to after the methylene dichloride dissolving in the ice methyl alcohol, sedimentation and filtration gone out and with the ice methanol wash, dry must white powder, promptly linear polystyrene-supported 5,5-diphenyl-oxazole alkane ketone (0.41g, 67%).IR：3278，3026，2924，2853，1762，1610，1583，1510，1493，1377，1243，1177，1112，1004，909，821，760，731，700cm
-1；
1HNMR：δ7.52，7.34，7.22，7.00，6.88，6.56，4.89(m，OCH
2)，4.60(m，CH)，2.53(m，CH
2)，2.13(m，CH
2)，1.82-1.26(m，CH
2Ar)；
13CNMR：158.5，157.8，145.6，142.7，139.6，134.4，130.4，129.3，129.0，128.7，128.4，126.8，126.5，115.7，893，704，62.2，40.7，39.2；Elementary?analysis?calcd：C，82.81％；H，6.24％；N，2.48％；found：C，82.96％；H，6.28％；N，2.41％.
Embodiment 22
Get (S)-4-(4-(4-vinyl benzyloxy base) benzyl)-5; 5-diphenyl-oxazole alkane ketone (0.5g, 0.0011mol) be dissolved in add successively behind the THF (4mL) vinylbenzene (0.375mL, 0.0033mol), AIBN (0.002g; 1%mol), be warmed up to 80 ℃ of afterreaction 72h under the nitrogen protection.Post reaction mixture is with being added drop-wise to after the methylene dichloride dissolving in the ice methyl alcohol, sedimentation and filtration gone out and with the ice methanol wash, dry must white powder, promptly linear polystyrene-supported 5,5-diphenyl-oxazole alkane ketone (0.59g, 71%).IR：3278，3026，2924，2853，1762，1610，1583，1510，1493，1377，1243，1177，1112，1004，909，821，760，731，700cm
-1；
1HNMR：δ7.52，7.34，7.22，7.00，6.88，6.56，4.89(m，OCH
2)，4.60(m，CH)，2.53(m，CH
2)，2.13(m，CH
2)，1.82-1.26(m，CH
2Ar)；
13CNMR：158.5，157.8，145.6，142.7，139.6，134.4，130.4，129.3，129.0，128.7，128.4，126.8，126.5，115.7，89.3，70.4，62.2，40.7，39.2；Elementary?analysis?calcd：C，85.35％；H，6.64％；N，1.81％；found：C，85.54％；H，6.66％；N，1.76％.
Claims (4)
1. linear polystyrene-supported (4S)-5,5-two Qu Dai oxazolidinones 1 or 2, its structure is as follows:
M in the formula: n=1: 1-1: 3, Mw is 10000～14000.
2. described linear polystyrene-supported (4S)-5 of claim 1, the preparation method of 5-two Qu Dai oxazolidinones, it is characterized in that: compound 1 is through the method preparation of following (1), (2), (3), (4), (5), (6), and compound 2 prepares through the method for following (7), (8), (9), (10), (11):
(1) in methyl alcohol, under the effect of thionyl chloride, compound 3 and methyl alcohol generation esterification get compound 4, and temperature of reaction is 20 ℃～70 ℃, and the reaction times is 12～72h, and the mol ratio of above-claimed cpd is a compound 3: thionyl chloride=1: 1～3;
(2) in organic solvent, under the effect of triethylamine, compound 4 and the reaction of heavy carbonic di tert butyl carbonate obtain compound 5, and temperature of reaction is 20 ℃～40 ℃, reaction times is 12～48h, and the mol ratio of above-claimed cpd is a compound 4: triethylamine: heavy carbonic di tert butyl carbonate=1: 1～5: 1～1.5;
(3) in organic solvent, the reaction of the Grignard reagent of compound 5 and methyl iodide obtains compound 6, and temperature of reaction is 20 ℃～40 ℃, and the reaction times is 12～48h, and the mol ratio of above-claimed cpd is a compound 5: the Grignard reagent of methyl iodide=1: 5～10;
(4) in organic solvent, compound 6 encircle in effect ShiShimonoseki of sodium hydroxide compound 7, temperature of reaction is 50 ℃～70 ℃, the reaction times is 8～24h;
(5) in organic solvent, compound 7 under the effect of the crown ether of salt of wormwood and catalytic amount and to chloromethylation vinylbenzene react compound 8, temperature of reaction is 20 ℃～80 ℃, reaction times is 8～72h, and the mol ratio of above-claimed cpd is a compound 7: salt of wormwood: to chloromethylation vinylbenzene=1: 1～5: 1～2;
(6) in organic solvent, the copolymerization under action of evocating of compound 8 and vinylbenzene gets linear polystyrene-supported (4S)-5,5-Er methyl oxazolidinone 1, temperature of reaction is 60 ℃～80 ℃, reaction times is 12～72h, the mol ratio of above-claimed cpd is a compound 8: vinylbenzene=1: 1～3, and described initiator is a Diisopropyl azodicarboxylate;
Above-claimed cpd 3,4,5,6,7,8 has following structural formula:
(7) in organic solvent, the Grignard reagent reacting generating compound 9 of compound 4 and bromobenzene, temperature of reaction is 20 ℃～40 ℃, and the reaction times is 12～48h, and the mol ratio of above-claimed cpd is a compound 4: bromobenzene Grignard reagent=1: 6～10;
(8) in organic solvent, under the effect of salt of wormwood, compound 9 and Vinyl chloroformate react compound 10, temperature of reaction is 20 ℃～40 ℃, reaction times is 12～48h, and the mol ratio of above-claimed cpd is a compound 9: salt of wormwood: Vinyl chloroformate=1: 1～5: 1～1.5;
(9) under the effect of the salt of wormwood of catalytic amount, compound 10 pressure that reduces pressure closes ring less than the 20mm mercury column and generates compound 11, and temperature of reaction is 120 ℃～150 ℃, and the reaction times is 4～12h;
(10) in organic solvent, compound 11 under the effect of the crown ether of salt of wormwood and catalytic amount and to chloromethylation vinylbenzene react compound 12, temperature of reaction is 20 ℃～80 ℃, reaction times is 8～72h, and the mol ratio of above-claimed cpd is a compound 11: salt of wormwood: to chloromethylation vinylbenzene=1: 1～5: 1～2;
(11) in organic solvent, the copolymerization under the initiator effect of compound 12 and vinylbenzene obtains linear polystyrene-supported (4S)-5,5-diphenyl-oxazole alkane ketone 2, temperature of reaction is 60 ℃～80 ℃, reaction times is 12～72h, the mol ratio of above-claimed cpd is a compound 12: vinylbenzene=1: 1～3, and described initiator is a Diisopropyl azodicarboxylate;
Above-claimed cpd 9,10,11,12 has following structural formula:
3. preparation method as claimed in claim 2 is characterized in that: described organic solvent is methylene dichloride, trichloromethane, tetrahydrofuran (THF), methyl alcohol, ethanol, N, N '-dimethyl formamide or 1,4-dioxane.
4. described linear polystyrene-supported (4S)-5 of claim 1,5-two Qu Dai oxazolidinones are as the purposes of chiral auxiliary reagent in inducing asymmetric reaction.
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