CN1939911A - Chiral oxazoline and its production - Google Patents
Chiral oxazoline and its production Download PDFInfo
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- CN1939911A CN1939911A CN 200610096004 CN200610096004A CN1939911A CN 1939911 A CN1939911 A CN 1939911A CN 200610096004 CN200610096004 CN 200610096004 CN 200610096004 A CN200610096004 A CN 200610096004A CN 1939911 A CN1939911 A CN 1939911A
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- oxazoline
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Abstract
A 1-(2-(4S)-4-R-4,5-dihydro-2-oxazoline-ethyl-piperidine and its production are disclosed. In the formula, R is L, D-CH2CH (CH3)2 or L,D-CH2(CH3)2 or L,D-Ph or L,D-CH2Ph. The compound is prepared by taking hexahydro-pyrido-ethyl cyanide and chiral alkamine as raw materials and synthesizing under the existence of organic solvent and catalyst. It's simple and efficient, has excellent asymmetric catalytic activity and enantiomeric selectivity.
Description
One, technical field
The present invention relates to a kind of new compound and preparation method thereof, exactly is a kind of chiral oxazoline and preparation method thereof.
Two, background technology
Chiral oxazoline and rare earth metal coordination form chiral catalyst in the Diels-Alder cycloaddition reaction, the Michael addition reaction, the Friedel-Crafts reaction, the Aldol reaction, show the active and high enantioselectivity of good asymmetry catalysis in many reactions such as Cyclopropanated, thereby be subjected to paying close attention to widely.
The preparation of chiral oxazoline part starts from 1884, the history in existing more than 100 year, and its synthetic method mainly contains three kinds:
(1) the direct condensation of acyl chlorides and amino alcohol forms two hydroxyl acyl ammonia, closes ring by hydroxyl acyl ammonia then and generates bisoxazoline.
(2) directly form two hydroxyl acyl ammonia, close ring then and form bisoxazoline by carboxylicesters and amino alcohol condensation.
(3) the third method is to be set out by dicyan, generates polyurethane with the anhydrous chlorides of rase H-H reaction in ethanol, forms bisoxazoline with one step of amino alcohol condensation then.
Three, summary of the invention
The present invention is intended to provide novel chiral catalyst of a class and corresponding synthetic method thereof for asymmetric catalysis field.Technical problem to be solved is to make raw material closed loop generation under certain condition chiral oxazoline.
The alleged chiral oxazoline of the present invention is a compound shown below:
R is left-handed or dextral isobutyl-(L, D-CH in the formula
2CH (CH
3)
2Or sec.-propyl (L, D-CH (CH
3)
2Or phenyl (L, D-Ph) or benzyl (L, D-CH
2Ph).
Four kinds of chiral oxazolines that are made of above group are called for short 1a, 1b, 1c and 1d successively.Its chemical name: 1-[2-(4S)-4-R base-4,5-dihydro-2-oxazoline-ethyl] piperidines.
This chiral oxazoline is to be the raw material synthetic with hexahydropyridine propionitrile and chiral amino alcohol,
R is left-handed or dextral isobutyl-(L, D-CH in the formula
2CH (CH
3)
2Or sec.-propyl (L, D-CH (CH
3)
2Or phenyl (L, D-Ph) or benzyl (L, D-CH
2Ph).
That the preparation method of this chiral oxazoline comprises is synthetic, separation and purifying, described synthesizing is exactly that hexahydropyridine propionitrile and chiral amino alcohol reacted 40～50 hours in 115 ℃～150 ℃ under organic solvent and catalyzer existence condition, catalyst levels is the 1～3wt% (weight percent, down together) of material quantity.
Preferred 125 ℃～145 ℃ reactions 45～48 hours, catalyst levels is the 2wt% of material quantity.
The organic solvent that described organic solvent should select inert, its boiling point and temperature of reaction to adapt is such as methyl pyrrole heavy stone used as an anchor or chlorobenzene or dichlorobenzene or ethylbenzene or dimethylbenzene or propyl benzene or alkane or halogenated alkane etc.
Described catalyzer is selected from AlCl
3Or rare-earth metal chloride (trichlorine rare earth) or transition metal chloride (ZnCl
2, CuCl
2, NiCl
2, CoCl
2, FeCl
3, MnCl
2Deng) or alkoxide compound (tetraisopropoxy titanium, dimethyl dichloro stannane etc.).Preferred trichlorine rare earth or transition metal chloride.
Present method one-step synthesis chiral oxazoline part, yield 65%～85%, be a kind of simply, methodology of organic synthesis efficiently.This part can be used as the organic synthesis that catalyzer is used for asymmetric field.
Four, description of drawings
Fig. 1～Fig. 4 is carbon spectrogram, hydrogen spectrogram, infrared figure and the mass spectrum that characterizes chiral oxazoline 1a structure successively.
Fig. 5～Fig. 8 is carbon spectrogram, hydrogen spectrogram, infrared figure and the mass spectrum that characterizes chiral oxazoline 1b structure successively.
Fig. 9～Figure 12 is carbon spectrogram, hydrogen spectrogram, infrared figure and the mass spectrum that characterizes chiral oxazoline 1c structure successively.
Figure 13～Figure 16 is carbon spectrogram, hydrogen spectrogram, infrared figure and the mass spectrum that characterizes chiral oxazoline 1d structure successively.
Five, embodiment
Be example with L-amino alcohol (Ningbo of Zhejiang Seeking Truth Chemical Industry Science Co., Ltd product) now, non-limiting examples is described below.Another raw material hexahydropyridine propionitrile is import,
1a:1-[2-(4S)-4-isobutyl--4,5-dihydro-2-oxazoline-ethyl] preparation of piperidines
1-[2-(4S)-4-i-butyl-4,5-dihydro-oxazol-2-yl-ethyl]-preparation of piperidine
In the 100mL two-mouth bottle, add anhydrous ZnCl
260mg (0.37mmol), 20mL chlorobenzene or ethylbenzene or dimethylbenzene, (boiling point is followed successively by 132 ℃, 136 ℃, 139 ℃), hexahydropyridine propionitrile 1.0g (7.2mmol), L-isobutyl-leucinol 2g, with the mixture 46h that at high temperature refluxes, stopped reaction, decompression is desolvated to remove, with the residuum water dissolution, and use CHCl
3(20mL * 2) extraction, the organic phase anhydrous sodium sulfate drying, rotation removes and desolvates, and thick product with sherwood oil/methylene dichloride/ether (1: 4: 2) column chromatography, is got sorrel thickness oily liquids 1.24g productive rate 72%.
[a]5D＝-50.2°(c＝0.828，CH
2Cl
2)；1HNMR(300MHz，CDCl
3，27℃)，δ(ppm)＝4.18-4.24(t，7.95Hz，1H)，3.99～4.04(m，1H)，3.67～3.70(t，0.12Hz，1H)，2.56～2.61(m，2H)，2.33～2.42(m，6H)，1.63～1.70(m，1H)，1.47～1.55(m，4H)，1.35～1.39(m，2H)，1.14～1.24(m，1H)，0.84～0.88(m，6H).13CNMR，22.58(×2)，22.62，24.17，25.21，25.81(×2)，45.50，54.07(×2)，55.20，64.38，72.59，165.89.IR：3290，3076，2936，2867，2854，2810，1644，1553，1469，1444，1367，1275，1255，1155，1116，1041，1071；HRMS(EI)：m/z(％)：calcd?for?Cl
4H
26N
2O：238.2045；found：238.2036。
1b:1-[2-(4S)-4-sec.-propyl-4,5-dihydro-2-oxazoline-ethyl] preparation of piperidines
1-[2-(4S)-4-isopropyl-4,5-dihydro-oxazol-2-yl-ethyl]-preparation of piperidine
In two mouthfuls of flasks of 100ml, add anhydrous trichlorine rare earth 70mg, 25mL picoline (128 ℃～144 ℃ of boiling points), hexahydropyridine propionitrile 1.0g (7.2mmol), L-sec.-propyl leucinol 2g is with the mixture 46h that at high temperature refluxes, stopped reaction, decompression is desolvated to remove,,, and use CHCl with the residuum water dissolution
3(20mL * 2) extraction, the organic phase anhydrous sodium sulfate drying, rotation removes and desolvates, and thick product with sherwood oil/methylene dichloride/ether (1: 4: 2) column chromatography, is got sorrel thickness oily liquids 1.06g productive rate 65%.
[a]5D＝-46.9°(c＝0.677，CH
2Cl
2)，δ(ppm)＝4.08-4.13(m，1H)，3.79～3.87(m，1H)，2.55～2.61(m，2H)，2.33～2.42(m，6H)，1.63～1.70(m，2H)，1.47～1.55(m，4H)，1.35～1.39(m，2H)，1.14～1.24(m，1H)，0.86～0.88(d，3H)，0.78～0.81(d，3H，CH
3).13CNMR，17.84，18.58，24.21，25.77(×2)，25.85，32.36，53.77，54.10，55.32，69.53，71.92，166.01.IR：3306，2935，2854，2809，2775，2248，1668，1548，1469，1444，1379，1352，1302，1229，1156，1116，1042，991，913，862，748，401；HRMS(EI)：m/z(％)：calcd?for?Cl
4H
26N
2O：224.1889；found：224.1896。
1c:1-[2-(4S)-4-phenyl-4,5-dihydro-2-oxazoline-ethyl] preparation of piperidines
1-[2-(4S)-4-phenyl-4,5-dihydro-oxazol-2-yl-ethyl]-preparation of piperidine
In two mouthfuls of flasks of 100ml, add NiCl
265mg, 30mL octane or nonane or 1,2-ethylene dibromide or 1,1,2,2-tetrachloroethane, hexahydropyridine propionitrile 1.0g (7.2mmol), L-phenyl leucinol 2g, with the mixture 47h that at high temperature refluxes, stopped reaction, decompression is desolvated to remove,,, and use CHCl with the residuum water dissolution
3(20mL * 2) extraction, the organic phase anhydrous sodium sulfate drying, rotation removes and desolvates, and thick product with sherwood oil/methylene dichloride/ether (1: 4: 2) column chromatography, is got sorrel thickness oily liquids 1.87g productive rate 75%.
[a]5D＝-44.0°(c＝0.170，CH
2Cl
2)，δ(ppm)＝7.26～7.37(m，5H)，5.12～5.18(t，0.309Hz，1H)，4.55～4.61(m，1H)，4.04～4.10(t，0.93Hz，1H)，2.74～2.79(m，2H)，2.58～2.69(m，2H)，2.47(m，6H)，1.47～1.63(m，4H)，1.45～1.47(m，2H)，0.92～0.96(m，2H)；13CNMR，24.29，25.90，25.94，54.27(×2)，55.30，69.61，74.54，126.64(×2)，127.46，128.62(×2)，142.52，167.65.IR：2934，2852，2802，2773，1667，1493，1469，1454，1443，1379，1353，1302，1270，1226，1171，1156，1122，1116，991，961，913，759，700；HRMS(EI)：m/z(％)：calcd?for?Cl
4H
26N
2O：258.1732；found：258.1727。
1d:1-[2-(4S)-4-benzyl-4,5-dihydro-2-oxazoline-ethyl] preparation of piperidines
1-[2-(4S)-4-benzyl-4,5-dihydro-oxazol-2-yl-ethyl]-preparation of piperidine
In the 100mL two-mouth bottle, add anhydrous ZnCl
260mg (0.37mmol), 20mL chlorobenzene or ethylbenzene or dimethylbenzene, (boiling point is followed successively by 132 ℃, 136 ℃, 139 ℃), hexahydropyridine propionitrile 1.0g (7.2mmol), L-benzyl leucinol 2g, with the mixture 48h that at high temperature refluxes, stopped reaction, decompression is desolvated to remove, with the residuum water dissolution, and use CHCl
3(20mL * 2) extraction, the organic phase anhydrous sodium sulfate drying, rotation removes and desolvates, and thick product with sherwood oil/methylene dichloride/ether (1: 4: 2) column chromatography, is got sorrel thickness oily liquids 1.68g productive rate 85%.
[a]5D＝-50.7°(c＝0.148，CH
2Cl
2)，δ(ppm)＝7.18～7.32(m，5H)，4.35(m，1H)，4.11～4.16(t，3.66Hz，1H)，3.91～3.96(m，1H)，3.05～3.11(d，d，5.07，2.07，2H)，2.62～2.67(m，3H)，2.38～2.49(m，5H)，1.43～1.62(m，6H).13CNMR，24.42，25.99，26.07，41.84(×2)，54.37(×2)，55.41，67.31，71.58，126.60，128.61(×2)，129.38(×2)，138.04，167.05.IR：3306，3085，3061，3026，2933，2852，2802，2782，1740，1668，1632，1603，1583，1496，1454，1442，1380，1360，1306，1261，1225，1174，1156，1116，1040，988，942，924，862，802，750，700.HRMS(EI)：m/z(％)：calcd?for?Cl
4H
26N
2O：272.1889；found：272.1885.
Claims (5)
1, a kind of chiral oxazoline is characterized in that: by the compound of following chemical formulation, its chemical name is 1-[2-(4S)-4-R base-4,5-dihydro-2-oxazoline-ethyl] piperidines:
R is in the formula: L, D-CH
2CH (CH
3)
2Or L, D-CH
2(CH
3)
2Or
L, D-Ph or L, D-CH
2Ph.
2, by the preparation method of the described chiral oxazoline of claim 1, comprise synthetic, separation and purifying, it is characterized in that: described synthetic be the hexahydropyridine propionitrile and chiral amino alcohol reacted 40～50 hours in 115 ℃～150 ℃ under organic solvent and catalyzer existence condition, catalyst levels is 1～3wt% of material quantity.
3, preparation method according to claim 2 is characterized in that: in 125 ℃～145 ℃ reactions 45～48 hours, catalyst levels was the 2wt% of material quantity under organic solvent and catalyzer existence condition for hexahydropyridine propionitrile and chiral amino alcohol.
4, according to claim 2 or 3 described preparation methods, it is characterized in that: described catalyzer is selected from AlCl
3Or trichlorine rare earth compound or transition metal chloride or alkoxide compound.
5, preparation method according to claim 4 is characterized in that: described catalyzer is trichlorine rare earth compound or transition metal chloride.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101824031A (en) * | 2010-05-17 | 2010-09-08 | 合肥工业大学 | Chiral oxazoline and use thereof |
| CN101973952A (en) * | 2009-09-30 | 2011-02-16 | 合肥工业大学 | Chiral oxazoline and synthetic method thereof |
| CN102199130A (en) * | 2011-03-22 | 2011-09-28 | 罗梅 | Preparation and synthesis method for chiral oxazoline |
| CN102206215A (en) * | 2010-11-18 | 2011-10-05 | 罗梅 | Chiral compound |
| CN102212039A (en) * | 2011-04-06 | 2011-10-12 | 罗梅 | Chiral oxazoline and preparation method thereof |
| CN102229604A (en) * | 2011-04-22 | 2011-11-02 | 罗梅 | Preparation and synthetic method for chiral oxazoline |
| CN102627616A (en) * | 2012-03-21 | 2012-08-08 | 罗梅 | Chiral zinc complex |
| CN103130823A (en) * | 2013-03-16 | 2013-06-05 | 罗梅 | Chiral oxazolinyl zinc complex |
| CN103145742A (en) * | 2013-03-23 | 2013-06-12 | 罗梅 | Chiral oxazoline zinc complex |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2308415A1 (en) * | 1997-11-12 | 1999-05-20 | The Penn State Research Foundation | Transition metal-catalyzed reactions based on chiral amine oxazolinyl ligands |
| JP3464432B2 (en) * | 2000-03-10 | 2003-11-10 | 科学技術振興事業団 | Chiral rare earth metal catalyst and asymmetric aldol reaction method |
| GB0126935D0 (en) * | 2001-11-09 | 2002-01-02 | Ici Plc | Catalysts |
| CN1626524A (en) * | 2003-12-08 | 2005-06-15 | 北京大学 | Dual functions ligand compound of chirality dioxazoline, preparation and application |
| CN100389117C (en) * | 2004-08-20 | 2008-05-21 | 中国科学院上海有机化学研究所 | Oxazolinyl ring metal catalyst with chiral center, synthesis and use thereof |
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2006
- 2006-09-09 CN CNB200610096004XA patent/CN100425598C/en not_active Expired - Fee Related
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101973952A (en) * | 2009-09-30 | 2011-02-16 | 合肥工业大学 | Chiral oxazoline and synthetic method thereof |
| CN101824031A (en) * | 2010-05-17 | 2010-09-08 | 合肥工业大学 | Chiral oxazoline and use thereof |
| CN102206215A (en) * | 2010-11-18 | 2011-10-05 | 罗梅 | Chiral compound |
| CN102206215B (en) * | 2010-11-18 | 2012-08-01 | 罗梅 | Chiral compound |
| CN102199130A (en) * | 2011-03-22 | 2011-09-28 | 罗梅 | Preparation and synthesis method for chiral oxazoline |
| CN102212039A (en) * | 2011-04-06 | 2011-10-12 | 罗梅 | Chiral oxazoline and preparation method thereof |
| CN102229604A (en) * | 2011-04-22 | 2011-11-02 | 罗梅 | Preparation and synthetic method for chiral oxazoline |
| CN102627616A (en) * | 2012-03-21 | 2012-08-08 | 罗梅 | Chiral zinc complex |
| CN102627616B (en) * | 2012-03-21 | 2013-12-25 | 罗梅 | Chiral zinc complex |
| CN103130823A (en) * | 2013-03-16 | 2013-06-05 | 罗梅 | Chiral oxazolinyl zinc complex |
| CN103145742A (en) * | 2013-03-23 | 2013-06-12 | 罗梅 | Chiral oxazoline zinc complex |
| CN103145742B (en) * | 2013-03-23 | 2015-04-15 | 罗梅 | Chiral oxazoline zinc complex |
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|---|---|
| CN100425598C (en) | 2008-10-15 |
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