CN101671312A - Chiral oxazolines derivative and synthesis method thereof - Google Patents

Chiral oxazolines derivative and synthesis method thereof Download PDF

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CN101671312A
CN101671312A CN200910185165A CN200910185165A CN101671312A CN 101671312 A CN101671312 A CN 101671312A CN 200910185165 A CN200910185165 A CN 200910185165A CN 200910185165 A CN200910185165 A CN 200910185165A CN 101671312 A CN101671312 A CN 101671312A
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chiral
oxazolines
derivative
aniline
cyano
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罗梅
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Hefei University of Technology
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Hefei University of Technology
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Abstract

The invention relates to chiral oxazolines derivative of which the chemical name is expressed as the right chemical formula 2-[(4S)-4, 5-dihydro-4-R-3-oxazolines]aniline, wherein, R in the formula isselected from -CH2CH(CH3)2 or -CH(CH3)2 or -ph or -CH2ph. 3-aminobenzonitrile and chiral amino alcohols are reacted in an organic solvent for 20-30h at the temperature of 110-145 DEG C in the presenceof a catalyst, and then separated and purified to obtain the target product-chiral oxazolines derivant. The method can synthesize the chiral oxazolines derivative by one step, and organometallic complexes thereof have fine catalytic activity and high enantioselectvity in asymmetric synthesis of mandelic acid.

Description

A kind of chiral oxazolines derivative and synthetic method thereof
One, technical field
The present invention relates to a kind of new compound and preparation method thereof, particularly a kind of chipal compounds and preparation method thereof exactly is a kind of chiral oxazolines derivative and synthetic method thereof.
Two, background technology
The title complex of chiral oxazoline and metal shows the active and high enantioselectivity of good asymmetry catalysis in many reactions such as Diels-Alder (Di Le-Ai and spy) diene cycloaddition reaction, Michael (Mi Xieer) condensation reaction, Friedel-Crafts (Fu Ruide-carat Buddhist now) condensation reaction, Aldol (alcohol aldehyde) condensation reaction, thereby is subjected to paying close attention to widely.
The applicant is engaged in the development of asymmetric compound for a long time, once developing with hexahydropyridine propionitrile and chiral amino alcohol is the synthetic chiral oxazoline 1-[2-(4S) of raw material-R base-4,5-dihydro-2-oxazoline-ethyl] piperidines, and applied for patent of invention CN1939911A.
Three, summary of the invention
The present invention is intended to provide a kind of efficient chiral catalyst part-chiral oxazolines derivatives for the asymmetric synthesis field particularly prepares chiral drug, and technical problem to be solved is to select corresponding raw material and set up corresponding method synthesis of chiral catalyst ligand.
(1) the alleged chiral oxazolines derivative of the present invention is the compound shown in the following chemical formula:
Figure G200910185165XD00011
R is selected from isobutyl-(CH in the formula 2CH (CH 3) 2) or sec.-propyl (CH (CH 3) 2) or phenyl is (ph) or benzyl (CH 2Ph).
Four kinds of chiral oxazolines derivatives that are made of above group claim chiral oxazoline ligand 1 a, 1b, 1c, 1d in the following description successively, are the parts that constitutes a metal-organic complex.Its chemical name: 2-[(4S)-4,5-dihydro-4-R-3-oxazolinyl] aniline.
The synthetic method of this chiral oxazolines derivative is raw material with a cyano-aniline (3-cyano-aniline) with chiral amino alcohol, comprise synthetic, separation and purifying, described synthetic be exactly between cyano-aniline and chiral amino alcohol in organic solvent, have catalyzer to exist condition under reacted 20～30 hours in 110～145 ℃, catalyst levels is the 1～3wt% (weight percent, down together) of material quantity.
Preferred 120～140 ℃ of reactions 22～28 hours, catalyst levels is the 2wt% of material quantity
Its chemical equation is as follows:
Figure G200910185165XD00021
Described chiral 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 3-cyano-aniline respectively, the R base that it carries is followed successively by-CH 2CH (CH 3) 2,-CH (CH 3) 2,-Ph ,-CH 2Ph.
The organic solvent that described organic solvent selects inert, its boiling point and temperature of reaction to adapt is such as picoline or chlorobenzene or dichlorobenzene or ethylbenzene or dimethylbenzene or propyl benzene or alkane or halogenated alkane etc.At this moment synthetic can under refluxad carrying out.
Described catalyzer is selected from rare-earth metal chloride (trichlorine rare earth) or transition metal chloride (ZnCl 2, CuCl 2, NiCl 2, CoCl 2, FeCl 3, MnCl 2Deng) or AlCl 3Or alkoxide compound (tetraisopropoxy titanium, dimethyl dichloro stannane etc.).Preferred trichlorine rare earth or transition metal chloride.
Present method one-step synthesis chiral oxazoline ligand 1 a～1d, their warps respectively 1HNMR, IR, MS characterizes, and its a metal-organic complex shows good catalytic activity and high enantioselectivity in the amygdalic acid asymmetric synthesis.
Four, description of drawings
Fig. 1～2: be chiral oxazoline ligand 1 a successively 1HNMR figure, 13CNMR figure.
Fig. 3～4: be chiral oxazoline ligand 1 b successively 1HNMR figure, 13CNMR figure.
Fig. 5～6: be chiral oxazoline ligand 1 c successively 1HNMR figure, 13CNMR figure.
Fig. 7～8: be chiral oxazoline ligand 1 d successively 1HNMR figure, 13CNMR figure.
Five, embodiment
(the preparation of a) chiral oxazoline ligand 1 a～1d
1, ligand 1 a2-[(4S)-4,5-dihydro-4-(1 ', 1 '-dimethyl ethyl)-the 3-oxazolinyl] preparation of aniline in the 100mL two-mouth bottle, under the anhydrous and oxygen-free condition, add anhydrous ZnCl 260mg (0.37mmol), the 40mL chlorobenzene, a cyano-aniline 1.0g (8.47mmol), L-leucinol 3g, with mixture back flow reaction 24h, stopped reaction, decompression is desolvated to remove,,, and use CHCl with the residuum water dissolution 3(20mLx2) extraction, the organic phase anhydrous sodium sulfate drying, rotation removes and desolvates, and thick product is carried out column chromatography with sherwood oil/methylene dichloride (4: 1) for eluent, gets colourless oil liquid 1.1g, productive rate 66%;
[a] 5 D＝-58.21°(c＝0.46，CHCl 3)： 1HNMR(500MHz，CDCl 3，27℃)，δ(ppm)＝7.19～7.24(m，2H)，7.12(t，J＝0.5Hz，1H)，6.70(d，J＝8Hz，1H)，4.32(t，，1H)，4.18～4.22(m，2H)，3.85(t，1H)，3.78(s，1H)，1.70～1.73(m，1H)，1.58～1.64(m，1H)，1.24～1.29(m，1H)，0.86～0.89(m，6H)， 13CNMR(125MHz，CDCl 3，27℃)163.49(x2)，146.66，129.21，128.72，118.14，117.83，114.45，72.89，64.95，45.57，25.44，22.92，22.72.IR(KBr)：3451，3343，3219，3055，2956，2927，2870，1644，1603，1586，1496，1466，1385，1361，1330，1317，1287，1228，1169，1133，1083，1063，995，978，923，876，793，721，684，568，536，434；HRMS(EI)：m/z(％)：calcd?for?C 13H 18N 2O：218.1419；found：218.1423.
2, ligand 1 b 2-[(4S)-4,5-dihydro-4-(1 '-methylethyl)-3-oxazolinyl] preparation of aniline:
Get 3-cyano-aniline 1.0g (5.6mmol), L-valerian ammonia alcohol 3g, the preparation method is with example 1.Productive rate 65%, [a] 5 D=-71.02 ° of (c=0.14, CHCl 3): 1HNMR (500MHz, CDCl 3, 27 ℃), δ (ppm)=7.24～7.28 (m, 2H), 7.12 (t, J=0.5Hz, 1H), 6.63 (d, J=7.5Hz, 1H), 4.32 (t, J=0.5Hz, 1H), 4.02～4.08 (m, 2H), 1.78～1.82 (m, and 1H) 0.86～0.98 (dd, J=6.5,6.5Hz, 6H) 13CNMR (125MHz, CDCl 3, 27 ℃) and 163.52,146.39,129.16,118.25,117.78,114.46,72.32,69.87,32.68,18.89,17.94.IR (KBr): 3451,3343,3219,3055,3019,2959,2928,2903,2873,2721,2644,1933,1849,1648,1605,1586,1533,1495,1465,1386,1359,1325,1292,1269,1230,1178,1165,1115,1106,1083,1067,995,973,925,876,853,793,715,684,564,536,441; HRMS (EI): m/z (%): calcd for C 13H 18N 2O:204.1263; Fbund:204.1258.
3, ligand 1 c 2-[(4S)-4,5-dihydro-4-(phenyl)-3-oxazolinyl] preparation of aniline:
Get 3-cyano-aniline 1.0g, L-benzene glycinol 3g, reactions steps is with example 1, productive rate 60%; [a] 5 D=-10.46 ° of (c=0.09, CHCl 3): 1HNMR (500MHz, CDCl 3, 27 ℃), δ (ppm)=7.18～7.40 (m, 8H), 6.80 (d, J=7.5Hz, 1H), 5.34 (t, 1H), 4.75 (t, J=0.5Hz, 1H), 4.23 (t, J=0.5Hz, 1H), 3.75 (s, 2H), 13CNMR (125MHz, CDCl 3, 27 ℃) and 165.02,146.52,142.46,129.41,128.81,127.68,126.83,118.25,118.66,118.26,114.78,74.90,70.05.IR (KBr): 3451,3343,3219,3055,3019,2959,2928,2903,2873,2721,2644,1933,1849,1648,1605,1586,1533,1495,1465,1386,1359,1325,1292,1269,1230,1178,1165,1115,1106,1083,1067,995,973,925,876,853,793,715,684,564,536,441; HRMS (EI): m/z (%): calcd for C 15H 14N 2O:238.1106; Found:238.1109.
4, ligand 1 d 2-[(4S)-4,5-dihydro-4-(benzyl)-3-oxazolinyl] preparation of aniline:
Get 3-cyano-aniline 1.0g, L-phenylalaninol 3g, reactions steps is with example 1, productive rate 63%; [a] 5 D=+7.66 ° of (c=0.32, CHCl 3): δ (ppm)=7.15～7.32 (m, 8H), 6.74 (d, J=8Hz, 1H), 4.52～4.56 (m, 1H), 4.29 (t, 1H), 4.09 (t, 1H), 3.73 (s, 2H), 3.19～3.23 (dd, J=5,4.5Hz, 1H), 2.68～2.72 (dd, J=9,9.5Hz, 1H) 13CNMR (125MHz, CDCl 3, 27 ℃) and 164.30,146.52,138.04,129.33,128.62,126.56,118.46,118.09,114.59,71.86,67.78,41.88.IR (KBr): 3455,3343,3216,3060,3026,2898,1947,1644,1602,1533,1496,1463,1454,1360,1320,1291,1230,1180,1165,1085,1030,995,975,928,874,793,754,704,590,561,535,504; HRMS (EI): m/z (%): calcd for C 16H 16N 2O:252.1263; Found:252.1262.

Claims (3)

1, a kind of chiral oxazolines derivative is characterized in that: by following chemical formulation, its chemical name is 2-[(4S)-4,5-dihydro-4-R-3-oxazolinyl] aniline
Figure A2009101851650002C1
R is selected from-CH in the formula 2CH (CH 3) 2Or-CH (CH 3) 2Or-ph or-CH 2Ph.
2, the synthetic method of chiral oxazolines derivative as claimed in claim 1, with a cyano-aniline and chiral amino alcohol is raw material, comprise synthetic, separation and purifying, it is characterized in that: described synthesizing is that a cyano-aniline and chiral amino alcohol have in organic solvent under the catalyzer existence condition in 110～145 ℃ of following reactions 20～30 hours, catalyst levels is 1～3wt% of material quantity, and described catalyzer is selected from rare-earth metal chloride or transition metal chloride or AlCl 3Or alkoxide compound.
3, synthetic method according to claim 2, it is characterized in that: synthesize in organic solvent, to have under the catalyzer existence condition and reacted 22～28 hours down in 120～140 ℃, catalyst levels is the 2wt% of material quantity, and described catalyzer is selected from rare earth metal oxychloride or transition metal chloride.
CN200910185165A 2009-09-30 2009-09-30 Chiral oxazolines derivative and synthesis method thereof Pending CN101671312A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
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
CN102225915A (en) * 2011-05-16 2011-10-26 罗梅 Chiral oxazoline and synthesis method thereof
CN102229604A (en) * 2011-04-22 2011-11-02 罗梅 Preparation and synthetic method for chiral oxazoline
CN102898393A (en) * 2012-11-08 2013-01-30 罗梅 Method for synthesizing chiral oxazoline
CN113861243A (en) * 2021-09-14 2021-12-31 中国科学院上海有机化学研究所 NCP ligand, metal iridium complex thereof, preparation method and application

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Publication number Priority date Publication date Assignee Title
CN103044346B (en) * 2013-01-12 2014-05-07 罗梅 Chiral oxazoline and synthesis method thereof
CN103319428B (en) * 2013-07-07 2015-01-07 罗梅 Chiral oxazoline and synthesis method thereof
CN103342685A (en) * 2013-07-10 2013-10-09 罗梅 Chiral oxazoline and synthetic method thereof

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CN100425598C (en) * 2006-09-09 2008-10-15 合肥工业大学 Chiral oxazoline and its production
CN100493714C (en) * 2007-07-31 2009-06-03 合肥工业大学 Use of chiral oxazoline
CN101279954A (en) * 2008-05-14 2008-10-08 合肥工业大学 Chiral oxazoline and synthetic method thereof
CN101671312A (en) * 2009-09-30 2010-03-17 合肥工业大学 Chiral oxazolines derivative and synthesis method thereof

Cited By (7)

* Cited by examiner, † Cited by third party
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
CN102229604A (en) * 2011-04-22 2011-11-02 罗梅 Preparation and synthetic method for chiral oxazoline
CN102225915A (en) * 2011-05-16 2011-10-26 罗梅 Chiral oxazoline and synthesis method thereof
CN102225915B (en) * 2011-05-16 2012-12-19 罗梅 Chiral oxazoline and synthesis method thereof
CN102898393A (en) * 2012-11-08 2013-01-30 罗梅 Method for synthesizing chiral oxazoline
CN113861243A (en) * 2021-09-14 2021-12-31 中国科学院上海有机化学研究所 NCP ligand, metal iridium complex thereof, preparation method and application
CN113861243B (en) * 2021-09-14 2023-05-12 中国科学院上海有机化学研究所 NCP ligand, metal iridium complex thereof, preparation method and application

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