CN102225915B - Chiral oxazoline and synthesis method thereof - Google Patents

Chiral oxazoline and synthesis method thereof Download PDF

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CN102225915B
CN102225915B CN 201110126305 CN201110126305A CN102225915B CN 102225915 B CN102225915 B CN 102225915B CN 201110126305 CN201110126305 CN 201110126305 CN 201110126305 A CN201110126305 A CN 201110126305A CN 102225915 B CN102225915 B CN 102225915B
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metal chloride
aniline
chiral oxazoline
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CN102225915A (en
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罗梅
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Abstract

The invention provides chiral oxazoline which is characterized in that the chemical name of chiral oxazoline is 2-[(4R)-4,5-dihydro-4-R-3-oxazolinyl]phenylamine represented in a chemical formula as shown in the specification. In the formula, R is selected from -CH2CH(CH3)2 or -CH(CH3)2 or -Ph or-CH2Ph. The synthesis method comprises the following steps: reacting m-cyanoaniline with chiral alkamine for 20-30 hours in an organic solvent in the presence of a catalyst at the temperature of 110-145 DEG C; and then separating and purifying so as to obtain the target product, namely chiral oxazoline.

Description

A kind of chiral oxazoline and compound 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 oxazoline and compound method thereof.
Two, background technology
The title complex of chiral oxazoline and metal shows good catalytic activity and high enantioselectivity in many reactions such as asymmetric catalysis field 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 receives widely and paying close attention to.
Three, summary of the invention
The present invention is intended to for the asymmetric synthesis field particularly prepares chiral drug a kind of chiral catalyst efficiently is provided, and technical problem to be solved is to select corresponding raw material and set up corresponding method synthesis of chiral catalyzer.
(1) the alleged chiral oxazoline of the present invention is the compound shown in the following chemical formula:
Figure BSA00000496885400011
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 by above group constitutes are claimed 1a, 1b, 1c, 1d successively, its chemical name: 2-[(4R)-4,5-dihydro-4-R-3-oxazolinyl] aniline
That the compound method of this chiral oxazoline comprises is synthetic, separation and purifying; Described synthetic be exactly between cyano-aniline and chiral D-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 reaction formula is following:
Figure BSA00000496885400021
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 YLENE 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 1a～1d, their warps respectively 1HNMR, IR, MS characterizes, and it shows good catalytic activity as catalyzer in the Henle reaction of phenyl aldehyde.
Four, description of drawings
Fig. 1～2: be catalyzer 1a successively 1HNMR figure, 13CNMR figure.
Fig. 3～4: be catalyzer 1b successively 1HNMR figure, 13CNMR figure.
Fig. 5～6: be catalyzer 1c successively 1HNMR figure, 13CNMR figure.
Fig. 7～8: be catalyzer 1d successively 1HNMR figure, 13CNMR figure.
Five, embodiment
(1) preparation of midbody 1a～1d
1, midbody 1a2-[(4R)-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 2120mg (0.74mmol), the 40mL chlorobenzene, 3-itrile group aniline 6.0g, D-leucinol 10.0g, with the mixture 24h that at high temperature refluxes, stopped reaction, decompression is desolvated to remove,, residuum is used water dissolution, and uses CHCl 3(20mLx2) extraction, organic phase is used anhydrous sodium sulfate drying, and rotation removes and desolvates, and thick product with sherwood oil/methylene dichloride (4: 1) column chromatography, is got colourless oil liquid, productive rate 70%; [a] 5 D=+36.40 ° of (c=0.412, CH 2Cl 2): 1HNMR (500MHz, CDCl 3, 27 ℃), δ (ppm)=7.22～7.27 (m, 3H), 6.71 (d, J=7Hz, 1H), 4.42 (t,, 1H), 4.18～4.22 (m, 1H), 3.91 (t, 1H), 3.70 (s, 1H), 1.74～1.76 (m, 2H), 1.31～1.33 (m, 0.91～0.94 (m, 6H), 13CNMR (125MHz, CDCl 3, 27 ℃) and 163.23 (x2), 146.29,129.01,118.02,117.61,114.24,72.79,64.77; 45.37,25.24,22.72,22.49.IR (KBr): 3452,3322,3206,3031,2968; 2902,1644,1601,1461,1358,1321,1296,1228; 1069,963,787,762,712,699,684,549; HRMS (EI): m/z (%): calcd forC 13H 18N 2O:218.1419; Found:218.1423.
2, the preparation of midbody 1b 2-[(4R)-4,5-dihydro-4-(1 '-methylethyl)-3-oxazolinyl] aniline:
Get 3-cyano-aniline 5.0g (28.0mmol), D-valerian ammonia alcohol 10g, the preparation method is with example 1.Productive rate 75%.[a] 5 D＝+62.83°(c＝0.374，CH 2Cl 2)： 1HNMR(500MHz，CDCl 3，27℃)，δ(ppm)＝7.28～7.34(m，2H)，7.18(t，1H)，6.76～6.79(m，1H)，4.36～4.30(m，1H)，4.07～4.14(m，2H)，3.69(s，1H)，1.85～1.87(m，1H)，0.91～1.04(dd，J＝11，11Hz，6H)， 13CNMR(125MHz，CDCl 3，27℃)163.57，146.63，129.72，129.18，128.80，126.44，117.78，114.52，72.48，69.96，32.80，18.92，18.07IR(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 12H 16N 2O：204.1263；found：204.1259.
3, the preparation of midbody 1c 2-[(4S)-4,5-dihydro-4-(phenyl)-3-oxazolinyl] aniline:
Get 3-cyano-aniline 5.0g, L-benzene glycinol 10g, reactions step is with example 1, productive rate 65%; [a] 5 D=+71.21 ° of (c=0.267, CH 2Cl 3): 1HNMR (500MHz, CDCl 3, 27 ℃), δ (ppm)=7.26～7.41 (m, 8H), 6.78 (d, J=7Hz, 1H), 5.34 (t, 1Hz, 1H), 4.74 (t, J=1.5Hz, 1H), 4.23 (t, J=0.5Hz, 1H), 3.74 (s, 2H), 13CNMR (125MHz, CDCl 3, 27 ℃) and 164.59,146.19,142.07,128.98,128.39,127.25,126.41,118.15; 117.81,114.33,74.26,69.83IR (KBr): 3451,3343,3218,2956,2927,2870; 1645,1603,1586,1466,1361,1317,1228,1083,1063; 995,978,876,793,721,684,564,569; HRMS (EI): m/z (%): calcd forC 15H 14N 2O:238.1106; Found:238.1108
4, the preparation of midbody 1d 2-[(4S)-4,5-dihydro-4-(benzyl)-3-oxazolinyl] aniline:
Get 3-cyano-aniline 5.0g, D-phenylalaninol 10g, reactions step is with example 1, productive rate 68%; [a] 5 D=50.07 ° of (c=0.849, CH 2Cl 2): δ (ppm)=7.15～7.33 (m, 8H), 6.75 (d, J=7.5Hz, 1H), 4.52～4.56 (m, 1H), 4.29 (t, 1H), 4.09 (t, 1H), 3.78 (s, 2H), 3.18～3.22 (dd, J=5,5Hz, 1H), 2.68～2.73 (dd, J=9,9Hz, 1H), 13CNMR (125MHz, CDCl 3, 27 ℃) and 163.84,146.20,137.65,128.92,128.20,117.95,117.65,114.14,71.43,67.37; 41.49.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:252.1258.
5, Henle reaction is used
The preparation of 2-nitro-1 phenylethyl alcohol
Figure BSA00000496885400031
The catalyzer 1a-1d (catalytic amount is 20%) that gets 0.20mmol adds 2 milliliters anhydrous tetrahydrofuran solution, then in the little flask of 25mL; In above-mentioned solution, add the phenyl aldehyde of 0.1mL and the Nitromethane 99Min. of 0.5mL; Stirring at normal temperature, the reaction hour, carry out nmr analysis.Data are seen table 1. 1H?NMR(300MHz，CDCl 3)7.28～7.32(m，5H，Ar-H)，5.32～5.35(d，J＝9.18Hz，1H，-CH)，4.38～4.56(m，2H，-CH 2)，3.89(br，1H，-OH).
The Henle reaction catalytic effect of table 1 catalyzer 1a-1d
Catalyzer Solvent Temperature (℃) Reaction times (my god) Transformation efficiency %
1a Anhydrous THF 20-30 3d 41.3
1b Anhydrous THF 20-30 3d 33.2
1c Anhydrous THF 20-30 3d 20.4
1d Anhydrous THF 20-30 3d 20.3

Claims (3)

1. chiral oxazoline is characterized in that: by following chemical formulation, its chemical name is 2-[(4R)-4,5-dihydro-4-R-3-oxazolinyl] aniline
R is selected from-CH (CH in the formula 3) 2Or-benzyl.
2. by the compound method of the described chiral oxazoline of claim 1; Comprise synthetic, separation and purifying; It is characterized in that: described synthetic be a cyano-aniline and chiral D-amino alcohol reacted 20～30 hours down in organic solvent, 110～145 ℃ under the condition that catalyzer exists; 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. compound method according to claim 2; It is characterized in that: synthesize under the catalyzer condition and reacted 22～28 hours in organic solvent, 120～140 ℃ of refluxed; Catalyst levels is the 2wt% of material quantity, and described catalyzer is selected from rare-earth metal chloride or transition metal chloride.
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CN102659707B (en) * 2012-04-26 2014-10-08 罗梅 Preparation and application of chiral compound
CN102659706B (en) * 2012-05-10 2014-10-08 罗梅 Preparation and synthetic methodof chiral oxazoline
CN103012444A (en) * 2013-01-15 2013-04-03 罗梅 Chiral zinc complex
CN103012445B (en) * 2013-01-15 2015-12-09 罗梅 A kind of chiral zinc nitrogen complexes
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
CN103980316A (en) * 2014-06-01 2014-08-13 罗梅 Chiral phosphoramide crystal compound and use
CN104496835B (en) * 2014-12-27 2016-02-03 罗梅 A kind of generation and synthesis method of chirality ammonium salt crystal
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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CN101671312A (en) * 2009-09-30 2010-03-17 合肥工业大学 Chiral oxazolines derivative and synthesis method thereof
CN101973951A (en) * 2010-08-30 2011-02-16 罗梅 Chiral D-oxazoline and application thereof
CN102212078A (en) * 2011-04-22 2011-10-12 罗梅 Chiral oxazoline-zinc complex

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101671312A (en) * 2009-09-30 2010-03-17 合肥工业大学 Chiral oxazolines derivative and synthesis method thereof
CN101973951A (en) * 2010-08-30 2011-02-16 罗梅 Chiral D-oxazoline and application thereof
CN102212078A (en) * 2011-04-22 2011-10-12 罗梅 Chiral oxazoline-zinc complex

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