CN1765503A - Quarternary ammonium salt of quinine compound, its preparation method and use - Google Patents
Quarternary ammonium salt of quinine compound, its preparation method and use Download PDFInfo
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- CN1765503A CN1765503A CN200510041391.2A CN200510041391A CN1765503A CN 1765503 A CN1765503 A CN 1765503A CN 200510041391 A CN200510041391 A CN 200510041391A CN 1765503 A CN1765503 A CN 1765503A
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- njucci
- quaternary amine
- compound
- cinchona alkaloid
- alkaloid compound
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- -1 quinine compound Chemical class 0.000 title claims abstract description 25
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Natural products C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 title claims description 35
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 title claims description 33
- 235000001258 Cinchona calisaya Nutrition 0.000 title claims description 18
- 229960000948 quinine Drugs 0.000 title claims description 18
- 238000002360 preparation method Methods 0.000 title claims description 17
- 150000003863 ammonium salts Chemical class 0.000 title 1
- 241000157855 Cinchona Species 0.000 claims abstract description 38
- 235000021513 Cinchona Nutrition 0.000 claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 63
- 150000001412 amines Chemical group 0.000 claims description 36
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 22
- 229930013930 alkaloid Natural products 0.000 claims description 18
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 18
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 18
- 238000001556 precipitation Methods 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 16
- 239000012047 saturated solution Substances 0.000 claims description 15
- 239000003444 phase transfer catalyst Substances 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- GZHPNIQBPGUSSX-UHFFFAOYSA-N 2-bromo-1-(3-nitrophenyl)ethanone Chemical group [O-][N+](=O)C1=CC=CC(C(=O)CBr)=C1 GZHPNIQBPGUSSX-UHFFFAOYSA-N 0.000 claims description 6
- MBUPVGIGAMCMBT-UHFFFAOYSA-N 2-bromo-1-(4-nitrophenyl)ethanone Chemical compound [O-][N+](=O)C1=CC=C(C(=O)CBr)C=C1 MBUPVGIGAMCMBT-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 3
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical group [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 claims description 2
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 32
- 239000003054 catalyst Substances 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical group [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 abstract 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 37
- 238000006243 chemical reaction Methods 0.000 description 29
- 235000019441 ethanol Nutrition 0.000 description 26
- 239000000243 solution Substances 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000002329 infrared spectrum Methods 0.000 description 13
- 241000288027 Chrysolophus pictus Species 0.000 description 12
- 238000013019 agitation Methods 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 238000000151 deposition Methods 0.000 description 12
- 239000012264 purified product Substances 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- 238000002447 crystallographic data Methods 0.000 description 9
- 238000006555 catalytic reaction Methods 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical class CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 6
- ARKIFHPFTHVKDT-UHFFFAOYSA-N 1-(3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=CC([N+]([O-])=O)=C1 ARKIFHPFTHVKDT-UHFFFAOYSA-N 0.000 description 4
- YQYGPGKTNQNXMH-UHFFFAOYSA-N 4-nitroacetophenone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1 YQYGPGKTNQNXMH-UHFFFAOYSA-N 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 238000003408 phase transfer catalysis Methods 0.000 description 4
- 239000003513 alkali Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 150000002373 hemiacetals Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- JTWHVBNYYWFXSI-UHFFFAOYSA-N 2-nitro-1-phenylethanone Chemical compound [O-][N+](=O)CC(=O)C1=CC=CC=C1 JTWHVBNYYWFXSI-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 238000006008 O'Donnell synthesis reaction Methods 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- CGPHVFCVSXSPEY-UHFFFAOYSA-N pentan-3-one;pyridine Chemical compound CCC(=O)CC.C1=CC=NC=C1 CGPHVFCVSXSPEY-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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Abstract
Disclosed a quaternary amines salt of cinchona bases compound is in following structural formula: the R' is H or CH3O; the Ar is 3-nitrobenzene, 4-nitrobenzene or 4-pyridinyl. The inventive quaternary amines salt of cinchona bases compound is a half ketal formed by 9-hydroxy of cinchona bases compound and the carbonyl of aryl ethanone to form a six-membered ring. Compared to the ether linkage formed by 9-hydroxy and alkyl of second generation and third generation handle transfer catalyst, the C-O-C linkage of said annular half ketal has stronger rigidity; while the inventive handle transfer catalyst has five handle centers compared to four handle centers of common one. Therefore, the invention is a better handle transfer catalyst. In addition, the invention discloses its manufacturing method.
Description
Technical field
The present invention relates to cinchona alkaloid quaternary amine and asymmetry catalysis phase transfer catalyst.
Background technology
The asymmetry catalysis phase transfer catalysis (PTC) since it easy and simple to handle, reaction condition is gentle and environmental protection is considered to a field exciting and the most with fastest developing speed in organic chemistry is synthetic, therefore the research of asymmetric phase transfer catalysis (PTC) aspect has also obtained swift and violent development in the past few years.Derive and the quaternary amine that comes has been an important part all chiral phase-transfer catalysts that grow up from golden pheasant soda compounds, developed into the third generation so far.After the N-benzyl cinchonine salt of developing continue pioneer Dolling research group is as catalyst, the use that O ' Donnell etc. are successful this catalyst asymmetry catalysis the asymmetric alkylation reaction of glycine tertiary butyl ester derivative, Corey and Lygo etc. have then found the golden pheasant soda derivative of 9 replacement anthracene methyl classes simultaneously, this compounds has well shielded nitrogen-atoms, having improved the level of asymmetric induction greatly, was the development that a series of reports of representative have then well promoted novel golden pheasant soda derivative with the catalyst of Jew-Park dimer class afterwards.In addition, also asymmetric phase-transfer-catalyzed reactions, represented very high catalytic activity (seeing Table 1) from the synthetic C2-axle amine salt of chirality binaphthol now.
Table 1
Summary of the invention
The inventor finds, in golden pheasant soda compounds (quinine, chinidine, cinchonine and cinchonidine) and during the N alkylated reaction of the nitrated acetophenone of 2-bromo-3 ' (or 4 '-) or 2-bromo-4 '-pyridine ethyl ketone, generate an amazing quaternary amine, this compound is different from the quaternary amine of the corresponding golden pheasant soda compounds that we expect, but has formed intramolecular hemiketal between the carbonyl of the 9-hydroxyl of golden pheasant soda compounds and nitro-acetophenone or pyridine ethyl ketone and constituted a hexatomic ring.X-ray single crystal diffraction has been determined their structure, the hemiketal hexatomic ring that tangible compound as can be seen has a boat form from structure chart, compare with the ehter bond that alkyl forms with 9-hydroxyl in the chiral phase-transfer catalyst of the second generation and the third generation, the C-O-C key of this ring-type hemiketal class has stronger rigidity.Simultaneously, the chiral phase-transfer catalyst that we synthesized has five chiral centres and general has only four chiral centres, (sees Fig. 1～Figure 10) make them become a better chiral phase-transfer catalyst just because of its strong rigidity and more chiral centre.
Technical scheme of the present invention is as follows:
The quaternary amine of one class cinchona alkaloid compound, it has following general structure:
Wherein R is H or CH
3O; Ar is 3-nitrobenzophenone, 4-nitrobenzophenone or 4-pyridine radicals.
A kind of method for preparing the quaternary amine of above-mentioned cinchona alkaloid compound, it be with cinchona alkaloid compound in alcohol saturated solution with the 2-bromine aryl methyl ketone alcohol saturated solution that waits amount of substance in stirring at room, separate out precipitation, precipitation is the quaternary amine of cinchona alkaloid compound of the present invention.
The preparation method of the quaternary amine of above-mentioned cinchona alkaloid compound, described cinchona alkaloid compound is quinine, chinidine, cinchonine or cinchonidine.
The preparation method of the quaternary amine of above-mentioned cinchona alkaloid compound, described 2-bromine aryl methyl ketone can be 2-bromo-3 '-nitro-acetophenone, 2-bromo-4 '-nitro-acetophenone or 2-bromo-4 '-pyridine ethyl ketone.
The quaternary amine of above-mentioned cinchona alkaloid compound can be used as chiral phase-transfer catalyst.
The hemiacetal class hexatomic ring quaternary amine of deriving from the golden pheasant soda has rigidity and contains various N, O functional group, and this just makes them that potential application is arranged in organic catalysis.We derive and the quaternary ammonium salts chiral phase-transfer catalyst that comes is used for the alkylated reaction of tert-butyl glycinate derivative from quinine this, and this class reaction can be used as a very useful approach of synthesis of natural or artificial a-amino acid.With above-mentioned quaternary amine is catalyst, and we have studied the reactivity and the enantio-selectivity of the reaction of benzyl Beckman.Reaction is to add the phase transfer catalyst of 10mol% to carry out under 4 ℃ or room temperature condition in toluene and KOH mixed solution.As shown in table 2, all chiral quaternary ammonium salts all show high yield and good enantio-selectivity to this benzyl reaction.Chiral phase-transfer catalyst NJUCCI-2 and NJUCCI-5 have enantio-selectivity up to 90%-92%, will increase if reaction temperature is reduced to-25 ℃ then chiral selectivity from 4 ℃.And NJUCCI-1～NJUCCI-12 has caused different chiral configurations to the chiral selectivity difference of product.We also utilize NJUCCI-2 with nucleopilic reagent tert-butyl glycinate to be carried out alkylated reaction as chiral phase-transfer catalyst under reaction condition as above.The results are shown in table 3.Under all conditions, all obtained the high chemical yield of 73-90%, best enantio-selectivity is up to 97%.The selectivity ratios golden pheasant alkali benzyl quaternary amine of enantiomer and 9-anthracene methyl golden pheasant alkali quaternary amine high 5-10% under similarity condition.It should be noted that the configuration of the product that obtains to some extent all be S, and all be the R configuration with the product of 9-anthracene methyl golden pheasant alkali quaternary amine catalysis.In addition, chiral phase-transfer catalyst can well be recycled from aqueous solvent.
In a word, we have synthesized a class and have had the novel golden pheasant sodium quaternary amine of the novelty of rigid structure, and have determined the hemiacetal six-membered ring structure of this compounds by X-ray single crystal diffraction.Then this class golden pheasant sodium quaternary amine there is good enantio-selectivity as the asymmetric alkylation reaction that chiral phase-transfer catalyst applies to the tert-butyl glycinate derivative.
Description of drawings
Fig. 1 is the crystal structure figure of NJUCCI-1 compound;
Fig. 2 is the crystal structure figure of NJUCCI-2 compound;
Fig. 3 is the crystal structure figure of NJUCCI-3 compound;
Fig. 4 is the crystal structure figure of NJUCCI-4 compound;
Fig. 5 is the crystal structure figure of NJUCCI-5 compound;
Fig. 6 is the crystal structure figure of NJUCCI-6 compound;
Fig. 7 is the crystal structure figure of NJUCCI-7 compound;
Fig. 8 is the crystal structure figure of NJUCCI-9 compound;
Fig. 9 is the crystal structure figure of NJUCCI-10 compound;
Figure 10 is the crystal structure figure of NJUCCI-11 compound.
The specific embodiment
Equation 1
The preparation of embodiment 1.NJUCCI-1 compound
After waiting the quinine of amount of substance and 2-bromo-4 '-nitro-acetophenone to be made into saturated solution with the ethanol dissolving respectively, the latter's solution is at room temperature splashed into the former, drip and finish, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-1) of thick product quinine 4 '-nitro-acetophenone quaternary amine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 81%.10
-3Mol/L[α]=-76.33 (methanol solutions).Elementary analysis (%): C59.11 (59.20); H5.28 (5.30); N9.85 (9.93) is C based on molecular formula
28H
30N
4O
5Br
Infrared spectrum data: (KBr, cm
-1): 3436 (m), 2889 (w), 1620 (m), 1546 (s), 1509 (m), 1458 (w), 1352 (s), 1233 (m), 1058m), 830 (w), 695 (w).
Crystallographic data: space group: P2 (1) 2 (1) 2 (1)
Cell parameter: a=7.9889 (13) , b=15.601 (3) , c=25.589 (5)
α＝90.00°；β＝90.00°；γ＝90.00°
V＝3189.2(9)
3，Z＝4
The compound crystal structure is seen Fig. 1.
The preparation of embodiment 2.NJUCCI-2
With after waiting the quinine of amount of substance and 2-bromo-3 '-nitro-acetophenone dissolving being made into saturated solution in ethanol respectively, the latter's solution is at room temperature splashed into the former, drip and finish, at room temperature continue magnetic agitation, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-2) of thick product quinine 3 '-nitro-acetophenone quaternary amine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 85%.10
-3Mol/L[α]=+ 99.24 (methanol solutions).Elementary analysis (%): C59.11 (59.21); H5.28 (5.31); N9.85 (9.95) is C based on molecular formula
28H
30N
4O
5Br.
Infrared spectrum data: (KBr, cm
-1): 3341 (m), 2956 (w), 1620 (m), 1521 (s), 1468 (w), 1342 (s), 1236 (m), 1051 (m), 856 (m), 704 (w).
Crystallographic data: space group: P2 (1) 2 (1) 2 (1)
α＝90.00°，β＝90.00°，γ＝90.00°
V＝2579.5(6)，Z＝4
The compound crystal structure is seen Fig. 2.
The preparation of embodiment 3.NJUCCI-3
With after waiting the quinine of amount of substance and 2-bromo-4 '-pyridine dissolving being made into saturated solution in ethanol respectively, the latter's solution is at room temperature splashed into the former, drip and finish, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-3) of thick product quinine 4 '-pyridine ethyl ketone quaternary amine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 79%.10
-3Mol/L[α]=-76.33 (methanol solutions).
Infrared spectrum data: (KBr, cm
-1): 3407 (m), 2939 (w), 1617 (m), 1513 (s), 1467 (m), 1238 (m), 1066 (m), 861 (s), 740 (w). elementary analysis (%): C61.90 (61.85); H5.73 (5.60); N8.02 (8.10) is C based on molecular formula
27H
30N
3O
3Br.
Carry out X-ray diffraction because the NJUCCI-3 Bromide is difficult to obtain suitable monocrystal, we are with NJUCCI-3 ethanolic solution and KPF
6Aqueous solution come cocrystallization to obtain good NJUCCI-3-PF
6Monocrystalline (not having Br), the X ray crystal diffraction has obtained NJUCCI-3-PF
6Crystal structure, undoubtedly Fig. 3 has shown in the process of quinine and the reaction of 2-bromo-4 '-pyridine ethyl ketone intramolecular hemiketal reaction has taken place equally.
The crystallographic data of its hexafluorophosphate: space group: P2 (1) 2 (1) 2 (1)
Cell parameter: a=7.96 (3) , b=18.28 (5) , c=19.31 (6)
α＝90.00°，β＝90.00°，γ＝90.00°
V＝2809(14)，Z＝4
The compound crystal structure is seen Fig. 3.
Equation 2
The preparation of embodiment 4.NJUCCI-4
With after waiting the quinine set of amount of substance and 2-bromo-4 '-nitro-acetophenone dissolving being made into saturated solution in ethanol respectively, the latter's solution is at room temperature splashed into the former, drip and finish, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-4) of thick product quinine set 4 '-nitro-acetophenone quaternary amine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 82%.10
-3Mol/L[α]=+ 118.32 (methanol solutions).Elementary analysis (%): C59.11 (59.20); H5.28 (5.30); N9.85 (9.93) is C based on molecular formula
28H
30N
4O
5Br.
Infrared spectrum data: (KBr, cm
-1): 3421 (m), 2968 (w), 1620 (m), 1521 (s), 1463 (w), 1351 (s), 1228 (m), 1026 (m), 856 (m), 704 (w).
Crystallographic data: space group: P2 (1) 2 (1) 2 (1)
Cell parameter: a=8.4226 (11) , b=12.5454 (16) , c=30.435 (4)
α＝90.00°，β＝90.00°，γ＝90.00°
V＝3215.9(7)
3，Z＝4
The compound crystal structure is seen Fig. 4.
The preparation of embodiment 5.NJUCCI-5
With after waiting the quinine set of amount of substance and 2-bromo-3 '-nitro-acetophenone dissolving being made into saturated solution in ethanol respectively, the latter's solution is at room temperature splashed into the former, drip and finish, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-5) of thick product quinine set 3 '-nitro-acetophenone quaternary amine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 83%.10
-3Mol/L[α]=+ 118.32 (methanol solutions).Elementary analysis (%): C59.11 (59.20); H5.28 (5.30); N9.85 (9.93) is C based on molecular formula
28H
30N
4O
5Br.
Infrared spectrum data: (KBr, cm
-1): 3180 (m), 2987 (w), 1619 (m), 1533 (s), 1460 (w), 1349 (s), 1232 (m), 1019 (m), 861 (m), 740 (w).
Crystallographic data: space group: P2 (1) 2 (1) 2 (1)
Cell parameter: a=18.650 (4) , b=18.650 (4) , c=8.396 (3)
α＝90.00°，β＝90.00°，γ＝90.00°
V＝2920.5(13)
3，Z＝4
The compound crystal structure is seen Fig. 5.
The preparation of embodiment 6.NJUCCI-6
With after waiting the quinine set of amount of substance and 2-bromo-4 '-pyridine ethyl ketone dissolving being made into saturated solution in ethanol respectively, the latter's solution is at room temperature splashed into the former, drip and finish, at room temperature continue magnetic agitation, react, TLC determines reaction end, there are a large amount of precipitations to generate, filtering-depositing gets the hemiketal (code name is NJUCCI-6) of thick product quinine set 4 '-pyridine ethyl ketone quaternary amine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 80%.
Infrared spectrum data: (KBr, cm
-1): 3446 (br, s), 2997 (w), 1613 (m), 1507 (w), 1469 (m), 1233 (m), 1107 (s), 1080 (m), 924 (w), 837 (m). elementary analysis (%): C61.90 (61.85); H5.73 (5.60); N8.02 (8.10) is C based on molecular formula
27H
30N
3O
3Br.
Crystallographic data: space group: P2 (1)
Cell parameter: a=10.4737 (7) , b=8.0932 (5) , c=16.3073 (11)
α＝90.00°，β＝91.5980(10)(2)°，γ＝90.00°
V＝1381.76(16)
3，Z＝2
The compound crystal structure of its perchlorate is seen Fig. 6.
Equation 3
The preparation of embodiment 7.NJUCCI-7
Fixed and 2-bromo-4 '-nitro-acetophenone is after dissolving is made into saturated solution in ethanol respectively with the cinchonine that waits amount of substance, and the latter's solution is at room temperature splashed into the former, drips complete, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-7) of the fixed 4 '-nitro-acetophenone quaternary amine of thick product cinchonine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 85%
Infrared spectrum data: (KBr, cm
-1): 3406 (M), 3159 (W), 2043 (W), 1521 (S), 1468 (W), 1351 (M) 1107 (S), 994 (W), 768 (W). elementary analysis (%): C60.17 (60.25); H5.20 (5.22); N10.40 (10.48) is C based on molecular formula
27H
28N
4O
4Br.
Crystallographic data: space group: P2 (1) 2 (1) 2 (1)
Cell parameter: a=8.6875 (12) , b=14.061 (2) , c=15.702 (3)
α＝90.00°，β＝90.00°，γ＝90.00°
V＝2903.4(7)
3，Z＝4
The compound crystal structure of its perchlorate is seen Fig. 7.
The preparation of embodiment 8.NJUCCI-8
Fixed and 2-bromo-3 '-nitro-acetophenone is after dissolving is made into saturated solution in ethanol respectively with the cinchonine that waits amount of substance, and the latter's solution is at room temperature splashed into the former, drips complete, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-8) of the fixed 3 '-nitro-acetophenone quaternary amine of thick product cinchonine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 76%
Infrared spectrum data: (KBr, cm
-1): IR spectrum (KBr, cm
-1): 3376 (m), 3175 (w), 1620 (m), 1533 (s), 1461 (m), 1351 (s), 1223 (w), 1054 (m), 861 (m), 719 (w). elementary analysis (%): C61.90 (61.85); H5.73 (5.60); N8.02 (8.10) is C based on molecular formula
27H
30N
3O
3Br.
The preparation of embodiment 9.NJUCCI-9
Fixed and 2-bromo-4 '-pyridine ethyl ketone is after dissolving is made into saturated solution in ethanol respectively with the cinchonine that waits amount of substance, and the latter's solution is at room temperature splashed into the former, drips complete, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-9) of the fixed 4 '-pyridine ethyl ketone quaternary amine of thick product cinchonine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 84%
Infrared spectrum data: (KBr, cm
-1): 3412 (br, s), 2958 (m), 2474 (w), 1621 (s), 1510 (s), 1432 (m), 1231 (s), 1108 (s), 1025 (m), 922 (w), 832 (m). elementary analysis (%): C63.22 (63.25); H5.67 (5.64); N8.51 (8.60) is C based on molecular formula
26H
22N
3O
2Br.
Crystallographic data: space group: P2 (1) 2 (1) 2 (1)
Cell parameter: a=8.0120 (16) , b=17.451 (4) , c=17.865 (4)
α＝90.00°，β＝90.00°，γ＝90.00°
V＝2497.8(9)
3，Z＝4
The compound crystal structure of its perchlorate is seen Fig. 8.
Equation 4
The preparation of embodiment 10.NJUCCI-10
With after waiting the cinchonine of amount of substance and 2-bromo-4 '-nitro-acetophenone dissolving being made into saturated solution in ethanol respectively, the latter's solution is at room temperature splashed into the former, drip and finish, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-10) of thick product cinchonine 4 '-nitro-acetophenone quaternary amine, and 95% ethyl alcohol recrystallization purified product gets white crystal.Productive rate 81%
Infrared spectrum data: (KBr, cm
-1): 3416 (m), 2973 (w), 1598 (m), 1521 (s), 1464 (m), 1350 (s), 1289 (w), 1049 (s), 857 (m), 740 (w). elementary analysis (%): C61.90 (61.85); H5.73 (5.60); N8.02 (8.10) is C based on molecular formula
27H
30N
3O
3Br.
The compound crystal structure of its perchlorate is seen Fig. 9.
The preparation of embodiment 11.NJUCCI-11
With after waiting the cinchonine of amount of substance and 2-bromo-3 '-nitro-acetophenone dissolving being made into saturated solution in ethanol respectively, the latter's solution is at room temperature splashed into the former, drip and finish, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-11) of thick product cinchonine 3 '-nitro-acetophenone quaternary amine, and 95% ethyl alcohol recrystallization purified product gets white crystal, productive rate 81%.
Infrared spectrum data: (KBr, cm
-1): 3345 (m), 3210 (w), 1700 (m), 1531 (s), 1462 (w), 1351 (s), 1223 (w), 1086 (b, m), 857 (m), 740 (w). elementary analysis (%): C61.90 (61.85); H5.73 (5.60); N8.02 (8.10) is C based on molecular formula
27H
30N
3O
3Br.
The compound crystal structure:
Crystallographic data: space group: P2 (1)
Cell parameter: a=12.470 (2) , b=14.061 (2) , c=15.702 (3)
α＝90.00°，β＝90.09(2)°，γ＝90.00°
V＝2753.2(9)
3，Z＝2
The compound crystal structure of its hexafluorophosphate is seen Figure 10.
The preparation of embodiment 12.NJUCCI-12
Deng the cinchonine of amount of substance and 2-bromo-4 '-pyridine ethyl ketone after dissolving is made into saturated solution in ethanol respectively, the latter's solution is at room temperature splashed into the former, drip and finish, at room temperature continue magnetic agitation, react, TLC determines reaction end, has a large amount of precipitations to generate.Filtering-depositing gets the hemiketal (code name is NJUCCI-12) of thick product cinchonine 4 '-pyridine ethyl ketone quaternary amine, and 95% ethyl alcohol recrystallization purified product gets white crystal.Productive rate 78%
Infrared spectrum data: (KBr, cm
-1): 3396 (br, s), 3003 (m), 2720 (w), 1608 (m), 1511 (m), 1460 (m), 1223 (w), 1124 (m), 1062 (s), 1010 (m), 829 (m), 775 (m). elementary analysis (%): C63.22 (63.25); H5.67 (5.64); N8.51 (8.60) is C based on molecular formula
26H
22N
3O
2Br.
Embodiment 13. application of compound of the present invention in asymmetric catalysis
29.6mg tert-butyl glycinate and 12 μ L benzyl bromines add 10mol% in 1ml toluene and 0.1ml concentration are 50% KOH mixed solution compound of the present invention is as phase transfer catalyst 18-20 hour (equation 5) of reaction under 4 ℃ or room temperature condition, TLC follows the tracks of reaction, ultimate yield is calculated as gross production rate, and the e.e value obtains by the high pressure liquid chromatographic analysis that uses the DAICELCHIRALOD-H post.NJUCCI-(1-6) catalytic activity (configuration is determined reference literature) more as shown in table 2
Equation 5
Table 2
| Sequence number | Catalyst | Productive rate (%) | ee(％) | Configuration |
| 1 2 3 4 5a 6 7 | NJUCCI 1 NJUCCI 3 NJUCCI 2 NJUCCI 4 NJUCCI 4 NJUCCI 5 NJUCCI 6 | 90 86 85 81 83 71 77 | 80 72 90 92 87 55 65 | R R R S S R S |
Annotate: reaction is at room temperature carried out.
Catalyst substitutes catalyst in the above-mentioned table 2 with NJUCCI-7～NJUCCI-12, and the gained productive rate is all at 70-95%, and ee (%) be 50-99%, mainly is configured as R or then looks substituent difference difference for S.
Embodiment 14. application of compound N JUCCI-2 of the present invention in asymmetric catalysis
With 10mol%NJUCCI-2 is catalyst, it with the tert-butyl glycinate reaction (equation 6) under 4 ℃ of temperature in listed solvent of the alkylating reagent (solvent and KOH consumption such as embodiment 13) of substrate and 1.2 times of amount of substances as table 3, TLC follows the tracks of reaction, ultimate yield is calculated as gross production rate, and the e.e value obtains by the high pressure liquid chromatographic analysis that uses DAICEL CHIRAL OD-H post.NJUCCI-2 catalytic activity (configuration is determined reference literature) more as shown in table 3.
Equation 6
Table 3
| Sequence number | RX | Time (h) | Productive rate (%) | ee(％) | Configuration |
| 1 2 3 4 5 6 | CH 3I CH 3CH 2I CH 2＝CHCH 2Br PhCH 2Br 4-BrC 6H 4CH 2Br 4-ClC 6H 4CH 2Cl | 6 12 18 12 6 18 | 80 71 73 81 90 78 | 92 97 81 92 91 88 | S S S S S S |
Claims (5)
1. the quaternary amine of a class cinchona alkaloid compound is characterized in that it has following general structure:
Or
Wherein R is H or CH
3O; Ar is 3-nitrobenzophenone, 4-nitrobenzophenone or 4-pyridine radicals.
2. method for preparing the quaternary amine of the described cinchona alkaloid compound of claim 1, it is characterized in that: it be with cinchona alkaloid compound and the 2-bromine aryl methyl ketone that waits amount of substance in alcohol saturated solution in stirring at room, separate out precipitation, precipitation is the quaternary amine of cinchona alkaloid compound.
3. the preparation method of the quaternary amine of cinchona alkaloid compound according to claim 2, it is characterized in that: described cinchona alkaloid compound is quinine, chinidine, cinchonine or cinchonidine.
4. the preparation method of the quaternary amine of cinchona alkaloid compound according to claim 2, it is characterized in that: described 2-bromine aryl methyl ketone is 2-bromo-3 '-nitro-acetophenone, 2-bromo-4 '-nitro-acetophenone or 2-bromo-4 '-pyridine ethyl ketone.
5. the quaternary amine of cinchona alkaloid compound according to claim 1 is used as chiral phase-transfer catalyst.
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| CN101531658B (en) * | 2008-12-31 | 2012-05-09 | 中国人民解放军第四军医大学 | Cinchona alkaloid quaternary ammonium salt derivatives as well as preparation method and application thereof |
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| CN101531658B (en) * | 2008-12-31 | 2012-05-09 | 中国人民解放军第四军医大学 | Cinchona alkaloid quaternary ammonium salt derivatives as well as preparation method and application thereof |
| CN101735368B (en) * | 2009-12-15 | 2011-11-16 | 上海第二工业大学 | Sulfonated porous crosslinked polystyrene resin loaded cinchona alkaloid compound and preparation method thereof |
| CN102167698A (en) * | 2011-03-22 | 2011-08-31 | 中国人民解放军第四军医大学 | Difunctional thioamide organic micromolecule catalyst, preparation method thereof and application thereof |
| CN102167698B (en) * | 2011-03-22 | 2013-09-18 | 中国人民解放军第四军医大学 | Difunctional thioamide organic micromolecule catalyst, preparation method thereof and application thereof |
| CN105017269A (en) * | 2014-04-24 | 2015-11-04 | 中国科学院大连化学物理研究所 | Chiral spiro isotetrortic acid derivative and preparation for same |
| CN105732387A (en) * | 2016-04-14 | 2016-07-06 | 大连理工大学 | Novel method for asymmetric alpha-hydroxylation of photo-oxygenation beta-dicarbonyl compound based on C-2' phase transfer catalyst |
| CN105753703A (en) * | 2016-04-14 | 2016-07-13 | 大连理工大学 | Novel method for asymmetric alpha-hydroxylation of beta-dicarbonyl compound by photo-oxidation under action of quinine derived N-O phase transfer catalyst |
| CN105753703B (en) * | 2016-04-14 | 2019-03-05 | 大连理工大学 | A kind of method of novel quinine N-O phase transfer catalyst photooxidation beta-dicarbonyl compound asymmetry 'alpha '-hydroxylation |
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