CN110724112A - Bisoxazoline ligand compound and synthetic method thereof - Google Patents
Bisoxazoline ligand compound and synthetic method thereof Download PDFInfo
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- 239000003446 ligand Substances 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 title claims abstract description 11
- 238000010189 synthetic method Methods 0.000 title description 7
- -1 (S) - (3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester Chemical compound 0.000 claims abstract description 28
- OOGXPBHKDGWXBI-JTQLQIEISA-N (3s)-3-amino-2-methyl-4-phenylbutan-2-ol Chemical compound CC(C)(O)[C@@H](N)CC1=CC=CC=C1 OOGXPBHKDGWXBI-JTQLQIEISA-N 0.000 claims abstract description 16
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims description 70
- 238000006243 chemical reaction Methods 0.000 claims description 63
- 238000001914 filtration Methods 0.000 claims description 35
- 239000007832 Na2SO4 Substances 0.000 claims description 34
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 238000004440 column chromatography Methods 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 20
- 238000000605 extraction Methods 0.000 claims description 20
- 238000012544 monitoring process Methods 0.000 claims description 20
- 238000010791 quenching Methods 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 10
- CJXQAYQWVNXIQE-UHFFFAOYSA-N 2,2-dimethylpropanedioyl dichloride Chemical compound ClC(=O)C(C)(C)C(Cl)=O CJXQAYQWVNXIQE-UHFFFAOYSA-N 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- LWLPYZUDBNFNAH-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CCC[CH2-] LWLPYZUDBNFNAH-UHFFFAOYSA-M 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 1
- 238000011914 asymmetric synthesis Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- GGDLWZJFQIPCGI-ZDUSSCGKSA-N tert-butyl N-[(2S)-3-hydroxy-3-methyl-1-phenylbutan-2-yl]carbamate Chemical compound OC([C@H](CC1=CC=CC=C1)NC(OC(C)(C)C)=O)(C)C GGDLWZJFQIPCGI-ZDUSSCGKSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000004809 thin layer chromatography Methods 0.000 description 25
- 238000001228 spectrum Methods 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000005698 Diels-Alder reaction Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 3
- HIBSYUPTCGGRSD-UHFFFAOYSA-N 3-prop-2-enoyl-1,3-oxazolidin-2-one Chemical class C=CC(=O)N1CCOC1=O HIBSYUPTCGGRSD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003325 scandium Chemical class 0.000 description 2
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- MFROBPWVRCYKCP-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;pyridine Chemical compound C1CN=CO1.C1CN=CO1.C1=CC=NC=C1 MFROBPWVRCYKCP-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000006459 hydrosilylation reaction Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- WGJJZRVGLPOKQT-UHFFFAOYSA-K lanthanum(3+);trifluoromethanesulfonate Chemical compound [La+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F WGJJZRVGLPOKQT-UHFFFAOYSA-K 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/12—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals containing only hydrogen and carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention provides a bisoxazoline ligand compound and a synthesis method thereof, wherein the invention synthesizes (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2 through L-phenylalanine methyl ester hydrochloride 1, then synthesizes (S) - (3-hydroxy-3-methyl-1-phenylbutan-2-yl) carbamic acid tert-butyl ester 3 or (S) - (3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester 5, synthesizes (S) -3-amino-2-methyl-4-phenylbutan-2-ol 4 or (S) -3-amino-2-methyl-4-phenylbutan-2-ol 6 by utilizing the substances, finally, the compound is synthesized, and the preparation method is simple and easy to purify and has higher yield; the substance synthesized by the method has a good ee value and is better applied to asymmetric synthesis.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, in particular to a bisoxazoline ligand compound and a synthesis method thereof.
Background
Chiral synthesis is the leading research direction of organic chemistry and catalytic chemistry at present, and has been successfully used for asymmetric synthesis such as double-pass reaction, Aldol reaction, hydrosilation reaction and the like with the increasing proportion of chiral drugs in the market. In view of the excellent performance of bisoxazoline ligands in some asymmetric synthesis reactions, we have attracted our interest in having bis-nitrogen ligands. The Diels-Alder (DA) reaction has wide application in the synthesis of natural products and fine chemicals and is an important method for synthesizing six-membered cyclic compounds, which can form up to four chiral centers by a one-step reaction. Among various catalysts, the catalyst combined by chiral bisoxazoline ligand and Lewis acid shows good catalytic performance, and can obtain excellent enantioselectivity in DA reaction. Although pyridine bisoxazoline ligands have found some applications in acid-catalyzed reactions, many applications are still under investigation.
Fukuzawa et al found that a complex formed by 2, 6-bis [4 '(S) -isopropyl oxazoline-2' - ] pyridine ligand and scandium salt (III) can be used for catalyzing DA reaction of alpha, beta-unsaturated N-acyl oxazolidinone, but the dosage of the catalyst is large (10% mol), the enantioselectivity of the product is mostly relatively low (65% -82%), and the preparation of the catalyst under a harsh condition of-78 ℃ is also required for the better enantioselectivity (90% ee).
Desimoni et al found that complexes formed by 2, 6-bis [4 '(S) -isopropyloxazoline-2' - ] pyridine ligand and scandium triflate and complexes formed by 2, 6-bis [4 '(S) -phenyloxazoline-2' - ] pyridine ligand and lanthanum triflate were able to catalyze the reaction of α, β -unsaturated N-acryloyl oxazolidinone, and after 16 hours of reaction, quantitative yields were obtained with enantioselectivities of 84% and 78% for both catalysts, respectively. On the one hand, however, such catalysts are used in relatively large amounts (10 mol%); on the other hand, the reaction temperature is harsh (-78 ℃); and the activity and enantioselectivity of the catalyst are also relatively low.
Desimoni et al have also recently found that a complex of (4 ' S, 5 ' S) -2, 6-bis [4 ' - (triisopropylsilyl) oxymethyl-5 ' -phenyl-1 ', 3 ' -oxazoline-2 ' - ] pyridine and scandium triflate ligand can achieve 99% enantioselectivity when used to catalyze the DA reaction of α, β -unsaturated N-acryloyl oxazolidinone, but also suffer from the disadvantages of high catalyst usage (10% mol) and harsh reaction temperatures (-50 ℃).
From the above, it can be seen that although the system of the ligand is already sound, compared to PyboxLigand, BoxLigand nd lacks a class of corresponding ligands having substituents on the carbon attached to the oxygen atom in the structure.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a bisoxazoline ligand compound and a synthesis method thereof.
The invention provides a bisoxazoline ligand compound, which has a structural formula 7 or 8 as follows:
wherein nBu is N-butyl, Me is methyl, N is nitrogen atom, and O is oxygen atom.
The technical scheme of the invention is as follows: a synthetic method of a bisoxazoline ligand comprises the following steps:
s1), dissolving 5-10g of L-phenylalanine methyl ester hydrochloride 1 in 100-200mL of DCM, and adding 8-16.2mL of Et3N or iPr2Net, then 6-13.8mL of Boc was added dropwise in an ice bath2O, then transferring to room temperature, stirring for 5h, monitoring by TLC, after the reaction of the raw materials is finished, adding about 100-200mL of 5% citric acid aqueous solution to quench the reaction, extracting by DCM, and then using 5% NaHCO as the organic phase3(aq.) Wash, Water Wash, anhydrous Na2SO4Drying, filtering, spin-drying and column-passing to obtain (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2;
s2), 2.6-5g of (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2 prepared in step S1) are dissolved in 10-20mL of THF, then 45-90mL of tetrahydrofuran solution of methyl magnesium bromide is slowly added dropwise under ice bath or at room temperature, then the mixture is transferred to room temperature and stirred, TLC monitors that the raw materials are completely reacted, and NH is added4Cl (aq., sat.) quench reaction, EA extraction, anhydrous Na2SO4Drying, filtering, spin-drying and separating by column chromatography to obtain white tert-butyl (S) - (3-hydroxy-3-methyl-1-phenylbut-2-yl) carbamate 3;
s3), dissolving tert-butyl (S) - (3-hydroxy-3-methyl-1-phenylbutan-2-yl) carbamate 3 synthesized in step S2) in DCM and CF3COOH, and stirring at room temperature, TLC to monitor the reaction of the raw materials, and then NaHCO is added3(aq., sat.) to pH 8, DCM extraction, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain colorless oily (S) -3-amino-2-methyl-4-phenylbutan-2-ol 4;
s4), dissolving (S) -3-amino-2-methyl-4-phenylbutan-2-ol 4 in DCM, adding Et3N after ice bath, slowly adding dimethyl malonyl dichloride DCM solution dropwise, transferring to room temperature, stirring overnight, monitoring the reaction by TLC, adding 1N Cl for washing, DCM extracting, and anhydrous Na2SO4Drying, filtering and spin-drying to obtain a corresponding amide crude product;
s5), dissolving the crude product in DCM, adding MsOH (10equiv.) dropwise in ice bath, heating to 50 ℃, reacting overnight, monitoring the reaction completion by TLC, adding NaHCO3(aq., sat.) quench the reaction, DCM extraction, water wash, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain white solid substance
(4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dimethyl-4, 5-dihydrooxazole) 7
Further, in step S1), in the column passing, PE: EA is 5: 1.
further, in step S2), in the case of column chromatography, PE: EA is 5: 1.
further, in step S3), the DCM and the CF3Of COOHThe volume ratio is 4: 1 or 7: 1.
the invention also provides another synthetic method of the bisoxazoline ligand, which comprises the following steps:
s21), dissolving 5-10g of L-phenylalanine methyl ester hydrochloride 1 in 100-200mL of DCM, and adding 8-16.2mL of Et3N or iPr2Net, then 6-13.8mL of Boc was added dropwise in an ice bath2O, then transferring to room temperature, stirring for 5h, monitoring by TLC, after the reaction of the raw materials is finished, adding about 100-200mL of 5% citric acid aqueous solution to quench the reaction, extracting by DCM, and then using 5% NaHCO as the organic phase3(aq.) Wash, Water Wash, anhydrous Na2SO4Drying, filtering, spin-drying and column-passing to obtain (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2;
s22), 2.6g-5g of (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2 is dissolved in 10ml-20ml of THF, then the prepared tetrahydrofuran solution of n-butyl magnesium bromide is slowly added dropwise under ice bath or room temperature, then the mixture is transferred to room temperature and stirred, TLC monitors that the raw materials are completely reacted, NH is added4Cl (aq.) quench reaction, EA extraction, anhydrous Na2SO4Drying, filtering, spin-drying and separating by column chromatography to obtain a white solid substance (S) - (3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester 5;
s23), dissolving (S) -3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester 5(1.0equiv.) in DCM and CF3COOH, and stirring at room temperature, TLC to monitor the reaction of the raw materials, and then NaHCO is added3Neutralizing to pH 8, extracting with DCM, and extracting with anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain (S) -3-amino-2-methyl-4-phenylbutan-2-ol 6 as light yellow oil;
s24), dissolve (S) -3-amino-2-methyl-4-phenylbutan-2-ol 6(2.1equiv.) in DCM, add Et3N (4equiv.), then adding a DCM solution of dimethylmalonyl dichloride (1equiv.) slowly and dropwise under an ice bath, then transferring to room temperature and stirring overnight, monitoring the reaction by TLC, adding 1N Cl for washing, DCM extracting, and anhydrous Na2SO4Drying, filtering and spin-drying to obtain a corresponding amide crude product;
s25), dissolving the crude product in DCM, dropwise adding MsOH (10equiv.) in ice bath, heating to 50 ℃, reacting overnight, monitoring the reaction completion by TLC, adding NaHCO3(aq., sat.) quench the reaction, DCM extraction, water wash, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain yellowish oily substance
(4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dibutyl-4, 5-dihydrooxazole) 8:
further, in step S22), during the column chromatography separation, the PE: EA is 5: 1.
further, in step S23), DCM and CF3The volume ratio of COOH was 4: 1 or 7: 1.
the invention has the beneficial effects that: the preparation method is simple and easy to purify, and has high yield; the PyboxLigand with substituent on the carbon connected to oxygen atom has excellent ee value of enantioselectivity in asymmetric reaction. Has wide application.
Drawings
FIG. 1 is a hydrogen spectrum of (S) - (3-hydroxy-3-methyl-1-phenylbutan-2-yl) carbamic acid tert-butyl ester prepared according to the present invention;
FIG. 2 is a carbon spectrum of (S) - (3-hydroxy-3-methyl-1-phenylbutan-2-yl) carbamic acid tert-butyl ester prepared according to the present invention;
FIG. 3 is a hydrogen spectrum diagram of (4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dimethyl-4, 5-dihydrooxazole);
FIG. 4 is a carbon spectrum diagram of (4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dimethyl-4, 5-dihydrooxazole);
FIG. 5 is a hydrogen spectrum of (S) -3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester;
FIG. 6 is a carbon spectrum diagram of (S) -3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester;
FIG. 7 is a hydrogen spectrum diagram of (4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dibutyl-4, 5-dihydrooxazole);
FIG. 8 is a carbon spectrum diagram of (4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dibutyl-4, 5-dihydrooxazole).
Detailed Description
The following further describes embodiments of the present invention with reference to the accompanying drawings:
example 1
Bisoxazoline ligand compound
The structural formula 7 or 8 is as follows:
wherein nBu is N-butyl, Me is methyl, N is nitrogen atom, and O is oxygen atom.
Example 2
A synthetic method of a bisoxazoline ligand comprises the following steps:
s1), 5g of L-phenylalanine methyl ester hydrochloride 1 was dissolved in 100mL of DCM, and 8mL of Et was added3N or iPr2Net, then 6mL of Boc was added dropwise in an ice bath2O, then transferred to room temperature and stirred for 5h, monitored by TLC, the reaction of the raw materials is finished, then about 100mL of 5% citric acid aqueous solution is added to quench the reaction, DCM is used for extraction, and the organic phase is subjected to 5% NaHCO3(aq.) Wash, Water Wash, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying with column to obtain (tert-butoxycarbonyl) -L-phenylalanine2, methyl ester;
s2), 2.6g of (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2 prepared in step S1) was dissolved in 10mL of THF, and then 45mL of a tetrahydrofuran solution of methyl magnesium bromide was slowly added dropwise under ice bath or at room temperature, followed by stirring at room temperature, TLC was used to monitor completion of the reaction of the starting materials, and NH was added4Cl (aq., sat.) quench reaction, EA extraction, anhydrous Na2SO4Drying, filtering, spin-drying and separating by column chromatography to obtain white tert-butyl (S) - (3-hydroxy-3-methyl-1-phenylbut-2-yl) carbamate 3;
s3), dissolving tert-butyl (S) - (3-hydroxy-3-methyl-1-phenylbutan-2-yl) carbamate 3 synthesized in step S2) in DCM and CF3COOH, and stirring at room temperature, TLC to monitor the reaction of the raw materials, and then NaHCO is added3(aq., sat.) to pH 8, DCM extraction, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain colorless oily (S) -3-amino-2-methyl-4-phenylbutan-2-ol 4;
s4), dissolving (S) -3-amino-2-methyl-4-phenylbutan-2-ol 4 in DCM, adding Et3N after ice bath, slowly adding dimethyl malonyl dichloride DCM solution dropwise, transferring to room temperature, stirring overnight, monitoring the reaction by TLC, adding 1N Cl for washing, DCM extracting, and anhydrous Na2SO4Drying, filtering and spin-drying to obtain a corresponding amide crude product;
s5), dissolving the crude product in DCM, adding MsOH (10equiv.) dropwise in ice bath, heating to 50 ℃, reacting overnight, monitoring the reaction completion by TLC, adding NaHCO3(aq., sat.) quench reaction, DCM extraction, water wash, dryNa2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain white solid substance
(4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dimethyl-4, 5-dihydrooxazole) 7
Example 3
A synthetic method of a bisoxazoline ligand specifically comprises the following steps:
s21), 10g of L-phenylalanine methyl ester hydrochloride 1 was dissolved in 200mL of DCM, and 16.2mL of Et was added3N or iPr2Net, then 13.8mL of Boc was added dropwise in an ice bath2O, then transferring to room temperature, stirring for 5h, monitoring by TLC, reacting the raw materials, adding about 200mL of 5% citric acid aqueous solution to quench the reaction, extracting with DCM, and extracting the organic phase with 5% NaHCO3(aq.) Wash, Water Wash, anhydrous Na2SO4Drying, filtering, spin-drying and column-passing to obtain (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2;
s22), dissolving 5g of (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2 in 10ml-20ml of THF, slowly adding dropwise the prepared n-butyl magnesium bromide solution in tetrahydrofuran under ice bath or at room temperature, transferring to room temperature, stirring, TLC (thin layer chromatography) for monitoring the reaction of the raw materials, and adding NH4Cl (aq.) quench reaction, EA extraction, anhydrous Na2SO4Drying, filtering, spin-drying and separating by column chromatography to obtain a white solid substance (S) - (3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester 5;
s23), mixing (S) -3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester 5(1.0 equiv).) dissolve in DCM and CF3COOH, and stirring at room temperature, TLC to monitor the reaction of the raw materials, and then NaHCO is added3Neutralizing to pH 8, extracting with DCM, and extracting with anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain (S) -3-amino-2-methyl-4-phenylbutan-2-ol 6 as light yellow oil;
s24), dissolve (S) -3-amino-2-methyl-4-phenylbutan-2-ol 6(2.1equiv.) in DCM, add Et3N (4equiv.), then adding a DCM solution of dimethylmalonyl dichloride (1equiv.) slowly and dropwise under an ice bath, then transferring to room temperature and stirring overnight, monitoring the reaction by TLC, adding 1N Cl for washing, DCM extracting, and anhydrous Na2SO4Drying, filtering and spin-drying to obtain a corresponding amide crude product;
s25), dissolving the crude product in DCM, dropwise adding MsOH (10equiv.) in ice bath, heating to 50 ℃, reacting overnight, monitoring the reaction completion by TLC, adding NaHCO3(aq., sat.) quench the reaction, DCM extraction, water wash, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain yellowish oily substance
(4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dibutyl-4, 5-dihydrooxazole) 8:
example 4
A synthetic method of a bisoxazoline ligand comprises the following steps:
s1), 10g of L-phenylalanine methyl ester hydrochloride 1 was dissolved in 200mL of DCM, and 16.2mL of Et was added3N or iPr2Net (2.5equiv.), then 13.8mL of Boc was added dropwise in an ice bath2O, then transferred to room temperature and stirred for 5h, monitored by TLC, after the reaction of the starting materials was completed, the reaction was quenched by adding about 200mL of 5% aqueous citric acid, extracted with DCM (200mLx3), and the organic phase was separatedWith 5% NaHCO3(aq.) Wash, Water Wash, anhydrous Na2SO4Drying, filtering, spin-drying and column chromatography to obtain (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2(12g, 92%);
s2), 2.6g of (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2 prepared in step S1) was dissolved in 10mL of THF, and then 45mL of a tetrahydrofuran solution of methyl magnesium bromide was slowly added dropwise under ice bath or at room temperature, followed by stirring at room temperature, TLC was used to monitor completion of the reaction of the starting materials, and NH was added4Cl (aq., sat.) quench reaction, EA extraction, anhydrous Na2SO4Drying, filtering, spin-drying, and separating by column chromatography (petroleum ether (PE): Ethyl Acetate (EA) ═ 5: 1) to give white tert-butyl (S) - (3-hydroxy-3-methyl-1-phenylbutan-2-yl) carbamate 3;
s3), dissolving tert-butyl (S) - (3-hydroxy-3-methyl-1-phenylbut-2-yl) carbamate 3 synthesized in step S2) in a solvent at a volume ratio of 7: DCM and CF of 13COOH, and stirring at room temperature, TLC to monitor the reaction of the raw materials, and then NaHCO is added3(aq., sat.) to pH 8, DCM extraction, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain colorless oily (S) -3-amino-2-methyl-4-phenylbutan-2-ol 4;
s4), dissolving (S) -3-amino-2-methyl-4-phenylbutan-2-ol 4 in DCM, adding Et3N after ice bath slowly adding dimethyl malonyl dichloride DCM solution, then transferring to room temperature and stirring overnight, TLC monitoring reaction complete, adding 1N Cl washing, DCM extraction, anhydrous Na2SO4Drying, filtering and spin-drying to obtain the corresponding amideCoarse products;
s5), dissolving the crude product in DCM, adding MsOH (10equiv.) dropwise in ice bath, heating to 50 ℃, reacting overnight, monitoring the reaction completion by TLC, adding NaHCO3(aq., sat.) quench the reaction, DCM extraction, water wash, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain white solid substance
(4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dimethyl-4, 5-dihydrooxazole) 7
Wherein FIGS. 1, 3, 5 and 7 are tert-butyl (S) - (3-hydroxy-3-methyl-1-phenylbutan-2-yl) carbamate, (4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dimethyl-4, 5-dihydrooxazole), (S) -3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamate, (4S, hydrogen spectrum of 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dibutyl-4, 5-dihydrooxazole);
FIGS. 2, 4, 6, 8 are (S) - (3-hydroxy-3-methyl-1-phenylbutan-2-yl) carbamic acid tert-butyl ester (4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dimethyl-4, 5-dihydrooxazole), (S) -3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester, (4S, carbon spectrum of 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dibutyl-4, 5-dihydrooxazole).
The foregoing embodiments and description have been presented only to illustrate the principles and preferred embodiments of the invention, and various changes and modifications may be made therein without departing from the spirit and scope of the invention as hereinafter claimed.
Claims (8)
1. A bisoxazoline ligand compound, which is characterized in that: the structural formula 7 or 8 is as follows:
wherein nBu is N-butyl, Me is methyl, N is nitrogen atom, and O is oxygen atom.
2. A method of synthesizing the compound of claim 1, comprising the steps of:
s1), dissolving 5-10g of L-phenylalanine methyl ester hydrochloride 1 in 100-200mL of DCM, and adding 8-16.2mL of Et3N or iPr2Net, then 6-13.8mL of Boc was added dropwise in an ice bath2O, then transferring to room temperature, stirring for 5h, monitoring by TLC, after the reaction of the raw materials is finished, adding about 100-200mL of 5% citric acid aqueous solution to quench the reaction, extracting by DCM, and then using 5% NaHCO as the organic phase3(aq.) Wash, Water Wash, anhydrous Na2SO4Drying, filtering, spin-drying and column-passing to obtain (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2;
s2), 2.6-5g of (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2 prepared in step S1) are dissolved in 10-20mL of THF, then 45-90mL of tetrahydrofuran solution of methyl magnesium bromide is slowly added dropwise under ice bath or at room temperature, then the mixture is transferred to room temperature and stirred, TLC monitors that the raw materials are completely reacted, and NH is added4Cl (aq., sat.) quench reaction, EA extraction, anhydrous Na2SO4Drying, filtering, spin-drying and separating by column chromatography to obtain white tert-butyl (S) - (3-hydroxy-3-methyl-1-phenylbut-2-yl) carbamate 3;
s3), dissolving tert-butyl (S) - (3-hydroxy-3-methyl-1-phenylbutan-2-yl) carbamate 3 synthesized in step S2) in DCM and CF3COOH, and stirring at room temperature, TLC to monitor the reaction of the raw materials, and then NaHCO is added3(aq., sat.) to pH 8, DCM extraction, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain colorless oily (S) -3-amino-2-methyl-4-phenylbutan-2-ol 4;
s4), dissolving (S) -3-amino-2-methyl-4-phenylbutan-2-ol 4 in DCM, adding Et3N after ice bath, slowly adding dimethyl malonyl dichloride DCM solution dropwise, transferring to room temperature, stirring overnight, monitoring the reaction by TLC, adding 1N Cl for washing, DCM extracting, and anhydrous Na2SO4Drying, filtering and spin-drying to obtain a corresponding amide crude product;
s5), dissolving the crude product in DCM, adding MsOH (10equiv.) dropwise in ice bath, heating to 50 ℃, reacting overnight, monitoring the reaction completion by TLC, adding NaHCO3(aq., sat.) quench the reaction, DCM extraction, water wash, anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain white solid substance
(4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dimethyl-4, 5-dihydrooxazole) 7
3. The method of claim 2, wherein: step S1), when passing through the column, PE: EA is 5: 1.
4. the method of claim 2, wherein: step S2), during column chromatography, PE: EA is 5: 1.
5. the method of claim 2, wherein: in step S3), the DCM and the CF3The volume ratio of COOH was 4: 1 or 7: 1.
6. a process for the synthesis of a compound according to claim 1, comprising the steps of:
s21), dissolving 5-10g of L-phenylalanine methyl ester hydrochloride 1 in 100-200mL of DCM, and adding 8-16.2mL of Et3N or iPr2Net, then 6-13.8mL of Boc was added dropwise in an ice bath2O, then transferring to room temperature, stirring for 5h, monitoring by TLC, after the reaction of the raw materials is finished, adding about 100-200mL of 5% citric acid aqueous solution to quench the reaction, extracting by DCM, and then using 5% NaHCO as the organic phase3(aq.) Wash, Water Wash, anhydrous Na2SO4Drying, filtering, spin-drying and column-passing to obtain (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2;
s22), 2.6g-5g of (tert-butoxycarbonyl) -L-phenylalanine methyl ester 2 is dissolved in 10ml-20ml of THF, then the prepared tetrahydrofuran solution of n-butyl magnesium bromide is slowly added dropwise under ice bath or room temperature, then the mixture is transferred to room temperature and stirred, TLC monitors that the raw materials are completely reacted, NH is added4Cl (aq.) quench reaction, EA extraction, anhydrous Na2SO4Drying, filtering, spin-drying and separating by column chromatography to obtain a white solid substance (S) - (3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester 5;
s23), dissolving (S) -3-butyl-3-hydroxy-1-phenylhept-2-yl) carbamic acid tert-butyl ester 5(1.0equiv.) in DCM and CF3COOH, and stirring at room temperature, TLC to monitor the reaction of the raw materials, and then NaHCO is added3Neutralizing to pH 8, extracting with DCM, and extracting with anhydrous Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography to obtain (S) -3-amino-2-methyl-4-phenylbutan-2-ol 6 as light yellow oil;
s24), dissolve (S) -3-amino-2-methyl-4-phenylbutan-2-ol 6(2.1equiv.) in DCM, add Et3N (4equiv.), then adding a DCM solution of dimethylmalonyl dichloride (1equiv.) slowly and dropwise under an ice bath, then transferring to room temperature and stirring overnight, monitoring the reaction by TLC, adding 1N Cl for washing, DCM extracting, and anhydrous Na2SO4Drying, filtering and spin-drying to obtain a corresponding amide crude product;
s25), dissolving the crude product in DCM, dropwise adding MsOH (10equiv.) in ice bath, heating to 50 ℃, reacting overnight, monitoring the reaction completion by TLC, adding NaHCO3(aq., sat.) quench the reaction, DCM extraction, water wash, anhydrous Na2SO4Drying, filtering, spin-drying, and performing column chromatography separation and purification to obtain a light yellow oily substance:
(4S, 4 'S) -2, 2' - (propane-2, 2-diyl) bis (4-benzyl-5, 5-dibutyl-4, 5-dihydrooxazole) 8:
7. the method of claim 6, wherein: step S22), in the column chromatography separation process, PE: EA is 5: 1.
8. the method of claim 6, wherein: step S23), DCM and CF3The volume ratio of COOH was 4: 1 or 7: 1.
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| CN113105444A (en) * | 2021-04-19 | 2021-07-13 | 南方科技大学 | Chiral pyridine bisoxazoline ligand and preparation method and application thereof |
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| CN111606868B (en) * | 2020-06-23 | 2023-02-17 | 温州大学新材料与产业技术研究院 | Preparation method of bidentate oxazoline chiral ligand |
| CN113105444A (en) * | 2021-04-19 | 2021-07-13 | 南方科技大学 | Chiral pyridine bisoxazoline ligand and preparation method and application thereof |
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