CN112898218A - Method for synthesizing trifluoromethyl oxazolone compound by one-pot method - Google Patents
Method for synthesizing trifluoromethyl oxazolone compound by one-pot method Download PDFInfo
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- CN112898218A CN112898218A CN202010035131.9A CN202010035131A CN112898218A CN 112898218 A CN112898218 A CN 112898218A CN 202010035131 A CN202010035131 A CN 202010035131A CN 112898218 A CN112898218 A CN 112898218A
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- oxazolone
- trifluoromethyl
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- 238000000034 method Methods 0.000 title claims abstract description 39
- -1 trifluoromethyl oxazolone compound Chemical class 0.000 title claims abstract description 18
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- DHIRGTQTUUJMKA-UHFFFAOYSA-N 4-(trifluoromethyl)-3H-1,3-oxazol-2-one Chemical class OC1=NC(C(F)(F)F)=CO1 DHIRGTQTUUJMKA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000002576 ketones Chemical class 0.000 claims abstract description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- WACNXHCZHTVBJM-UHFFFAOYSA-N 1,2,3,4,5-pentafluorobenzene Chemical compound FC1=CC(F)=C(F)C(F)=C1F WACNXHCZHTVBJM-UHFFFAOYSA-N 0.000 claims description 2
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 abstract description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 24
- 238000000746 purification Methods 0.000 description 23
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000003921 oil Substances 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 4
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical class C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012434 nucleophilic reagent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 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 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- 241000157855 Cinchona Species 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 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 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 125000003410 quininyl group Chemical group 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
Classifications
-
- 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
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0241—Imines or enamines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
- B01J31/0249—Ureas (R2N-C(=O)-NR2)
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/19—Catalysts containing parts with different compositions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention discloses a method for synthesizing trifluoromethyl oxazolone compounds by a one-pot method, belonging to the field of organic chemistry. N-trifluoroacetyl amino acid (1) and alpha, beta-unsaturated ketone (2) are adopted to react in a one-pot method with high stereo and high enantioselectivity under the action of thiourea catalyst and DCC to obtain trifluoromethyl oxazolone compounds (3). The one-pot reaction of the invention can shorten the time, save a plurality of complicated steps, and obtain the trifluoromethyl oxazolone compound with high optical purity and high stereoselectivity.
Description
Technical Field
The invention belongs to the technical field of asymmetric synthesis in organic chemistry, and particularly relates to a method for synthesizing trifluoromethyl oxazolone compounds by a one-pot method.
Background
The one-pot method is an organic synthesis method with a very promising prospect, the multi-step series reaction in the one-pot reaction can directly obtain molecules with complex structures from relatively simple and easily obtained raw materials without separation of intermediates, a large amount of time can be saved, a plurality of complicated processing steps are omitted, and the method is obviously more favorable in economy and environmental friendliness.
However, the one-pot method is a series of multi-step reactions, which are more reactions and thus more difficult to control, and the one-pot method mostly occurs in the biosynthesis method at present, and still has great challenges in the organic chemical synthesis.
α-CF3The asymmetric catalytic reaction in which the compound directly participates as a nucleophilic reagent is limited, and in the face of the challenge, the applicant finds that 2-trifluoromethyl-oxazole-5 (2H) -ketone can be used as a nucleophilic reagent to directly participate in the asymmetric catalytic reaction to synthesize a compound containing trifluoromethyl oxazolone, but 2-trifluoromethyl-oxazole-5 (2H) -ketone is not stable, is easy to deteriorate, is not timely treated, and can influence the yield and the ee value of the reaction.
Disclosure of Invention
In order to solve the problems, the invention discloses a method for synthesizing trifluoromethyl oxazolone compounds by a one-pot method. The 2-trifluoromethyl-oxazole-5 (2H) -ketone intermediate is directly put into a reaction asymmetric catalysis one-pot method without separation for synthesis, so that a large amount of time can be saved, a plurality of complicated steps are omitted, and the product has a compound with high optical purity and high stereoselectivity.
The invention relates to a method for synthesizing trifluoromethyl oxazolone compounds by a one-pot method, which comprises the following steps:
the method comprises the following steps:
reacting N-trifluoroacetyl amino acid (1) with alpha, beta-unsaturated ketone (2) in an organic solvent in the presence of a thiourea catalyst and DCC to obtain a trifluoromethyl oxazolone compound (3); wherein Ar is phenyl, halophenyl, trifluoromethylphenyl, nitrophenyl, C1-C3 alkylphenyl, C1-C3 alkoxyphenyl, thienyl, furyl or naphthyl; r1Is carboxylate, phenylcarbonyl, alkylcarbonyl or phenylalkyl; r2Is C1-C6 alkyl, phenyl or benzyl.
Further, in the above technical scheme, Ar is C6H5、4-CF3C6H5、4-FC6H5、4-ClC6H5、4-BrC6H5、4-NO2C6H5、4-MeC6H5、3-CF3C6H5、3-FC6H5、3-ClC6H5、3-MeOC6H5、3-MeC6H5、2-BrC6H5、2-MeC6H5、3,4-Cl2C6H52-thienyl, 3-thienyl, 2-furyl or 2-naphthyl; r1Is C (O) OEt, C (O) OMe, C (O) C6H5Or CH2CH2C6H5；R2Is CH3、C2H5、C4H9、C6H5、CH2C6H5Or C6H11。
Further, in the above technical scheme, the thiourea catalyst is selected from C1-C10, and has the following specific structure:
wherein Ar is 3,5- (CF)3)2Ph。
Further, in the above technical solution, the thiourea catalyst is preferably C10.
Further, in the technical scheme, the molar ratio of the N-trifluoroacetyl amino acid (1), the alpha, beta-unsaturated ketone (2), the DCC and the thiourea catalyst is 1.2-1.5:1.0:1.2-1.5: 0.05-0.10. The molar ratio of the four is preferably 1.5:1.0:1.5: 0.10.
Further, in the above technical solution, the organic solvent is selected from toluene, pentafluorobenzene, chlorobenzene, bromobenzene, trifluoromethylbenzene, xylene, bromotoluene or trimethylbenzene.
Furthermore, in the technical scheme, the reaction temperature is 20-30 ℃, and the reaction time is 1-2 hours.
Further, in the above technical scheme, 1mL of solvent is added per 0.1mmol of the α, β -unsaturated ketone (2).
Advantageous effects of the invention
N-trifluoroacetyl amino acid (1) and alpha, beta-unsaturated ketone (2) are adopted to react in a one-pot method with high stereo and high enantioselectivity under the catalysis of thiourea catalyst and DCC to obtain trifluoromethyl oxazolone compounds (3). The one-pot reaction of the invention can shorten the time, save a plurality of complicated steps, and obtain the trifluoromethyl oxazolone compound with high optical purity and high stereoselectivity.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following specific examples, but the scope of the present invention is not limited thereto. In all examples, the d.r. values were >20:1, unless otherwise specified. Instruments and primary chemical reagents
Nuclear magnetic resonance apparatus of the type Bruker AVANCE NEO (switzerland) and Bruker AVANCE III HD 600MHZ (switzerland); UltiMate3000 siemer on-the-fly high performance liquid chromatograph (usa).
The raw materials and solvents used in the implementation process of the invention are all purchased from commercial sources.
Example 1:
the racemic compound 3 is synthesized by the following steps:
n-trifluoroacetyl amino acid 1(0.15mmol,1.5eq), catalyst (0.01mmol,0.1eq), DCC (0.15mmol,1.5eq), 1mL of organic solvent (reference example 2) and α, β -unsaturated ketone 2(0.1mmol,1.0eq) were charged into a reaction flask, reacted at 25 ℃, thin-layer plate (TLC) monitored for reaction, and after completion of the reaction, column chromatography (eluent PE: EA ═ 50:1-10:1) was performed to obtain racemic compound 3.
The catalyst is selected from various organic bases or inorganic bases such as triethylamine, tetramethylguanidine, DBU, sodium hydroxide and the like. The solvent is selected from halogenated alkane, nitrile, ether, benzene and other solvents, the amount of the solvent only influences the reaction rate, and has no other influence.
Example 2:
a1a (0.075mmol), Cat. (0.005mmol), 2a (0.05mmol), solvent (0.5mL) unless otherwise noted.bIsolated yield.cThe dr values were obtained by hydrogen spectroscopic analysis of the crude product.dThe ee value was obtained by chiral column HPLC analysis. EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, DCC: n, N' -dicyclohexylcarbodiimide.
In the process of screening reaction conditions, the influence of different chiral catalysts on the reaction is firstly examined (entries 1-10), and C10 is found to be the best chiral catalyst, and in addition, in addition to the catalysts listed in the table, products with different ee values can be obtained by using a plurality of catalysts, such as various alkaloid catalysts of amino acid derivatives, quinines, quinidine and the like. Thereafter, the effect of different condensing agents on the reaction was examined (entries 11-13), and DCC was finally determined as the optimum condensing agent. Finally, the effect of different solvents on the reaction was examined (entries 13-25) and mesitylene was found to be the best solvent.
Considering the reaction conditions (taking the entry 25 as an example), the synthesis procedure of the compound 3a is as follows:
adding compound 1a (0.075mmol,1.5eq), catalyst (0.005mmol,0.1eq), DCC (0.075mmol,1.5eq), 0.5mL mesitylene and compound 2a (0.05mmol,1.0eq) into a reaction flask, reacting at 25 deg.C, and monitoring the reaction by thin layer plate (TLC)After 1h, column chromatography (eluent PE: EA ═ 50:1-10:1) separated to give 3a as a yellow oil, 93% ee, 94% yield.1H NMR(600MHz,CDCl3)δ7.91-7.86(m,2H),7.54-7.50(m,1H),7.43-7.38(m,2H),4.11-3.98(m,2H),3.96(dd,J＝10.5,3.4Hz,1H),3.63(dd,J＝18.1,10.5Hz,1H),3.48(dd,J＝18.1,3.4Hz,1H),1.29(s,9H),1.20(t,J＝7.2Hz,3H).
Example 3:
compound 1a (0.15mmol,1.5eq), catalyst (0.01mmol,0.1eq), DCC (0.15mmol,1.5eq), 1mL mesitylene and compound 2b (0.1mmol,1.0eq) were added to a reaction flask and reacted at 25 ℃, thin layer plate (TLC) was used to monitor the reaction, and after 2h of reaction, column chromatography (eluent PE: EA ═ 50:1-10:1) was performed to obtain white solid 3b, 91% ee, 90% yield.1H NMR(400MHz,CDCl3)δ8.07(d,J＝8.2Hz,2H),7.76(d,J＝8.2Hz,2H),4.21-4.06(m,2H),4.04(dd,J＝10.3,3.5Hz,1H),3.73(dd,J＝18.3,10.3Hz,1H),3.57(dd,J＝18.3,3.5Hz,1H),1.37(s,9H),1.28(t,J＝7.1Hz,3H).
Example 4:
the compound 2a from example 3 was replaced by 2c and reacted for 1h, the other experimental steps and purification were carried out according to example 3 to give 3c as a colorless oil in 93% ee and 85% yield.1H NMR(400MHz,CDCl3)δ8.02-7.95(m,2H),7.19-7.11(m,2H),4.20-4.05(m,2H),4.01(dd,J＝10.4,3.5Hz,1H),3.67(dd,J＝18.1,10.4Hz,1H),3.52(dd,J＝18.1,3.5Hz,1H),1.35(s,9H),1.27(t,J＝7.2Hz,3H).
Example 5:
the compound 2a from example 3 was changed to 2d and reacted for 2h, and the other experimental steps and purification were carried out according to example 3 to give 3d as a white solid in 92% ee and 88% yield.1H NMR(600MHz,CDCl3)δ7.89(d,J＝8.1Hz,2H),7.46(d,J＝8.1Hz,2H),4.18-4.11(m,1H),4.11-4.04(m,1H),4.01(dd,J＝10.5,3.3Hz,1H),3.66(dd,J＝18.1,10.5Hz,1H),3.51(dd,J＝18.1,3.3Hz,1H),1.36(s,9H),1.27(t,J＝7.2Hz,3H).
Example 6:
the compound 2a from example 3 was replaced by 2e and reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to give 3e as a colorless oil in 93% ee and 93% yield.1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,2H),4.20-4.11(m,1H),4.11-4.04(m,1H),4.01(dd,J＝10.4,3.5Hz,1H),3.66(dd,J＝18.2,10.4Hz,1H),3.51(dd,J＝18.2,3.5Hz,1H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 7:
the compound 2a from example 3 was changed to 2f and reacted for 1h, and the other experimental procedures and purification were carried out according to example 3 to obtain white crystals 3f in 88% ee with a yield of 90%.1H NMR(600MHz,CDCl3)δ8.33(d,J＝8.1Hz,2H),8.12(d,J＝8.1Hz,2H),4.20-4.13(m,1H),4.12-4.05(m,1H),4.02(dd,J＝10.4,3.4Hz,1H),3.75(dd,J＝18.2,10.4Hz,1H),3.59(dd,J＝18.2,3.4Hz,1H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 8:
the compound 2a from example 3 was exchanged for 2g, reacted for 1h, whichThe procedure and purification were carried out as described in example 3, giving 3g of a pale yellow oil in 96% ee and 96% yield.1H NMR(600MHz,CDCl3)δ7.93(d,J＝8.0Hz,2H),6.94(d,J＝8.0Hz,2H),4.17-4.04(m,2H),4.02(dd,J＝10.5,3.3Hz,1H),3.87(s,3H),3.63(dd,J＝18.0,10.5Hz,1H),3.50(dd,J＝18.0,3.3Hz,1H),1.36(s,9H),1.26(t,J＝7.1Hz,3H).
Example 9:
the compound 2a from example 3 was changed to 2h, reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to give 3h as a pale yellow oil with 95% ee and 90% yield.1H NMR(600MHz,CDCl3)δ7.85(d,J＝7.9Hz,2H),7.27(d,J＝7.9Hz,2H),4.17-4.11(m,1H),4.10-4.04(m,1H),4.02(dd,J＝10.6,3.4Hz,1H),3.66(dd,J＝18.1,10.6Hz,1H),3.53(dd,J＝18.1,3.4Hz,1H),2.42(s,3H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 10:
the compound 2a from example 3 was replaced by 2i and reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to give 3i as a white solid in 85% ee and 80% yield.1H NMR(400MHz,CDCl3)δ8.20(s,1H),8.14(d,J＝7.8Hz,1H),7.86(d,J＝7.8Hz,1H),7.64(t,J＝7.8Hz,1H),4.21-4.05(m,2H),4.05-4.01(m,1H),3.72(dd,J＝18.2,10.4Hz,1H),3.56(dd,J＝18.2,3.4Hz,1H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 11:
the compound 2a in example 3 was replaced by 2j, reacted for 2h, and other experimental procedures and purification methods were conducted in accordance with the examples3 to give 3j as a colorless oil in 90% ee and 96% yield.1H NMR(400MHz,CDCl3)δ7.76-7.72(m,1H),7.65-7.60(m,1H),7.51-7.43(m,1H),7.33-7.26(m,1H),4.20-4.03(m,2H),4.01(dd,J＝10.4,3.5Hz,1H),3.67(dd,J＝18.2,10.4Hz,1H),3.52(dd,J＝18.2,3.5Hz,1H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 12:
the compound 2a from example 3 was changed to 2k and reacted for 2h, and the other experimental steps and purification were carried out according to example 3 to obtain 3k as a white solid with 90% ee and 96% yield.1H NMR(400MHz,CDCl3)δ7.94-7.89(m,1H),7.85-7.80(m,1H),7.59-7.54(m,1H),7.43(t,J＝7.8Hz,1H),4.20-4.04(m,2H),4.01(dd,J＝10.3,3.5Hz,1H),3.67(dd,J＝18.3,10.3Hz,1H),3.52(dd,J＝18.3,3.5Hz,1H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 13:
the compound 2a from example 3 was changed to 2l and reacted for 2h, and the other experimental steps and purification were carried out according to example 3 to obtain 3l of white crystals in 94% ee with a yield of 85%.1H NMR(600MHz,CDCl3)δ7.56-7.52(m,1H),7.46(s,1H),7.41-7.36(m,1H),7.16-7.12(m,1H),4.18-4.11(m,1H),4.11-4.05(m,1H),4.02(dd,J＝10.5,3.4Hz,1H),3.86(s,3H),3.67(dd,J＝18.1,10.5Hz,1H),3.54(dd,J＝18.1,3.4Hz,1H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 14:
the compound 2a in example 3 was changed to 2m, reacted for 1h, and other experimental procedures and purification were carried out with reference to example 3 to obtainWhite solid 3m, 94% ee, 93% yield.1H NMR(600MHz,CDCl3)δ7.75(m,2H),7.40(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),4.19-4.05(m,2H),4.03(dd,J＝10.7,3.3Hz,1H),3.68(dd,J＝18.2,10.7Hz,1H),3.54(dd,J＝18.2,3.3Hz,1H),2.41(s,3H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 15:
the compound 2a from example 3 was changed to 2n and reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to give 3n as colorless oil in 92% ee and 86% yield.1H NMR(400MHz,CDCl3)δ8.05-7.01(m,1H),7.80-7.75(m,1H),7.60-7.55(m,1H),4.20-4.03(m,2H),4.00(dd,J＝10.3,3.5Hz,1H),3.66(dd,J＝18.3,10.3Hz,1H),3.50(dd,J＝18.3,3.5Hz,1H),1.36(s,9H),1.28(t,J＝7.2Hz,3H).
Example 16:
the compound 2a from example 3 was changed to 2o and reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to give 3o as colorless oil in 72% ee and 80% yield.1H NMR(600MHz,CDCl3)δ7.44(d,1H),7.46-7.39(m,2H),7.37-7.32(m,1H),4.22-4.07(m,2H),4.00(dd,J＝10.5,3.5Hz,1H),3.64(dd,J＝18.5,10.5Hz,1H),3.52(dd,J＝18.5,3.5Hz,1H),1.36(s,9H),1.29(t,J＝7.1Hz,3H).
Example 17:
the compound 2a from example 3 was changed to 2p and reacted for 2h, and the other experimental steps and purification were carried out according to example 3 to give 3p as a yellow oil in 68% ee and 90% yield.1H NMR(400MHz,CDCl3)δ7.66-7.60(m,1H),7.49-7.44(m,1H),7.42-7.36(m,1H),7.36-7.30(m,1H),4.24-4.06(m,2H),4.00(dd,J＝10.3,3.7Hz,1H),3.62(dd,J＝18.5,10.3Hz,1H),3.51(dd,J＝18.5,3.7Hz,1H),1.36(s,9H),1.30(t,J＝7.2Hz,3H).
Example 18:
the compound 2a from example 3 was changed to 2q, reacted for 1h, and the other experimental procedures and purification were carried out with reference to example 3 to give 3q as a colorless oil in 60% ee and 97% yield.1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,1H),7.33-7.23(m,2H),4.24-4.05(m,2H),4.02(dd,J＝10.5,3.5Hz,1H),3.62(dd,J＝18.1,10.5Hz,1H),3.43(dd,J＝18.1,3.5Hz,1H),2.48(s,3H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 19:
the compound 2a in example 3 was changed to 2r, reacted for 1h, and the other experimental procedures and purification were carried out according to example 3 to obtain white crystals 3r in 93% ee and 94% yield.1H NMR(600MHz,CDCl3)δ8.49(s,1H),8.02-7.97(m,2H),7.92-7.86(m,2H),7.63(t,J＝7.5Hz,1H),7.58(t,J＝7.5Hz,1H),4.20-4.13(m,1H),4.13-4.06(m,2H),3.85(dd,J＝17.9,10.4Hz,1H),3.71(dd,J＝17.9,3.4Hz,1H),1.38(s,9H),1.28(t,J＝7.2Hz,3H).
Example 20:
the compound 2a from example 3 was changed to 2s, reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to obtain a white solid 3s in 94% ee and 87% yield.1H NMR(400MHz,CDCl3)δ8.10(dd,J＝2.9,1.3Hz,1H),7.53(dd,J＝5.1,1.3Hz,1H),7.34(dd,J＝5.1,2.9Hz,1H),4.18-4.10(m,1H),4.10-4.04(m,1H),4.00(dd,J＝10.3,3.6Hz,1H),3.59(dd,J＝17.9,10.3Hz,1H),3.46(dd,J＝17.9,3.6Hz,1H),1.35(s,9H),1.26(t,J＝7.1Hz,3H).
Example 21:
the compound 2a from example 3 was changed to 2t and reacted for 1h, and the other experimental procedures and purification were carried out according to example 3 to give 3t as colorless oil in 95% ee and 95% yield.1H NMR(600MHz,CDCl3)δ7.78-7.75(m,1H),7.69-7.66(m,1H),7.17-7.14(m,1H),4.17-4.10(m,1H),4.10-4.04(m,1H),4.01(dd,J＝10.5,3.4Hz,1H),3.62(dd,J＝17.6,10.5Hz,1H),3.50(dd,J＝17.6,3.4Hz,1H),1.36(s,9H),1.26(t,J＝7.3Hz,3H).
Example 22:
the compound 2a from example 3 was replaced by 2u and reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to give 3u as a yellow oil in 85% ee.1H NMR(600MHz,CDCl3)δ7.60(d,J＝1.7Hz,1H),7.24(d,J＝3.6Hz,1H),6.56(dd,J＝3.6,1.7Hz,1H),4.17-4.04(m,2H),3.98(dd,J＝10.5,3.7Hz,1H),3.52(dd,J＝18.0,10.5Hz,1H),3.42(dd,J＝18.0,3.7Hz,1H),1.36(s,9H),1.26(t,J＝7.1Hz,3H).
Example 23:
the compound 2a from example 3 was changed to 2v and reacted for 1h, and the other experimental procedures and purification were carried out according to example 3 to give 3v as a white solid in 93% ee and 88% yield.1H NMR(400MHz,CDCl3)δ7.98-7.92(m,2H),7.63-7.56(m,1H),7.52-7.44(m,2H),4.05(dd,J＝10.5,3.5Hz,1H),3.76-3.66(m,4H),3.57(dd,J＝18.3,3.5Hz,1H),1.36(s,9H).
Example 24:
the compound 2a from example 3 was changed to 2w and reacted for 1h, and the other experimental procedures and purification were carried out according to example 3 to obtain a white solid 3w in 89% ee and 70% yield.1H NMR(600MHz,CDCl3)δ8.07(d,J＝7.7Hz,2H),7.96(d,J＝7.7Hz,2H),7.66-7.56(m,2H),7.51(t,J＝7.7Hz,2H),7.46(t,J＝7.7Hz,2H),5.23(dd,J＝10.4,2.9Hz,1H),4.10(dd,J＝18.5,10.4Hz,1H),3.80(dd,J＝18.5,2.9Hz,1H),1.06(s,9H).
Example 24:
the compound 2a from example 3 was changed to 2x and reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to obtain a white solid 3x with 91% ee and 86% yield.1H NMR(400MHz,CDCl3)δ7.97-7.91(m,2H),7.63-7.55(m,1H),7.51-7.43(m,2H),4.18(dd,J＝11.1,2.8Hz,1H),3.84(dd,J＝18.5,11.1Hz,1H),3.61(dd,J＝18.5,2.8Hz,1H),2.45(s,3H),1.34(s,9H).
Example 25:
the compound 2a from example 3 was changed to 2y and reacted for 2h, and the other experimental steps and purification were carried out according to example 3 to give 3y as a colorless oil in 88% ee and 92% yield.1H NMR(400MHz,CDCl3)δ8.50-8.46(m,1H),8.01-7.94(m,2H),7.91-7.83(m,2H),7.65-7.54(m,2H),4.27(dd,J＝11.1,2.7Hz,1H),4.00(dd,J＝18.4,11.1Hz,1H),3.76(dd,J＝18.4,2.7Hz,1H),2.49(s,3H),1.36(s,9H).
Example 26:
compound 1a (0.15mmol,1.5eq), catalyst C10(0.01mmol,0.1eq), DCC (0.15mmol,1.5eq), 1mL mesitylene and compound 2z (0.10mmol,1.0eq) were added to a reaction flask and reacted at 25 ℃, thin layer plate (TLC) monitoring the reaction for 2h, and column chromatography (eluent PE: EA ═ 100:1-20:1) was performed to isolate compound 3z, 92% ee, 40% yield.1H NMR(400MHz,CDCl3)δ7.96-7.91(m,2H),7.61-7.55(m,1H),7.51-7.44(m,2H),7.25-7.20(m,2H),7.19-7.13(m,1H),7.03-7.07(m,2H),3.59-3.48(m,1H),3.23-3.12(m,1H),3.07-2.96(m,1H),2.71-2.61(m,2H),2.02-1.90(m,1H),171-1.59(m,1H),1.34(s,9H).
The method has the following advantages: the one-pot reaction can save a large amount of time, save a plurality of complicated steps and obtain better compounds with high optical purity and high stereoselectivity.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (9)
1. The method for synthesizing trifluoromethyl oxazolone compounds by a one-pot method is characterized in that the synthetic route is as follows:
the method comprises the following steps:
reacting N-trifluoroacetyl amino acid (1) with alpha, beta-unsaturated ketone (2) in the presence of thiourea catalyst and DCCReacting in an organic solvent to obtain a compound (3) containing trifluoromethyl oxazolone; wherein Ar is phenyl, halophenyl, trifluoromethylphenyl, nitrophenyl, C1-C3 alkylphenyl, C1-C3 alkoxyphenyl, thienyl, furyl or naphthyl; r1Is carboxylate, phenylcarbonyl, alkylcarbonyl or phenylalkyl; r2Is C1-C6 alkyl, phenyl or benzyl.
2. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 1, characterized in that: ar is C6H5、4-CF3C6H5、4-FC6H5、4-ClC6H5、4-BrC6H5、4-NO2C6H5、4-MeC6H5、3-CF3C6H5、3-FC6H5、3-ClC6H5、3-MeOC6H5、3-MeC6H5、2-BrC6H5、2-MeC6H5、3,4-Cl2C6H52-thienyl, 3-thienyl, 2-furyl or 2-naphthyl; r1Is C (O) OEt, C (O) OMe, C (O) C6H5Or CH2CH2C6H5；R2Is CH3、C2H5、C4H9、C6H5、CH2C6H5Or C6H11。
3. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 1, characterized in that: the thiourea catalyst is selected from
Wherein Ar is 3,5- (CF)3)2Ph。
4. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 3, characterized in that: the thiourea catalyst was selected from C10.
5. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 1, characterized in that: the molar ratio of the N-trifluoroacetyl amino acid (1), the alpha, beta-unsaturated ketone (2), the DCC and the thiourea catalyst is 1.2-1.5:1.0:1.2-1.5: 0.05-0.10.
6. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 5, characterized in that: the molar ratio of the N-trifluoroacetyl amino acid (1), the alpha, beta-unsaturated ketone (2), the DCC and the thiourea catalyst is 1.5:1.0:1.5: 0.10.
7. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 1, characterized in that: the organic solvent is selected from toluene, pentafluorobenzene, chlorobenzene, bromobenzene, trifluoromethylbenzene, xylene, bromotoluene or trimethylbenzene.
8. The process for producing a trifluoromethyl-oxazolone-containing compound according to any one of claims 1 to 7, characterized in that: the reaction temperature is 20-30 ℃, and the reaction time is 1-2 hours.
9. The process for producing a trifluoromethyl-oxazolone-containing compound according to any one of claims 1 to 7, characterized in that: for every 0.1mmol of the α, β -unsaturated ketone (2), 1mL of the solvent was added.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114634471A (en) * | 2022-04-14 | 2022-06-17 | 河南师范大学 | Method for synthesizing gamma-hydroxy-gamma-perfluoromethyl exocyclic double bond butyrolactone compound |
| CN114634471B (en) * | 2022-04-14 | 2023-05-19 | 河南师范大学 | Method for synthesizing gamma-hydroxy-gamma-perfluoromethyl exocyclic double bond butyrolactone compound |
| CN115322151A (en) * | 2022-08-23 | 2022-11-11 | 河南师范大学 | Method for synthesizing chiral multi-stereocenter pyrazolidine compounds by copper catalysis |
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