CN103467227B - Method for preparing chiral piperidone - Google Patents
Method for preparing chiral piperidone Download PDFInfo
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- CN103467227B CN103467227B CN201310384399.3A CN201310384399A CN103467227B CN 103467227 B CN103467227 B CN 103467227B CN 201310384399 A CN201310384399 A CN 201310384399A CN 103467227 B CN103467227 B CN 103467227B
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- IWBNHVGNLFNPPD-BQYQJAHWSA-N C/C(/c(cc1)ccc1OC)=C\C(Cl)=O Chemical compound C/C(/c(cc1)ccc1OC)=C\C(Cl)=O IWBNHVGNLFNPPD-BQYQJAHWSA-N 0.000 description 1
- 0 CC(C[C@@](*)(CCC1)NC1=O)=O Chemical compound CC(C[C@@](*)(CCC1)NC1=O)=O 0.000 description 1
- ZKMNUMMKYBVTFN-UHFFFAOYSA-N CCCN(CCCC1)C1C(Nc1c(C)cccc1C)=O Chemical compound CCCN(CCCC1)C1C(Nc1c(C)cccc1C)=O ZKMNUMMKYBVTFN-UHFFFAOYSA-N 0.000 description 1
- GQUZKPQUFGLOSQ-LLVKDONJSA-N FC(c1c2nc(C(F)(F)F)cc(C[C@@H]3NCCCC3)c2ccc1)(F)F Chemical compound FC(c1c2nc(C(F)(F)F)cc(C[C@@H]3NCCCC3)c2ccc1)(F)F GQUZKPQUFGLOSQ-LLVKDONJSA-N 0.000 description 1
- XEEQGYMUWCZPDN-IUODEOHRSA-N O[C@@H]([C@@H]1NCCCC1)c1cc(C(F)(F)F)nc2c1cccc2C(F)(F)F Chemical compound O[C@@H]([C@@H]1NCCCC1)c1cc(C(F)(F)F)nc2c1cccc2C(F)(F)F XEEQGYMUWCZPDN-IUODEOHRSA-N 0.000 description 1
Abstract
The invention discloses a method for preparing chiral piperidone. The method for preparing the chiral piperidone comprises the following steps: dissolving a cinchona alkaloid catalyst shown as a formula II and organic alkali into an organic solvent, adding aldimine shown as a formula III and an unsaturated chloride compound shown as a formula IV, uniformly mixing, and performing cycloaddition reaction to obtain a compound shown as a formula I. The method is simple and convenient in process, the yield is high, and the preparation can be carried out in a gram level; more importantly, by the method, piperidones with different substituents at various substituent positions and with excellent enantioselectivity (with the highest enantioselectivity of 99% ee) can be simultaneously prepared; therefore, the method has a significant application value.
Description
Technical field
The invention belongs to pharmaceutical intermediate crucial skeleton synthesis field, be specifically related to a kind of method preparing chiral piperidone.
Background technology
Calendar year 2001, Americanized scholar Sha Pulisi and Knowles and Japanese chemists Ryoji Noyori professor have shared Nobel chemistry Prize, are used for commending them in the new method and technique of development catalysis chirality and asymmetric synthesis and the initiative contribution that is applied in industrial production research field thereof.In the vitochemical development of 20th century, one of most important breakthrough is the research success of catalysis chirality and asymmetric synthesis.As everyone knows, organism is chiral can be identified, same, and the configuration that the activity of drug molecule is also concrete to it is relevant.And most medicine is all chiral molecules, and drug molecule must match with intracellular acceptor, and in some cases, another one enantiomer may be harmful.Phase early 1960s, tranquilizer reaction stops once being used to alleviate the early stage nauseating sense of pregnant woman, but this medicine also can cause the Deformities of Limbs of baby, and this tragedy also just more effectively describes this point.Therefore, the U.S. and European Bureau of Drugs Supervision require that all medicines containing chirality must obtain single enantiomer and could go on the market.
The high enantioselective synthesis of chiral drug is all subject to extensive concern at chemistry, chemical industry, biology and field of medicaments.Chiral piperidine, piperidone, piperidine alcohols and nipecotic acid derivative are the important heterocyclic compounds of a class, and they have unique physiology and pharmacologically active, are subject to the favor of scientist.Paroxetine (paxil/seroxat) is a kind of antidepressant final drug, just comprises piperidine structure unit (S.Brandau, A.Landa, J.Franz é n, M.Marigo, the K.A. of a chirality in its structure
angw.Chem.Int.Ed.2006,45,4305).And same containing piperidines or the such minor structure of piperidone in a large amount of natural product, the natural product adalinine(S.G..Davies of biological example bases, P.M.Roberts, A.D.Smith, Org.Biomol.Chem.2007,5,1405).The anti-malaria medicaments Lariam(mefloquine be used widely) in very crucial minor structure be then piperidine alcohols structural unit (J.Ding, D.G.Hall, Angw.Chem.Int.Ed.2013, DOI:10.1002/anie.201303931).Nipecotic acid is a kind of important ring-type alpha-non-natural amino acid, and it is extensively present in plant and fungi, and is widely used in and prepares chiral drug (A.A.Cant, A.Sutherland, Synthesis, 2012,44,1935).Such as local anaesthetics ropivacaine (Ropivacaine) of new generation, antipsychotics thioridazine (Thioridazine), Rapamycin (Rapamycin) and antitumor antibiotics (Sandramycin) etc. are all for prepared by main raw material with nipecotic acid or derivatives thereof.
In view of the important use of piperidines, a lot of document and its chiral synthesize of patent report is had in the decades in past, the formation of organic molecule asymmetry catalysis carbonnitrogen bond, thus the have bioactive compound of synthesis containing piperidine structure unit is one of current heat subject.
Summary of the invention
The object of this invention is to provide a kind of method preparing chiral piperidone.
The method of compound shown in preparation formula I provided by the invention (being also chiral piperidone), comprises the steps:
The alkaline catalysts of cinchona alkaloid shown in formula II and organic bases are dissolved in after in organic solvent, then add the chlorine compound of unsaturated acyl shown in aldimine and formula IV shown in formula III mixing carry out cycloaddition reaction, obtain compound shown in formula I;
Described formula I in formula IV,
R
1all be selected from hydrogen, the alkyl of C1-C6, the aryl of C6-C10, aryl containing substituent C8-C10, heteroaryl and containing any one in substituent heteroaryl;
Wherein, described containing substituent aryl with containing in substituent heteroaryl, substituting group is all selected from least one in halogen, nitro, the alkoxyl group of C1-C2 and the alkyl of C1-C2;
R
2and R
4all be selected from the alkyl of hydrogen and C1-C6 any one;
R
5during for carbalkoxy shown in ROCO-, R
3for trichloromethyl, trisbromomethyl, trifluoromethyl, cyano group, nitro;
In carbalkoxy shown in described ROCO-, R is the alkyl of C1-C6, preferred tertiary butyl, and the protecting group namely on nitrogen is Boc;
R
3during for the ester group of formic acid-COOR ' Suo Shi, R
5for p-toluenesulfonyl (Ts), adjacent tosyl group, a tosyl group, benzenesulfonyl (Bs), to chlorobenzenesulfonyl, adjacent chlorobenzenesulfonyl or a chlorobenzenesulfonyl;
In formic acid ester group shown in described-COOR ', R be the alkyl of C1-C6, aryl, containing substituent aryl, heteroaryl or containing substituent heteroaryl, the preferred ethyl of R;
Wherein, described containing substituent aryl with containing in substituent heteroaryl, substituting group is all selected from least one in halogen, nitro, the alkoxyl group of C1-C2 and the alkyl of C1-C2;
R
6be selected from hydrogen, the alkyl of C1-C6, silica-based, the benzyl (Bn) that replaces of alkyl of C1-C9 and benzoyl (Bz) any one.
In aforesaid method, described aryl is phenyl or naphthyl;
Described is to bromophenyl, o-bromophenyl, a bromophenyl, rubigan, Chloro-O-Phenyl, a chloro-phenyl-, p-nitrophenyl, p-methoxyphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, 3 containing substituent aryl, 4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,5-3,5-dimethylphenyl or 3,5-Dimethoxyphenyl;
Described heteroaryl is selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 4-pyridyl, 3-pyridyl or 2-pyridyl;
Describedly be specially 5-methyl-2-furyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl or 5-methyl-2-thienyl containing substituent heteroaryl.
Described R
6in, the alkyl of C1-C9 replace silica-based in, the carbonatoms of alkyl is specially 1-4;
More specifically, the silica-based of alkyl replacement of described C1-C9 is trimethyl silicon based (TMS), t-Butyldimethylsilyl (TBS) or triisopropylsilyl (TIPS).
Described organic bases is selected from 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), 1, at least one in 4-diazabicylo [2.2.2] octane (DABCO), triethylamine (TEA), diethylamine and DIPEA (DIPEA).The effect of organic bases is: raw material acyl chlorides is sloughed a part hydrogenchloride, then reacts with aldimine.
Shown in cinchona alkaloid alkaline catalysts shown in described formula II and organic bases, formula III, shown in aldimine and formula IV, the molar ratio of unsaturated acyl chlorine compound is 0.001-1:1-50:1-20:1-100, being specially 0.01-0.5:2-10:1:1-50, is more specifically 0.1:4:1:2.
Described organic solvent is all selected from toluene, dimethylbenzene, chlorobenzene, benzene, dioxane, tetrahydrofuran (THF) (THF), ether, trichloromethane, methylene dichloride (DCM), 1, at least one in 2-ethylene dichloride, ethyl acetate (EtOAc), acetone, acetonitrile and DMF (DMF).
In described cycloaddition reaction step, temperature be-80 DEG C to room temperature;
Time is 3-48 hour.
In described cycloaddition reaction step, temperature of reaction is room temperature, and the reaction times is 3-24 hour; Or,
Temperature of reaction is-10 DEG C, and the reaction times is 6-8 hour; Or,
Temperature of reaction is-40 DEG C, and the reaction times is 16-26 hour, is specially 24 hours; Or,
Temperature of reaction is-80 to-78 DEG C, and the reaction times is 24-48 hour.
The present invention, using unsaturated acyl chlorides as raw material, using alkaloid as catalyzer, carries out asymmetric cyclization with aldimine (III) in organic solvent, generates the unsaturated piperidines ketone of chirality.The method simple process, productive rate are high and can the preparation of gram level, the more important thing is and can obtain that various position replaces simultaneously and have the piperidone of different substituents, and all have outstanding enantioselectivity (being up to 99%ee), have important using value.
Accompanying drawing explanation
Fig. 1 prepares compound shown in gained formula I-I1 for embodiment 25
1h NMR collection of illustrative plates.
Fig. 2 prepares compound shown in gained formula I-I1 for embodiment 25
13c NMR collection of illustrative plates.
Fig. 3 prepares the HPLC of two kinds of possibility isomer of compound shown in gained formula I-I1 (raceme) for embodiment 25.
Fig. 4 prepares the HPLC of compound shown in gained formula I-I1 for embodiment 25.
Fig. 5 prepares compound shown in gained formula I-II1 for embodiment 34
1h NMR collection of illustrative plates.
Fig. 6 prepares compound shown in gained formula I-II1 for embodiment 34
13c NMR collection of illustrative plates.
Fig. 7 prepares the HPLC of two kinds of possibility isomer of compound shown in gained formula I-II1 (raceme) for embodiment 34.
Fig. 8 prepares the HPLC of compound shown in gained formula I-II1 for embodiment 34.
Fig. 9 prepares the X-ray monocrystalline figure of compound shown in gained formula I-II3 for embodiment 27.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.Described method is conventional method if no special instructions.Described material all can obtain from open commercial sources if no special instructions.
The enantiomeric excess (ee) of product, to represent in reaction product excessive to another enantiomorph of an enantiomorph, usually represent with percentage ratio, its calculation formula is: ee=([S]-[R])/([S]+[R]) x100%.
The enantioselectivity of formula I-I1 of the present invention, the i.e. enantiomeric excess (i.e. ee value) of product is that the product after purifying is calculated by the peak area of (S)-anomeric product in Chiral high pressure liquid chromatogram (chirality OD-H post or chirality AD-H post) with (R)-anomeric product.
Synthesize example with formula I-I1, circular is as follows: can learn from accompanying drawing three, accompanying drawing four, and the retention time of (S) I-I1 is 13.2 points, and the retention time of its enantiomorph (R) I-I1 is 15.3 points; With reference to the accompanying drawings three, shown in accompanying drawing four, retention time is the peak area percent of the principal product of 12.6 points is 100, retention time is that the peak of the product of 14.7 points is invisible, namely peak area percent is 0, so the absolute configuration of product is (S), enantiomeric excess is: (100-0) ÷ (100+0) × 100%=100%.Consider the intrinsic instrumental error of HPLC, so its enantiomeric excess is denoted as: >99%.
The absolute configuration of Chinese style I of the present invention is determined by single crystal diffraction, and the cultivation of monocrystalline is then obtain by slowly being volatilized in the mixing solutions of sherwood oil, ethyl acetate and methylene dichloride by compound dissolution.
Unsaturated acyl chlorides used (3-(4-chloro-phenyl-)-crotyl acyl chlorides in following embodiment 1 step 1)) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add parachloroacetophenone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 80-83 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-(4-chloro-phenyl-)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-1) is correct.
Wittig-hornor preparation method of reagent thereof is as follows: under room temperature, adds ethyl bromoacetate 150g and triethyl-phosphite 150g in reaction flask, slowly reflux 3h under stirring, and cut 180 DEG C/2mm Hg is collected in decompression.Compared by nuclear-magnetism and standard spectrum, can confirm that wittig-hornor reagent is correct
In following embodiment 26 step 1), unsaturated acyl chlorides used (3-phenyl-crotyl acyl chlorides) is prepared as follows and obtains:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add methyl phenyl ketone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 60-61 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-phenyl-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-2) is correct.
Unsaturated acyl chlorides used (3-(4-p-methylphenyl)-crotyl acyl chlorides in following embodiment 27) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add p-methyl aceto phenone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 64 –, 66 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-(4-aminomethyl phenyl)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-3) is correct.
Unsaturated acyl chlorides used (3-(4-p-methoxy-phenyl)-crotyl acyl chlorides in following embodiment 28) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add p-methoxy-acetophenone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 70 –, 71 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-(4-p-methoxy-phenyl)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-4) is correct.
Unsaturated acyl chlorides used (3-(4-bromophenyl)-crotyl acyl chlorides in following embodiment 29) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add parabromoacetophenone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 90 –, 91 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-(4-bromophenyl)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-5) is correct.
Unsaturated acyl chlorides used (3-(3-chloro-phenyl-)-crotyl acyl chlorides in following embodiment 30 step 1)) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add m chloroacetophenone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 80-81 DEG C/3mmHg after decompression is spin-dried for low-boiling point material is 3-(3-chloro-phenyl-)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-6) is correct.
Unsaturated acyl chlorides used (3-(beta-naphthyl)-crotyl acyl chlorides in following embodiment 31) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add 2-naphthyl methyl ketone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 100-105 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-(beta-naphthyl)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-7) is correct.
Unsaturated acyl chlorides used (3-(2-thienyl)-crotyl acyl chlorides in following embodiment 32) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add 2-thienyl methyl ketone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 60 –, 65 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-(2-thienyl)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-8) is correct.
Unsaturated acyl chlorides used (3-(2-furyl)-crotyl acyl chlorides in following embodiment 33 step 1)) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add 2-furyl methyl ketone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 50-52 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-(2-furyl)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-9) is correct.
Unsaturated acyl chlorides used (3-(4-nitrophenyl)-crotyl acyl chlorides in following embodiment 59) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add p-nitroacetophenone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 105-107 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-(4-nitrophenyl)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-10) is correct.
Unsaturated acyl chlorides used (3-(2-chloro-phenyl-)-crotyl acyl chlorides in following embodiment 60) be prepared as follows and obtain:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add o-chloroacetophenone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 77-80 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-(2-chloro-phenyl-)-crotyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-11) is correct.
In following embodiment 61, unsaturated acyl chlorides used (3,4-dimethyl-pentenyl acyl chlorides) is prepared as follows and obtains:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add 3-espeleton 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 45-48 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3, 4-dimethyl-pentenyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-12) is correct.
In following embodiment 62, unsaturated acyl chlorides used (3-methyl-pentenyl acyl chlorides) is prepared as follows and obtains:
By wittig-hornor reagent ((EtO)
2oPCH
2cO
2et) 0.05mol and 100mL tetrahydrofuran (THF) is added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, 30min is stirred under zero degree, add butanone 0.05mol, stir under zero degree and spend the night, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds 200mL shrend and goes out, extraction into ethyl acetate (3x30mL), merge organic phase gained concentrated solution back hydrolysis in the 10%NaOH aqueous solution substantially to disappear to organic layer, cool to room temperature aqueous phase is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, methylene dichloride 30mL is dissolved in after filtration cakes torrefaction, add oxalyl chloride 0.1mol stirred at ambient temperature 15h, the cut collecting 25-28 DEG C/3mm Hg after decompression is spin-dried for low-boiling point material is 3-methyl-pentenyl acyl chlorides.Compared by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-13) is correct.
Following embodiment 1-33 aldimine used (formula III-I) is prepared as follows and obtains:
Trichoro-aldehyde (1.0eq) is dissolved in appropriate organic solvent, adds wittig reagent Ph
3p=NBoc (1.0eq), reflux one hour, be then spin-dried for solvent, underpressure distillation can obtain target product imines, is white solid, by nuclear-magnetism and standard spectrum comparison, confirms that product is correct.
Ph
3p=NBoc preparation method: Boc hydrazine (1.0eq) is dissolved in the mixing solutions of acetic acid and water, be cooled to 0 DEG C, the aqueous solution of slow dropping Sodium Nitrite (1.2eq), continue to react 30min at such a temperature, use extracted with diethyl ether 3-5 time, merge organic phase, use water (repeatedly), NaHCO
3solution, NaCl saturated solution washs, anhydrous sodium sulfate drying.This solution is cooled to 0 DEG C, slowly adds triphenylphosphine, after adding completely, be warming up to room temperature reaction 30min, separate out a large amount of white solid, use washed with diethylether, after vacuum-drying, obtain pure target product.
Following embodiment 34-62 aldimine used (formula III-II) is prepared as follows and obtains:
Glyoxylic acid ethyl ester solution (1.0eq) is dissolved in organic solvent, then p-Methyl benzenesulfonyl isocyanate (1.0eq) is added, reflux three days, then solvent is spin-dried for, underpressure distillation can obtain target product imines, for colourless liquid, by nuclear-magnetism and standard spectrum comparison, can confirm that product is correct.
Following embodiment 2-7 R used
6obtain for cinchona alkaloid alkaline catalysts shown in the formula II of the silica-based or benzyl (Bn) of C1-C6 alkyl replacement is prepared as follows:
Quinine (1.0eq) is dissolved in DMF (DMF), adds sodium hydride (NaH, 1.3eq), then add corresponding alkyl bromo-derivative or benzyl bromine (R
6br, 1.5eq), room temperature reaction spends the night.After reacting completely, the cancellation that adds water is reacted, extraction into ethyl acetate 3 times, and merge organic phase, column chromatography for separation can obtain target product.By nuclear-magnetism and standard spectrum comparison, confirm that product is correct.
Following embodiment 12,14 and 15 R used
6obtain for cinchona alkaloid alkaline catalysts shown in the silica-based formula II that C3-C9 alkyl replaces is prepared as follows:
Quinine (1.0eq) to be dissolved in methylene dichloride in (DCM), to add triethylamine (TEA, 3.0eq), then add corresponding silica-based chloro thing (R
6cl, 1.5eq), room temperature is spent the night to backflow.After reacting completely, the cancellation that adds water is reacted, extraction into ethyl acetate 3 times, and merge organic phase, column chromatography for separation can obtain target product.By nuclear-magnetism and standard spectrum comparison, confirm that product is correct.
Following embodiment 13 R used
6obtain for cinchona alkaloid alkaline catalysts shown in the formula II of benzoyl (Bz) is prepared as follows:
Be dissolved in tetrahydrofuran (THF) (THF) by quinine (1.0eq), add triethylamine (TEA, 3.0eq), then add Benzoyl chloride (BzCl, 1.5eq), room temperature reaction spends the night.After reacting completely, the cancellation that adds water is reacted, extraction into ethyl acetate 3 times, and merge organic phase, column chromatography for separation can obtain target product.By nuclear-magnetism and standard spectrum comparison, confirm that product is correct.
Embodiment 1-25 temperature, solvent and screening of catalyst
(the R of compound shown in preparation formula I-I1
1for rubigan)
Be added in two-mouth bottle by the alkaline catalysts of cinchona alkaloid shown in formula II 0.02mmol, solvent 1.5mL and organic bases 0.8mmol to be added in system more at room temperature stirring and dissolving and, after 30 minutes, to add Compound C l shown in formula III-I in reaction flask
3cCH=NBoc 0.2mmol, by the chloro-phenyl-of 3-(4-shown in formula IV-1) the solution 0.5mL of-crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24 hours in following temperature, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-I1 after concentrating and separating.
Wherein, the concrete title of the alkaline catalysts of cinchona alkaloid shown in formula II, solvent, organic bases and temperature of reaction all list in table 1;
Productive rate and the ee% of compound shown in gained formula I-I1 also list in table 1.
Table 1, various reaction conditions and formula I productive rate and ee%
During note: formula II arranges, except the group of R6 part in Qd representative formula II, be also
1H NMR(300MHz,CDCl
3)δ7.37(dd,J=9.0,9.0Hz,4H),6.27(s,1H),5.59(d,J=8.0Hz,1H),3.45(d,J=19.3Hz,1H),3.20(dd,J=19.2,7.9Hz,1H),1.51(s,9H).
13C NMR(75MHz,CDCl
3)δ162.1,152.2,147.9,136.8,134.9,129.5,127.5,120.9,102.4,84.6,65.3,28.1,27.6.
Nuclear magnetic spectrogram (as depicted in figs. 1 and 2) and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-I1.
Compound (R shown in embodiment 26, preparation formula I-2
1substituting group is phenyl)
Cinchona alkaloid shown in formula II (TMS-Qd) catalyzer 0.02mmol is added in two-mouth bottle, solvents tetrahydrofurane 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving and, after 30 minutes, to add Compound C l shown in formula III-I in reaction flask
3cCH=NBoc 0.2mmol, the solution 0.5mL of the phenyl of 3-shown in formula IV-2-crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and in-40 temperature, carries out cycloaddition reaction 24 hours, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-I2 after concentrating and separating.
1H NMR(300MHz,CDCl
3)δ7.46-7.44(m,2H),7.38-7.35(m,3H),6.27(d,J=2.4Hz,1H),5.59(d,J=7.9Hz,1H),3.49(d,J=19.4Hz,1H),3.21(ddd,J=19.4,8.0,2.5Hz,1H),1.50(s,9H).
13C NMR(75MHz,CDCl
3)δ162.3,152.2,149.2,136.4,130.5,129.1,126.2,120.5,102.4,84.4,65.4,28.1,27.6.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-I2.
Compound (R shown in embodiment 27, preparation formula I-I3
1for p-methylphenyl)
Cinchona alkaloid shown in formula II (TMS-Qd) catalyzer 0.02mmol is added in two-mouth bottle, solvents tetrahydrofurane 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving and, after 30 minutes, to add Compound C l shown in formula III-I in reaction flask
3cCH=NBoc 0.2mmol, by the aminomethyl phenyl of 3-(4-shown in formula IV-3)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h at-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-I3 after concentrating and separating.
1H NMR(300MHz,CDCl
3)δ7.36(d,J=7.8Hz,2H),7.17(d,J=7.7Hz,2H),6.26(s,1H),5.58(d,J=8.0Hz,1H),3.48(d,J=19.3Hz,1H),3.19(dd,J=19.3,8.0Hz,1H),2.31(s,3H).
13C NMR(75MHz,CDCl
3)δ162.4,152.2,149.1,141.1,133.5,129.8,126.1,119.6,102.5,84.3,65.4,28.1,27.5,21.4.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-I3.
X-ray monocrystalline figure as shown in Figure 9.As seen from the figure, the steric configuration of this compound is as shown in structural formula.
Compound (R shown in embodiment 28, preparation formula I-I4
1for p-methoxyphenyl)
Cinchona alkaloid shown in formula II (TMS-Qd) catalyzer 0.02mmol is added in two-mouth bottle, solvents tetrahydrofurane 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving and, after 30 minutes, to add Compound C l shown in formula III-I in reaction flask
3cCH=NBoc 0.2mmol, by the p-methoxy-phenyl of 3-(4-shown in formula IV-4)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h at-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-I4 after concentrating and separating.
1H NMR(300MHz,CDCl
3)δ7.42(d,J=8.7Hz,2H),6.88(d,J=8.7Hz,2H),6.22(d,J=2.1Hz,1H),5.57(d,J=7.9Hz,1H),3.77(s,3H),3.48(d,J=19.3Hz,1H),3.17(ddd,J=19.2,8.0,2.2Hz,1H).
13C NMR(75MHz,CDCl
3)δ162.5,161.7,152.2,148.6,128.5,127.7,118.5,114.5,102.5,84.2,65.4,55.5,28.1,27.4.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-I4.
Compound (R shown in embodiment 29, preparation formula I-I5
1for to bromophenyl)
Cinchona alkaloid shown in formula II (TMS-Qd) catalyzer 0.02mmol is added in two-mouth bottle, solvents tetrahydrofurane 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving and, after 30 minutes, to add Compound C l shown in formula III-I in reaction flask
3cCH=NBoc 0.2mmol, by the bromophenyl of 3-(4-shown in formula IV-5)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-5 after concentrating and separating.
1H NMR(300MHz,CDCl
3)δ7.58(d,J=8.6Hz,2H),7.39(d,J=8.6Hz,2H),6.34(d,J=2.5Hz,1H),5.66(d,J=7.5Hz,1H),3.51(d,J=19.3Hz,1H),3.27(ddd,J=19.3,8.0,2.6Hz,1H),1.58(s,9H).
13C NMR(75MHz,CDCl
3)δ162.0,152.2,148.0,135.3,132.4,127.7,125.1,120.9,102.4,84.6,65.3,28.1,27.5.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-I5.X-ray monocrystalline figure as shown in Figure 9.As seen from the figure, the steric configuration of this product is configuration shown in formula I-I5.
Compound (R shown in embodiment 30, preparation formula I-I6
1for a chloro-phenyl-)
Cinchona alkaloid shown in formula II (TMS-Qd) catalyzer 0.02mmol is added in two-mouth bottle, solvents tetrahydrofurane 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving and, after 30 minutes, to add Compound C l shown in formula III-I in reaction flask
3cCH=NBoc 0.2mmol, by the chloro-phenyl-of 3-(3-shown in formula IV-6)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-6 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-I6.
Compound (R shown in embodiment 31, preparation formula I-I7
1for beta-naphthyl)
Cinchona alkaloid shown in formula II (TMS-Qd) catalyzer 0.02mmol is added in two-mouth bottle, solvents tetrahydrofurane 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving and, after 30 minutes, to add Compound C l shown in formula III-I in reaction flask
3cCH=NBoc 0.2mmol, by the naphthyl of 3-(beta-shown in formula IV-7)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-7 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-I7.
Compound (R shown in embodiment 32, preparation formula I-I8
1for 2-thienyl)
Cinchona alkaloid shown in formula II (TMS-Qd) catalyzer 0.02mmol is added in two-mouth bottle, solvents tetrahydrofurane 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving and, after 30 minutes, to add Compound C l shown in formula III-I in reaction flask
3cCH=NBoc 0.2mmol, by the thienyl of 3-(2-shown in formula IV-8)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-I8 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-8.
Compound (R shown in embodiment 33, preparation formula I-I9
1for 2-furyl)
Cinchona alkaloid shown in formula II (TMS-Qd) catalyzer 0.02mmol is added in two-mouth bottle, solvents tetrahydrofurane 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving and, after 30 minutes, to add Compound C l shown in formula III-I in reaction flask
3cCH=NBoc 0.2mmol, by the furyl of 3-(2-shown in formula IV-9)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-9 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-I9.
Embodiment 34 – 50, temperature, solvent and screening of catalyst
(the R of compound shown in preparation formula I-II1
1for rubigan)
The alkaline catalysts of cinchona alkaloid shown in formula II 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2after CCH=NTs 0.2mmol, by the chloro-phenyl-of 3-(4-shown in formula IV-1) the solution 0.5mL of-crotyl acyl chlorides 0.4mmol is added in two-mouth bottle, cycloaddition reaction 24h is carried out in following temperature, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II1 after concentrating and separating.
Wherein, the concrete title of the alkaline catalysts of cinchona alkaloid shown in formula II, solvent and temperature of reaction all list in table 2;
Productive rate and the ee% of compound shown in gained formula I-II1 also list in table 2.
Table 2, various reaction conditions and formula I productive rate and ee%
1H NMR(300MHz,CDCl
3)δ8.03(d,J=8.2Hz,2H),7.39(s,4H),7.33(d,J=8.1Hz,2H),6.14(d,J=2.3Hz,1H),5.53(d,J=4.7Hz,1H),4.12(dd,J=14.2,7.0Hz,2H),3.45(d,J=16.8Hz,1H),3.19(dd,J=17.8,3.7Hz,1H),2.44(s,3H),1.10(t,J=7.1Hz,3H).
13C NMR(75MHz,CDCl
3)δ169.7,162.3,150.6,145.1,136.9,135.7,134.5,129.8,129.4,129.1,127.6,119.7,62.6,56.3,30.7,21.8,14.0.
Nuclear magnetic spectrogram (as shown in Figure 5 and Figure 6) and Mass Spectrometric Identification product are as above structure, and be compound shown in formula I-II1, HPLC spectrogram as shown in Figure 8.
Compound (R shown in embodiment 51, preparation formula I-II2
1for phenyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) alkaline catalysts 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; The solution 0.5mL of the phenyl of 3-shown in formula IV-2-crotyl acyl chlorides 0.4mmol is added in two-mouth bottle, addition reaction 24h is carried out in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II2 after concentrating and separating.
1H NMR(300MHz,CDCl
3)δ7.95(d,J=8.3Hz,2H),7.35(m,5H),7.23(d,J=8.3Hz,2H),6.07(d,J=2.4Hz,1H),5.45(dd,J=6.2,1.9Hz,1H),4.22–3.83(m,2H),3.41(dd,J=17.7,1.5Hz,1H),3.11(ddd,J=17.7,6.2,2.4Hz,1H),2.33(s,3H),1.01(t,J=7.1Hz,3H).
13C NMR(75MHz,CDCl
3)δ169.7,162.4,151.9,144.9,136.1,135.8,130.7,129.7,129.0,126.3,119.4,62.4,56.3,30.8,21.7,14.0.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II2.
Compound (R shown in embodiment 52, preparation formula I-II3
1for p-methylphenyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) alkaline catalysts 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By the aminomethyl phenyl of 3-(4-shown in formula IV-3)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II3 after concentrating and separating.
1H NMR(300MHz,CDCl
3)δ7.95(d,J=8.3Hz,2H),7.28(d,J=8.2Hz,2H),7.23(d,J=8.1Hz,2H),7.12(d,J=8.1Hz,1H),6.05(d,J=2.4Hz,1H),5.44(dd,J=6.2,1.8Hz,1H),4.11–3.90(m,2H),3.41(dd,J=17.7,1.8Hz,1H),3.08(ddd,J=17.7,6.2,2.5Hz,1H),2.34(s,3H),2.28(s,3H),1.00(t,J=7.1Hz,3H).
13CNMR(75MHz,CDCl
3)δ169.8,162.6,151.8,144.9,141.2,135.8,133.1,129.7,129.0,126.2,118.4,62.4,56.3,30.7,21.7,21.4,14.0.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II3.
Compound (R shown in embodiment 53, preparation formula I-II4
1for p-methoxyphenyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By the p-methoxy-phenyl of 3-(4-shown in formula IV-4)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II4 after concentrating and separating.
1H NMR(300MHz,CDCl
3)δ8.03(d,J=8.4Hz,2H),7.44(d,J=8.9Hz,2H),7.32(d,J=8.3Hz,2H),6.92(d,J=8.9Hz,2H),6.10(d,J=2.4Hz,1H),5.51(dd,J=6.2,1.9Hz,1H),4.19–3.99(m,2H),3.50(dd,J=17.6,2.0Hz,1H),3.14(ddd,J=17.6,6.2,2.5Hz,1H),2.43(s,3H),1.09(t,J=7.1Hz,3H).
13C NMR(75MHz,CDCl
3)δ169.9,162.7,161.8,151.3,144.9,135.9,129.8,129.0,128.2,128.0,117.2,114.5,62.4,56.3,55.5,30.6,21.8,14.0.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II4.
Compound (R shown in embodiment 54, preparation formula I-II5
1for to bromophenyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By the bromophenyl of 3-(4-shown in formula IV-5)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II5 after concentrating and separating.
1H NMR(300MHz,CDCl
3)δ7.94(d,J=8.2Hz,2H),7.45(d,J=8.5Hz,2H),7.24(d,J=8.3Hz,4H),6.06(d,J=2.3Hz,1H),5.45(m,1H),4.03(m,2H),3.36(dd,J=17.6,1.6Hz,1H),3.11(ddd,J=17.7,6.1,2.4Hz,1H),2.31(d,J=24.6Hz,3H),1.01(t,J=7.1Hz,3H).
13C NMR(75MHz,CDCl
3)δ169.6,162.2,150.7,145.0,135.6,135.0,132.3,129.8,129.1,127.8,125.2,119.7,62.5,56.3,30.7,21.7,14.0.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II5.
Compound (R shown in embodiment 55, preparation formula I-II6
1for a chloro-phenyl-)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By the chloro-phenyl-of 3-(3-shown in formula IV-6)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II6 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II6.
Compound (R shown in embodiment 56, preparation formula I-II7
1for beta-naphthyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By the naphthyl of 3-(beta-shown in formula IV-7)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II7 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II7.
Compound (R shown in embodiment 57, preparation formula I-II8
1for 2-thienyl base)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By the thienyl of 3-(2-shown in formula IV-8)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II8 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II8.
Compound (R shown in embodiment 58, preparation formula I-II9
1for 2-furyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds the compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By the furyl of 3-(2-shown in formula IV-9)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II9 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II9.
Compound (R shown in embodiment 59, preparation formula I-II10
1for p-nitrophenyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By the nitrophenyl of 3-(4-shown in formula IV-10)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II10 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II10.
Compound (R shown in embodiment 60, preparation formula I-II11
1for Chloro-O-Phenyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By the chloro of 3-(2-shown in formula IV-11)-solution the 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II11 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II11.
Compound (R shown in embodiment 61, preparation formula I-II12
1for sec.-propyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds the compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; By shown in formula IV-12 3,4-dimethyl-solution the 0.5mL of pentenyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II12 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II12.
Compound (R shown in embodiment 62, preparation formula I-II13
1for ethyl)
Cinchona alkaloid shown in formula II (n-Bu-Qd) catalyzer 0.02mmol is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, N-diisopropyl ethyl amine, i.e. DIPEA) 0.8mmol to be added in system more at room temperature stirring and dissolving 30 minutes, adds compd E tO shown in formula III-II in reaction flask
2cCH=NTs 0.2mmol; The methyl of 3-shown in the formula IV-13-solution 0.5mL of pentenyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 DEG C, disappear to thin-layer chromatography contrast display raw material imines, be raised to room temperature, by in light yellow for gained reaction solution impouring frozen water, leave standstill, layering, aqueous phase is extracted with ethyl acetate three times; Merge organic liquor, dry, obtain compound shown in formula I-II13 after concentrating and separating.
Nuclear magnetic spectrogram and Mass Spectrometric Identification product are as above structure, are compound shown in formula I-II13.
Claims (9)
1. a method for compound shown in preparation formula I, comprises the steps:
The alkaline catalysts of cinchona alkaloid shown in formula II and organic bases are dissolved in after in organic solvent, then add the chlorine compound of unsaturated acyl shown in aldimine and formula IV shown in formula III mixing carry out cycloaddition reaction, obtain compound shown in formula I;
Described formula I in formula IV,
Work as R
5during for Boc, R
3for trichloromethyl, R
1for rubigan, phenyl, p-methylphenyl, p-methoxyphenyl, to bromophenyl, a chloro-phenyl-, 2-thienyl or 2-furyl, R
2=R
4=H;
Work as R
5during for Ts, R
3for CO
2et, R
1for rubigan, phenyl, p-methylphenyl, p-methoxyphenyl, a chloro-phenyl-, 2-thienyl, 2-furyl, p-nitrophenyl, Chloro-O-Phenyl, R
2=R
4=H;
R
6be selected from hydrogen, the alkyl of C1-C6, trimethyl silicon based, t-Butyldimethylsilyl, triisopropylsilyl, benzyl and benzoyl any one.
2. method according to claim 1, it is characterized in that: described organic bases is selected from 1, at least one in 8-diazabicylo [5.4.0] 11 carbon-7-alkene, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane, triethylamine, diethylamine and DIPEA.
3. method according to claim 1, is characterized in that: shown in cinchona alkaloid alkaline catalysts shown in described formula II and organic bases, formula III, shown in aldimine and formula IV, the molar ratio of unsaturated acyl chlorine compound is 0.001-1:1-50:1-20:1-100.
4. method according to claim 3, is characterized in that: shown in cinchona alkaloid alkaline catalysts shown in described formula II and organic bases, formula III, shown in aldimine and formula IV, the molar ratio of unsaturated acyl chlorine compound is 0.01-0.5:2-10:1:1-50.
5. method according to claim 4, is characterized in that: shown in cinchona alkaloid alkaline catalysts shown in described formula II and organic bases, formula III, shown in aldimine and formula IV, the molar ratio of unsaturated acyl chlorine compound is 0.1:4:1:2.
6. method according to claim 1, it is characterized in that: described organic solvent is all selected from toluene, dimethylbenzene, chlorobenzene, benzene, dioxane, tetrahydrofuran (THF), ether, trichloromethane, methylene dichloride, 1, at least one in 2-ethylene dichloride, ethyl acetate, acetone, acetonitrile and DMF.
7. method according to claim 1, is characterized in that: in described cycloaddition reaction step, temperature be-80 DEG C to room temperature;
Time is 3-48 hour.
8., according to the arbitrary described method of claim 1-7, it is characterized in that: in described cycloaddition reaction step, temperature of reaction is room temperature, and the reaction times is 3-24 hour; Or,
Temperature of reaction is-10 DEG C, and the reaction times is 6-24 hour; Or,
Temperature of reaction is-40 DEG C, and the reaction times is 16-26 hour; Or,
Temperature of reaction is-80 to-78 DEG C, and the reaction times is 24-48 hour.
9. method according to claim 8, is characterized in that: in described cycloaddition reaction step, temperature of reaction is-40 DEG C, and the reaction times is 24 hours.
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