CN103467227A - Method for preparing chiral piperidone - Google Patents

Method for preparing chiral piperidone Download PDF

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CN103467227A
CN103467227A CN2013103843993A CN201310384399A CN103467227A CN 103467227 A CN103467227 A CN 103467227A CN 2013103843993 A CN2013103843993 A CN 2013103843993A CN 201310384399 A CN201310384399 A CN 201310384399A CN 103467227 A CN103467227 A CN 103467227A
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CN103467227B (en
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叶松
贾文强
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Institute of Chemistry CAS
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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

A kind of method for preparing chiral piperidine ketone
Technical field
The invention belongs to the synthetic field of the crucial skeleton of pharmaceutical intermediate, be specifically related to a kind of method for preparing chiral piperidine ketone.
Background technology
Calendar year 2001, Americanized scholar Sha Pulisi and Knowles and Japanization scholar Ryoji Noyori professor have shared Nobel chemistry Prize, are used for commending their the initiative contribution in the novel method technology of development catalysis chirality and asymmetric synthesis and in being applied to the industrial production research field.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 can identify chirality, same, and the activity of the drug molecule also configuration concrete to it is relevant.And most medicines are all chiral molecules, and drug molecule must be complementary with intracellular acceptor, and in some cases, the another one enantiomer may be harmful to.Phase early 1960s, the tranquilizer reaction stops once being used to alleviate the early stage nauseating sense of pregnant woman, but this medicine also can cause baby's Deformities of Limbs, and this tragedy has also just more effectively illustrated this point.Therefore, the U.S. and European Bureau of Drugs Supervision require all medicines containing chirality must obtain single enantiomer could to go on the market.
The high enantioselectivity of chiral drug synthesizes at chemistry, chemical industry, biology and field of medicaments and all is subject to extensive concern.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 scientist's favor.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
Figure BDA00003740013500011
angw.Chem.Int.Ed.2006,45,4305).And contain equally piperidines or the such minor structure of piperidone, the natural product adalinine(S.G..Davies of biological example bases, P.M.Roberts, A.D.Smith, Org.Biomol.Chem.2007,5,1405 in a large amount of natural products).The anti-malaria medicaments Lariam(mefloquine be used widely) in, very crucial minor structure is 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 extensively is 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 of new generation (Ropivacaine), antipsychotics thioridazine (Thioridazine), Rapamycin (Rapamycin) and antitumor antibiotics (Sandramycin) etc. is all to take the nipecotic acid or derivatives thereof as the main raw material preparation.
Figure BDA00003740013500021
Important use in view of piperidines, in the decades in past, there are a lot of documents and its chirality of patent report synthetic, the formation of organic molecule asymmetry catalysis carbonnitrogen bond, thus synthetic to contain the bioactive compound of having of piperidine structure unit be one of current heat subject.
Summary of the invention
The purpose of this invention is to provide a kind of method for preparing chiral piperidine ketone.
The method of compound shown in preparation formula I provided by the invention (being also chiral piperidine ketone), comprise the steps:
After being dissolved in organic solvent by cinchona alkaloid catalyzer shown in formula II and organic bases, then add unsaturated acyl chlorine compound shown in aldimine shown in formula III and formula IV to mix to carry out cycloaddition reaction, obtain compound shown in formula I;
Figure BDA00003740013500022
Described formula I to formula IV,
R 1all be selected from the alkyl of hydrogen, C1-C6, the aryl of C6-C10, the aryl that contains substituent C8-C10, heteroaryl and contain any one in substituent heteroaryl;
Wherein, the described substituent aryl and containing in substituent heteroaryl of containing, substituting group all is selected from least one in the alkyl of the alkoxyl group of halogen, nitro, C1-C2 and C1-C2;
R 2and R 4all be selected from any one in the alkyl of hydrogen and C1-C6;
R 5during for carbalkoxy shown in ROCO-, R 3for trichloromethyl, trisbromomethyl, trifluoromethyl, cyano group, nitro;
Shown in described ROCO-in carbalkoxy, the alkyl that R is C1-C6, the preferred tertiary butyl, the protecting group on nitrogen is Boc;
R 3during for formic acid ester group shown in-COOR ', R 5for p-toluenesulfonyl (Ts), adjacent tosyl group, a tosyl group, benzenesulfonyl (Bs), to chlorobenzene alkylsulfonyl, adjacent chlorobenzene alkylsulfonyl or m-chloro benzenesulfonyl;
Shown in described-COOR ' in the formic acid ester group, the alkyl that R is C1-C6, aryl, contain substituent aryl, heteroaryl or contain substituent heteroaryl, the preferred ethyl of R;
Wherein, the described substituent aryl and containing in substituent heteroaryl of containing, substituting group all is selected from least one in the alkyl of the alkoxyl group of halogen, nitro, C1-C2 and C1-C2;
R 6silica-based, the benzyl (Bn) that is selected from that the alkyl of alkyl, the C1-C9 of hydrogen, C1-C6 replaces and any one in benzoyl (Bz).
In aforesaid method, described aryl is phenyl or naphthyl;
Describedly contain substituent aryl for 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, 3,4-3,5-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 contain substituent heteroaryl and be specially 5-methyl-2-furyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl or 5-methyl-2-thienyl.
Described R 6in, the alkyl of C1-C9 replaces silica-based in, the carbonatoms of alkyl is specially 1-4;
More specifically, the silica-based of the alkyl of described C1-C9 replacement is trimethyl silicon based (TMS), t-Butyldimethylsilyl (TBS) or triisopropylsilyl (TIPS).
Described organic bases is selected from least one in 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU), Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO), triethylamine (TEA), diethylamine and DIPEA (DIPEA).The effect of organic bases is: the raw material acyl chlorides is sloughed to a part hydrogenchloride, then react with aldimine.
Shown in described formula II, the molar ratio of unsaturated acyl chlorine compound shown in aldimine shown in cinchona alkaloid catalyzer and organic bases, formula III and formula IV 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 all is 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 ℃ 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 ℃, and the reaction times is 6-8 hour; Or,
Temperature of reaction is-40 ℃, and the reaction times is 16-26 hour, is specially 24 hours; Or,
Temperature of reaction is-80 to-78 ℃, and the reaction times is 24-48 hour.
The present invention is usingd unsaturated acyl chlorides as raw material, usings alkaloid as catalyzer, in organic solvent, with aldimine (III), carries out asymmetric cyclization, generates the unsaturated piperidines ketone of chirality.The method simple process, productive rate is high and can the gram level preparation, the more important thing is and can obtain that replace and the piperidone that there is different substituents in various positions simultaneously, and all there is outstanding enantioselectivity (being up to 99%ee) to there is important using value.
The accompanying drawing explanation
Fig. 1 is that embodiment 25 prepares compound shown in gained formula I-I1 1h NMR collection of illustrative plates.
Fig. 2 is that embodiment 25 prepares compound shown in gained formula I-I1 13c NMR collection of illustrative plates.
Fig. 3 is the HPLC that embodiment 25 prepares two kinds of possibility isomer of compound (raceme) shown in gained formula I-I1.
Fig. 4 is the HPLC that embodiment 25 prepares compound shown in gained formula I-I1.
Fig. 5 is that embodiment 34 prepares compound shown in gained formula I-II1 1h NMR collection of illustrative plates.
Fig. 6 is that embodiment 34 prepares compound shown in gained formula I-II1 13c NMR collection of illustrative plates.
Fig. 7 is the HPLC that embodiment 34 prepares two kinds of possibility isomer of compound (raceme) shown in gained formula I-II1.
Fig. 8 is the HPLC that embodiment 34 prepares compound shown in gained formula I-II1.
Fig. 9 is the X-ray monocrystalline figure that embodiment 27 prepares compound shown in gained formula I-II3.
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 of product (ee), mean in reaction product excessive to another enantiomorph of an enantiomorph, usually with percentage ratio, means, its calculation formula is: ee=([S]-[R])/([S]+[R]) x100%.
The enantioselectivity of formula I-I1 of the present invention, being the enantiomeric excess (being the ee value) of product, is that the product after purifying is calculated by (S)-configuration product in chirality high pressure liquid chromatography figure (chirality OD-H post or chirality AD-H post) and the peak area of (R)-configuration product.
With formula, I-I1 synthesizes example, and circular is as follows: from accompanying drawing three, accompanying drawing four, can learn, (S) retention time of I-I1 is 13.2 minutes, and the retention time of its enantiomorph (R) I-I1 is 15.3 minutes; With reference to the accompanying drawings three, shown in accompanying drawing four, the peak area per-cent of the principal product that retention time is 12.6 minutes is 100, the peak of the product that retention time is 14.7 minutes is invisible, be that peak area per-cent 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 determines by single crystal diffraction, the cultivation of monocrystalline be by by compound dissolution in the mixing solutions of sherwood oil, ethyl acetate and methylene dichloride slowly volatilization obtain.
Unsaturated acyl chlorides used (3-(4-chloro-phenyl-)-crotyl acyl chlorides in following embodiment 1 step 1)) be prepared as follows and obtain:
Figure BDA00003740013500051
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add parachloroacetophenone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(4-chloro-phenyl-that decompression is spin-dried for the cut of collecting 80-83 ℃/3mm Hg after low-boiling point material)-the crotyl acyl chlorides.Compare by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-1) is correct.
The wittig-hornor preparation method of reagent thereof is as follows: under room temperature, add ethyl bromoacetate 150g and triethyl-phosphite 150g in reaction flask, and reflux 3h slowly under stirring, decompression is collected 180 ℃/2mm of cut Hg and is got final product.Compare by nuclear-magnetism and standard spectrum, can confirm that wittig-hornor reagent is correct
Unsaturated acyl chlorides used in following embodiment 26 step 1) (3-phenyl-crotyl acyl chlorides) is prepared as follows and obtains:
Figure BDA00003740013500061
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add methyl phenyl ketone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is 3-phenyl-crotyl acyl chlorides that decompression is spin-dried for the cut of collecting 60-61 ℃/3mm Hg after low-boiling point material.Compare 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:
Figure BDA00003740013500062
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add p-methyl aceto phenone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(4-aminomethyl phenyl that decompression is spin-dried for after low-boiling point material the cut of collecting 66 ℃/3mm of 64 – Hg)-the crotyl acyl chlorides.Compare 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:
Figure BDA00003740013500071
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add p-methoxy-acetophenone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(4-p-methoxy-phenyl that decompression is spin-dried for after low-boiling point material the cut of collecting 71 ℃/3mm of 70 – Hg)-the crotyl acyl chlorides.Compare 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:
Figure BDA00003740013500072
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add parabromoacetophenone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(4-bromophenyl that decompression is spin-dried for after low-boiling point material the cut of collecting 91 ℃/3mm of 90 – Hg)-the crotyl acyl chlorides.Compare 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) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add m chloroacetophenone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(3-chloro-phenyl-that decompression is spin-dried for the cut of collecting 80-81 ℃/3mmHg after low-boiling point material)-the crotyl acyl chlorides.Compare 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:
Figure BDA00003740013500081
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add 2-naphthyl methyl ketone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(beta-naphthyl that decompression is spin-dried for the cut of collecting 100-105 ℃/3mm Hg after low-boiling point material)-the crotyl acyl chlorides.Compare 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:
Figure BDA00003740013500082
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add 2-thienyl methyl ketone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(2-thienyl that decompression is spin-dried for after low-boiling point material the cut of collecting 65 ℃/3mm of 60 – Hg)-the crotyl acyl chlorides.Compare 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:
Figure BDA00003740013500091
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add 2-furyl methyl ketone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(2-furyl that decompression is spin-dried for the cut of collecting 50-52 ℃/3mm Hg after low-boiling point material)-the crotyl acyl chlorides.Compare 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:
Figure BDA00003740013500092
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add p-nitroacetophenone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(4-nitrophenyl that decompression is spin-dried for the cut of collecting 105-107 ℃/3mm Hg after low-boiling point material)-the crotyl acyl chlorides.Compare 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:
Figure BDA00003740013500093
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add o-chloroacetophenone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is the 3-(2-chloro-phenyl-that decompression is spin-dried for the cut of collecting 77-80 ℃/3mm Hg after low-boiling point material)-the crotyl acyl chlorides.Compare by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-11) is correct.
Unsaturated acyl chlorides used in following embodiment 61 (3,4-dimethyl-pentenyl acyl chlorides) is prepared as follows and obtains:
Figure BDA00003740013500101
By wittig-hornor reagent ((EtO) 2oPCH 2cO 2et) 0.05mol and 100mL tetrahydrofuran (THF) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add 3-espeleton 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is 3 that decompression is spin-dried for the cut of collecting 45-48 ℃/3mm Hg after low-boiling point material, 4-dimethyl-pentenyl acyl chlorides.Compare by nuclear-magnetism and standard spectrum, can confirm that acyl chlorides (formula IV-12) is correct.
Unsaturated acyl chlorides used in following embodiment 62 (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) are added in two-mouth bottle, add the sodium hydride that 0.06mol content is 40% in ice-water bath in batches, stir 30min under zero degree, add butanone 0.05mol, stir and spend the night under zero degree, decompression is spin-dried for tetrahydrofuran (THF) after completion of the reaction, residue adds the 200mL shrend and goes out, ethyl acetate extraction (3x30mL), merging organic phase gained concentrated solution back hydrolysis to organic layer in the 10%NaOH aqueous solution disappears substantially, the cool to room temperature water is extracted with ethyl acetate (2x10mL), aqueous phase as acidified obtains sour, suction filtration, be dissolved in methylene dichloride 30mL after filtration cakes torrefaction, add under oxalyl chloride 0.1mol room temperature and stir 15h, it is 3-methyl-pentenyl acyl chlorides that decompression is spin-dried for the cut of collecting 25-28 ℃/3mm Hg after low-boiling point material.Compare 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:
Figure BDA00003740013500111
Trichoro-aldehyde (1.0eq) is dissolved in appropriate organic solvent, adds wittig reagent Ph 3p=NBoc (1.0eq), reflux one hour, then is spin-dried for solvent, and underpressure distillation can obtain the target product imines, is white solid, by nuclear-magnetism and standard spectrum, compares, and 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 ℃, slowly drip the aqueous solution of Sodium Nitrite (1.2eq), continuation is reacted 30min at this temperature, use extracted with diethyl ether 3-5 time, merge organic phase, make water (repeatedly), NaHCO 3solution, the washing of NaCl saturated solution, anhydrous sodium sulfate drying.This solution is cooled to 0 ℃, slowly adds triphenylphosphine, after adding fully, be warming up to room temperature reaction 30min, separate out a large amount of white solids, use the ether washing, obtain pure target product after vacuum-drying.
Following embodiment 34-62 aldimine used (formula III-II) is prepared as follows and obtains:
Figure BDA00003740013500112
Glyoxylic acid ethyl ester solution (1.0eq) is dissolved in organic solvent, then add p-Methyl benzenesulfonyl isocyanate (1.0eq), reflux three days, then be spin-dried for solvent, underpressure distillation can obtain the target product imines, for colourless liquid, by nuclear-magnetism and standard spectrum, compare, can confirm that product is correct.
Following embodiment 2-7 R used 6shown in the formula II of the silica-based or benzyl (Bn) replaced for the C1-C6 alkyl, the cinchona alkaloid catalyzer is prepared as follows and obtains:
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, add the shrend reaction of going out, ethyl acetate extraction 3 times, merge organic phase, and column chromatography for separation can obtain target product.Compare by nuclear-magnetism and standard spectrum, confirm that product is correct.
Following embodiment 12,14 and 15 R used 6for being prepared as follows, cinchona alkaloid catalyzer shown in the silica-based formula II of C3-C9 alkyl replacement obtains:
Quinine (1.0eq) is dissolved in methylene dichloride in (DCM), adds triethylamine (TEA, 3.0eq), then add corresponding silica-based chloro thing (R 6cl, 1.5eq), room temperature is spent the night to refluxing.After reacting completely, add the shrend reaction of going out, ethyl acetate extraction 3 times, merge organic phase, and column chromatography for separation can obtain target product.Compare by nuclear-magnetism and standard spectrum, confirm that product is correct.
Following embodiment 13 R used 6for being prepared as follows, cinchona alkaloid catalyzer shown in the formula II of benzoyl (Bz) obtains:
Quinine (1.0eq) is dissolved in tetrahydrofuran (THF) (THF), adds triethylamine (TEA, 3.0eq), then add Benzoyl chloride (BzCl, 1.5eq), room temperature reaction spends the night.After reacting completely, add the shrend reaction of going out, ethyl acetate extraction 3 times, merge organic phase, and column chromatography for separation can obtain target product.Compare by nuclear-magnetism and standard spectrum, 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)
The 0.02mmol of cinchona alkaloid catalyzer shown in formula II is added in two-mouth bottle, and solvent 1.5mL and organic bases 0.8mmol are added in system more at room temperature stirring and dissolving and, after 30 minutes, add the l of Compound C shown in formula III-I in reaction flask 3cCH=NBoc 0.2mmol, by 3-(4-chloro-phenyl-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, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-I1 after concentrating and separating.
Wherein, the concrete title of cinchona alkaloid catalyzer shown in formula II, solvent, organic bases and temperature of reaction are all listed in table 1;
Shown in gained formula I-I1, the productive rate of compound and ee% also list in table 1.
Table 1, various reaction conditions and formula I productive rate and ee%
Figure BDA00003740013500121
Figure BDA00003740013500131
Annotate: in formula II row, Qd represents the group that removes the R6 part in formula II, is also
Figure BDA00003740013500132
Figure BDA00003740013500141
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving and, after 30 minutes, adds the l of Compound C 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 carries out cycloaddition reaction 24 hours in-40 temperature, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, 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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving and, after 30 minutes, adds the l of Compound C shown in formula III-I in reaction flask 3cCH=NBoc 0.2mmol, by 3-(4-aminomethyl phenyl shown in formula IV-3)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h at-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-I3 after concentrating and separating.
Figure BDA00003740013500151
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving and, after 30 minutes, adds the l of Compound C shown in formula III-I in reaction flask 3cCH=NBoc 0.2mmol, by 3-(4-p-methoxy-phenyl shown in formula IV-4)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h at-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-I4 after concentrating and separating.
Figure BDA00003740013500152
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving and, after 30 minutes, adds the l of Compound C shown in formula III-I in reaction flask 3cCH=NBoc 0.2mmol, by 3-(4-bromophenyl shown in formula IV-5)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-5 after concentrating and separating.
Figure BDA00003740013500161
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving and, after 30 minutes, adds the l of Compound C shown in formula III-I in reaction flask 3cCH=NBoc 0.2mmol, by 3-(3-chloro-phenyl-shown in formula IV-6)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-6 after concentrating and separating.
Figure BDA00003740013500162
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 the 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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving and, after 30 minutes, adds the l of Compound C shown in formula III-I in reaction flask 3cCH=NBoc 0.2mmol, by 3-(beta-naphthyl shown in formula IV-7)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-7 after concentrating and separating.
Figure BDA00003740013500171
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 the 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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving and, after 30 minutes, adds the l of Compound C shown in formula III-I in reaction flask 3cCH=NBoc 0.2mmol, by 3-(2-thienyl shown in formula IV-8)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-I8 after concentrating and separating.
Figure BDA00003740013500172
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 the 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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving and, after 30 minutes, adds the l of Compound C shown in formula III-I in reaction flask 3cCH=NBoc 0.2mmol, by 3-(2-furyl shown in formula IV-9)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-9 after concentrating and separating.
Figure BDA00003740013500173
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 0.02mmol of cinchona alkaloid catalyzer shown in formula II is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2after CCH=NTs 0.2mmol, by 3-(4-chloro-phenyl-shown in formula IV-1)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle, carry out cycloaddition reaction 24h in following temperature, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II1 after concentrating and separating.
Wherein, the concrete title of cinchona alkaloid catalyzer, solvent shown in formula II and temperature of reaction are all listed in table 2;
Shown in gained formula I-II1, the productive rate of compound and ee% also list in table 2.
Table 2, various reaction conditions and formula I productive rate and ee%
Figure BDA00003740013500181
Figure BDA00003740013500191
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, are compound shown in formula I-II1, and the HPLC spectrogram as shown in Figure 8.
Compound (R shown in embodiment 51, preparation formula I-II2 1for phenyl)
Biological (n-Bu-Qd) alkaline catalysts 0.02mmol of quinine shown in formula II is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E 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, carry out addition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II2 after concentrating and separating.
Figure BDA00003740013500193
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)
Biological (n-Bu-Qd) alkaline catalysts 0.02mmol of quinine shown in formula II is added in two-mouth bottle, toluene solvant 1.5mL and organic bases (N, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2cCH=NTs 0.2mmol; By 3-(4-aminomethyl phenyl shown in formula IV-3)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II3 after concentrating and separating.
Figure BDA00003740013500201
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2cCH=NTs 0.2mmol; By 3-(4-p-methoxy-phenyl shown in formula IV-4)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II4 after concentrating and separating.
Figure BDA00003740013500202
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2cCH=NTs 0.2mmol; By 3-(4-bromophenyl shown in formula IV-5)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II5 after concentrating and separating.
Figure BDA00003740013500211
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2cCH=NTs 0.2mmol; By 3-(3-chloro-phenyl-shown in formula IV-6)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II6 after concentrating and separating.
Figure BDA00003740013500212
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 the 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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2cCH=NTs 0.2mmol; By 3-(beta-naphthyl shown in formula IV-7)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II7 after concentrating and separating.
Figure BDA00003740013500221
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2cCH=NTs 0.2mmol; By 3-(2-thienyl shown in formula IV-8)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II8 after concentrating and separating.
Figure BDA00003740013500222
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 the 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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is 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 3-(2-furyl shown in formula IV-9)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II9 after concentrating and separating.
Figure BDA00003740013500231
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2cCH=NTs 0.2mmol; By 3-(4-nitrophenyl shown in formula IV-10)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II10 after concentrating and separating.
Figure BDA00003740013500232
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2cCH=NTs 0.2mmol; By 3-(2-chloro shown in formula IV-11)-the solution 0.5mL of crotyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II11 after concentrating and separating.
Figure BDA00003740013500233
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is 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, the solution 0.5mL of 4-dimethyl-pentenyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, obtain compound shown in formula I-II12 after concentrating and separating.
Figure BDA00003740013500241
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, the N-diisopropyl ethyl amine, being DIPEA) 0.8mmol is added in system more at room temperature stirring and dissolving 30 minutes, adds the tO of compd E shown in formula III-II in reaction flask 2cCH=NTs 0.2mmol; The solution 0.5mL of the methyl of 3-shown in formula IV-13-pentenyl acyl chlorides 0.4mmol is added in two-mouth bottle and carries out cycloaddition reaction 24h in-40 ℃, show that to the thin-layer chromatography contrast raw material imines disappears, be raised to room temperature, by in the light yellow reaction solution impouring of gained frozen water, standing, layering, water is extracted with ethyl acetate three times; Merge organic liquor, drying, 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 (7)

1. the method for compound shown in a preparation formula I, comprise the steps:
After being dissolved in organic solvent by cinchona alkaloid catalyzer shown in formula II and organic bases, then add unsaturated acyl chlorine compound shown in aldimine shown in formula III and formula IV to mix to carry out cycloaddition reaction, obtain compound shown in formula I;
Figure FDA00003740013400011
Described formula I to formula IV,
R 1all be selected from the alkyl of hydrogen, C1-C6, the aryl of C6-C10, the aryl that contains substituent C8-C10, heteroaryl and contain any one in substituent heteroaryl;
Wherein, the described substituent aryl and containing in substituent heteroaryl of containing, substituting group all is selected from least one in the alkyl of the alkoxyl group of halogen, nitro, C1-C2 and C1-C2;
R 2and R 4all be selected from any one in the alkyl of hydrogen and C1-C6;
R 5during for carbalkoxy shown in ROCO-, R 3for trichloromethyl, trisbromomethyl, trifluoromethyl, cyano group or nitro;
Shown in described ROCO-in carbalkoxy, the alkyl that R is C1-C6;
R 3during for formic acid ester group shown in-COOR ', R 5for p-toluenesulfonyl, adjacent tosyl group, a tosyl group, benzenesulfonyl, to chlorobenzene alkylsulfonyl, adjacent chlorobenzene alkylsulfonyl or m-chloro benzenesulfonyl;
Shown in described-COOR ' in the formic acid ester group, alkyl, the aryl that R ' is C1-C6, contain substituent aryl, heteroaryl or contain substituent heteroaryl;
Wherein, the described substituent aryl and containing in substituent heteroaryl of containing, substituting group all is selected from least one in the alkyl of the alkoxyl group of halogen, nitro, C1-C2 and C1-C2;
R 6silica-based, the benzyl that is selected from that the alkyl of alkyl, the C1-C9 of hydrogen, C1-C6 replaces and any one in benzoyl.
2. method according to claim 1, it is characterized in that: in described formula I-formula IV, aryl is phenyl or naphthyl;
Describedly contain substituent aryl for 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, 3,4-3,5-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;
It is described that to contain substituent heteroaryl be 5-methyl-2-furyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl or 5-methyl-2-thienyl.
3. method according to claim 1 and 2, 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.
4. according to the arbitrary described method of claim 1-3, it is characterized in that: shown in described formula II, the molar ratio of unsaturated acyl chlorine compound shown in aldimine shown in cinchona alkaloid catalyzer and organic bases, formula III and formula IV 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.
5. according to the arbitrary described method of claim 1-4, it is characterized in that: described organic solvent all is 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.
6. method according to claim 1 is characterized in that: in described cycloaddition reaction step, temperature be-80 ℃ to room temperature;
Time is 3-48 hour.
7. exist according to the arbitrary described method of claim 1-6, 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 ℃, and the reaction times is 6-24 hour; Or,
Temperature of reaction is-40 ℃, and the reaction times is 16-26 hour, is specially 24 hours; Or,
Temperature of reaction is-80 to-78 ℃, and the reaction times is 24-48 hour.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101790516A (en) * 2007-06-29 2010-07-28 托伦特药物有限公司 Novel substituted piperidones as hsp inducers
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Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101790516A (en) * 2007-06-29 2010-07-28 托伦特药物有限公司 Novel substituted piperidones as hsp inducers
US20130053565A1 (en) * 2011-08-29 2013-02-28 University Of Utah Research Foundation Substituted 3-piperidone compounds

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