CN110003139B - Preparation method of alpha, beta-epoxy ketone compound - Google Patents
Preparation method of alpha, beta-epoxy ketone compound Download PDFInfo
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- CN110003139B CN110003139B CN201910374774.3A CN201910374774A CN110003139B CN 110003139 B CN110003139 B CN 110003139B CN 201910374774 A CN201910374774 A CN 201910374774A CN 110003139 B CN110003139 B CN 110003139B
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- 238000002360 preparation method Methods 0.000 title claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 192
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 239000011259 mixed solution Substances 0.000 claims abstract description 25
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 17
- 150000002576 ketones Chemical class 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 238000003476 Darzens condensation reaction Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Chemical group 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000005504 styryl group Chemical group 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000012267 brine Substances 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 8
- 239000001257 hydrogen Substances 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 2
- 238000001308 synthesis method Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 14
- 238000002156 mixing Methods 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000000126 substance Substances 0.000 description 10
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- CCHNWURRBFGQCD-UHFFFAOYSA-N 2-chlorocyclohexan-1-one Chemical compound ClC1CCCCC1=O CCHNWURRBFGQCD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- -1 α' -hydrogen) Chemical compound 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/32—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epoxy Compounds (AREA)
Abstract
The invention provides a method for efficiently generating alpha, beta-epoxy ketone compounds with various aldehydes under the action of DBU or DBN by taking alpha-halogenated ketone containing alpha-hydrogen as a raw material. The mixed solution of alpha-halogenated ketone and aldehyde dichloromethane is slowly dripped into DBU or DBN dichloromethane solution under the protection of inert gas and at the temperature of minus 20 ℃, and the alpha, beta-epoxy ketone compound is obtained through separation and purification after the reaction is finished. The synthesis method disclosed by the invention has the advantages of easily available raw materials, low cost, easiness in operation and control, fewer side reactions, simplicity in post-treatment, higher product yield, great saving in production cost, better economic benefit and suitability for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis and chemical product synthesis, and in particular relates to a method for preparing an alpha, beta-epoxy ketone compound by using DBN or DBU as alkali and performing Darzen reaction on alpha-halogenated ketone and aldehyde.
Background
Many natural products and medicines contain ethylene oxide structural units, and the ethylene oxide has high activity and is easily converted into other functional groups, so the compounds are important intermediates in the chemical industry field and are used for preparing other substances with various complex structures. Alpha, beta-epoxyketone belongs to one of the epoxyethane compounds, wherein the dabber reaction is the most classical and most commonly used method for preparing the compounds. Namely, under the strong alkaline condition, the alpha-halogenated ketone can directly react with various aldehydes to obtain corresponding alpha, beta-epoxy ketone products. However, the other side of the carbonyl group of the α -haloketone used in the dabber reaction generally cannot contain hydrogen (i.e., α' -hydrogen), otherwise the favorsii rearrangement reaction easily occurs, resulting in failure to obtain the desired product.
Under the action of a special metal tin complex, alpha-halogenated ketone containing alpha' -hydrogen can react with various aldehydes to prepare alpha, beta-epoxy ketone with high efficiency (J.org. chem.1992, 57 (25), 6909-6914.). However, this method requires not only the preparation of equivalent metal tin complexes in advance, but also the use of equivalent HMPA as an additive, and the whole experimental operation procedure is complicated.
Disclosure of Invention
The invention aims to provide a method for efficiently generating alpha, beta-epoxy ketone compounds with various aldehydes under the action of DBU or DBN by taking alpha-halogenated ketone containing alpha-hydrogen as a raw material.
In order to achieve the above purpose, the technical scheme provided by the invention is as follows: in the presence of 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), carrying out Darzen reaction on alpha-halogenated ketone shown in the general formula (I) and aldehyde shown in the general formula (II) in a solvent to obtain alpha, beta-epoxy ketone compound shown in the general formula (III), wherein the chemical reaction formula is shown as follows:
wherein R is 1 Selected from C 1 -C 6 Alkyl or phenyl, R 2 Selected from H or C 1 -C 4 Alkyl of (a); or R is 1 And R is 2 Are linked together to form- (CH) 2 ) n -, wherein n=3-6; r is R 3 Selected from phenyl, substituted phenyl or styryl, wherein one or two substituents on the substituted phenyl are substitutedEach independently selected from C 1 -C 4 Alkyl, C of (2) 1 -C 4 Alkoxy or nitro; x is chlorine or bromine.
Preferably, R 1 Selected from C 1 -C 4 Alkyl or phenyl, R 2 Selected from H or C 1 -C 2 Alkyl of (a); or R is 1 And R is 2 Are linked together to form- (CH) 2 ) n -, wherein n=3-6; r is R 3 Selected from phenyl, substituted phenyl or styryl, wherein one or two substituents on the substituted phenyl are independently selected from C 1 -C 2 Alkyl, C of (2) 1 -C 2 Alkoxy or nitro, the position of the substituent being meta or para; x is chlorine or bromine.
Optimally, R 1 Selected from methyl, ethyl, propyl, isopropyl or phenyl, R 2 Selected from H or methyl; or R is 1 And R is 2 Are linked together to form- (CH) 2 ) n -, wherein n=3-6; r is R 3 Selected from phenyl, substituted phenyl or styryl, wherein one or two substituents on the substituted phenyl are selected independently from methyl, methoxy or nitro, and the position of the substituent is meta-position or para-position; x is selected from chlorine or bromine.
In the above preparation method, the solvent is selected from dichloromethane, chloroform, tetrahydrofuran or diethyl ether; preferably, the solvent is selected from dichloromethane.
In the preparation method, the reaction temperature of the Darzen reaction is-40 ℃; the molar ratio of the aldehyde, the alpha-halogenated ketone and the DBN or DBU is 1:1-1.5:1-2.
Preferably, the reaction temperature of the Darzen reaction is between-20 ℃ and 25 ℃; the molar ratio of the aldehyde, the alpha-halogenated ketone and the DBN or DBU is 1:1-1.2:1-1.4.
Optimally, the reaction temperature of the Darzen reaction is-20 ℃; the molar ratio of the aldehyde, the alpha-haloketone and the DBN or DBU is 1:1.1:1.2.
The preparation method comprises the following process steps: dissolving the aldehyde and the alpha-halogenated ketone in the solvent to obtain a mixed solution A; dissolving DBN or DBU in the solvent to obtain a mixed solution B; and (3) dropwise adding the mixed solution A into the mixed solution B, performing Darzen reaction, and separating and purifying after the reaction is finished to obtain the alpha, beta-epoxy ketone compound.
In the above preparation method, preferably, the reaction is carried out under an inert gas atmosphere.
The steps of the separation and purification of the preparation method are as follows: adding water into the mixed solution after the Darzen reaction is finished to quench the reaction, adding dichloromethane to extract, washing the obtained organic layer with brine, drying the organic layer with anhydrous sodium sulfate, concentrating the organic layer under reduced pressure, and separating the obtained concentrate by silica gel column chromatography to obtain the alpha, beta-epoxyketone compound.
In summary, the technical scheme of the invention adopts DBN or DBU as alkali, and alpha-halogenated ketone containing alpha-hydrogen and various aldehydes are subjected to Darzen reaction, so that the alpha, beta-epoxy ketone compound is synthesized in one step, the reaction system is simple, the used reagents are cheap and easy to obtain, the reaction condition is mild, the reaction speed is high, the side reaction is less, the subsequent products are convenient to separate, the reaction yield is high (71-94%), the industrial production can be realized, and the method has remarkable economic and social benefits.
Detailed Description
The present invention will be described in detail by the following examples, but the present invention is not limited to the examples.
Example 1: synthesis of epoxyketone III a
DBN (1.2 mmol) and dry dichloromethane (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of 2-chlorocyclohexanone I a (1.1 mmol), benzaldehyde (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing extraction under reduced pressure, and separating by silica gel column chromatography to obtain the target product III a as white solid with yield of 84% and melting point of 108-109 ℃.
1 H NMR(400MHz，CDCl 3 )δ7.47-7.25(m，5H)，4.06(s，1H)，2.82-2.63(m，1H)，2.46-2.42(m，1H)，2.12-1.89(m，2H)，1.79(d，J＝12.8Hz，2H)，1.72-1.56(m，1H)，1.45(dd，J＝8.0，5.9Hz，1H)； 13 C NMR(101MHz，CDCl 3 )δ206.47，133.59，128.35，128.29，126.67，65.99，64.02，41.89，27.47，24.66，23.38；IR(KBr，cm -1 )：3405，2934，1716，1455，1134，848，697.
Example 2: synthesis of epoxyketone III b
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I b (1.1 mmol), benzaldehyde (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing and extracting under reduced pressure, and separating by silica gel column chromatography to obtain the target product IIIb as yellow oily substance with the yield of 74%.
1 H NMR(400MHz，CDCl 3 )δ7.47-7.31(m，3H)，7.26(dd，J＝5.0，3.0Hz，2H)，4.24(s，1H)，2.52-2.31(m，2H)，2.20-2.01(m，2H)，1.89-1.65(m，2H)； 13 C NMR(101MHz，CDCl 3 )δ213.45，134.25，128.51，128.44，126.51，67.28，63.67，36.83，23.90，17.76；IR(KBr，cm -1 )：3660，2970，1747，1496，1209，1028，754，701，570，540.
Example 3: synthesis of epoxyketone III c
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I c (1.1 mmol), benzaldehyde (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing and extracting under reduced pressure, and separating by silica gel column chromatography to obtain the target product III c as colorless oily substance with the yield of 93%.
1 H NMR(400MHz，CDCl 3 )δ7.44-7.26(m，5H)，4.19(s，1H)，2.83-2.56(m，2H)，1.85-1.62(m，6H)，1.63-1.37(m，2H)； 13 C NMR(101MHz，CDCl 3 )δ208.93，134.30，128.27，128.17，126.68，67.31，64.02，43.06，30.40，27.37，25.20，24.87；IR(KBr，cm -1 )：3440，2929，2857，1709，1452，1275，758，705，560.
Example 4: synthesis of epoxyketone III d
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I c (1.1 mmol), benzaldehyde (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing and extracting under reduced pressure, and separating by silica gel column chromatography to obtain the target product III d as colorless oily substance with the yield of 94%.
1 H NMR(400MHz，CDCl 3 )δ7.44-7.20(m，5H)，4.07(s，1H)，2.74-2.51(m，2H)，2.26-2.09(m，1H)，2.09-1.75(m，3H)，1.73-1.58(m，2H)，1.58-1.44(m，2H)，1.44-1.36(m，2H)； 13 C NMR(101MHz，CDCl 3 )δ212.78，134.32，128.22，128.20，126.66，68.08，64.05，40.14，27.76，26.52，25.21，25.17，23.92；IR(KBr，cm -1 )：3392，3057，2934，2858，1709，1462，1289，1084，907，744，595，476；HRMS(ESI)calcd for C 15 H 19 O 2 (M+H) + ：231.1380，Found：231.1378.
Example 5: synthesis of epoxyketone III e
DBU (1.4 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I c (1.2 mmol), benzaldehyde (1.0 mmol) and dichloromethane (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing and extracting under reduced pressure, and separating by silica gel column chromatography to obtain the target product III e as colorless oily substance with the yield of 80%.
1 H NMR(400MHz，CDCl 3 )δ7.46-7.33(m，3H)，7.32-7.23(m，2H)，4.00(d，J＝1.7Hz，1H)，3.49(d，J＝1.8Hz，1H)，2.19(s，3H)； 13 C NMR(101MHz，CDCl 3 )δ204.19，135.07，129.06，128.73，125.73，63.50，57.78，24.82；IR(KBr，cm -1 )：3649，3403，3051，1709，1460，1411，1257，1103，835，698，563，483.
Example 6: synthesis of epoxyketone III f
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I c (1.1 mmol), benzaldehyde (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing and extracting under reduced pressure, and separating by silica gel column chromatography to obtain the target product III e as colorless oily substance with the yield of 71%.
1 H NMR(400MHz，CDCl 3 )δ7.43-7.32(m，3H)，7.28(dd，J＝10.0，3.2Hz，2H)，4.20(s，1H)，2.20(s，3H)，1.23(s，3H)； 13 C NMR(101MHz，CDCl 3 )δ207.79，133.80，128.36，126.58，66.15，61.35，23.68，11.62；IR(KBr，cm -1 )：3427，3121，1709，1615，1399，1291，1137，852，752，700，630.
Example 7: synthesis of epoxyketone III g
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I c (1.1 mmol), benzaldehyde (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing and extracting under reduced pressure, and separating by silica gel column chromatography to obtain the target product III g as colorless oily substance with the yield of 82%.
1 H NMR(400MHz，CDCl 3 )δ8.20-8.01(m，2H)，7.60(t，J＝7.4Hz，1H)，7.47(t，J＝7.7Hz，2H)，4.90(s，2H)，2.54(q，J＝7.3Hz，2H)，1.13(t，J＝7.3Hz，3H)； 13 C NMR(101MHz，CDCl 3 )δ204.71，165.94，133.45，129.90，128.51，68.24，32.22，29.72，7.16；IR(KBr，cm -1 )：3629，2926，2854，1724，1601，1452，1376，1277，1127，964，711，507.
Example 8: synthesis of epoxyketone III h
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I c (1.1 mmol), benzaldehyde (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing and extracting under reduced pressure, and separating by silica gel column chromatography to obtain the target product III h as colorless oily substance with the yield of 73%.
1 H NMR(400MHz，CDCl 3 )δ8.10(d，J＝7.4Hz，2H)，7.59(t，J＝7.4Hz，1H)，7.46(t，J＝7.7Hz，2H)，4.98(s，2H)，2.78(dt，J＝13.9，6.9Hz，1H)，1.19(d，J＝6.9Hz，6H)； 13 C NMR(101MHz，CDCl 3 )δ207.28，165.94，133.38，129.89，128.48，67.02，37.56，29.72，17.98；IR(KBr，cm -1 )：3629，2927，2854，1720，1452，1277，1055，986，711，516.
Example 9: synthesis of epoxyketone III i
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I a (1.1 mmol), IIb (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing extraction under reduced pressure, and separating by silica gel column chromatography to obtain the target product III i as white solid with the yield of 94% and the melting point of 104-105 ℃.
1 H NMR(400MHz，CDCl 3 )δ7.19(s，4H)，4.02(s，1H)，2.71(dd，J＝16.3，2.4Hz，1H)，2.52-2.38(m，1H)，2.38(S，3H)，2.11-1.88(m，2H)，1.88-1.72(m，2H)，1.71-1.58(m，1H)，1.46(dd，J＝9.7，6.5Hz，1H)； 13 C NMR(101MHz，CDCl 3 )δ206.67，138.22，130.55，129.01，126.64，66.04，64.17，41.91，27.44，24.69，23.45，21.26；IR(KBr，cm -1 )：2923，1716，1515，1157，963，812，753，589，499.
Example 10: synthesis of epoxyketone III j
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I a (1.1 mmol), IIc (1.0 mmol) and dichloromethane (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing extraction under reduced pressure, and separating by silica gel column chromatography to obtain the target product III j as pale yellow solid with yield of 90% and melting point of 70-71 ℃.
1 H NMR(400MHz，CDCl 3 )δ7.23(d，J＝8.7Hz，2H)，6.91(d，J＝8.7Hz，2H)，4.00(s，1H)，3.82(s，3H)，2.77-2.61(m，1H)，2.49-2.33(m，1H)，2.09-1.86(m，2H)，1.86-1.74(m，2H)，1.64(dd，J＝13.9，2.3Hz，1H)，1.45(d，J＝13.8Hz，1H)； 13 C NMR(101MHz，CDCl 3 )δ206.65，159.68，127.93，125.47，113.77，66.13，64.01，55.29，41.87，27.34，24.66，23.43；IR(KBr，cm -1 )：3005，2859，1717，1616，1518，1440，1303，1277，1158，835，757，587，535.
Example 11: synthesis of epoxyketone III k
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I a (1.1 mmol), IId (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing extraction under reduced pressure, and separating by silica gel column chromatography to obtain the target product III k as pale yellow solid with the yield of 93% and the melting point of 108-109 ℃.
1 H NMR(400MHz，CDCl 3 )δ6.89(s，2H)，6.81(s，1H)，4.01(s，1H)，3.90(s，6H)，2.71(ddd，J＝16.1，6.3，3.8Hz，1H)，2.44(ddd，J＝16.2，12.4，6.2Hz，1H)，2.13-1.89(m，2H)，1.82(ddd，J＝16.2，8.3，3.9Hz，2H)，1.74-1.62(m，1H)，1.47(dt，J＝7.6，3.0Hz，1H)； 13 C NMR(101MHz，CDCl 3 )δ206.52，149.04，148.85，125.98，119.21，110.96，109.58，66.11，64.05，55.98，55.93，41.87，27.40，24.64，23.49；IR(KBr，cm -1 )：3002，2940，1708，1604，1460，1234，1017，865，617，442；HRMS(ESI)calcd for C 15 H 19 O 4 (M+H) + ：263.1278，Found：263.1275.
Example 12: synthesis of epoxyketone III l
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I a (1.1 mmol), II e (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing extraction under reduced pressure, and separating by silica gel column chromatography to obtain the target product III I as pale yellow solid with yield of 85% and melting point of 134-135 ℃.
1 H NMR(400MHz，CDCl 3 )δ8.24(d，J＝8.7Hz，2H)，7.49(d，J＝8.7Hz，2H)，4.15(s，1H)，2.73(dd，J＝16.4，2.1Hz，1H)，2.47(dd，J＝11.9，6.1Hz，1H)，2.13-1.91(m，2H)，1.82(dd，J＝9.7，3.0Hz，2H)，1.58-1.40(m，2H)； 13 C NMR(101MHz，CDCl 3 )δ205.31，147.94，141.01，127.68，123.63，66.12，62.79，41.83，27.53，24.52，23.29；IR(KBr，cm -1 )：3734，2924，2857，1712，1460，1346，1152，942，784，585，489.
Example 13: synthesis of epoxyketone III m
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I a (1.1 mmol), II f (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing extraction under reduced pressure, and separating by silica gel column chromatography to obtain the target product III m as pale yellow solid with 77% yield and 100-101 ℃ melting point.
1 H NMR(400MHz，CDCl 3 )δ8.20(dd，J＝8.8，8.2Hz，2H)，7.62(dt，J＝15.7，7.7Hz，2H)，4.16(s，1H)，2.74(ddd，J＝16.3，6.1，4.0Hz，1H)，2.56-2.37(m，1H)，2.14-1.92(m，2H)，1.93-1.73(m，2H)，1.61-1.36(m，2H)； 13 C NMR(101MHz，CDCl 3 )δ205.39，148.31，136.05，132.70，129.56，123.45，121.75，65.98，62.65，41.82，27.51，24.52，23.29；IR(KBr，cm -1 )：2943，1709，1529，1353，1136，1121，914，777693，590，523.
Example 14: synthesis of epoxyketone III n
DBU (1.2 mmol) and dry methylene chloride (5 mL) were added to a 25mL two-necked flask under nitrogen and cooled to-20deg.C. A mixed solution of I a (1.1 mmol), II g (1.0 mmol) and methylene chloride (5 mL) was then slowly dropped under stirring. After completion of the reaction (monitored by TLC), the reaction was quenched by the addition of water (10 mL) and extracted with dichloromethane (3X 10 mL). Concentrating the dichloromethane solution obtained by mixing extraction under reduced pressure, and separating by silica gel column chromatography to obtain the target product III n as yellow solid with the yield of 78%.
1 H NMR(400MHz，CDCl 3 )δ8.05-7.97(m，2H)，7.65-7.59(m，1H)，7.49(dd，J＝10.7，4.8Hz，2H)，7.44-7.32(m，5H)，4.30(d，J＝1.9Hz，1H)，4.08(d，J＝1.8Hz，1H)；IR(KBr，cm -1 )：3441，1628，1398，1289，1149，852，743，594.
Claims (5)
1. The preparation method of the alpha, beta-epoxyketone compound is characterized in that the reaction is carried out under the protection of inert gas, alpha-halogenated ketone shown in a general formula (I) and aldehyde shown in a general formula (II) are reacted in a solvent to obtain the alpha, beta-epoxyketone compound shown in a general formula (III) in the presence of DBN or DBU, and the chemical reaction formula is shown as follows:
wherein R is 1 Selected from methyl, ethyl, propyl, isopropyl, R 2 Selected from H or methyl; or R is 1 And R is 2 Are linked together to form- (CH) 2 ) n -, wherein n=3-6; r is R 3 Selected from phenyl, substituted phenyl or styryl, wherein one or two substituents on the substituted phenyl are selected independently from methyl, methoxy or nitro, and the position of the substituent is meta-position or para-position; x is selected from chlorine or bromine;
the method comprises the following process steps: dissolving the aldehyde and the alpha-halogenated ketone in the solvent to obtain a mixed solution A; dissolving DBN or DBU in the solvent to obtain a mixed solution B; dropwise adding the mixed solution A into the mixed solution B, performing Darzen reaction, and separating and purifying after the reaction is finished to obtain the alpha, beta-epoxyketone compound;
the solvent is selected from dichloromethane, chloroform, tetrahydrofuran or diethyl ether; the reaction temperature of the Darzen reaction is-40 ℃; the molar ratio of the aldehyde, the alpha-halogenated ketone and the DBN or DBU is 1:1-1.5:1-2.
2. The method of claim 1, wherein the solvent is methylene chloride.
3. The method of claim 1, wherein the Darzen reaction has a reaction temperature of-20 ℃ to 25 ℃; the molar ratio of the aldehyde, the alpha-halogenated ketone and the DBN or DBU is 1:1-1.2:1-1.4.
4. The method of claim 3, wherein the Darzen reaction has a reaction temperature of-20 ℃; the molar ratio of the aldehyde, the alpha-haloketone and the DBN or DBU is 1:1.1:1.2.
5. The method of claim 1, wherein the steps of separating and purifying are: adding water into the mixed solution after the Darzen reaction is finished to quench the reaction, adding dichloromethane to extract, washing the obtained organic layer with brine, drying the organic layer with anhydrous sodium sulfate, concentrating the organic layer under reduced pressure, and separating the obtained concentrate by silica gel column chromatography to obtain the alpha, beta-epoxyketone compound.
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