CN110627647A - High diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative and preparation method thereof - Google Patents
High diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative and preparation method thereof Download PDFInfo
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- YQBZNNFVXOBDSJ-UHFFFAOYSA-N 2-[hydroxy(phenyl)methyl]cyclohexan-1-one Chemical class C=1C=CC=CC=1C(O)C1CCCCC1=O YQBZNNFVXOBDSJ-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 51
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 25
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000012043 crude product Substances 0.000 claims abstract description 15
- 150000003935 benzaldehydes Chemical class 0.000 claims abstract description 12
- 239000000047 product Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 239000002841 Lewis acid Substances 0.000 claims abstract description 10
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 10
- 239000012074 organic phase Substances 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 238000004821 distillation Methods 0.000 claims abstract description 5
- 238000000605 extraction Methods 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 238000001953 recrystallisation Methods 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 6
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 5
- 229960002089 ferrous chloride Drugs 0.000 claims description 5
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 229910021630 Antimony pentafluoride Inorganic materials 0.000 claims description 2
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 claims description 2
- 229930182820 D-proline Natural products 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- 229930182821 L-proline Natural products 0.000 claims description 2
- VBVBHWZYQGJZLR-UHFFFAOYSA-I antimony pentafluoride Chemical compound F[Sb](F)(F)(F)F VBVBHWZYQGJZLR-UHFFFAOYSA-I 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229960002429 proline Drugs 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 239000013078 crystal Substances 0.000 abstract 2
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- -1 hydroxy (2-nitrophenyl) methyl Chemical group 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000009776 industrial production Methods 0.000 description 5
- 230000007613 environmental effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 2
- 238000005882 aldol condensation reaction Methods 0.000 description 2
- 238000007036 catalytic synthesis reaction Methods 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of synthetic chemistry, and discloses a high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative and a preparation method thereof. The chemical structure of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is shown as a formula (1), wherein R is nitro;the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is prepared by adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and stirring for reaction at room temperature; after the reaction is finished, adding water to fully dilute the dimethyl sulfoxide in the system, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product; dissolving the crude product with ethyl acetate at 40-55 ℃, adding n-hexane, standing at-10 ℃, and performing heavy cakingAnd (4) filtering and washing the crystal to obtain the crystal. The method has mild preparation conditions and simple operation steps, and can effectively improve the diastereoselectivity of the product.
Description
Technical Field
The invention belongs to the technical field of synthetic chemistry, and particularly relates to a high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative and a preparation method thereof.
Background
Chiral organic compounds and their properties are important research directions in stereochemistry, and play important roles in natural product chemistry, biochemistry, pharmaceutical chemistry, and polymer chemistry. When a chiral drug molecule acts on an organism, the enantiomeric interactions produced by drug molecules of different configurations tend to be different and even diametrically opposed, resulting in distinct pharmacological and toxicological effects. A typical example is the "reaction stop" event occurring in Europe at the end of the 50 th century, the tragic nature of seal malformation of pregnant women caused by taking thalidomide (also known as "reaction stop"), and it was subsequently discovered that the reaction stop drug contained two different optical isomers, the (R) -isomer had a sedative effect and the (S) -isomer had a teratogenic effect. Therefore, in the preparation process of organic molecules, the method for solving the stereochemistry problem and developing a high-selectivity method has important significance.
The aldol condensation reaction is an important synthetic method for increasing a carbon chain in organic synthesis, and plays an important role in drug synthesis and functional molecule construction. Wherein the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is an important fine chemical intermediate, and the compound is prepared by developing a high-selectivity method, is particularly suitable for developing a method for industrial production, and has important economic value.
At present, the main methods for obtaining the compounds with high stereoselectivity are as follows: (1) racemate resolution, by which racemate is the most commonly used method in the acquisition of chiral drugs. (2) Asymmetric synthesis methods, which mainly comprise chemical asymmetric catalytic synthesis and biological asymmetric catalytic synthesis. At present, the first method is mainly separation by chromatography, but is not suitable for industrial production; the second method is difficult, expensive and time-consuming to develop. Therefore, the development of a method for obtaining 2- (hydroxy (phenyl) methyl) cyclohexanone derivatives with high diastereoselectivity, which can be industrially produced, is an urgent problem to be solved.
Disclosure of Invention
In order to solve the above-mentioned disadvantages and drawbacks of the prior art, the present invention is primarily directed to a 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity. The derivative is a product with high diastereoselectivity in a trans-configuration, has higher diastereoselectivity, and has a ratio of the trans-configuration to a cis-configuration (anti: syn) of 50: 1.
the invention also aims to provide a preparation method of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity. The method has the advantages of lower requirements on equipment, mild reaction conditions, simple operation, no need of using expensive chiral catalysts, environmental friendliness and the like, can efficiently carry out chiral resolution, and simultaneously obtains the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity. The multiple asymmetric aldol condensation products can directly obtain high diastereoselectivity products by using a recrystallization method through the method, are suitable for industrial production, and provide a basis for mass production and subsequent research of fine chemical engineering and biological medicine.
The purpose of the invention is realized by the following technical scheme:
a high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative has a chemical structure shown in a formula (1), wherein R is nitro;
the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is prepared by adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and fully stirring at room temperature to react; after the reaction is finished, adding water to fully dilute the dimethyl sulfoxide in the system, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product; and (3) completely dissolving the crude product by using ethyl acetate at 40-55 ℃, adding n-hexane, standing at-10 ℃ for recrystallization, filtering, and washing to obtain the product.
Preferably, the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative has the structural formula:
preferably, the lewis acid is one or more of ferrous chloride tetrahydrate, ferric chloride, zinc chloride, aluminum chloride or antimony pentafluoride.
Preferably, the catalyst is racemic D, L-proline, D-proline or L-proline.
Preferably, the cyclohexanone accounts for 1-3 equivalents of the benzaldehyde derivative.
Preferably, the catalyst is 10-30 mol% of the benzaldehyde derivative, and the Lewis acid is 10-30 mol% of the benzaldehyde derivative.
The preparation method of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity comprises the following specific steps:
s1, adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and stirring at room temperature for full reaction;
s2, adding water to fully dilute the dimethyl sulfoxide in the system after the reaction in the step S1 is finished, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product;
s3, completely dissolving the crude product by using ethyl acetate at 40-55 ℃, adding n-hexane while hot, and standing at-10 ℃; filtering while the solution is cold, washing the residual solid with n-hexane, and then using the washed residual solid to prepare the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative.
Preferably, the reaction time in the step S1 is 24-168 h.
Preferably, the standing time in the step S3 is 0.5-168 h.
The high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is applied to the field of catalytic chemistry or medicines.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention takes cyclohexanone and benzaldehyde derivatives as raw materials, Lewis acid and a catalyst are added, and the diastereoselectivity of the product is improved directly by a recrystallization method after the synthesized crude product is extracted and concentrated. The method has mild conditions, and is safe and reliable; the method has the advantages of greatly reducing the consumption of solvents consumed in the purification by silica gel column chromatography in the traditional method, along with simple operation steps, environmental protection, and improvement of efficiency and resource utilization rate.
2. The invention utilizes cheap and easily obtained solvents, such as n-hexane and ethyl acetate, to carry out recrystallization so as to directly and effectively improve the diastereoselectivity of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative. Compared with the enzymatic resolution, the high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative has lower cost and does not need to carry out complicated enzyme screening process; compared with the preparative chromatography, the method has the advantages of less resolving solvent consumption and less time.
3. In the prior art, the common diastereoisomer resolution mode of the compounds is to use chromatography for purification and separation, the chromatography resolution is suitable for a small amount of compounds, the separation difficulty is high, and the industrial production is difficult to realize. Besides high requirements on equipment and sites, the use of a large amount of eluent increases the production cost and does not accord with the industrial concept of environmental protection; it is also a waste of time and human resources, however, the purification results are often not very desirable. The invention carries out diastereoisomer resolution by recrystallization, improves the diastereoisomer ratio (dr) more efficiently, can complete the resolution of a large amount of compounds, and is suitable for industrial production; the method has the advantages of less solvent, low equipment and instrument requirements, environmental protection and good purification effect, and the trans-configuration and cis-configuration (anti: syn) can reach 50: 1.
drawings
FIG. 1 shows NMR of 2- (hydroxy (2-nitrophenyl) methyl) cyclohex-1-one in example 1: (1H-NMR) profile;
FIG. 2 shows NMR of 2- (hydroxy (2-nitrophenyl) methyl) cyclohex-1-one in example 1: (13C-NMR) profile;
FIG. 3 shows 2- (hydroxy (3-nitrophenyl) methyl) group in example 2Nuclear magnetic resonance of cyclohex-1-ones (1H-NMR) profile;
FIG. 4 is the NMR of 2- (hydroxy (3-nitrophenyl) methyl) cyclohex-1-one in example 2: (NMR)13C-NMR) profile;
FIG. 5 is the NMR of 2- (hydroxy (4-nitrophenyl) methyl) cyclohex-1-one in example 3: (NMR)1H-NMR) profile;
FIG. 6 shows NMR of 2- (hydroxy (4-nitrophenyl) methyl) cyclohex-1-one in example 3: (13C-NMR).
Detailed Description
The following examples are presented to further illustrate the present invention and should not be construed as limiting the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. The reagents, methods and apparatus employed in the present invention are conventional in the art, except as otherwise indicated.
EXAMPLE 12 preparation of hydroxy (2-nitrophenyl) methyl) cyclohex-1-one
1. Preparation: 1.2g (8mmol, 1.0equiv) of o-nitrobenzaldehyde, 184mg (1.6mmol, 0.2equiv) of racemic D, L-proline and 159mg (0.8mmol, 0.1equiv) of ferrous chloride tetrahydrate were added to 848. mu.L of dimethyl sulfoxide, followed by 2.5mL (24mmol, 3.0equiv) of cyclohexanone, and reacted at room temperature for 48 hours. Adding a large amount of water to dilute the thionyl chloride in the system, extracting with ethyl acetate for three times, combining organic phases, and concentrating under reduced pressure. At 55 ℃, dissolving the crude product into a saturated solution by using a proper amount of ethyl acetate, adding a large amount of n-hexane while the solution is hot, standing at a low temperature overnight, filtering while the solution is cold, and washing by using a small amount of n-hexane, so that 1.49g of yellow solid is obtained through separation and purification, and the yield is 75%. In nuclear magnetic resonance (1H-NMR) spectrogram, a double peak with a chemical shift of 5.44-5.45 is a characteristic peak of a product in a trans configuration; the single peak with a chemical shift of 5.96 is the characteristic peak of the cis configuration of the product, from which the trans configuration of the diastereomer ratio (dr) before recrystallization can be calculated: the cis configuration (anti: syn) is 8: 1; trans configuration of diastereomer ratio (dr) after recrystallization: the cis configuration (anti: syn) is > 50: 1.
2.2- (hydroxy (2-nitrophenyl) methyl) cyclohex-1-one has the molecular structure:
3. and (3) structural identification: the structure of the obtained compound is subjected to nuclear magnetic resonance (1H-NMR) characterization results are shown in fig. 1:1H NMR(400MHz,CDCl3) δ 7.83(dd, J ═ 8.1,0.7Hz,1H),7.76(d, J ═ 7.3Hz,1H),7.64(dd, J ═ 11.2,4.0Hz,1H), 7.48-7.40 (m,1H),5.44(d, J ═ 7.2Hz,1H),4.21(s,1H),2.77(dt, J ═ 12.4,6.1Hz,1H), 2.53-2.40 (m,1H),2.34(td, J ═ 13.1,6.2Hz,1H),2.09(ddd, J ═ 12.4,5.6,2.7Hz,1H), 1.92-1.80 (m,1H), 1.78-1.49 (m, 4H); the structure of the obtained compound is subjected to nuclear magnetic resonance (13C-NMR) characterization results are shown in fig. 2:13C NMR(100MHz,CDCl3)δ214.86,148.76,136.56,133.07,129.04,128.42,124.03,69.63,57.31,42.79,31.06,27.76,24.94。
EXAMPLE 22 preparation of hydroxy (3-nitrophenyl) methyl) cyclohex-1-one
1. Preparation: 1.2g (8mmol, 1.0equiv) of m-nitrobenzaldehyde, 184mg (1.6mmol, 0.2equiv) of racemic D, L-proline and 159mg (0.8mmol, 0.1equiv) of ferrous chloride tetrahydrate were added to 848. mu.L of dimethyl sulfoxide, followed by 2.5mL (24mmol, 3.0equiv) of cyclohexanone at room temperature for 48 hours. Adding a large amount of water to dilute the thionyl chloride in the system, extracting with ethyl acetate for three times, combining organic phases, and concentrating under reduced pressure. At the temperature of 55 ℃, a proper amount of ethyl acetate is used for dissolving the crude product into a saturated solution, a large amount of n-hexane is added while the solution is hot, then the solution is placed at a low temperature for standing overnight, and after the solution is filtered while the solution is cold, a small amount of n-hexane is used for washing, so that 1.65g of yellow solid is obtained through separation and purification, and the yield is 83%. In nuclear magnetic resonance (1H-NMR) spectrogram, a double peak with a chemical shift of 4.91-4.94 is a characteristic peak of a product in a trans configuration; the single peak with a chemical shift of 5.50 is a characteristic peak of cis-configuration of the product, and thus dr before recrystallization can be calculated to be anti: syn: 5: 1; after recrystallization, dr is anti, syn is 7: 1.
2.2 molecular Structure of (hydroxy (3-nitrophenyl) methyl) cyclohex-1-one
3. And (3) structural identification: the structure of the obtained compound is subjected to nuclear magnetic resonance (1H-NMR) characterization results are shown in fig. 3:1H NMR(400MHz,CDCl3) δ 8.39-8.03 (m,1H),7.68(d, J ═ 7.6Hz,1H),7.53(t, J ═ 7.9Hz,1H),4.92(d, J ═ 8.3Hz,1H),4.23(s,1H),2.67(ddd, J ═ 13.3,8.2,5.6Hz,1H), 2.56-2.45 (m,1H),2.40(dt, J ═ 19.4,9.6Hz,1H), 2.16-2.01 (m,1H),1.83(d, J ═ 12.8Hz,1H), 1.75-1.49 (m,2H), 1.48-1.30 (m, 1H); the structure of the obtained compound is subjected to nuclear magnetic resonance (13C-NMR) characterization results are shown in fig. 4:13C NMR(100MHz,CDCl3)δ214.78,148.20,143.43,133.30,129.27,122.75,121.94,73.79,57.07,42.58,30.66,27.63,24.57。
EXAMPLE 32 preparation of hydroxy (4-nitrophenyl) methyl) cyclohex-1-one
1. Preparation: 1.2g (8mmol, 1.0equiv) of o-nitrobenzaldehyde, 184mg (1.6mmol, 0.2equiv) of racemic D, L-proline and 159mg (0.8mmol, 0.1equiv) of ferrous chloride tetrahydrate were added to 848. mu.L of dimethyl sulfoxide, followed by 2.5mL (24mmol, 3.0equiv) of cyclohexanone, and reacted at room temperature for 48 hours. Adding a large amount of water to dilute the thionyl chloride in the system, extracting with ethyl acetate for three times, combining organic phases, and concentrating under reduced pressure. At the temperature of 55 ℃, the crude product is dissolved into a saturated solution by using a proper amount of ethyl acetate, a large amount of n-hexane is added while the solution is hot, then the mixture is placed at a low temperature for standing overnight, and after the solution is filtered while the solution is cold, a small amount of n-hexane is used for washing, so that 1.09g of yellow solid is obtained through separation and purification, and the yield is 55%. In nuclear magnetic resonance (1H-NMR) spectrogram, the chemical shift is 4.89-4, and a doublet of 91 is a characteristic peak of a product in a trans configuration; the single peak with a chemical shift of 5.48 is a characteristic peak of the cis configuration of the product, and thus dr before recrystallization can be calculated to be anti: syn: 7: 1; after recrystallization, dr is anti, syn is 30: 1.
2.2 molecular Structure of (hydroxy (4-nitrophenyl) methyl) cyclohex-1-one
3. And (3) structural identification: the structure of the obtained compound is subjected to nuclear magnetic resonance (1H-NMR) characterization results are shown in fig. 5:1H NMR(400MHz,CDCl3) δ 8.19(d, J ═ 8.7Hz,1H),7.52(d, J ═ 8.6Hz,1H),4.92(d, J ═ 8.2Hz,1H),4.19(s,1H),2.64(ddd, J ═ 13.3,7.9,5.6Hz,1H), 2.56-2.44 (m,1H),2.38(td, J ═ 13.1,6.1Hz,1H),2.11(ddd, J ═ 8.9,5.7,2.8Hz,1H),1.83(d, J ═ 13.0Hz,1H), 1.75-1.48 (m,2H), 1.47-1.32 (m,1H),1.28(d, J ═ 10.7, 1H); the structure of the obtained compound is subjected to nuclear magnetic resonance (13C-NMR) characterization results are shown in fig. 6:13C NMR(100MHz,CDCl3)δ214.59,148.63,147.45,127.89,123.45,73.76,57.12,42.58,30.68,27.63,24.60。
the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is characterized in that the chemical structure of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is shown as a formula (1), wherein R is a nitro group;
the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is prepared by adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and fully stirring at room temperature to react; after the reaction is finished, adding water to fully dilute the dimethyl sulfoxide in the system, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product; and (3) completely dissolving the crude product by using ethyl acetate at 40-55 ℃, adding n-hexane, standing at-10 ℃ for recrystallization, filtering and washing to obtain the product.
2. The highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative has a formula:
3. the highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the Lewis acid is one or more of ferrous chloride tetrahydrate, ferric chloride, zinc chloride, aluminum chloride, and antimony pentafluoride.
4. The highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the catalyst is racemic D, L-proline, D-proline or L-proline.
5. The high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the cyclohexanone is 1 to 3 equivalents of benzaldehyde derivative.
6. The high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the catalyst is 10 to 30 mol% of the benzaldehyde derivative, and the Lewis acid is 10 to 30 mol% of the benzaldehyde derivative.
7. Process for the preparation of highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivatives according to any of claims 1 to 6, characterized in that it comprises the following specific steps:
s1, adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and fully stirring at room temperature to react;
s2, adding water to fully dilute the dimethyl sulfoxide in the system after the reaction in the step S1 is finished, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product;
s3, completely dissolving the crude product by using ethyl acetate at 40-55 ℃, adding n-hexane while the crude product is hot, and standing at-10 ℃ for recrystallization; after filtration and washing of the remaining solid with n-hexane, a 2- (hydroxy (phenyl) methyl) cyclohexanone derivative was obtained.
8. The method for preparing 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity according to claim 7, wherein the reaction time in step S1 is 24-168 h.
9. The method for preparing 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity according to claim 7, wherein the standing time in step S3 is 0.5-168 h.
10. Use of the highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to any one of claims 1 to 6 in the field of catalytic chemistry or medicine.
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