CN115745823B - Preparation method and application of compound - Google Patents
Preparation method and application of compound Download PDFInfo
- Publication number
- CN115745823B CN115745823B CN202211370482.0A CN202211370482A CN115745823B CN 115745823 B CN115745823 B CN 115745823B CN 202211370482 A CN202211370482 A CN 202211370482A CN 115745823 B CN115745823 B CN 115745823B
- Authority
- CN
- China
- Prior art keywords
- acetamide
- nitrophenyl
- ethyl
- hydroxymethyl
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 title abstract description 10
- -1 N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide Chemical compound 0.000 claims abstract description 45
- 239000003054 catalyst Substances 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 12
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 21
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 20
- 239000003446 ligand Substances 0.000 claims description 20
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 16
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 12
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 12
- 150000002085 enols Chemical class 0.000 claims description 12
- 238000006266 etherification reaction Methods 0.000 claims description 12
- 229910052710 silicon Inorganic materials 0.000 claims description 12
- 239000010703 silicon Substances 0.000 claims description 12
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 238000005575 aldol reaction Methods 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 239000003223 protective agent Substances 0.000 claims description 5
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 4
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 claims description 4
- 229920002866 paraformaldehyde Polymers 0.000 claims description 4
- 239000005046 Chlorosilane Substances 0.000 claims description 3
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 3
- 229960005091 chloramphenicol Drugs 0.000 claims description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 27
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 229920002554 vinyl polymer Polymers 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 238000013022 venting Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- IOPQYDKQISFMJI-UHFFFAOYSA-N [1-[2-bis(4-methylphenyl)phosphanylnaphthalen-1-yl]naphthalen-2-yl]-bis(4-methylphenyl)phosphane Chemical compound C1=CC(C)=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC(C)=CC=1)C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 IOPQYDKQISFMJI-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method and application of a compound, namely a preparation method and application of N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide. The catalyst used in the invention has low price, can be recycled, has high reaction yield and good enantioselectivity, and is an effective method for asymmetrically synthesizing optical pure N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide.
Description
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method and application of a compound, namely a preparation method and application of N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide.
Background
N- [ (1R, 2S) -2-Hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide (common name: N- [ (1R, 2S) -2-Hydroxy-1-Hydroxy-methyl-2- (4-nitro-phenyl) -ethyl ] -acetamide, CAS: 15376-53-1) is an important pharmaceutical and pesticide synthesis intermediate. At present, the enantioselective synthesis method of N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide is mainly realized by chiral resolution of tartaric acid. The process has high cost and low efficiency, and does not meet the development requirement of green economic chemistry, so that the existing synthesis method is urgently needed to be improved.
Enantioselective synthesis of N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide has long been difficult to realize mass production, and the main reasons are that the chiral catalyst used is expensive, low in catalytic efficiency and poor in enantioselectivity.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the first aspect of the present invention provides a method for producing N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide, wherein the catalyst of the method is inexpensive, can be recycled, has high reaction yield and good enantioselectivity, and is an effective method for asymmetrically synthesizing optically pure N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide.
The second aspect of the invention provides the use of the preparation method of N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide in the preparation of chloramphenicol.
According to a first aspect of the present invention, there is provided a process for the preparation of N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide comprising the steps of:
s1: carrying out enol silicon etherification reaction on N- [2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide (a compound shown in a formula 1) to obtain N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide (a compound shown in a formula 2);
s2: carrying out asymmetric Aldol reaction on N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide (a compound of formula 2) to obtain N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide (a compound of formula 3);
s3: n- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide (compound of formula 3) is subjected to asymmetric catalytic hydrogenation reaction to obtain N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide (compound of formula 4).
In some embodiments of the invention, the alkaline agent of the enol silicon etherification reaction includes at least one of potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine and pyridine; preferably, the molar ratio of the alkaline agent to the N- [2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide is (2-4): 1.
in some preferred embodiments of the present invention, the catalyst for the enol silicon etherification reaction comprises at least one of potassium iodide, sodium iodide, elemental iodine, sodium methoxide, potassium tert-butoxide and triethylamine; preferably, the molar ratio of the catalyst to the N- [2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide is (2-4): 1.
in some more preferred embodiments of the present invention, the carbonyl protecting agent of the enol silicon etherification reaction is an alkyl chlorosilane comprising any one of trimethylchlorosilane, triethylchlorosilane, triisopropylchlorosilane or tert-butyldimethylsilyl chloride. Preferably, the molar ratio of the carbonyl protecting agent to the N- [2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide is (2-4): 1.
in some more preferred embodiments of the invention, the solvent for the enol silicon etherification reaction is diethyl ether.
In some more preferred embodiments of the present invention, the temperature of the enol silicon etherification reaction is in the range of-30 ℃ to-10 ℃.
In some more preferred embodiments of the invention, the time for the enol silicon etherification reaction is 30h to 36h.
In some more preferred embodiments of the invention, the specific operation of the enol silicon etherification reaction is: n- [2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide, alkaline agent and catalyst are placed in a solvent, and carbonyl protective agent is added in an inert atmosphere at the temperature of minus 30 ℃ to minus 10 ℃ and stirred for 30h to 36h at the temperature of 20 ℃ to 35 ℃ to prepare the N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide.
In some more preferred embodiments of the present invention, S1 further comprises a step of purifying the product of the enol silicon etherification reaction, wherein the specific operation of the purification is as follows: and (3) after the reaction is finished, the excessive carbonyl protective agent, the alkaline agent and the catalyst are spun out to obtain a mud-like substance, the mud-like substance is washed and filtered by a solvent, and the purified N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide is prepared by reduced pressure distillation after the solvent is spun out.
In some more preferred embodiments of the present invention, the asymmetric Aldol-reacted aldehyde comprises formaldehyde or paraformaldehyde; preferably, the molar ratio of said aldehyde to said N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide is 1: (150-300); preferably 1: (180-250); further preferably 1:200.
in some more preferred embodiments of the present invention, the catalyst for the asymmetric Aldol reaction is a Cu-BOX ligand catalyst. Preferably, the Cu-BOX ligand catalyst is mixed with the N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl group]-acetamide in a molar ratio of 1: (150-300); preferably 1: (180-250); further preferably 1:200; further preferably, the Cu-BOX ligand catalyst is formed by complexing a Cu catalyst and a BOX ligand, the Cu catalyst comprising Cu (OTf) 2 、Cu(OAc) 2 Any one of CuI and CuCl; the BOX ligand is selected from CH 2 i Any one of Pr-BOX, 4-phenyl-BOX, iPr-BOX and iPr-Pyox; still more preferably, the molar ratio of Cu catalyst to BOX ligand is 1: (1-4).
In some more preferred embodiments of the present invention, the solvent for the asymmetric Aldol reaction comprises any of methylene chloride, chloroform, 1, 2-dichloroethane, or 1, 4-dioxane.
In some more preferred embodiments of the present invention, the asymmetric Aldol reaction temperature is 20 ℃ to 35 ℃.
In some more preferred embodiments of the present invention, the asymmetric Aldol reaction is specifically operated by: adding a solvent into a Cu catalyst and a chiral bisoxazoline ligand in an inert atmosphere for complexation reaction, and then adding aldehyde and N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide for reaction to obtain N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide.
In some more preferred embodiments of the present invention, S2 further comprises a step of purifying the product of the asymmetric Aldol reaction, wherein the specific operation of the purification is: after the reaction, the mixture is extracted by a solvent, dried, filtered, concentrated in vacuum and subjected to column chromatography to obtain the purified N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide.
In some more preferred embodiments of the invention, the catalyst for the asymmetric catalytic hydrogenation reaction is a chiral phosphine ligand comprising a metal catalyst; preferably, the chiral phosphine ligand containing the metal catalyst is mixed with the N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl]-acetamide in a molar ratio of 1: (150-300); preferably 1: (180-250); further preferably 1:200; further preferably, the metal catalyst comprises Cu (OTf) 2 、Cu(OAc) 2 Any one of CuI and CuCl; the chiral phosphine ligand comprises any one of BINAP, p-Tol-BINAP, indol-Phos, (R) -SIPHOS; still further preferred, the molar ratio of the metal catalyst to chiral phosphine ligand is 1: (1-4).
In some more preferred embodiments of the invention, the solvent for the asymmetric catalytic hydrogenation reaction is formaldehyde or ethanol.
In some more preferred embodiments of the invention, the hydrogen source of the asymmetric catalytic hydrogenation reaction is hydrogen.
In some more preferred embodiments of the invention, the asymmetric catalytic hydrogenation reaction is specifically operated by: the metal catalyst, chiral phosphine ligand and N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide are dissolved in a solvent, and reacted overnight under the hydrogen range to prepare the N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide.
In some more preferred embodiments of the present invention, S3 further comprises a step of purifying the product of the asymmetric catalytic hydrogenation reaction, wherein the specific operation of the purification is as follows: after the reaction, the mixture is filtered and concentrated to obtain the purified N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide.
According to a second aspect of the present invention there is provided the use of the method for the preparation of N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide in the preparation of chloramphenicol.
The beneficial effects of the invention are as follows:
1. the synthesis scheme of the invention has the advantages of high reaction efficiency, mild condition, safe and simple operation of the whole reaction, ideal yield and enantioselectivity value, and potential commercial value and use value.
2. The catalyst used in the invention has low price, can be recycled, has high reaction yield and good enantioselectivity, and is an effective method for asymmetrically synthesizing optical pure N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
Example 1
This example prepared N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide by the following procedure:
s1: preparation of N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide:
9.7. 9.7g N- [2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide and 4.6g anhydrous triethylamine were added to a 100mL round bottom flask equipped with magnetic stirring and stirred well to dissolve in 40mL anhydrous diethyl ether. The reaction temperature was then reduced to-30 ℃ by venting with nitrogen. 5.07g of redistilled trimethylchlorosilane were added in one portion using a 10mL syringe and after stirring for 10 minutes, the reaction was allowed to warm to room temperature and stirred for 36 hours. After the reaction was completed, excess trimethylchlorosilane and triethylamine were spun off to give a slurry and washed with 100mL of diethyl ether, filtered, and after the diethyl ether was spun off, the residue was purified by distillation under reduced pressure to give N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide (yield 89%, purity 97.8% by HPLC).
S2: preparation of N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide:
cu (OTf) 2 (0.018 g,0.05 mmol) and chiral bisoxazoline ligand CH 2 i Pr-BOX (16 mg,0.055 mmol) was dissolved in 2mL of dry dichloromethane and stirred at room temperature under nitrogen for 2 hours, at which time a dark blue CH was obtained 2 i Pr-BOX-Cu (II) complex. Then, paraformaldehyde was dissolved in 0.5mL of dried methylene chloride and injected into the reaction system by a syringe, followed by stirring at room temperature for 20 minutes. Then, the temperature was lowered to-78℃and after 10 minutes trifluoroethanol (0.060 g,1.2 mmol) and N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl were added in this order]Acetamide (2 mmol). The progress of the reaction was checked by TLC, and after completion of the reaction, 5mL of water was injected by syringe, and the reaction was quenched. Then extracted with dichloromethane (3X 10 mL), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give crude N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl)]Acetamide, purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 0.122g of white solid in 90% yield, 92% ee.
S2 structural characterization of the product: 1 H-NMR(400MHz,CDCl 3 )δ8.37-8.34(m,4H),5.16(t,J＝2.8Hz,1H),4.94(s,1H),4.06-3.84(m,2H),1.83(s,3H).MS：calcd for[C 11 H 13 N 2 O 5 ,M+H] + :253.0819,Found:253.0820。
92％ee[Daicel Chiralpak ID,hexane/2-propanol＝90/10,ν＝1.0mL/min,λ＝254nm,t(major)＝23.24min,t(minor)＝42.05min]。
s3: preparation of N- [ (1 r,2 s) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide:
a transition metal catalyst (0.05 mmol), a commercial phosphine ligand (0.05 mmol), N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide (5 mmol) was added sequentially to the reaction flask, followed by 150mL of methanol under 5bar of hydrogen for 6h, the reaction was completed, filtered through celite, the methanol was spun off, and silica gel column purified to give N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide as a white solid in 98% yield, 81% ee.
The total yield of the three steps of synthesizing N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide is 79%.
Structural characterization of S3 product: 1 H-NMR(400MHz,CDCl 3 )δ8.16(d,J＝8.3Hz,2H),7.65(d,J＝8.3Hz),5.39(d,J＝7.2Hz,1H),5.17(s,1H)4.48(s,1H),3.98-3.86(m,1H),3.56-3.25(m,2H).MS：calcd for[C 11 H 15 N 2 O 5 ,M+H] + :255.0907,Found:255.0910。
81％ee[Daicel Chiralpak ID,hexane/2-propanol＝90/10,ν＝1.0mL/min,λ＝254nm,t(major)＝16.90min,t(minor)＝28.00min]
example 2
This example prepared N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide by the following procedure:
s1: preparation of N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide:
into a 100mL round bottom flask equipped with magnetic stirring was added 9.7. 9.7g N- [2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide and 4.6g anhydrous triethylamine, which were stirred well to dissolve in 40mL tetrahydrofuran. The reaction temperature was then reduced to-20 ℃ by venting with nitrogen. 5.07g of redistilled trimethylchlorosilane were added in one portion using a 10mL syringe and after stirring for 30 minutes, the reaction was allowed to warm to room temperature and stirred for 32 hours. After the reaction was completed, excess trimethylchlorosilane and triethylamine were spun off to give a slurry and washed with 100mL of tetrahydrofuran, filtered, and after the tetrahydrofuran was spun off, the residue was purified by distillation under reduced pressure to give N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl ] -acetamide (yield 87%, HPLC purity 98.8%).
Structural characterization of the S1 product: 1 H-NMR(400MHz,CDCl 3 )δ8.72-7.60(m,5H),1.86(s,3H),0.21(s,9H).MS：calcd for[C 13 H 19 N 2 O 4 Si,M+H] + :295.1109,Found:295.1108。
s2: preparation of N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide:
cu (OTf) 2 (0.018 g,0.05 mmol) and chiral bisoxazoline ligand CH 2 i Pr-BOX (16 mg,0.055 mmol) was dissolved in 2mL of dry dichloroethane and stirred at room temperature under nitrogen for 2 hours, at which time a dark blue CH was obtained 2 i Pr-BOX-Cu (II) complex. Then, paraformaldehyde was dissolved in 0.5mL of dried dichloroethane, and injected into the reaction system by a syringe, followed by stirring at room temperature for 20 minutes. Then, the temperature was lowered to-60℃and after 10 minutes trifluoroethanol (0.060 g,1.2 mmol) and N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl were added in this order]Acetamide (2 mmol). The progress of the reaction was checked by TLC, and when the reaction was complete, 5mL of water was injected by syringe, the reaction was quenched. Then extracted with dichloroethane (3X 10 mL), the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give crude N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl]Acetamide, purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 0.122g of white solid in 91% yield, 94% ee.
Structural characterization of S2 product: 1 H-NMR(400MHz,CDCl 3 )δ8.37-8.34(m,4H),5.16(t,J＝2.8Hz,1H),4.94(s,1H),4.06-3.84(m,2H),1.83(s,3H).MS：calcd for[C 11 H 13 N 2 O 5 ,M+H] + :253.0819,Found:253.0820。
92％ee[Daicel Chiralpak ID,hexane/2-propanol＝90/10,ν＝1.0mL/min,λ＝254nm,t(major)＝23.24min,t(minor)＝42.05min]。
s3: preparation of N- [ (1 r,2 s) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide:
a transition metal catalyst (0.05 mmol), a commercial phosphine ligand (0.05 mmol), N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl ] -acetamide (5 mmol) was added sequentially to the reaction flask, followed by 150mL of ethanol under 5bar of hydrogen for 6h, the reaction was completed, filtered through celite, methanol was spun off, and silica gel column was purified to give N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide as a white solid in 95% yield of 84% ee.
The total yield of the three steps of synthesizing N- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl ] -acetamide is 75%.
Structural characterization of S3 product: 1 H-NMR(400MHz,CDCl 3 )δ8.16(d,J＝8.3Hz,2H),7.65(d,J＝8.3Hz),5.39(d,J＝7.2Hz,1H),5.17(s,1H)4.48(s,1H),3.98-3.86(m,1H),3.56-3.25(m,2H).MS：calcd for[C 11 H 15 N 2 O 5 ,M+H] + :255.0907,Found:255.0910。
81％ee[Daicel Chiralpak ID,hexane/2-propanol＝90/10,ν＝1.0mL/min,λ＝254nm,t(major)＝16.90min,t(minor)＝28.00min]。
while the embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (10)
1. The method comprises the following steps ofN- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl]-a process for the preparation of acetamide, characterized in that: the method comprises the following steps:
S1：N- [2- (4-nitrophenyl) -2-carbonyl-ethyl ]]The acetamide is prepared by enol silicon etherification reactionN- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl group]-acetamide;
S2：N- [2- (4-nitrophenyl) -2-trimethylsilyl ether-vinyl group]The acetamide is prepared by asymmetric Aldol reactionN- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl]-acetamide;
S3：N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl]The acetamide is prepared by asymmetric catalytic hydrogenationN- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl]-acetamide.
2. The method of manufacturing according to claim 1, characterized in that: the carbonyl protecting agent for the enol silicon etherification reaction is alkyl chlorosilane, and the alkyl chlorosilane is any one of trimethyl chlorosilane, triethyl chlorosilane, triisopropyl chlorosilane or tert-butyl dimethyl chlorosilane.
3. The method of manufacturing according to claim 1, characterized in that: the temperature of the enol silicon etherification reaction is-30 ℃ to-10 ℃.
4. The method of manufacturing according to claim 1, characterized in that: the aldehyde of the asymmetric Aldol reaction is formaldehyde or paraformaldehyde.
5. The method of manufacturing according to claim 1, characterized in that: the catalyst of the asymmetric Aldol reaction is a Cu-BOX ligand catalyst.
6. The method of manufacturing according to claim 1, characterized in that: the catalyst for asymmetric catalytic hydrogenation reaction is chiral phosphine ligand containing metal catalyst.
7. The method of manufacturing according to claim 1, characterized in that: the hydrogen source of the asymmetric catalytic hydrogenation reaction is hydrogen.
8. The method of manufacturing according to claim 6, wherein: chiral phosphine ligand of the metal-containing catalyst and the metal-containing catalystN- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl]-acetamide in a molar ratio of 1: (150-300).
9. The method of manufacturing according to claim 1, characterized in that: the specific operation of the asymmetric catalytic hydrogenation reaction is as follows: metal catalyst, chiral phosphine ligand,N- [ (1R) -1-hydroxymethyl-2- (4-nitrophenyl) -2-carbonyl-ethyl]Dissolving acetamide in solvent, and reacting overnight under hydrogen range to obtainN- [ (1R, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-nitrophenyl) -ethyl]-acetamide.
10. Use of the preparation method according to any one of claims 1 to 9 for the preparation of chloramphenicol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211370482.0A CN115745823B (en) | 2022-11-03 | 2022-11-03 | Preparation method and application of compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211370482.0A CN115745823B (en) | 2022-11-03 | 2022-11-03 | Preparation method and application of compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115745823A CN115745823A (en) | 2023-03-07 |
| CN115745823B true CN115745823B (en) | 2024-02-23 |
Family
ID=85357667
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211370482.0A Active CN115745823B (en) | 2022-11-03 | 2022-11-03 | Preparation method and application of compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115745823B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1649829A (en) * | 2002-03-08 | 2005-08-03 | 先灵-普劳有限公司 | Novel florfenicol-type antibiotics |
| WO2008106226A2 (en) * | 2007-02-28 | 2008-09-04 | Rib-X Pharmaceuticals, Inc. | Macrolide compounds and methods of making and using the same |
| WO2012125832A2 (en) * | 2011-03-15 | 2012-09-20 | Rib-X Pharmaceuticals, Inc. | Antimicrobial agents |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007025284A1 (en) * | 2005-08-24 | 2007-03-01 | Rib-X Pharmaceuticals, Inc. | Triazole compounds and methods of making and using the same |
-
2022
- 2022-11-03 CN CN202211370482.0A patent/CN115745823B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1649829A (en) * | 2002-03-08 | 2005-08-03 | 先灵-普劳有限公司 | Novel florfenicol-type antibiotics |
| WO2008106226A2 (en) * | 2007-02-28 | 2008-09-04 | Rib-X Pharmaceuticals, Inc. | Macrolide compounds and methods of making and using the same |
| WO2012125832A2 (en) * | 2011-03-15 | 2012-09-20 | Rib-X Pharmaceuticals, Inc. | Antimicrobial agents |
Non-Patent Citations (1)
| Title |
|---|
| The preparation of high specific activity [3H]-chloramphenicol base and chloramphenicol labeled in the propanediol side chain;Vanin, Elio F.等;Analytical Biochemistry;第76卷(第1期);259-268 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115745823A (en) | 2023-03-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3989377B2 (en) | Process for producing prostaglandin derivatives and stereospecific starting materials thereof | |
| JP2016504303A5 (en) | ||
| CN111620869B (en) | Synthesis method of tert-butyl-1, 7-diazaspiro [3.5] nonane-1-formyloxy ester | |
| JP4147516B2 (en) | Novel intermediate compound and method for producing optically active octanoic acid derivative | |
| JP6584696B2 (en) | Process for producing 3-((2S, 5S) -4-methylene-5- (3-oxopropyl) tetrahydrofuran-2-yl) propanol derivative and intermediate therefor | |
| CN115286559A (en) | Preparation method of anti-new crown drug Parovirid key intermediate | |
| CN115745823B (en) | Preparation method and application of compound | |
| JP6547087B1 (en) | Optically active 2,3-bisphosphinopyrazine derivative, method for producing the same, method for producing transition metal complex and organic boron compound | |
| CN116685567A (en) | Hydroxy thienoimidazole derivative, vinyl thioether derivative, n-butylidene thioether derivative, and process for producing saturated straight-chain hydrocarbon-substituted thienoimidazole derivative | |
| JP5102505B2 (en) | Process for producing optically active dialkylphosphinomethane derivatives | |
| JP3885497B2 (en) | Method for producing 1,2,4-butanetriol | |
| CN111039767B (en) | Method for preparing deuterated aldehyde by using triazole carbene as catalyst | |
| CN109503660B (en) | Chiral monophosphine catalyst Le-Phos with cyclic phosphine skeleton and preparation method and application of full configuration thereof | |
| JP4807549B2 (en) | Siloxanes, silanols and silanes, and methods for producing the same | |
| CN113831366B (en) | Cinchona alkaloid ligand and preparation method and application thereof | |
| US11084835B2 (en) | 2,3-bisphosphinopyrazine derivative, method for producing same, transition metal complex, asymmetric catalyst, and method for producing organic boron compound | |
| CN117720537B (en) | Axial chiral indole-furan catalyst and preparation method and application thereof | |
| JP3610014B2 (en) | Improved process for asymmetric hydrogenation | |
| JP3254745B2 (en) | Diol compound and method for producing the same | |
| US9029571B2 (en) | Device and method for evaluating organic material for organic solar cell | |
| JP2737214B2 (en) | Method for producing 4-hydroxy-2-cyclopentenone derivative | |
| KR100461571B1 (en) | A process for preparing (S)-1,2,4-butanetriol | |
| KR100364010B1 (en) | the New Manganese-chiral Compound and the Method for Using the Above-Compound as Catalyst in Enantioselective Epoxidation of Olefins | |
| CN116444406A (en) | Method for constructing tertiary carbon or quaternary carbon compound by oxygen-sulfur ylide through rearrangement reaction | |
| JP2023500501A (en) | Novel transition metal catalyst |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |