CN114105935A - Method for preparing beta-nitro or azido alcohol by high-selectivity asymmetric catalytic carbonyl reduction - Google Patents
Method for preparing beta-nitro or azido alcohol by high-selectivity asymmetric catalytic carbonyl reduction Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 23
- KIPMDPDAFINLIV-UHFFFAOYSA-N 2-nitroethanol Chemical group OCC[N+]([O-])=O KIPMDPDAFINLIV-UHFFFAOYSA-N 0.000 title claims abstract description 16
- UGUUDTWORXNLAK-UHFFFAOYSA-N azidoalcohol Chemical compound ON=[N+]=[N-] UGUUDTWORXNLAK-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 title claims abstract description 13
- 230000003197 catalytic effect Effects 0.000 title claims abstract description 13
- 239000000758 substrate Substances 0.000 claims abstract description 21
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims abstract description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 34
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 33
- 239000003054 catalyst Substances 0.000 claims description 30
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 16
- 235000019253 formic acid Nutrition 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- -1 nitro, cyano, methyl Chemical group 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001033 ether group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000002253 acid Substances 0.000 abstract description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 2
- 150000002576 ketones Chemical class 0.000 abstract description 2
- 238000010531 catalytic reduction reaction Methods 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 239000012530 fluid Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000006842 Henry reaction Methods 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 4
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- 125000006357 methylene carbonyl group Chemical group [H]C([H])([*:1])C([*:2])=O 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A method for preparing beta-nitro or azido alcohol by asymmetric catalytic carbonyl reduction with high selectivity comprises the following steps:
wherein R is1、R2、R3、R4And R5Each independently selected from any one of H, halogen, nitro, cyano, alkyl, aryl, phenolic hydroxyl and ether; the method of the invention uses RhCl [ (S, S) -TsDPEN]The (p-cymene) asymmetric catalytic reduction of beta-nitro (or azido) ketone can quickly and efficiently construct beta-nitro (or azido) alcohol with high optical activity, and the substrate has wider application range and is suitable for acid-sensitive substrates.
Description
Technical Field
The invention belongs to the field of preparation of organic matters, and relates to a preparation method of chiral beta-nitro/azido alcohol compounds. In particular, the invention relates to a method for preparing beta-nitro/azido alcohol by asymmetric catalytic carbonyl reduction with high selectivity.
Background
The structural formula of the beta-amino alcohol compound is shown as follows, and the beta-chiral amino alcohol compound is an important organic synthesis intermediate and has an extremely important role in the field of biological pharmacy.
The current methods for preparing beta-aminoalcohol compounds mainly include the following schemes: 1) starting from asymmetric Henry reaction, reacting aldehyde substrates with nitroalkane to obtain a beta-nitroalcohol intermediate, and reducing the intermediate through nitro to obtain beta-aminoalcohol; 2) the optically pure beta-nitroalcohol or beta-azido alcohol intermediate is obtained by asymmetrically reducing beta-nitroketone or beta-azido ketone, and the intermediate is reduced by nitryl or azido to obtain beta-amino alcohol.
Subject group (Angew. chem. int. Ed.2006,45, 929-931) in Henk Hiemstra, the Netherlands reported an asymmetric Henry reaction catalyzed by a quinine-derived small organic molecule catalyst, the reaction scheme is shown above. Under the condition of 10mol percent of catalyst dosage, the beta-chiral nitroalcohol can be obtained with high yield and high selectivity. However, in order to further enlarge the production, the 10 mol% of the catalyst inventory makes the overall catalyst product higher, the atom economy is poorer, the preparation of the catalyst is relatively complex, the use cost is further promoted, and the method is also the biggest disadvantage of the organic small molecular catalyst in the industrial enlarged production.
Subject group (angelw. chem. int. ed.2002,41,861) taught by the american teaching of Barry m.trost reported an asymmetric Henry reaction catalyzed by chiral organozinc, the reaction scheme is shown above. Beta-chiral nitro alcohols can also be prepared with high selectivity. In the reaction process, the catalyst dosage is still high, an equivalent amount of flammable reagent diethyl zinc is needed, and the atom economy is poor; in addition, in order to improve the yield, the dosage of nitromethane also needs 10 equivalents, the reaction conditions are harsh, and the feasibility of industrial amplification is low.
The problem group in professor d.a.evans in the united states (j.am.chem.soc.,2003,125,12692) reported that copper catalyzed asymmetric Henry reaction using chiral bisoxazoline as ligand, the reaction scheme is shown above. Although this scheme has a great improvement over the previous reaction conditions and catalyst usage, the 5 mol% equivalent of catalyst is still high and the cost of the chiral ligand is high.
Iridium metal catalyzed asymmetric transfer hydrogenation of beta-nitroketones to beta-nitro alcohols was reported by professor Erick m carreira, federal institute of technology, zurich (angelw, chem, int, ed, 2011,50,8979), with the reaction scheme shown above. The scheme has higher efficiency, the dosage of the catalyst is further reduced to a level of five thousandths, and the optical selectivity is higher. However, acid-sensitive substrates cannot be used in this method.
In summary, although various schemes are available at present for preparing chiral β -amino alcohol precursors, further improvements in catalyst efficiency, substrate applicability, etc. are urgently needed.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for preparing a chiral β -amino alcohol precursor compound to further improve the catalyst efficiency and extend the applicability of the substrate.
According to one embodiment of the present invention, the first and second electrodes are, for example,
in the substrate structure: r1、R2、R3、R4And R5Each independently selected from any one of H, halogen, nitro, cyano, alkyl, aryl, phenolic hydroxyl and ether; preferably, R1、R2、R3、R4And R5Each independently selected from any one of H, nitro, methyl, ethyl, benzene ring, phenolic hydroxyl and ether group; r1、R2、R3、R4And R5The reaction center is far away from the periphery of the reaction center, so that the reaction process is not fundamentally influenced, and the selection range is wide.
The desired metal catalyst is RhCl [ (S, S) -TsDPEN ] (p-cymene) (CAS No.192139-90-5), a commercial catalyst, readily available.
The required reducing agent is HCO2H/Et3The N system and triethylamine are matched with formic acid for use, so that the acidity of the formic acid is inhibited, the whole system is neutral to alkalescent, the reducibility of the formic acid can be kept, and the reaction system can still be suitable for acid-sensitive groups; specifically, the methylene carbonyl protecting group of the substrate is sensitive to acid, and if formic acid is directly used as a reducing agent, the methylene carbonyl protecting group can be damaged by the formic acid, and the formic acid-triethylamine system used in the invention can effectively prevent the methylene carbonyl protecting group from being damaged. Preferably, the volume ratio of triethylamine to formic acid is 1.5-2.5: 1, preferably 1.8 to 2.3: 1, further preferably 2.2: 1.
the desired reaction solvent is N, N' -dimethylformamide.
The embodiment of the invention provides a method for preparing beta-nitro or azido alcohol by high-selectivity asymmetric catalytic carbonyl reduction, which comprises the following steps:
wherein R is1、R2、R3、R4And R5Each independently selected from any one of H, halogen, nitro, cyano, alkyl, aryl, phenolic hydroxyl and ether;
preferably, R1、R2、R3、R4And R5Each independently selected from any one of H, halogen, nitro, cyano, C1-C18 alkyl, aryl under C20, phenolic hydroxyl and ether under C20;
preferably, R1、R2、R3、R4And R5Each independently selected from H, halogen, nitro, cyano, methyl, ethyl, benzene ring, phenolic hydroxyl and ether groups of C15 or less.
According to one embodiment of the invention, for example, the method is routed as follows:
that is, the catalyst is RhCl [ (S, S) -TsDPEN ] (p-cymene), and the structure of the catalyst is shown on the right side of the above route; the reaction takes a mixture of triethylamine and formic acid as a reducing agent.
According to one embodiment of the invention, for example, the molar ratio of triethylamine to substrate 1 is 1-2:1, preferably 1.5-1.8:1, more preferably 1.58: 1;
preferably, the volume ratio of triethylamine to formic acid is 1.5-2.5: 1, preferably 1.8 to 2.3: 1, further preferably 2.2: 1.
according to one embodiment of the invention, for example, the mole percentages of catalyst on substrate 1 are: 0.1 to 0.5 mol%, preferably 0.15 to 0.3 mol%, and more preferably 0.2 mol%.
According to one embodiment of the invention, for example, the reaction is carried out under the protection of inert gas, the reaction is carried out in N, N' -dimethylformamide as a solvent, and the reaction temperature is controlled at 40-60 ℃;
preferably, the molar ratio of N, N' -dimethylformamide to substrate 1 is 100-200:1, preferably 100-150:1, more preferably 128: 1.
According to one embodiment of the invention, for example, the method is routed as follows:
according to one embodiment of the invention, for example, the method comprises:
adding a substrate 1 into a reaction container, adding a catalyst RhCl [ (S, S) -TsDPEN ] (p-cymene) under the protection of nitrogen, and then adding N, N' -dimethylformamide; adding triethylamine and formic acid into another reaction vessel, fully mixing and stirring, then adding a mixture of formic acid and triethylamine into the reaction vessel, heating to 50 ℃, and stirring to react for 8-16 hours, preferably 12 hours; after the reaction is finished, diluting the reaction solution with water, then extracting with ethyl acetate, and washing the extracted organic phase with saturated saline solution; and (4) desolventizing under a reduced pressure condition to obtain a target product.
The invention has the beneficial effects that: the scheme adopts RhCl [ (S, S) -TsDPEN ] (p-cymene) to asymmetrically catalyze and reduce beta-nitro (or azido) ketone, can quickly and efficiently construct beta-nitro (or azido) alcohol with high optical activity, has wider substrate application range, and is suitable for acid and alkali sensitive substrates. In particular, when the reduction system is triethylamine-formic acid, reaction substrates with different properties can be matched by adjusting the acid-base property of the system.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description only relate to some embodiments of the present invention and are not limiting on the present invention.
Fig. 1 is a chiral supercritical fluid chromatogram of a racemate of compound 2a prepared in the example.
Fig. 2 is a chiral supercritical fluid chromatogram of compound 2a prepared in the example.
FIG. 3 is a nuclear magnetic hydrogen spectrum of Compound 2a prepared in the example.
Fig. 4 is a chiral supercritical fluid chromatogram of racemate of compound 2b prepared in the example.
Fig. 5 is a chiral supercritical fluid chromatogram of compound 2b prepared in the example.
FIG. 6 is a nuclear magnetic hydrogen spectrum of Compound 2b prepared in the example.
Detailed Description
The method for preparing beta-nitro/azido alcohol by highly selective asymmetric catalytic carbonyl reduction according to the present invention will be further illustrated with reference to the following specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Example 1
Synthesis of chiral beta-nitroalcohols 2a
Weighing substrate 1a (250mg, 1.0mmol) and adding into Schlenk tube, adding catalyst RhCl [ (S, S) -TsDPEN ] under nitrogen protection](p-cymene) (1.3mg, 0.2 mol%) followed by addition of N, N' -dimethylformamide (10 mL). Then triethylamine (0.22mL) and formic acid (0.1mL) were added to another reaction flask and mixed for 3 minutes before the formic acid-triethylamine mixture was added to the schlenk tube. The temperature is raised to 50 ℃, and the reaction is stirred for 12 hours. After completion of the reaction, the reaction mixture was diluted with 50mL of water, followed by extraction with ethyl acetate (30mL × 2), and the extracted organic phase was washed with saturated brine (20mL × 2). Desolventizing under reduced pressure gave the title product 2a, 220mg, 87.3% yield, 96.3% ee. The yield of example 1 according to the invention is close to the highest level compared to the existing synthesis route and the catalyst inventory is minimal compared to the existing synthesis route (the catalyst inventory according to the invention can be as low as 0.2 mol%, whereas the existing route requires at least 0.5 mol%), so it can be said that the catalyst is catalyzedThe efficiency of the agent is improved.1H NMR(400MHz,CDCl3) Delta 7.25(1H, s),7.09-7.10(1H, d),6.95(1H, s),6.77-6.78(1H, d),4.80(2H, s),4.36(1H, s),3.61-3.70(2H, d),1.51(6H, s). The racemate chiral supercritical fluid chromatogram of the target product 2a is shown in the attached figure 1, the chiral supercritical fluid chromatogram is shown in the attached figure 2, and the nuclear magnetic hydrogen chromatogram is shown in the attached figure 3.
Example 2
Synthesis of chiral beta-azido alcohols 2b
The substrate 1b (247mg, 1.0mmol) was weighed into a Schlenk tube and the catalyst RhCl [ (S, S) -TsDPEN was added under nitrogen protection](p-cymene) (1.3mg, 0.2 mol%) followed by addition of N, N' -dimethylformamide (10 mL). Then triethylamine (0.22mL) and formic acid (0.1mL) were added to another reaction flask and mixed for 3 minutes before the formic acid-triethylamine mixture was added to the schlenk tube. The temperature is raised to 50 ℃, and the reaction is stirred for 12 hours. After completion of the reaction, the reaction mixture was diluted with 50mL of water, followed by extraction with ethyl acetate (30mL × 2), and the extracted organic phase was washed with saturated brine (20mL × 2). Desolventizing under reduced pressure gave the title product 2b, 225mg, 89.3% yield, 89.9% ee. The yield of example 1 according to the invention is close to the highest level compared to the existing synthesis route, and the catalyst inventory is the lowest compared to the existing synthesis route (the catalyst inventory according to the invention can be as low as 0.2 mol%, whereas the existing route requires at least 0.5 mol%), so it can be said that the catalyst efficiency is improved.1H NMR(400MHz,CDCl3) δ 7.11-7.13(1H, dd),6.99(1H, s),6.79-6.80(1H, d),4.82(1H, s),4.77-4.78(1H, dd),3.37-3.46(2H, m),1.51(6H, s). the racemate chiral supercritical fluid chromatogram of the target product 2b is shown in fig. 4, the chiral supercritical fluid chromatogram is shown in fig. 5, and the nuclear magnetic hydrogen chromatogram is shown in fig. 6.
Claims (7)
1. A method for preparing beta-nitro or azido alcohol by high-selectivity asymmetric catalytic carbonyl reduction is characterized in that the route of the method is as follows:
wherein R is1、R2、R3、R4And R5Each independently selected from any one of H, halogen, nitro, cyano, alkyl, aryl, phenolic hydroxyl and ether;
preferably, R1、R2、R3、R4And R5Each independently selected from any one of H, halogen, nitro, cyano, C1-C18 alkyl, aryl under C20, phenolic hydroxyl and ether under C20;
preferably, R1、R2、R3、R4And R5Each independently selected from H, halogen, nitro, cyano, methyl, ethyl, benzene ring, phenolic hydroxyl and ether groups of C15 or less.
2. The method for preparing beta-nitro or azido alcohol by high-selectivity asymmetric catalytic carbonyl reduction according to claim 1, characterized in that the method route is as follows:
that is, the catalyst is RhCl [ (S, S) -TsDPEN ] (p-cymene), and the structure of the catalyst is shown on the right side of the above route; the reaction takes a mixture of triethylamine and formic acid as a reducing agent.
3. The method for preparing beta-nitro or azido alcohol by highly selective asymmetric catalytic carbonyl reduction according to claim 1 or 2, characterized in that the molar ratio of triethylamine to substrate 1 is 1-2:1, preferably 1.5-1.8:1, further preferably 1.58: 1;
preferably, the volume ratio of triethylamine to formic acid is 1.5-2.5: 1, preferably 1.8 to 2.3: 1, further preferably 2.2: 1.
4. the method for preparing beta-nitro or azido alcohol by high-selectivity asymmetric catalytic carbonyl reduction according to any of the claims 1 to 3, characterized in that the mole percentage of the catalyst in the substrate 1 is: 0.1 to 0.5 mol%, preferably 0.15 to 0.3 mol%, and more preferably 0.2 mol%.
5. The method for preparing beta-nitro or azido alcohol by high-selectivity asymmetric catalytic carbonyl reduction according to any one of claims 1 to 4, characterized in that, the reaction is carried out under the protection of inert gas, the reaction is carried out in N, N' -dimethylformamide as solvent, and the reaction temperature is controlled at 40-60 ℃;
preferably, the molar ratio of N, N' -dimethylformamide to substrate 1 is 100-200:1, preferably 100-150:1, more preferably 128: 1.
6. The process for preparing beta-nitro or azido alcohol by highly selective asymmetric catalytic carbonyl reduction according to any of the claims 1 to 5, characterized by the following scheme:
7. the method for preparing beta-nitro or azido alcohol by highly selective asymmetric catalytic carbonyl reduction according to any of the claims 1 to 6, characterized in that the method comprises:
adding a substrate 1 into a reaction container, adding a catalyst RhCl [ (S, S) -TsDPEN ] (p-cymene) under the protection of nitrogen, and then adding N, N' -dimethylformamide; adding triethylamine and formic acid into another reaction vessel, fully mixing and stirring, then adding a mixture of formic acid and triethylamine into the reaction vessel, heating to 50 ℃, and stirring to react for 8-16 hours, preferably 12 hours; after the reaction is finished, diluting the reaction solution with water, then extracting with ethyl acetate, and washing the extracted organic phase with saturated saline solution; and (4) desolventizing under a reduced pressure condition to obtain a target product.
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| CN115286521B (en) * | 2022-07-11 | 2023-11-03 | 上海医药集团(本溪)北方药业有限公司 | Synthesis method of levosalbutamol hydrochloride |
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