CN104892496A - Asymmetric catalytic hydrogenation method for 2-pyridinone compounds - Google Patents
Asymmetric catalytic hydrogenation method for 2-pyridinone compounds Download PDFInfo
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- CN104892496A CN104892496A CN201510346906.3A CN201510346906A CN104892496A CN 104892496 A CN104892496 A CN 104892496A CN 201510346906 A CN201510346906 A CN 201510346906A CN 104892496 A CN104892496 A CN 104892496A
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- NKBVQIYUSJOXFE-UHFFFAOYSA-N O=C1c2nc(-c3ccccc3)ccc2CCC1 Chemical compound O=C1c2nc(-c3ccccc3)ccc2CCC1 NKBVQIYUSJOXFE-UHFFFAOYSA-N 0.000 description 1
- ZLTYJKVWFQPIQS-CQSZACIVSA-N O[C@H]1c2nc(-c3ccccc3)ccc2CCC1 Chemical compound O[C@H]1c2nc(-c3ccccc3)ccc2CCC1 ZLTYJKVWFQPIQS-CQSZACIVSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
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- C—CHEMISTRY; METALLURGY
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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Abstract
The invention belongs to the chemical field of medicine synthesis, and relates to an asymmetric catalytic hydrogenation method for 2-pyridinone compounds. The asymmetric catalytic hydrogenation method includes steps of firstly, enabling chiral ligand and metal rhodium precursors to react with one another in organic solvents for 0.5-2 hours at the temperatures of 20-40 DEG C to obtain in-situ catalysts; secondly, arranging reaction systems in an autoclave, adding the 2-pyridinone compounds into the autoclave, enabling the reaction systems and the 2-pyridinone compounds to react with one another for 20-24 hours in hydrogen atmosphere at the reaction temperatures of 0-50 DEG C under the hydrogen pressures of 2-50 atmospheric pressures. The chiral ligand is (R)-Binapine. The asymmetric catalytic hydrogenation method has the advantages that the asymmetric catalytic hydrogenation method is high in catalytic efficiency, and products can be quickly obtained within short time under low-pressure conditions; only a few catalysts are utilized; most 2-pyridone substrates can have conversion rates of 99% and the optimal stereoselectivity of 99%, and accordingly the asymmetric catalytic hydrogenation method has an excellent industrial prospect.
Description
Technical field
The invention belongs to pharmaceutical synthesis chemical field, relate to a kind of method of ketone compounds being carried out to asymmetric hydrogenation, be specifically related to a kind of asymmetric catalytic hydrogenation method of 2-pyridine compounds.
Background technology
The application of optically active alcohol compound in the fine chemistry industries such as medicine, agricultural chemicals, spices is very extensive, in recent years, increasing to the research of its various synthetic method.The asymmetric hydrogenation of prochiral ketones is one of most important method preparing optical activity alcohol.The method catalytic activity is high, and the reaction times is fast, and Atom economy is good, convenient product separation, and aftertreatment is simple, and side reaction is few, thus causes and pays close attention to widely.
Based on this reason, numerous chiral ligand is developed the asymmetric hydrogenation being applied to prochiral ketones, wherein the representative chiral spiro ligands being the chiral binaphthyl part invented of Japanese Scientists Ryoji Noyori (Ryoji Noyori) and Chinese Academy of Sciences academician Zhou Qilin and inventing, all achieves good selectivity to the asymmetric hydrogenation of simple aromatic ketone compounds.For the asymmetric hydrogenation of 2-pyridine aryl ketones compounds, only has fewer report at present, and existing report has significant limitation for substrate---when substrate is 2-pyridine-aryl ketones, the ortho position of aryl must have substituting group guarantee to obtain higher enantioselectivity, otherwise very low.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of asymmetric catalytic hydrogenation method of 2-pyridine compounds, breach original limitation (when substrate is 2-pyridine-aryl ketones, the ortho position of aryl must have substituting group guarantee to obtain higher enantioselectivity).Can easy and synthesis of optically active 2-pyridine aryl (alkyl) alcohol compound efficiently by the method, thus the field such as medical and health and fine chemistry industry can be applied to.
Technical scheme provided by the present invention is specific as follows:
An asymmetric catalytic hydrogenation method for 2-pyridine compounds, comprises the steps:
Step one, by chiral ligand and metal rhodium precursor in organic solvent, carry out reaction 0.5 ~ 2 hour at 20 ~ 40 DEG C, obtain catalyzer, chiral ligand is (R)-Binapine or (S)-Binapine, and structural formula is:
Step 2, is placed in autoclave by reaction system, adds 2-pyridine compounds, under an atmosphere of hydrogen, and temperature of reaction 20 DEG C ~ 50 DEG C, hydrogen pressure 5 ~ 50 normal atmosphere, reaction 20-24 hour.
As preferably of the present invention, metal rhodium precursor is two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium.
As preferably of the present invention, the molar ratio of described metal rhodium precursor and described chiral ligand is 1: 0.8 ~ 1.2.
As preferably of the present invention, the mol ratio of situ catalytic agent and 2-pyridine compounds is 1:100 ~ 5000.
As preferably of the present invention, described organic solvent be selected from methyl alcohol, ethanol, Virahol, trifluoroethanol, methylene dichloride, ethyl acetate, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), ether, toluene any one or a few.
In addition, the present invention is preferred, and 2-pyridine compounds is the compound that following general formula A1 represents.
In general formula A1, R
2for C
1-C
15the alkyl or alkenyl of straight or branched, or C
3-C
15cyclic saturated hydrocarbon base, or have aromatic group or the aromatic heterocycle group of substituting group and unsubstituted; R
1for-Cl ,-Br ,-I, C
1-C
15alkyl or alkenyl, the C of straight or branched
3-C
15cyclic saturated hydrocarbon base or have aromatic group or the aromatic heterocycle group of substituting group and unsubstituted.
The catalyzer that the present invention obtains in step one is not separated separately, carries out step 2 continuously.
Advantage major embodiment of the present invention is in the following areas: (1) catalytic efficiency is high: under short period of time and lower pressure, can obtain product faster; (2) catalyst levels is few: so Atom economy is high; (3) excellent catalytic effect: the conversion of 99% and the stereoselectivity of the highest 99% can be realized to most of 2-pyridone substrate.Based on above many merits, the method for asymmetric reduction of the present invention has extraordinary industrial prospect.
The present invention is simple to operate, transformation efficiency and selectivity high, with low cost, have that Atom economy is high, advantages of environment protection, there is very bright industrial applications prospect.
Embodiment
In the methods of the invention, when making 2-pyridine compounds generation asymmetric hydrogenation, the molar ratio of 2-pyridine compounds and situ catalytic agent is 100 ~ 5000: 1.Now, in fact for the molar ratio of 2-pyridone and situ catalytic agent without any restriction, because the height of the catalytic efficiency of situ catalytic agent makes when using the situ catalytic agent of seldom amount, also the asymmetric hydrogenation of 2-pyridone can be made successfully to carry out, and very high transformation efficiency and inducing effect can be obtained.This point also can be known from following examples.
In the present invention, when making 2-pyridine compounds generation asymmetric hydrogenation, temperature of reaction can set arbitrarily as required, but consider from reaction efficiency and processing safety, temperature of reaction is 20 ~ 50 DEG C, preferably 20 ~ 30 DEG C.
In addition, in the present invention, when making 2-pyridine compounds generation asymmetric hydrogenation, do not limit the reaction times, but consider from reaction yield, the preferred reaction time is 20 ~ 24 hours.
In the present invention, when making ketone compounds generation asymmetric hydrogenation, hydrogen pressure is not limited, but consider from reaction yield, the preferred reaction time is 5 ~ 50 normal atmosphere (below be sometimes called for short " atm "), more preferably 5 ~ 30 normal atmosphere, further preferred 5 ~ 10 normal atmosphere.
Elaborate to embodiments of the invention below, the present embodiment is implemented under premised on technical solution of the present invention, give detailed embodiment and concrete operating process, but protection scope of the present invention is obviously not limited to following embodiment.
In the examples below, the molar percentage of this material relative to 2-pyridine compounds is represented with " mol% ".
Embodiment 1: prepare (2a) by (1a) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1a (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtain sterling 2a, product is colourless liquid, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1h NMR (400MHz, CDCl
3) δ 8.53 (d, J=4.8Hz, 1H), 7.70 (td, J=8.0,2.0Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.19 – 7.22 (m, 1H), 4.90 (dd, J=12.8,6.4Hz, 1H), 4.53 (s, 1H), 1.51 (d, J=6.8Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 163.1,148.1,136.8,122.2,119.8,68.9,24.3; Wherein the structural formula of chiral ligand (R)-Binapine is:
Embodiment 2: prepare (2b) by (1b) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1b (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2b, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=91%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.51(d,J＝4.8Hz,1H),7.67(td,J＝7.6,1.2Hz,1H),7.28(d,J＝8.0Hz,1.0H),7.16-7.19(m,1H),4.68(dd,J＝6.4,5.2Hz,1H),4.48(s,1H),1.84-1.89(m,1H),1.67-1.76(m,1H),0.93(t,J＝7.6Hz,3H)；
13C NMR(101MHz,CDCl
3)δ162.2,148.1,136.6,122.2,120.4,74.0,31.2,9.5。
Embodiment 3: prepare (2c) by (1c) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1c (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2c, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=84%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.57(d,J＝4.8Hz,1H),7.70(td,J＝7.6,1.6Hz,1H),7.20-7.27(m,2H),4.58(d,J＝4.4Hz,1H),4.26(s,1H),2.01-2.09(m,1H),1.04(d,J＝7.2Hz,3H),0.81(d,J＝6.8Hz,1H)；
13C NMR(101MHz,CDCl
3)δ161.2,148.0,136.4,122.2,121.0,77.1,35.2,19.5,16.0。
Embodiment 4: prepare (2d) by (1d) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1d (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2d, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=90%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.56(d,J＝4.8Hz,1H),7.70(td,J＝7.6,1.6Hz,1H),7.23(d,J＝8.4Hz,1H),7.22(td,J＝5.6,0.8Hz,1H),4.76(dd,J＝7.6,4.4Hz,1H),4.23(s,1H),1.81-1.85(m,1H),1.70-1.74(m,1H),1.38-1.45(m,4H),0.92(t,J＝7.2Hz,3H)；
13C NMR(101MHz,CDCl
3)δ162.3,148.2,136.6,122.2,120.3,72.8,38.4,27.4,22.7,14.1。
Embodiment 5: prepare (2e) by (1e) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1e (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2e, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=90%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.49(d,4.0Hz,1H),7.65(td,J＝7.6,1.6Hz,1H),7.27(d,J＝8.0Hz,1H),7.15(td,J＝6.0,0.8Hz,1H),4.72(dd,J＝7.6,4.4Hz,1H),4.53(s,1H),1.76-1.82(m,1H),1.66-1.72(m,1H),1.34-1.42(m,2H),1.22-1.32(m,4H),0.79-0.87(m,3H)；
13C NMR(101MHz,CDCl
3)δ162.7,148.1,136.6,122.1,120.3,73.0,38.5,31.8,25.0,22.6,14.0。
Embodiment 6: prepare (2f) by (1f) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1f (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2f, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.60(d,J＝4.8Hz,1H),7.65(td,J＝7.6,1.6Hz,1H),7.35-7.43(m,4H),7.23(dd,J＝6.8,4.8Hz,1H),7.17(dd,J＝7.6,0.4Hz,1H),5.78(s,1H),5.35(s,1H)；
13C NMR(101MHz,CDCl
3)δ160.8,147.8,143.2,136.9,128.6,127.9,127.1,122.5,121.4,74.9。
Embodiment 7: prepare (2g) by (1g) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1g (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2g, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.61(d,J＝4.8Hz,1H),7.63(td,J＝7.6,1.6Hz,1H),7.28(d,J＝8.0Hz,1H),7.18-7.25(m,4H),7.06(d,J＝8.0Hz,1H),6.01(s,1H),5.30(s,1H),2.37(s,3H)；
13C NMR(101MHz,CDCl
3)δ160.9,147.8,140.7,136.9,136.3,130.9,128.1,127.9,126.2,122.4,121.3,72.9,19.5。
Embodiment 8: prepare (2h) by (1h) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1h (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2h, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.60(d,J＝4.8Hz,1H),7.65(t,J＝7.6Hz,1H),7.18-7.29(m,5H),7.12(d,J＝7.2Hz,1H),5.75(s,1H),5.33(s,1H),2.36(s,3H)；
13C NMR(101MHz,CDCl
3)δ160.9,147.8,143.2,138.3,136.8,128.6,128.5,127.7,124.2,122.4,121.4,75.0,21.5。
Embodiment 9: prepare (2i) by (1i) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1i (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2i, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.59(d,J＝4.8Hz,1H),7.64(td,J＝7.6,1.6Hz,1H),7.28-7.30(m,2H),7.17-7.23(m,4H),5.76(s,1H),5.30(s,1H),2.36(s,1H)；
13C NMR(101MHz,CDCl
3)δ161.1,147.8,140.3,137.5,136.8,129.3,127.0,122.4,121.3,74.8,21.2。
Embodiment 10: prepare (2j) by (1j) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1j (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2j, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.59(d,J＝4.8Hz,1H),7.66(td,J＝7.6,1.6Hz,1H),7.29-7.37(m,4H),7.24(dd,J＝7.6,4.8Hz,1H)；
13C NMR(101MHz,CDCl
3)δ160.3,147.9,141.7,137.0,133.6,128.8,128.4,122.7,121.3,74.3。
Embodiment 11: prepare (2k) by (1k) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1k (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2k, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.59(d,J＝4.4Hz,1H),7.64(td,J＝8.0,2.0Hz,1H),7.29-7.33(m,2H),7.22(dd,J＝6.8,4.8Hz,1H),7.16(d,J＝8.0Hz,1H),6.90(dt,J＝8.8,2.0Hz,2H),5.74(s,1H),5.28(s,1H),3.82(s,3H)；
13C NMR(101MHz,CDCl
3)δ161.2,159.3,147.8,136.8,135.5,128.4,122.4,121.3,114.0,74.5,55.3。
Embodiment 12: prepare (2l) by (1l) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1l (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2l, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.61(d,J＝4.8Hz,1H),7.67(td,J＝7.6,1.6Hz,1H),7.58(dd,J＝31.2,8.4Hz,4H),7.25-7.28(m,1H),7.18(d,J＝8.0Hz,1H),5.84(s,1H),5.44(s,1H)；
13C NMR(101MHz,CDCl
3)δ159.9,148.1,147.1,137.1,127.3,125.6,125.5,122.8,121.3,74.4。
Embodiment 13: prepare (2m) by (1m) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1m (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2m, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.61(d,J＝4.8Hz,1H),7.65(td,J＝7.2,2.0Hz,1H),7.37(t,J＝2.0Hz,1H),7.19-7.24(m,4H),5.78(s,1H),1.33(s,18H)；
13C NMR(101MHz.CDCl
3)δ161.1,150.9,147.7,142.2,136.8,122.3,122.0,121.5,121.4,34.9,31.5。
Embodiment 14: prepare (2n) by (1n) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1n (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2n, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=92%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.57(d,J＝4.8Hz,1H),7.66(td,J＝7.6,1.6Hz,1H),7.22-7.33(m,4H),7.15-7.21(m,3H),5.01(dd,J＝12.8,5.6Hz,1H),4.01(dd,J＝5.6Hz,1H),3.10(ddd,J＝35.6,13.6,4.2Hz,2H)；
13C NMR(101MHz,CDCl
3)δ161.2,148.4,137.8,136.5,129.6,128.4,126.5,122.5,120.8,74.1,45.2。
Embodiment 15: prepare (2o) by (1o) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1o (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2o, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=80%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.60(d,J＝4.8Hz,1H),7.68(td,J＝7.6,1.6Hz,1H),7.22-7.27(m,3H),7.16(dd,J＝7.6Hz,1H),7.10(d,J＝8.0Hz,2H),4.11(d,J＝4.4Hz,1H),3.07(dq,J＝39.2,5.2Hz,2H)；
13C NMR(101MHz,CDCl
3)δ160.7,148.4,136.6,136.2,132.3,131.0,128.4,122.6,120.7,73.6,44.4。
Embodiment 16: prepare (2p) by (1p) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1p (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2p, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=96%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.59(dd,J＝5.6,2.0Hz,1H),7.68(td,J＝7.6,2.0Hz,1H),7.35(dd,J＝6.4,1.2Hz,2H),7.22-7.25(m,2H),7.17(d,J＝8.0Hz,2H),4.98-5.00(m,1H),3.89(d,J＝4.4Hz,1H),3.13(dd,J＝13.6,4.4Hz,1H),2.98(dd,J＝13.6,4.4H,1H),1.34(s,9H)；
13C NMR(101MHz,CDCl
3)δ161.5,149.3,148.4,136.5,134.8,129.2,125.4,122.4,120.7,74.2,44.7,34.4,31.4。
Embodiment 17: prepare (2q) by (1q) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1q (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2q, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=97%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.55(d,J＝4.0Hz,1H),7.72(td,J＝7.6,1.2Hz,1H),7.43(d,J＝7.6Hz,1H),7.23(t,J＝6.0Hz,1H),5.20(d,J＝4.8Hz,1H),4.43(s,1H),3.73(s,3H),2.93(dd,J＝16.0,4.0Hz,1H),2.78(dd,J＝12.0,8.8Hz,1H)；
13C NMR(101MHz,CDCl
3)δ172.4,160.7,148.5,136.9,122.6,120.3,70.0,51.9,42.4。
Embodiment 18: prepare (2r) by (1r) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1r (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2r, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.01-8.04(m,2H),7.61(d,J＝8.0Hz,1H),7.48-7.53(m,3H),7.42-7.46(m,1H),4.75-4.79(m,1H),4.37(s,1H),2.87-2.91(m,2H),2.38-2.43(m,1H),2.05-2.09(m,1H),1.83-1.89(m,2H)；
13C NMR(101MHz,CDCl
3)δ157.7,154.2,138.9,137.7,129.9,128.9,128.7,126.7,119.2,69.2,30.7,28.0,19.7。
Embodiment 19: prepare (2s) by (1s) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1s (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2s, and product is through nmr analysis, and transformation efficiency is 90%, analyzes, record ee value (ee=92%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.00(d,J＝8.0Hz,1H),7.90(d,J＝8.0Hz,1H),7.51(t,J＝7.6Hz,1H),7.40(t,J＝7.6Hz,1H),5.28(q,J＝6.4Hz,1H),3.65(s,1H),1.74(d,J＝6.4Hz,3H)；
13C NMR(101MHz,CDCl
3)δ176.9,152.9,134.9,126.1,125.0,122.9,121.9,68.6,24.1。
Embodiment 20: prepare (2t) by (1t) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1t (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2t, and product is through nmr analysis, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ7.99(d,J＝8.0Hz,1H),7.86(d,J＝8.0Hz,1H),7.55(d,J＝6.8Hz,2H),7.48(t,J＝8.0Hz,1H),7.34–7.43(m,4H),6.71(s,1H),4.25(s,1H)；
13C NMR(101MHz,CDCl
3)δ175.1,152.6,140.9,135.2,128.9,128.7,126.8,126.2,125.2,123.1,121.8,74.4。
Embodiment 21: prepare (2j) by (1j) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 1 hour under 25 DEG C of conditions, add compound 1j (5mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 25 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtains sterling 2j, and product is through nmr analysis, and transformation efficiency is 89%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.59(d,J＝4.8Hz,1H),7.66(td,J＝7.6,1.6Hz,1H),7.29-7.37(m,4H),7.24(dd,J＝7.6,4.8Hz,1H)；
13C NMR(101MHz,CDCl
3)δ160.3,147.9,141.7,137.0,133.6,128.8,128.4,122.7,121.3,74.3。
Embodiment 22: prepare (2a) by (1a) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 0.5 hour under 20 DEG C of conditions, add compound 1a (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 20 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtain sterling 2a, product is colourless liquid, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.53(d,J＝4.8Hz,1H),7.70(td,J＝8.0,2.0Hz,1H),7.30(d,J＝7.6Hz,1H),7.19–7.22(m,1H),4.90(dd,J＝12.8,6.4Hz,1H),4.53(s,1H),1.51(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl
3)δ163.1,148.1,136.8,122.2,119.8,68.9,24.3。
Embodiment 23: prepare (2a) by (1a) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 0.5 hour under 40 DEG C of conditions, add compound 1a (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 20 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtain sterling 2a, product is colourless liquid, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.53(d,J＝4.8Hz,1H),7.70(td,J＝8.0,2.0Hz,1H),7.30(d,J＝7.6Hz,1H),7.19–7.22(m,1H),4.90(dd,J＝12.8,6.4Hz,1H),4.53(s,1H),1.51(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl
3)δ163.1,148.1,136.8,122.2,119.8,68.9,24.3。
Embodiment 24: prepare (2a) by (1a) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 2 hours under 20 DEG C of conditions, add compound 1a (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 20 DEG C and H
2(10atm) stirring reaction 20 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtain sterling 2a, product is colourless liquid, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.53(d,J＝4.8Hz,1H),7.70(td,J＝8.0,2.0Hz,1H),7.30(d,J＝7.6Hz,1H),7.19–7.22(m,1H),4.90(dd,J＝12.8,6.4Hz,1H),4.53(s,1H),1.51(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl
3)δ163.1,148.1,136.8,122.2,119.8,68.9,24.3。
Embodiment 25: prepare (2a) by (1a) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 0.5 hour under 20 DEG C of conditions, add compound 1a (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 20 DEG C and H
2(5atm) stirring reaction 24 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtain sterling 2a, product is colourless liquid, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.53(d,J＝4.8Hz,1H),7.70(td,J＝8.0,2.0Hz,1H),7.30(d,J＝7.6Hz,1H),7.19–7.22(m,1H),4.90(dd,J＝12.8,6.4Hz,1H),4.53(s,1H),1.51(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl
3)δ163.1,148.1,136.8,122.2,119.8,68.9,24.3。
Embodiment 26: prepare (2a) by (1a) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 0.5 hour under 20 DEG C of conditions, add compound 1a (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 20 DEG C and H
2(50atm) stirring reaction 24 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtain sterling 2a, product is colourless liquid, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400MHz,CDCl
3)δ8.53(d,J＝4.8Hz,1H),7.70(td,J＝8.0,2.0Hz,1H),7.30(d,J＝7.6Hz,1H),7.19–7.22(m,1H),4.90(dd,J＝12.8,6.4Hz,1H),4.53(s,1H),1.51(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl
3)δ163.1,148.1,136.8,122.2,119.8,68.9,24.3。
Embodiment 27: prepare (2a) by (1a) hydrogenation
In glove box, by two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium (0.41mg, 0.001mmol, 1mol%) and chiral ligand (R)-Binapine, 0.0011mmol, 0.81mg, 1.1mol%) be dissolved in methylene dichloride (1mL), stir 0.5 hour under 20 DEG C of conditions, add compound 1a (0.1mmol), methylene dichloride (1mL).Reaction system is placed in autoclave, at 50 DEG C and H
2(5atm) stirring reaction 24 hours under condition.Then removal of solvent under reduced pressure, column chromatography for separation (taking silicagel column, eluent: ethyl acetate/petroleum ether=1/2), obtain sterling 2a, product is colourless liquid, and transformation efficiency is 99%, analyzes, record ee value (ee=99%) through HPLC.
1H NMR(400 MHz,CDCl
3)δ8.53(d,J＝4.8Hz,1H),7.70(td,J＝8.0,2.0Hz,1H),7.30(d,J＝7.6Hz,1H),7.19–7.22(m,1H),4.90(dd,J＝12.8,6.4Hz,1H),4.53(s,1H),1.51(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl
3)δ163.1,148.1,136.8,122.2,119.8,68.9,24.3。
Claims (6)
1. an asymmetric catalytic hydrogenation method for 2-pyridine compounds, comprises the steps:
Step one, by chiral ligand and metal rhodium precursor in organic solvent, carry out reaction 0.5 ~ 2 hour at 20 ~ 40 DEG C, obtain catalyzer, chiral ligand is (R)-Binapine or (S)-Binapine, and structural formula is:
Step 2, is placed in autoclave by reaction system, adds 2-pyridine compounds, under an atmosphere of hydrogen, and temperature of reaction 20 DEG C ~ 50 DEG C, hydrogen pressure 5 ~ 50 normal atmosphere, reaction 20-24 hour.
2. asymmetric catalytic hydrogenation method according to claim 1, is characterized in that, metal rhodium precursor is two (1,5-cyclooctadiene) Tetrafluoroboric acid rhodium.
3. asymmetric catalytic hydrogenation method according to claim 1, is characterized in that, the molar ratio of described metal rhodium precursor and described chiral ligand is 1: 0.8 ~ 1.2.
4. asymmetric catalytic hydrogenation method according to claim 1, is characterized in that, the mol ratio of situ catalytic agent and 2-pyridine compounds is 1:100 ~ 5000.
5. asymmetric catalytic hydrogenation method according to claim 1, it is characterized in that,, described organic solvent be selected from methyl alcohol, ethanol, Virahol, trifluoroethanol, methylene dichloride, ethyl acetate, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), ether, toluene any one or a few.
6. asymmetric catalytic hydrogenation method according to claim 1, is characterized in that, described 2-pyridine compounds is the compound that following general formula A1 represents:
In general formula A1, R
2for C
1-C
15the alkyl or alkenyl of straight or branched, or C
3-C
15cyclic saturated hydrocarbon base, or have aromatic group or the aromatic heterocycle group of substituting group and unsubstituted; R
1for-Cl ,-Br ,-I, C
1-C
15alkyl or alkenyl, the C of straight or branched
3-C
15cyclic saturated hydrocarbon base or have aromatic group or the aromatic heterocycle group of substituting group and unsubstituted.
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| CN109879800A (en) * | 2019-03-11 | 2019-06-14 | 浙江工业大学 | A kind of preparation process of bepotastine pharmaceutical intermediate |
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| CN109824579A (en) * | 2019-03-11 | 2019-05-31 | 浙江工业大学 | A kind of preparation method of (S)-phenyl (pyridine -2- base) carbinol derivatives |
| CN109879800A (en) * | 2019-03-11 | 2019-06-14 | 浙江工业大学 | A kind of preparation process of bepotastine pharmaceutical intermediate |
| CN109824579B (en) * | 2019-03-11 | 2020-08-11 | 浙江工业大学 | Preparation method of (S) -phenyl (pyridine-2-yl) methanol derivative |
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