CN103755748A - Preparation process for chiral (R)-1-ferrocenyl ethyl dimethylamine - Google Patents
Preparation process for chiral (R)-1-ferrocenyl ethyl dimethylamine Download PDFInfo
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- CN103755748A CN103755748A CN201310734003.3A CN201310734003A CN103755748A CN 103755748 A CN103755748 A CN 103755748A CN 201310734003 A CN201310734003 A CN 201310734003A CN 103755748 A CN103755748 A CN 103755748A
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Abstract
The invention belongs to the technical field of organic synthesis and discloses a preparation process for chiral (R)-1-ferrocenyl ethyl dimethylamine. According to the preparation process, acetylferrocene is used as a raw material and is asymmetrically reduced to obtain R-architectonic ferrocenyl ethanol; then optically-pure (R)-1-ferrocenyl ethyl dimethylamine is obtained by an esterification and amination one-pot method. The method does not need resolution so that the synthesis yield of the (R)-1-ferrocenyl ethyl dimethylamine is greatly improved; the preparation process has the characteristics of moderate reaction conditions, high optical purity and the like; the synthesis yield of a ferrocene diphosphine ligand which takes the (R)-1-ferrocenyl ethyl dimethylamine as a key intermediate is improved; te production cost is reduced and the preparation process is suitable for industrial production.
Description
Technical field
The invention belongs to technical field of organic synthesis, relate to a kind of preparation technology of (R)-1-ferrocenyl ethyl dimethylamine of chirality.
Background technology
Chiral ferrocene diphosphine ligand is the important part in asymmetric catalytic hydrogenation reaction, and it has been widely used in industrial asymmetric hydrogenation.(R)-1-ferrocenyl ethyl dimethylamine is a key intermediate of this class chiral ligand, is also the focus of domestic and international chiral ligand field concern and the focus of research.
About the synthetic key point of (R)-1-ferrocenyl ethyl dimethylamine, be the structure of its chiral centre.In the method for prior art, be all the chiral centre that obtains ferrocenyl ethyl dimethylamine with the method for chiral separation, its yield is very low, operating process complexity; Or carry out asymmetric hydrogenation carbonyl with another very expensive chiral ligand and catalyzer, obtain its chiral centre.
Summary of the invention
The features such as the preparation technology who the object of this invention is to provide a kind of (R)-1-ferrocenyl ethyl dimethylamine of chirality, adopts chiral ligand cheap and easy to get to obtain its chiral centre, has mild condition, and yield is high, and ee value is high, and the reaction times is short.And (R)-1-ferrocenyl ethanol directly obtains (R)-1-ferrocenyl ethyl dimethylamine through " one kettle way " with higher yield.
For technical solution problem, the present invention adopts following technical scheme:
A preparation technology for (R)-1-ferrocenyl ethyl dimethylamine of chirality, its preparation process comprises successively:
Step 1, take acetylferrocene as raw material, under the existence of chiral ligand, react at-10 ℃～30 ℃ with reductive agent, generate (R)-1-ferrocenyl ethanol;
(the R)-1-ferrocenyl ethanol obtaining in step 2, step 1, under condition of no solvent, add alkali and catalyzer, 0 ℃～30 ℃ react 2～10h with acetic anhydride after, then adding massfraction is 30%～50% dimethylamine agueous solution and solvent, continue reaction 2～15h, obtain (R)-1-ferrocenyl ethyl dimethylamine.The esterification of this step and amination reaction, middle without the operations such as separation of purifying, " one kettle way " reaction obtains (R)-1-ferrocenyl ethyl dimethylamine.
Its operational path is as follows:
The present invention is without fractionation, reaction temperature and, yield is high, ee value is high, the reaction times is short, operating process is simple, each raw material and reagent are also cheap and easy to get, greatly reduce raw materials cost.
Preferably, in described step 1, in described step 1, chiral ligand is TarB-X, wherein X=H, NO
2, Cl, F or CF
3.
Preferably, in described step 2, in described step 1, reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE or lithium borohydride.
Preferably, in described step 2, alkali is pyridine, triethylamine or diisopropyl ethyl amine.
Preferably, in described step 2, catalyzer is Tetrabutyl amonium bromide (TBAB), tetrabutylammonium iodide or DMAP (DMAP).
Preferably, the preparation technology of (R)-1-ferrocenyl ethyl dimethylamine of this kind of chirality, its preparation process comprises successively:
Step 1, the tetrahydrofuran solution of acetylferrocene and TarB-X is added in there-necked flask, ice bath to 0 ℃ stirs 15min, add hydroborate, under room temperature, stir 2h, then reaction solution is proceeded in beaker, slowly adding concentration is the hydrochloric acid cancellation reaction of 1mol/L, add sodium hydrate solid that pH value is adjusted to 12, and 30min is stirred in continuation, standing separatory, water extracts with alkane, merge organic phase, wash with saturated sodium-chloride water solution, then use anhydrous sodium sulfate drying, revolve and steam except desolventizing, obtain colourless liquid, be (R)-1-ferrocenyl ethanol,
Step 2, (R)-1-ferrocenyl ethanol that step 1 is obtained add in another there-necked flask, and add acetic anhydride, alkali, catalyzer and methylene dichloride, stirring reaction 2h at 30 ℃, pressure reducing and steaming solvent, add methyl alcohol, ice bath cooling, slowly drips dimethylamine agueous solution, rise to room temperature reaction 10h, add the shrend reaction of going out, by dichloromethane extraction, then removal of solvent under reduced pressure, obtain N, N-dimethylaminoethyl ferrocene.
Preferably, in described step 1, for the alkane extracting, be normal hexane or pentane.
The present invention has following beneficial effect: the preparation technology who the invention discloses (R)-1-ferrocenyl ethyl dimethylamine of chirality, take acetylferrocene as raw material, through chirality reductive agent asymmetric reduction, obtain the ferrocenyl ethanol of R configuration, then obtain optically pure (R)-1-ferrocenyl ethyl dimethylamine through esterification, amination " one kettle way ".The method is without fractionation, greatly improved the synthesis yield of (R)-1-ferrocenyl ethyl dimethylamine, and there is reaction conditions gentleness, optical purity high, improved the synthesis yield take (R)-1-ferrocenyl ethyl dimethylamine as the ferrocene biphosphine ligand of key intermediate, reduce its production cost, be applicable to suitability for industrialized production.
Embodiment
The preparation technology embodiment 1 of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality of the present invention, its preparation process comprises successively:
In the there-necked flask that it is 500ml that step 1, tetrahydrofuran (THF) (THF) solution that is the TarB-H of 0.4mol/L (0.1mol) by 11.4g (0.05mol) acetylferrocene and 250ml concentration add with the volume of magnetic agitation, low-reading thermometer and drying tube, ice bath to 0 ℃ stirs 15min, adds 3.8g (0.1mol) sodium borohydride (NaBH
4), stirring at room 2h, then reaction solution is proceeded in the beaker that volume is 1L, slowly adding 300ml concentration is hydrochloric acid (HCl) the cancellation reaction of 1mol/L, add 28g sodium hydroxide (NaOH) solid that pH value is adjusted to 12, and 30min is stirred in continuation, standing separatory, normal hexane for water (200ml × 3) extraction, merges organic phase, with saturated sodium-chloride water solution (salt solution) washing, then use anhydrous sodium sulfate drying, revolve and steam except desolventizing, obtain colourless liquid, be (R)-1-diamyl iron-based ethanol; (the R)-1-ferrocenyl ethanol obtaining is 10.1g, and purity is that 88%, ee value is 96%.Wherein, the preparation process reference of TarB-H (BakthanSingaram, et al, Tetrahedron Letters, 43,2002,3649-3652).Ee is enantiomeric excess (enantiomeric excess), in two enantiomorphs of chiral molecules, each enantiomorph all rotates to certain angle plane polarized light, identical but the opposite direction of its numerical value, this character is called optical activity, and the enantiomorph of compound sample forms available term " enantiomeric excess (enantiomeric excess) " or " e.e.% " describes.Enantiomorph of its expression is excessive to another enantiomorph, conventionally with percentage ratio, represents, i.e. optical purity (e.e. value).
1H-NMR(CDCl
3)：δ＝4.50(s，1H)，4.24(s，9H)，1.79(s，1H)，1.45(d，J＝4.5Hz，3H)；
13C-NMR(CDCl
3)：δ＝24.1，65,8，66.2，66.4，68.1，68.3，68.5，95.3。
Step 2, it is in the there-necked flask of 250ml that (R)-1-ferrocenyl ethanol that 37.6g step 1 is obtained adds another volume, and add 25g acetic anhydride, 25.5g pyridine, 1.0g4-Dimethylamino pyridine (DMAP) and 100ml methylene dichloride, stirring reaction 2h at 30 ℃, pressure reducing and steaming solvent, add 100ml methyl alcohol, ice bath cooling, slowly drip the dimethylamine agueous solution that 72g massfraction is 40%, rise to room temperature reaction 10h, add the 200ml shrend reaction of going out, extract with methylene dichloride (200ml × 3), then removal of solvent under reduced pressure, obtain N, N-dimethylaminoethyl ferrocene, the N obtaining, N-dimethylaminoethyl ferrocene is 27g, yield 66%.
1H-NMR(CDCl
3)：δ＝4.08-4.01(m，9H)，3.51(q，J＝6.8Hz，1H)，2.01(s，6H)，1.36(d，J＝7.1Hz，3H)；
13C-NMR(CDCl
3)：δ＝87.8，69.4，68.8，67.5，67.4，67.2，58.7，40.7，16.2。
The preparation technology embodiment 2 of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality of the present invention, its preparation process is substantially similar to embodiment 1, difference is: in step 1, in the there-necked flask that it is 500ml that tetrahydrofuran (THF) (THF) solution that is the 4-F-TarB-H of 0.4mol/L (0.1mol) by 11.4g (0.05mol) acetylferrocene and 250ml concentration adds with the volume of magnetic agitation, low-reading thermometer and drying tube, ice bath to 0 ℃ stirs 15min, adds 5.4g (0.1mol) POTASSIUM BOROHYDRIDE (KBH
4), stirring at room 2h, subsequent step is identical.(R)-1-ferrocenyl ethanol that this step obtains is 9.8g, and purity is that 85.2%, ee value is 95.1%.Wherein, the preparation process reference of 4-F-TarB-H (BakthanSingaram, et al, Tetrahedron Letters, 43,2002,3649-3652).
1H-NMR(CDCl
3)：δ＝4.50(s，1H)，4.24(s，9H)，1.79(s，1H)，1.45(d，J＝4.5Hz，3H)；
13C-NMR(CDCl
3)：δ＝24.1，65,8，66.2，66.4，68.1，68.3，68.5，95.3。
In step 2, it is in the there-necked flask of 250ml that (R)-1-ferrocenyl ethanol that 37.6g step 1 is obtained adds another volume, and add 25g acetic anhydride, 18.0g triethylamine, 2.6g Tetrabutyl amonium bromide and 100ml methylene dichloride, stirring reaction 2h at 30 ℃, subsequent step is identical.The N that this step obtains, N-dimethylaminoethyl ferrocene is 26.7g, yield 65.0%.
1H-NMR(CDCl
3)：δ＝4.08-4.01(m，9H)，3.51(q，J＝6.8Hz，1H)，2.01(s，6H)，1.36(d，J＝7.1Hz，3H)；
13C-NMR(CDCl
3)：δ＝87.8，69.4，68.8，67.5，67.4，67.2，58.7，40.7，16.2。
The preparation technology embodiment 3 of (R)-1-ferrocenyl ethyl dimethylamine of the present invention's one handedness, its preparation process is substantially similar to embodiment 1, difference is: in step 1, in the there-necked flask that it is 500ml that tetrahydrofuran (THF) (THF) solution that is 4-trifluoromethyl-TarB-H of 0.4mol/L (0.1mol) by 11.4g (0.05mol) acetylferrocene and 250ml concentration adds with the volume of magnetic agitation, low-reading thermometer and drying tube, ice bath to 0 ℃ stirs 15min, and subsequent step is identical.(R)-1-ferrocenyl ethanol that this step obtains is 9.9g, and purity is that 86%, ee value is 95.4%.Wherein, the preparation process reference of 4-trifluoromethyl-TarB-H (BakthanSingaram, et al, Tetrahedron Letters, 43,2002,3649-3652).
1H-NMR(CDCl
3)：δ＝4.50(s，1H)，4.24(s，9H)，1.79(s，1H)，1.45(d，J＝4.5Hz，3H)；
13C-NMR(CDCl
3)：δ＝24.1，65,8，66.2，66.4，68.1，68.3，68.5，95.3。
In step 2, it is in the there-necked flask of 250ml that (R)-1-ferrocenyl ethanol that 37.6g step 1 is obtained adds another volume, and add 25g acetic anhydride, 31.0g diisopropyl ethyl amine, 2.96g tetrabutylammonium iodide and 100ml methylene dichloride, stirring reaction 2h at 30 ℃, subsequent step is identical.The N that this step obtains, N-dimethylaminoethyl ferrocene is 26.8g, yield 65.4%.
1H-NMR(CDCl
3)：δ＝4.08-4.01(m，9H)，3.51(q，J＝6.8Hz，1H)，2.01(s，6H)，1.36(d，J＝7.1Hz，3H)；
13C-NMR(CDCl
3)：δ＝87.8，69.4，68.8，67.5，67.4，67.2，58.7，40.7，16.2。
The preparation technology embodiment 4 of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality of the present invention, its preparation process is substantially similar to embodiment 1, difference is: in step 1, in the there-necked flask that it is 500ml that tetrahydrofuran (THF) (THF) solution that is the 4-Cl-TarB-H of 0.4mol/L (0.1mol) by 11.4g (0.05mol) acetylferrocene and 250ml concentration adds with the volume of magnetic agitation, low-reading thermometer and drying tube, ice bath to 0 ℃ stirs 15min, adds 2.2g (0.1mol) lithium potassium hydride KH (LiBH
4), stirring at room 2h, subsequent step is identical.(R)-1-ferrocenyl ethanol that this step obtains is 10.0g, and purity is that 87%, ee value is 95.8%.Wherein, the preparation process reference of 4-Cl-TarB-H (BakthanSingaram, et al, Tetrahedron Letters, 43,2002,3649-3652).
1H-NMR(CDCl
3)：δ＝4.50(s，1H)，4.24(s，9H)，1.79(s，1H)，1.45(d，J＝4.5Hz，3H)；
13C-NMR(CDCl
3)：δ＝24.1，65，8，66.2，66.4，68.1，68.3，68.5，95.3。
In step 2, it is in the there-necked flask of 250ml that (R)-1-ferrocenyl ethanol that 37.6g step 1 is obtained adds another volume, and add 25g acetic anhydride, 18.0g triethylamine, 1.0g4-Dimethylamino pyridine (DMAP) and 100ml methylene dichloride, stirring reaction 2h at 30 ℃, subsequent step is identical.The N that this step obtains, N-dimethylaminoethyl ferrocene is 27.3g, yield 66.4%.
1H-NMR(CDCl
3)：δ＝4.08-4.01(m，9H)，3.51(q，J＝6.8Hz，1H)，2.01(s，6H)，1.36(d，J＝7.1Hz，3H)；
13C-NMR(CDCl
3)：δ＝87.8，69.4，68.8，67.5，67.4，67.2，58.7，40.7，16.2。
The preparation technology embodiment 5 of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality of the present invention, its preparation process is substantially similar to embodiment 1, difference is: in step 1, by 11.4g (0.05mol) acetylferrocene and 250ml concentration, be the 4-NO of 0.4mol/L (0.1mol)
2in the there-necked flask that it is 500ml that tetrahydrofuran (THF) (THF) solution of-TarB-H adds with the volume of magnetic agitation, low-reading thermometer and drying tube, ice bath to 0 ℃ stirs 15min, and subsequent step is identical.(R)-1-ferrocenyl ethanol that this step obtains is 10.3g, and purity is that 89.6%, ee value is 96.2%.Wherein, 4-NO
2the preparation process reference (BakthanSingaram, et al, Tetrahedron Letters, 43,2002,3649-3652) of-TarB-H.
1H-NMR(CDCl
3)：δ＝4.50(s，1H)，4.24(s，9H)，1.79(s，1H)，1.45(d，J＝4.5Hz，3H)；
13C-NMR(CDCl
3)：δ＝24.1，65,8，66.2，66.4，68.1，68.3，68.5，95.3。
In step 2, it is in the there-necked flask of 250ml that (R)-1-ferrocenyl ethanol that 37.6g step 1 is obtained adds another volume, and add 25g acetic anhydride, 18.0g triethylamine, 1.0g4 Dimethylamino pyridine (DMAP) and 100ml methylene dichloride, stirring reaction 2h at 30 ℃, subsequent step is identical.The N that this step obtains, N-dimethylaminoethyl ferrocene is 27.5g, yield 66.9%.
1H-NMR(CDCl
3)：δ＝4.08-4.01(m，9H)，3.51(q，J＝6.8Hz，1H)，2.01(s，6H)，1.36(d，J＝7.1Hz，3H)；
13C-NMR(CDCl
3)：δ＝87.8，69.4，68.8，67.5，67.4，67.2，58.7，40.7，16.2。
The foregoing is only specific embodiments of the invention, but technical characterictic of the present invention is not limited to this, any those skilled in the art is in the field of the invention, and the variation of doing or modification are all encompassed among the scope of the claims of the present invention.
Claims (7)
1. a preparation technology for (R)-1-ferrocenyl ethyl dimethylamine of chirality, is characterized in that: its preparation process comprises successively:
Step 1, take acetylferrocene as raw material, under the existence of chiral ligand, react at-10 ℃～30 ℃ with reductive agent, generate (R)-1-ferrocenyl ethanol;
(the R)-1-ferrocenyl ethanol obtaining in step 2, step 1, under condition of no solvent, add alkali and catalyzer, 0 ℃～30 ℃ react 2～10h with acetic anhydride after, then adding massfraction is 30%～50% dimethylamine agueous solution and solvent, continue reaction 2～15h, obtain (R)-1-ferrocenyl ethyl dimethylamine.
2. the preparation technology of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality as claimed in claim 1, is characterized in that: in described step 1, chiral ligand is TarB-X, wherein X=H, NO
2, Cl, F or CF
3.
3. the preparation technology of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality as claimed in claim 1, is characterized in that: in described step 1, reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE or lithium borohydride.
4. the preparation technology of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality as claimed in claim 1, is characterized in that: in described step 2, alkali is pyridine, triethylamine or diisopropyl ethyl amine.
5. the preparation technology of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality as claimed in claim 1, is characterized in that: in described step 2, catalyzer is Tetrabutyl amonium bromide, tetrabutylammonium iodide or DMAP.
6. the preparation technology of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality as claimed in claim 1, is characterized in that: its preparation process comprises successively:
Step 1, the tetrahydrofuran solution of acetylferrocene and TarB-X is added in there-necked flask, ice bath to 0 ℃ stirs 15min, add hydroborate, under room temperature, stir 2h, then reaction solution is proceeded in beaker, slowly adding concentration is the hydrochloric acid cancellation reaction of 1mol/L, add sodium hydrate solid that pH value is adjusted to 12, and 30min is stirred in continuation, standing separatory, water extracts with alkane, merge organic phase, wash with saturated sodium-chloride water solution, then use anhydrous sodium sulfate drying, revolve and steam except desolventizing, obtain colourless liquid, be (R)-1-ferrocenyl ethanol,
Step 2, (R)-1-ferrocenyl ethanol that step 1 is obtained add in another there-necked flask, and add acetic anhydride, alkali, catalyzer and methylene dichloride, stirring reaction 2h at 30 ℃, pressure reducing and steaming solvent, add methyl alcohol, ice bath cooling, slowly drips dimethylamine agueous solution, rise to room temperature reaction 10h, add the shrend reaction of going out, by dichloromethane extraction, then removal of solvent under reduced pressure, obtain N, N-dimethylaminoethyl ferrocene.
7. the preparation technology of (R)-1-ferrocenyl ethyl dimethylamine of a kind of chirality as claimed in claim 6, is characterized in that: in described step 1, for the alkane extracting, be normal hexane or pentane.
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| CN114891836A (en) * | 2022-05-31 | 2022-08-12 | 重庆张邦医药科技有限责任公司 | Preparation method of chiral ferrocene derivative |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114539328A (en) * | 2022-01-11 | 2022-05-27 | 宝鸡文理学院 | Chiral Ugi amine synthesis process promoted by nonionic surfactant |
| CN114891836A (en) * | 2022-05-31 | 2022-08-12 | 重庆张邦医药科技有限责任公司 | Preparation method of chiral ferrocene derivative |
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