CN102976953A - Preparation method of chiral alpha-difluoromethyl phenyl ethylamine - Google Patents
Preparation method of chiral alpha-difluoromethyl phenyl ethylamine Download PDFInfo
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- CN102976953A CN102976953A CN2011102595291A CN201110259529A CN102976953A CN 102976953 A CN102976953 A CN 102976953A CN 2011102595291 A CN2011102595291 A CN 2011102595291A CN 201110259529 A CN201110259529 A CN 201110259529A CN 102976953 A CN102976953 A CN 102976953A
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Abstract
The invention relates to a preparation method of chiral alpha-difluoromethyl phenyl ethylamine, and mainly solves the technical problems of complex and high cost in a conventional synthesis method of the chiral alpha-difluoromethyl phenyl ethylamine compound. The preparation method of the chiral alpha-difluoromethyl phenyl ethylamine comprises the steps of a first step reaction for obtaining chiral (2,2-difluoromethyl-1-phenyl-ethyl)-tert-butyl sulfoximine (2) in a solvent via lewis acid catalytic condensation reaction and the effect with chiral tert-butanesulfinyl amide by using 2,2-difluoro-1-acetophenone (1) as a raw material; a second step reaction for obtaining chiral (2,2-difluoromethyl-1-phenyl-ethyl)-tert-butyl sulfinamide (3) by reacting the compound (2) with a reducing agent; and a third step reaction for obtaining a target product of chiral alpha-difluoromethyl phenyl ethylamine (A) by hydrolyzing the compound (3) in a mixed condition of the solvent and hydrochloric acid.
Description
Technical field
The present invention relates to chiral alpha-difluoromethyl phenyl ethylamine compounds and preparation method.
Background technology
The alpha-fluoro amino-complex is very important synthetic intermediate in medicine is synthetic.α-trifluoromethyl amino-complex is widely used in pharmaceutical industry, corresponding difluoromethyl compound is because difficult than trifluoromethyl compound on synthesizing, the attention rate that all the time is subject to is lower, because difluoromethyl (CF2H) is methylene radical hydroxyl (isostere CH2OH), be good hydrogen bond donor simultaneously and be again good lipophilic group, therefore alpha-difluoromethyl amine is paid close attention to more and more widely, and the chiral alpha that the present invention relates to-difluoromethyl phenyl ethylamine compounds is important a member of this compounds.
The high-efficiency synthesis method of the chiral alpha that the present invention relates to-difluoromethyl phenyl ethylamine compounds is less, up to the present only has the benzal fluoride of utilization methyl sulfone (PhSO
2CF
2H) prepare through the multistep complex reaction, the method cost is higher, and raw material is not easy to obtain, and operation is complicated, is difficult for suitability for industrialized production (patent CN 1724507 A).
Summary of the invention
The objective of the invention is to be to provide the preparation method of a kind of chiral alpha-difluoromethyl phenyl ethylamine compounds.The synthetic method that mainly solves present chiral alpha-difluoromethyl phenyl ethylamine compounds is complicated, and cost is high, and raw material is not easy to obtain, and problem that can not suitability for industrialized production.
Technical scheme of the present invention: the preparation of chiral alpha-difluoromethyl phenyl ethamine (A) may further comprise the steps:
The first step reaction is raw material with 2,2-, two fluoro-1-Phenyl ethyl ketones 1, obtains chirality (2,2-difluoromethyl-1-phenyl-ethyl)-tertiary butyl sulfenimide 2 through Louis acid catalysis condensation reaction and the effect of chirality t-butyl sulfonamide in solvent; Second step reaction, compound 2 obtain chirality (2,2-difluoromethyl-1-phenyl-ethyl)-t-butyl sulfonamide 3 with the reductive agent reaction in solvent; Three-step reaction, compound 3 obtains target product chiral alpha-difluoromethyl phenyl ethamine (A) at solvent and mixed in hydrochloric acid Water Under solution:
Described the first step reaction, Lewis acid is tetraethyl titanate or titanium isopropylate, solvent is tetrahydrofuran (THF).
The reaction of described second step, reductive agent is 3-sec-butyl lithium borohydride, and reaction is carried out under low temperature-78 ℃, and solvent is tetrahydrofuran (THF).
Described three-step reaction, solvent are a kind of in methyl alcohol or the ether.
Beneficial effect of the present invention: the invention provides a kind of simple and effective synthetic route, synthesized a kind of important organic synthesis intermediate chiral alpha-difluoromethyl phenyl ethamine.This technique is three-step reaction altogether, and total recovery can reach about 50%.
Embodiment
Following instance helps to understand content of the present invention, the present invention includes but is not limited to following related content.
Embodiment 1:(R)-preparation of alpha-difluoromethyl phenyl-ethyl amine
1:(2,2-difluoromethyl-1-phenyl-ethyl)-(R)-preparation of tertiary butyl sulfenimide
Reaction formula:
Operation steps:
Getting the round-bottomed flask of a 1000ml puts into magnetic stir bar and loads onto reflux condensing tube, to wherein adding 2,2-two fluoro-1-Phenyl ethyl ketone (74 g, 470 mmol), (R)-t-butyl sulfonamide (68.9 g, 570 mmol), tetraethyl titanate (159 g, 700 mmol) and 400 ml tetrahydrofuran (THF)s.This reaction mixture refluxed 3 hours under nitrogen protection.Cool to room temperature is poured this reaction solution in the 1L water into ethyl acetate extraction afterwards, the organic phase concentrating under reduced pressure, obtain (2,2-difluoromethyl-1-phenyl-ethyl)-(R)-tertiary butyl sulfenimide (89 g, 73%) with the silica gel chromatography column purification.
1 : (CDCl
3, 400 MHz) δ: 8.09 (br, 2H, Ar-H); 7.55 (m, 3H, Ar-H); 1.34 (s, 9H, t-Bu)。
2:(R)-preparation of (2,2-difluoromethyl-1-phenyl-ethyl)-(R)-t-butyl sulfonamide
Reaction formula:
Operation steps:
Getting the round-bottomed flask of a 1000ml puts into magnetic stir bar and loads onto constant pressure funnel, in flask, add (2,2-difluoromethyl-1-phenyl-ethyl)-(R)-tertiary butyl sulfenimide (72 g, 280 mmol) and 400 ml tetrahydrofuran (THF)s.This reaction mixture to-78 ℃, slowly drips the tetrahydrofuran solution (450 ml, 450 mmol) of 3-sec-butyl lithium borohydride at the nitrogen protection borehole cooling, finishes, and continues to stir 30 minutes.Afterwards, this reaction solution is poured in the 1L water, ethyl acetate extraction, the organic phase concentrating under reduced pressure obtains (R)-(2,2-difluoromethyl-1-phenyl-ethyl)-(R)-t-butyl sulfonamide (58 g, 80%) with the silica gel chromatography column purification.
1 : (CDCl
3, 400 MHz) δ: 7.39 (m, 5H, Ar-H). 5.93 (td, 1H, J=54.8 Hz J=4 Hz, CHF
2); 4.65 (m, 1H, CH); 3.87 (br, 1H, NH); 1.23 (s, 9H, t-Bu)。
3:(R)-preparation of alpha-difluoromethyl phenyl-ethyl amine
Reaction formula:
Get the round-bottomed flask of a 500ml and put into magnetic stir bar, in flask, add (R)-(2,2-difluoromethyl-1-phenyl-ethyl)-(R)-t-butyl sulfonamide (40 g, 153 mmol) and 200 ml ether, slowly drip afterwards 5N-hydrochloric acid-diethyl ether solution (100 ml, 500 mmol), finish, continue to stir 30 minutes.Afterwards, filter, filter cake washs 3 times with ether, and drying obtains (R)-alpha-difluoromethyl phenyl-ethyl amine hydrochloride (26.5 g, 89%, ee 98%).
1 : (DMSO, 400 MHz) δ: 9.39 (br, 3H, HCl-NH
2,); 7.63 (m, 2H, Ar-H). 7.48 (m, 3H, Ar-H), 6.55 (td, 1H, J=54.8 Hz J=4 Hz, CHF
2); 4.88 (m, 1H, CH).
19 F-NMR: (DMSO, 400 MHz) δ:-125.13 (q, 2F, J=62.4 Hz)；
MS: M+1=157.9。
Embodiment 2:(S)-preparation of alpha-difluoromethyl phenyl-ethyl amine
1:(2,2-difluoromethyl-1-phenyl-ethyl)-(S)-preparation of tertiary butyl sulfenimide
Reaction formula:
Operation steps:
Getting the round-bottomed flask of a 1000ml puts into magnetic stir bar and loads onto reflux condensing tube, to wherein adding 2,2-two fluoro-1-Phenyl ethyl ketone (66g, 420 mmol), (S)-t-butyl sulfonamide (60 g, 500 mmol), tetraethyl titanate (134 g, 625 mmol) and 400 ml tetrahydrofuran (THF)s.This reaction mixture refluxed 3 hours under nitrogen protection.Cool to room temperature is poured this reaction solution in the 1L water into ethyl acetate extraction afterwards, the organic phase concentrating under reduced pressure, obtain (2,2-difluoromethyl-1-phenyl-ethyl)-(R)-tertiary butyl sulfenimide (80 g, 74%) with the silica gel chromatography column purification.
1 : (CDCl
3, 400 MHz) δ: 8.09 (br, 2H, Ar-H); 7.55 (m, 3H, Ar-H); 1.34 (s, 9H, t-Bu)
。
2:(S)-preparation of (2,2-difluoromethyl-1-phenyl-ethyl)-(S)-t-butyl sulfonamide
Reaction formula:
Operation steps:
Getting the round-bottomed flask of a 1000ml puts into magnetic stir bar and loads onto constant pressure funnel, in flask, add (2,2-difluoromethyl-1-phenyl-ethyl)-(S)-tertiary butyl sulfenimide (90 g, 350 mmol) and 400 ml tetrahydrofuran (THF)s.This reaction mixture to-78 ℃, slowly drips the tetrahydrofuran solution (450 ml, 450 mmol) of 3-sec-butyl lithium borohydride at the nitrogen protection borehole cooling, finishes, and continues to stir 30 minutes.Afterwards, this reaction solution is poured in the 1L water, ethyl acetate extraction, the organic phase concentrating under reduced pressure obtains (S)-(2,2-difluoromethyl-1-phenyl-ethyl)-(R)-t-butyl sulfonamide (72 g, 80%) with the silica gel chromatography column purification.
1 : (CDCl
3, 400 MHz) δ: 7.39 (m, 5H, Ar-H). 5.93 (td, 1H, J=54.8 Hz J=4 Hz, CHF
2); 4.65 (m, 1H, CH); 3.87 (br, 1H, NH); 1.23 (s, 9H, t-Bu)。
3:(S)-preparation of alpha-difluoromethyl phenyl-ethyl amine
Reaction formula:
Get the round-bottomed flask of a 500ml and put into magnetic stir bar, in flask, add (S)-(2,2-difluoromethyl-1-phenyl-ethyl)-(S)-t-butyl sulfonamide (62 g, 237 mmol) and 300 ml ether, slowly drip afterwards 5N-hydrochloric acid-diethyl ether solution (200 ml, 500 mmol), finish, continue to stir 30 minutes.Afterwards, filter, filter cake washs 3 times with ether, and drying obtains (S)-alpha-difluoromethyl phenyl-ethyl amine hydrochloride (38 g, 84%, ee 98%).
1 : (DMSO, 400 MHz) δ: 9.39 (br, 3H, HCl-NH
2,); 7.63 (m, 2H, Ar-H). 7.48 (m, 3H, Ar-H), 6.55 (td, 1H, J=54.8 Hz J=4 Hz, CHF
2); 4.88 (m, 1H, CH).
19 F-NMR: (DMSO, 400 MHz) δ:-125.13 (q, 2F, J=62.4 Hz)；
MS: M+1=157.9。
Embodiment 3:(R)-preparation of alpha-difluoromethyl phenyl-ethyl amine
1:(2,2-difluoromethyl-1-phenyl-ethyl)-(R)-preparation of tertiary butyl sulfenimide
Reaction formula:
Operation steps:
Getting the round-bottomed flask of a 100ml puts into magnetic stir bar and loads onto reflux condensing tube, to wherein adding 2,2-two fluoro-1-Phenyl ethyl ketone (5 g, 32 mmol), (R)-t-butyl sulfonamide (5 g, 41 mmol), titanium isopropylate (14.2 g, 50 mmol) and 50 ml tetrahydrofuran (THF)s.This reaction mixture refluxed 3 hours under nitrogen protection.Cool to room temperature is poured this reaction solution in the 200ml water into ethyl acetate extraction afterwards, the organic phase concentrating under reduced pressure, obtain (2,2-difluoromethyl-1-phenyl-ethyl)-(R)-tertiary butyl sulfenimide (5.3 g, 64%) with the silica gel chromatography column purification.
1 : (CDCl
3, 400 MHz) δ: 8.09 (br, 2H, Ar-H); 7.55 (m, 3H, Ar-H); 1.34 (s, 9H, t-Bu)。
2:(R)-preparation of (2,2-difluoromethyl-1-phenyl-ethyl)-(R)-t-butyl sulfonamide
Reaction formula:
Operation steps:
Getting the round-bottomed flask of a 100ml puts into magnetic stir bar and loads onto constant pressure funnel, in flask, add (2,2-difluoromethyl-1-phenyl-ethyl)-(R)-tertiary butyl sulfenimide (5.3 g, 20.5 mmol) and 50 ml tetrahydrofuran (THF)s.This reaction mixture to-78 ℃, slowly drips the tetrahydrofuran solution (21 ml, 21 mmol) of 3-sec-butyl lithium borohydride at the nitrogen protection borehole cooling, finishes, and continues to stir 30 minutes.Afterwards, this reaction solution is poured in the 100mL water into ethyl acetate extraction, the organic phase concentrating under reduced pressure, obtain (R)-(2,2-difluoromethyl-1-phenyl-ethyl)-(R)-t-butyl sulfonamide (4.3 g, 81%) with the silica gel chromatography column purification.
1 : (CDCl
3, 400 MHz) δ: 7.39 (m, 5H, Ar-H). 5.93 (td, 1H, J=54.8 Hz J=4 Hz, CHF
2); 4.65 (m, 1H, CH); 3.87 (br, 1H, NH); 1.23 (s, 9H, t-Bu)。
3:(R)-preparation of alpha-difluoromethyl phenyl-ethyl amine
Reaction formula:
Get the round-bottomed flask of a 500ml and put into magnetic stir bar, in flask, add (R)-(2,2-difluoromethyl-1-phenyl-ethyl)-(R)-t-butyl sulfonamide (4.3 g, 16.3 mmol) with 10 ml methyl alcohol, slowly drip afterwards 5N-hydrochloric acid-methanol solution (20 ml, 100 mmol), finish, continue to stir 30 minutes.Concentrated, dry, obtain (R)-alpha-difluoromethyl phenyl-ethyl amine hydrochloride (3 g, 95%, ee 93%).
1 : (DMSO, 400 MHz) δ: 9.39 (br, 3H, HCl-NH
2,); 7.63 (m, 2H, Ar-H). 7.48 (m, 3H, Ar-H), 6.55 (td, 1H, J=54.8 Hz J=4 Hz, CHF
2); 4.88 (m, 1H, CH).
19 F-NMR: (DMSO, 400 MHz) δ:-125.13 (q, 2F, J=62.4 Hz)；
MS: M+1=157.9。
Claims (4)
1. the preparation method of chiral alpha-difluoromethyl phenyl ethamine is characterized in that may further comprise the steps:
The first step reaction is raw material with 2,2-, two fluoro-1-Phenyl ethyl ketones 1, obtains chirality (2,2-difluoromethyl-1-phenyl-ethyl)-tertiary butyl sulfenimide 2 through Louis acid catalysis condensation reaction and the effect of chirality t-butyl sulfonamide in solvent; Second step reaction, compound 2 obtain chirality (2,2-difluoromethyl-1-phenyl-ethyl)-t-butyl sulfonamide 3 with the reductive agent reaction in solvent; Three-step reaction, compound 3 obtains target product chiral alpha-difluoromethyl phenyl ethamine A at solvent and mixed in hydrochloric acid Water Under solution:
2. the preparation method of chiral alpha according to claim 1-difluoromethyl phenyl ethamine is characterized in that: described the first step reaction, and Lewis acid is tetraethyl titanate or titanium isopropylate, solvent is tetrahydrofuran (THF).
3. the preparation method of chiral alpha according to claim 1-difluoromethyl phenyl ethamine is characterized in that: described second step reaction, and reductive agent is 3-sec-butyl lithium borohydride, and reaction is carried out under low temperature-78 ℃, and solvent is tetrahydrofuran (THF).
4. the preparation method of chiral alpha according to claim 1-difluoromethyl phenyl ethamine, it is characterized in that: described three-step reaction, solvent are methyl alcohol or ether.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115232038A (en) * | 2022-06-09 | 2022-10-25 | 上海应用技术大学 | Mono-fluorine-bromine sulfenyl imide derivative and preparation and application thereof |
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| CN1724507A (en) * | 2005-07-07 | 2006-01-25 | 中国科学院上海有机化学研究所 | The method of optical purity α-difluoromethyl amine and highly-solid selectively preparation |
| WO2006127184A1 (en) * | 2005-05-20 | 2006-11-30 | Janssen Pharmaceutica N.V. | Process for preparation of sulfamide derivatives |
| CN101817775A (en) * | 2010-04-30 | 2010-09-01 | 浙江工业大学 | Preparation method of 2-pyrrole benzenylsulfonylamide compound |
| CN101875666A (en) * | 2010-07-28 | 2010-11-03 | 爱斯特（成都）医药技术有限公司 | Optical pure 1,3-alkamine compound as well as preparation method and application thereof in preparing Dapoxetine and analogues thereof |
| CN101993379A (en) * | 2010-10-22 | 2011-03-30 | 湖北能特科技股份有限公司 | Novel preparation method of cinacalcet hydrochloride |
-
2011
- 2011-09-05 CN CN2011102595291A patent/CN102976953A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006127184A1 (en) * | 2005-05-20 | 2006-11-30 | Janssen Pharmaceutica N.V. | Process for preparation of sulfamide derivatives |
| CN1724507A (en) * | 2005-07-07 | 2006-01-25 | 中国科学院上海有机化学研究所 | The method of optical purity α-difluoromethyl amine and highly-solid selectively preparation |
| CN101817775A (en) * | 2010-04-30 | 2010-09-01 | 浙江工业大学 | Preparation method of 2-pyrrole benzenylsulfonylamide compound |
| CN101875666A (en) * | 2010-07-28 | 2010-11-03 | 爱斯特（成都）医药技术有限公司 | Optical pure 1,3-alkamine compound as well as preparation method and application thereof in preparing Dapoxetine and analogues thereof |
| CN101993379A (en) * | 2010-10-22 | 2011-03-30 | 湖北能特科技股份有限公司 | Novel preparation method of cinacalcet hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| YA LI等: "Facile Synthesis of Chiral a-Difluoromethyl Amines from N-(tert-Butylsulfinyl)aldimines", 《ANGEWANDTE CHEMIE，INTERNATIONAL EDITION》, vol. 44, no. 36, 31 December 2005 (2005-12-31) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115232038A (en) * | 2022-06-09 | 2022-10-25 | 上海应用技术大学 | Mono-fluorine-bromine sulfenyl imide derivative and preparation and application thereof |
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