CN1724507A - The method of optical purity α-difluoromethyl amine and highly-solid selectively preparation - Google Patents
The method of optical purity α-difluoromethyl amine and highly-solid selectively preparation Download PDFInfo
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Abstract
The method and uses thereof that the purpose of this invention is to provide the preparation of a kind of optical purity alpha-difluoromethyl amine and derivative thereof, highly-solid selectively.This structural formula of compound is suc as formula I and their salt thereof, wherein, and R=C
1-12Alkyl, C
4～12Aryl, C
1～6Alkoxy aryl, halogenated aryl, furyls etc., described aryl can be phenyl, naphthyl; R
1=H or SO
2Ph; R
2=H or formula II are suc as formula III, formula IV etc.The preparation method has characteristics such as cost is low, favorable repeatability, and the optical purity of the alpha-difluoromethyl amine for preparing can reach the ee value greater than 99%.
Description
Technical field
The present invention relates to the method for the preparation of a kind of optical purity alpha-difluoromethyl amine and derivative and highly-solid selectively thereof.This chipal compounds is the synthetic building block of a kind of potential medicine, and method of the present invention is the preparation method of highly-solid selectively.
Background technology
Fluoric amine is very important synthetic building block in medicine is synthetic.Because difluoromethyl (CF
2H) can be regarded as methylene radical hydroxyl (electric body such as grade CH2OH) and wait polar body, and can be used as lipophilic hydrogen bond donor, so alpha-difluoromethyl amine (1) has been subjected to paying close attention to widely.
(R，R′＝alkyl，aryl，H，etc)
Though it is-difluoromethyl amine is expected in medicine, life science important application prospects is arranged, actually rare for the preparation method of-difluoromethyl amine.Especially the report for the method for the pure of efficient synthesizing optical-difluoromethyl amine does not still have at present.The preparation method of present racemic-difluoromethyl amine utilizes to contain the carbonyl compound (or their imine derivative) of difluoromethyl as raw material ((a) Kaneko, S.; Yamazaki, T.; Kitazume, T., J.Org.Chem.1993,58,2302. (b) Abe, H.; Amii, H.; Uneyama, K., Org.Lett.2001,3,313. (c) Fustero, S.et al.Org.Lett.2001,3,2621. (d) Volonterio, A.; Vergani, B.; Crucianelli, M.; Zanda, M., J.Org.Chem.1998,63,7236. (e) Funabiki, K.; Nagamori, M.; Goushi, S.; Matsui, M., Chem.Comm.2004,1928.) in 1978, people such as Pey once reported and have utilized freonll-11-22 multistep processes to synthesize alpha-difluoromethyl amine (Pey, P.; Schirlin, D., Tetrahedron Lett.1978,19,5225).But, up to the present, for the pure still still challenge of alpha-difluoromethyl amine of efficient synthesizing optical.In in the past 20 years, a lot of people did exploration for the preparation of chirality alpha-difluoromethyl amine, comprising: people such as (1) Uneyama have carried out the asymmetric hydrogenation of catalyzing by metal palladium to the difluoromethyl imidoether, but can only obtain very low enantioselectivity (ee value=30%) ((1) Abe, H.; Amii, H.; Uneyama, K., Org.Lett.2001,3,313); (2) the hydride reduction reaction to chirality difluoromethyl β-sulfinyl-N-aryl imine also can only obtain 82% de value (Fustero, S.et al.Org.Lett.2001,3,2621); (3) synthesize difluoro pyruvic aldehyde-N with three-step approach from difluoro acetate and chirality methyl p-methylphenyl sulfoxide, the S-acetal is also had to 72% ee value (Volonterio, A.; Vergani, B.; Crucianelli, M.; Zanda, M., J.Org.Chem.1998,63,7236); (4) utilize optical purity β-bromo-β, β-difluoro third ammonia derivative prepares β, and β-difluoro third ammonia derivative has but reduced optical purity (the ee value reduces to 80%) (Katagiri, T.; Handa, M.; Matsukawa, Y.; Kumar, J.S.D.; Uneyama, K., Tetrahedron:Asymmetry 2001,12, and 1303); (5) people such as Funabiki has attempted the asymmetric Mannich class reaction of the L-proline(Pro) catalysis of difluoromethyl aldimine, but finds that speed of reaction is very slow and to the applicable surface of substrate very narrow (Funabiki, K.; Nagamori, M.; Goushi, S.; Matsui, M., Chem.Comm.2004,1928).On the other hand, although people such as Prakash has reported utilization (trifluoromethyl) trimethyl silane and optical purity N-(tertiary butyl sulfinyl) aldimine asymmetric synthesis chirality α-trifluoromethyl amine in recent years, utilize similar approach (promptly to use R
3Si-CF
2H class reagent and optical purity N-(tertiary butyl sulfinyl) aldimine reaction) but very big ((a) Prakash, G.K.S. of difficulty of synthesis of chiral alpha-difluoromethyl amine; Mandal, M.; Olah, G..A., Angew.Chem.Int.Ed.2001,40,589; (b) Prakash, G.K.S.; Mandal, M., J.Am.Chem.Soc.2002,124,6538; (c) Hagiwara, T.; Fuchikami, T., Synlett 1995,717).Therefore, up to now, the method for directly utilizing the difluoromethyl reaction to carry out the pure alpha-difluoromethyl amine of height stereoselectivity synthesizing optical yet there are no report.A technical problem of Here it is Gonna breakthrough of the present invention.
In addition, the inventor and co-worker utilize difluoromethyl phenyl sulfone (PhSO
2CF
2H) a series of researchs ((a) Prakash, G.K.S. such as difluoromethylization, difluoro methyleneization, difluoro alkenyl had once been carried out; Hu, J.; Olah, G.A., J.Org.Chem.2003,68,4457; (b) Prakash, G.K.S.; Hu, J.; Mathew, T.; Olah, G.A., Angew.Chem.Int.Ed.2003,42,5216; (c) Prakash, G.K.S.; Hu, J.; Wang, Y.; Olah, G.A., Angew.Chem.Int.Ed.2004,43,5203; (d) Prakash, G.K.S.; Hu, J.; Wang, Y.; Olah, G.A., Org.Lett.2004,6,4315; (e) Prakash, G.K.S.; Hu, J.; Wang, Y.; Olah, G.A., Eur.J Org.Chem.2005,2218).But, utilize difluoromethyl phenyl sulfone (PhSO
2CF
2H) preparation of carrying out alpha-difluoromethyl amine but never was in the news.
Summary of the invention
The purpose of this invention is to provide a kind of optical purity α difluoromethyl amine and derivative thereof.
Another purpose of invention provides the preparation method of (particularly optical purity alpha-difluoromethyl amine) of a kind of highly-solid selectively of a kind of above-mentioned optical purity α difluoromethyl amine and derivative thereof.This preparation method has characteristics such as cost is low, productive rate is high, favorable repeatability, and the optical purity of the α difluoromethyl amine for preparing can reach the ee value greater than 99%.
Purpose of the present invention also provides the purposes of a kind of above-mentioned optical purity α difluoromethyl amine and derivative thereof.
Optical purity α difluoromethyl amine of the present invention and derivative thereof have the compound of following structural formula:
And their salt, wherein, R=C
1～12Alkyl, C
4～12Aryl, C
1-6Alkoxy aryl, halogenated aryl or furyl etc., described aryl can be a phenyl or naphthyl etc.; R
1=H or SO
2Ph; R
2=H or
As
Deng.
Method of the present invention can be represented with following typical reaction formula:
The method of the pure alpha-difluoromethyl amine of efficient synthesizing optical of the present invention is to utilize difluoromethyl phenyl sulfone, under the effect of alkali to (R) or (S)-the asymmetric benzenesulfonyl of tertiary butyl sulfoxide group aldimine generation nucleophilic difluoromethylization; Remove benzene sulfuryl and tertiary butyl sulfinyl then successively and just can obtain optically pure alpha-difluoromethyl amine.
Method of the present invention is in organic solvent, during-78 ℃～room temperature and alkali exist down, with difluoromethyl phenyl sulfone, (R) or (S)-tertiary butyl sulfoxide group aldimine reaction 0.1～1 hour, obtain structural formula and be
Compound; The mol ratio of described difluoromethyl phenyl sulfone, (R) or (S)-tertiary butyl sulfoxide group aldimine and alkali is 1: 0.8～1.5: 1～5; Described alkali can be hmds lithium (LHMDS), butyllithium, potassium tert.-butoxide, diisobutyl amine lithium (LDA) or sodium hydroxide etc.
With structural formula be
Compound in organic solvent, during 0 ℃～room temperature, C
1～4Pure and mild monovalence metal (perhaps the sulfone system is taken off in other reduction) exists down, and reaction generated optical purity alpha-difluoromethyl amine in 0.1～1 hour
, described monovalence metal is potassium or sodium.Reaction product is at C
1～4Alcoholic solution and excessive in hydrochloric acid reaction 0.1～1 hour generates the hydrochloride of optically pure alpha-difluoromethyl amine.
Described organic solvent is ether, toluene, methylene dichloride, acetonitrile or tetrahydrofuran (THF) (THF) etc.
The present invention is the best preparation method of the pure alpha-difluoromethyl amine of present known synthesizing optical.This preparation method's advantage is: (1) (R) or (S)-tertiary butyl sulfoxide group aldimine raw material is easy to prepare; (2) this preparation method condition is simple, the reaction times is short, productive rate is high, optical purity is high, and is easy to separate.
The preparation-obtained optical purity alpha-difluoromethyl of the present invention amine, this chipal compounds is the synthetic building block of a kind of potential chiral drug, can further in synthesizing of other biochemical activity material potential application be arranged, described optical purity difluoromethyl amine can also be used for synthetic fluorinated amino acids, polypeptide or enzyme inhibitors.
As following reaction is example:
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1
Typical case preparation method: in ether, toluene, methylene dichloride, acetonitrile or tetrahydrofuran (THF) organic solvent.2mmol phenyl difluoromethyl sulfone and 2mmol imines 2a are placed reaction flask.Under dry ice-propanone is bathed, add 2.2mmol LHMDS.Stir 30min under this temperature, temperature slowly rises to room temperature, after the saturated aqueous common salt cancellation, and ethyl acetate extraction (20ml).Anhydrous magnesium sulfate drying is spin-dried for solvent, promptly obtains pure product 3a (763mg).Productive rate 95%.Compound 3a characterization data is as follows: white solid, fusing point 144-146 ℃; Specific rotation [α]
D 25=-27.4 (c=0.8, CHCl
3). infrared spectra (coating method): 3066,2962,1584,1449,1349,1158,1087cm
-1. nuclear magnetic resonance map:
1H NMR: δ 7.89 (d, J=7.5Hz, 2H), 7.70-7.75 (m, 1H), 7.60 (t, J=7.5Hz, 2H), 7.37-7.44 (m, 5H), 5.24-5.36 (m, 1H), 4.04 (d, J=7.8Hz, 1H), 1.29 (s, 9H).
19F NMR: δ-102.51 (dd, J=235.5,8.7Hz, 1F) ,-108.55 (dd, J=235.5,15.1Hz, 1F).
13C NMR: δ 135.29,133.40,133.30,130.46,129.59,129.26,128.89,128.75,121.06 (t, J=292.0Hz), 60.72 (dd, J=23.5,19.4Hz), 57.37, the 22.40. mass spectrum (EI, m/z, %): 402 (M
++ 1,1.2), 140 (100.0). ultimate analysis (EA): theoretical value C
18H
21F
2NO
3S
2: C, 53.85; H, 5.27; N, 3.49; Experimental value: C, 53.67; H, 5.33; N, 3.35.
3a (1.9mmol) is dissolved in the 5ml methyl alcohol, is cooled to 0 ℃.Add 5.0mmol sodium (perhaps sodium amalgam) then.0 ℃ is stirred down 30min, ethyl acetate extraction then, anhydrous magnesium sulfate drying.Except that after desolvating, add 5ml methyl alcohol and 0.5N concentrated hydrochloric acid.Stirring at room 20min.Except that after desolvating, promptly obtain optically pure 4a (305mg).Productive rate 8396.Compound 4a characterization data is as follows: white solid.Specific rotation: [α]
D 25=25.4 (c=1.0, CH
3OH). infrared spectra (KBr): 2881,1596,1509,1457,1077cm
-1. nuclear magnetic resonance map:
1H NMR (CD
3OD): δ 7.51 (s, 5H), 6.33 (td, J=54.3,3.0Hz, 1H), 4.79-4.85 (m, 1H).
19F NMR (CD
3OD): δ-124.56 (ddd, J=285.9,53.8,10.4Hz, 1F) ,-129.37 (ddd, J=285.9,56.1,16.0Hz, 1F).
13C NMR (CD
3OD): δ 131.88,131.76 (t, J=2.2Hz), 131.00,129.90,115.90 (t, J=244.5Hz), 57.82 (dd, J=24.3,21.3Hz). mass spectrum (EI, m/z, %): 156 (0.7, M
+-HCl-1), and 106 (100.0). high resolution mass spec (EI): theoretical value C
8H
9F
2N (M
+-HCl): 157.07031; Experimental value: 157.07106.
Embodiment the results are shown in Table 1 and table 2 shown in.
Table 1
Annotate: the ratio of non-corresponding isomer is determined by the fluorine spectrum of crude product.
Table 2
Embodiment 2
Preparation method: 2mmol phenyl difluoromethyl sulfone and 2mmol imines 2b are placed reaction flask.Under dry ice-propanone is bathed, add 2.2mmol LHMDS.Stir 30min under this temperature, temperature slowly rises to room temperature, after the saturated aqueous common salt cancellation, and ethyl acetate extraction (20ml).Anhydrous magnesium sulfate drying is spin-dried for solvent, promptly obtains pure product 3, productive rate 96%.Compound 3b characterization data is as follows: white solid, fusing point 108-110 ℃. specific rotation [α]
D 25=-20.7 (c=0.7, CHCl
3). infrared spectra (coating method): 2961,1612,1585,1516,1158cm
-1. nuclear magnetic resonance map:
1H NMR: δ 7.88 (d, J=7.5Hz, 2H), 7.68-7.73 (m, 1H), 7.55 (t, J=7.5Hz, 2H), 7.35 (d, J=8.7Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 5.18-5.29 (m, 1H), 3.95 (d, J=8.4Hz, 1H), 3.79 (s, 3H), 1.27 (s, 9H).
19FNMR: δ-102.84 (dd, J=236.3,11.0Hz, 1F) ,-108.10 (dd, J=236.3,15.8Hz, 1F).
13C NMR: δ 160.44,135.20,133.42,130.39,129.98,129.18,125.19,121.07 (t, J=291.2Hz), 114.30,60.13 (dd, J=23.8,19.6Hz), 57.24,55.21, the 22.34. mass spectrum (EI, m/z, %): 433 (M
++ 2,6.3), 170 (100.0). ultimate analysis: theoretical value C
19H
24F
2NO
4S
2: C, 52.88; H, 5.37; N, 3.25; Experimental value: C, 52.76; H, 5.46; N, 3.09.
3b (1.9mmol) is dissolved in the 5ml methyl alcohol, is cooled to 0 ℃.Add 5.0mmol sodium (perhaps sodium amalgam) then.0 ℃ is stirred down 30min, ethyl acetate extraction then, anhydrous magnesium sulfate drying.Except that after desolvating, add 5ml methyl alcohol and 0.5N concentrated hydrochloric acid.Stirring at room 20min.Except that after desolvating, promptly obtain optically pure 4b, productive rate 96%.Compound 4b characterization data is as follows: white solid.Specific rotation: [α]
D 25=26.3 (c=0.7, CH
3OH). infrared spectra (KBr): 2949,1585,1521,1508,1259,1186cm
-1. nuclear magnetic resonance map:
1H NMR (CD
3OD): δ 7.46 (d, J=8.7Hz, 2H), 7.06 (d, J=8.7Hz, 2H), 6.30 (td, J=53.7,2.7Hz, 1H), 4.73-4.83 (m, 1H), 3.85 (s, 3H).
19F NMR (CD
3OD): δ-124.67 (ddd, J=285.3,53.0,9.6Hz, 1F) ,-131.52 (ddd, J=285.3,53.5,17.4Hz, 1F).
13C NMR (CD
3OD): δ 163.15,131.44,123.46 (t, J=5.7Hz), 116.35,115.99 (t, J=244.5Hz), 57.40 (t, J=22.7Hz), the 56.45. mass spectrum (ESI, m/z): 188.2 (M
+-Cl). high resolution mass spec (ESI) theoretical value C
9H
12F
2NO (M
+-Cl): 188.08814; Experimental value: 188.0882.
Embodiment 3
The preparation method is identical with embodiment 1 and 2.Compound 3c characterization data is as follows: white solid .Mp135-137 ℃. specific rotation [α]
D 25=-17.8 (c=0.6, CHCl
3). infrared spectra (film): 2962,1584,1494,1448,1349,1158cm
-1. nuclear magnetic resonance map:
1H NMR: δ 7.90 (d, J=7.8Hz, 2H), 7.74 (t, J=7.5Hz, 1H), 7.59 (t, J=7.8Hz, 2H), 7.34-7.41 (m, 4H), 5.22-5.34 (m, 1H), 4.06 (d, J=8.7Hz, 1H), 1.29 (s, 9H).
19F NMR: δ-102.49 (dd, J=238.0,9.6Hz, 1F) ,-108.88 (dd, J=238.0,18.0Hz, 1F).
13C NMR: δ 135.68,135.39,133.08,131.74,130.40,130.07,129.27,129.06,120.71 (t, J=292.5Hz), 60.12 (dd, J=24.2,19.7Hz), and 57.42, the 22.29. mass spectrum: (ESI, m/z): 436 (M
++ 1). ultimate analysis: theoretical value C
18H
20ClF
2NO
3S
2: C, 49.59; H, 4.62; N, 3.21; Experimental value: C, 49.57; H, 4.72; N, 3.04.
Compound 4c characterization data is as follows: white solid.Specific rotation: [α]
D 25=24.9 (c=0.5, CH
3OH). infrared spectra (KBr): 2858,1590,1535,1497,1396,1123,1057cm
-1. nuclear magnetic resonance map:
1H NMR (CD
3OD): δ 7.53 (s, 4H), 6.34 (td, J=53.4,3.0Hz, 1H), 4.83-4.93 (m, 1H).
19F NMR (CD
3OD): δ-125.15 (ddd, J=287.0,53.8,10.7Hz, 1F) ,-131.85 (ddd, J=287.0,56.4,16.0Hz, 1F).
13C NMR (CD
3OD): δ 137.81,131.53,130.93,130.38 (d, J=4.4Hz), 115.50 (t, J=244.5Hz), 56.96 (t, J=23.1Hz). mass spectrum (ESI, m/z): 192.1 (M
+-Cl). high resolution mass spectrum (ESI): theoretical value C
8H
9ClF
2N (M
+-Cl): 192.03860; Experimental value: 192.03889.
Embodiment 4
The preparation method is identical with embodiment 1 and 2.Compound 3d characterization data is as follows: white solid.Fusing point 125-126 ℃. specific rotation: [α]
D 25=-5.6 (c=1.0, CHCl
3). infrared spectra (film): 3062,2961,1601,1583,1448,1347,1157,1085cm
-1. nuclear magnetic resonance map:
1H NMR: δ 7.78-7.93 (m, 6H), 7.60-7.66 (m, 1H), 7.45-7.52 (m, 5H), 5.41-5.53 (m, 1H), 4.17 (d, J=8.4Hz, 1H), 1.29 (s, 9H).
19F NMR: δ-102.70 (dd, J=238.5,10.1Hz, 1F) ,-108.74 (dd, J=238.5,15.5Hz, 1F).
13C NMR: δ 135.18,133.62,133.25,132.97,130.54,130.36,129.11,128.94,128.80,128.30,127.62,126.89,126.49,125.16,121.15 (t, J=292.3Hz), 60.82 (dd, J=24.1,19.4Hz), 57.34,22.34. mass spectrum (EI, m/z, %): 454 (M
++ 3,1.4), 190 (100.0). high resolution mass spectrum (ESI): theoretical value C
22H
23F
2NO
3S
2Na (M
++ Na): 474.0979625; Experimental value: 474.0979510.
Compound 4d characterization data is as follows: white solid.Specific rotation: [α]
D 25=32.9 (c=0.6, CH
3OH). infrared spectra (KBr): 1588,1519,1403,1051cm
-1. nuclear magnetic resonance map:
1H NMR (CD
3OD): δ 7.92-8.07 (m, 4H), 7.57-7.62 (m, 3H), 6.45 (td, J=53.2,2.7Hz, 1H), 4.96-5.08 (m, 1H).
19F NMR (CD
3OD): δ-123.91 (dd, J=286.7,53.0Hz, 1F) ,-130.31 (ddd, J=286.7,55.2,15.7Hz, 1F).
13C NMR (CD
3OD): δ 135.52,134.80,134.74,129.97,129.59,129.14,128.89,128.82,128.46,125.95,115.77 (t, J=244.7Hz), 57.76 (t, J=23.0Hz). mass spectrum (ESI, m/z): 208.1 (M
+-Cl). high resolution mass spectrum (ESI): theoretical value C
8H
9ClF
2N (M
+-Cl): 208.09323; Experimental value: 208.09304.
Embodiment 5
The preparation method is identical with embodiment 1 and 2.Compound 3e characterization data is as follows: white solid. and fusing point 136-138 ℃. specific rotation [α]
D 25:=-45.5 (c=1.0, CHCl
3). infrared spectra (film): 2962,1584,1500,1475,1449,1349,1191cm
-1. nucleus magnetic resonance:
1H NMR: δ 7.92 (d, J=7.8Hz, 2H), 7.72-7.78 (m, 1H), 7.60 (t, J=7.8Hz, 2H), 7.45 (d, J=1.8Hz, 1H), 6.56 (d, J=3.3Hz, 1H), 6.39-6.40 (m, 1H), 5.31-5.43 (m, 1H), 4.06 (d, J=9.3Hz, 1H), 1.29 (s, 9H).
19F NMR: δ-103.55 (dd, J=237.7,13.5Hz, 1F) ,-107.54 (dd, J=237.7,16.0Hz, 1F).
13C NMR: δ 145.77,143.94,135.32,133.25,130.42,129.27,120.15 (t, J=293.5Hz), 111.34,110.85,57.40,55.24 (dd, J=24.5,21.8Hz), the 22.36. mass spectrum (EI, m/z, %): 392 (M
++ 1,0.8), 57 (100.0). ultimate analysis: theoretical value C
16H
19F
2NO
4S
2: C, 49.09; H, 4.89; N, 3.58; Experimental value: C, 49.05; H, 5.18; N, 3.45.
Compound 4e characterization data is as follows: white solid.Specific rotation: [α]
D 25=9.2 (c=0.55, CH
3OH). infrared spectra (KBr): 2865,1589,1501,1401,1150,1092cm
-1. nucleus magnetic resonance:
1H NMR (CD
3OD): δ 7.69-7.70 (m, 1H), 6.73 (d, J=3.6Hz, 1H), 6.54-6.56 (m, 1H), 6.40 (td, J=53.4,3.3Hz, 1H), 5.01-5.10 (m, 1H).
19F NMR (CD
3OD): δ-125.74 (ddd, J=288.2,53.2,9.0Hz, 1F) ,-130.35 (ddd, J=288.2,54.7,16.3Hz, 1F).
13C NMR (CD
3OD): δ 146.74,144.91 (t, J=3.2Hz), 114.54 (t, J=244.7Hz), 113.86,112.76,51.77 (dd, J=26.4,22.8Hz). mass spectrum (ESI, m/z): 148.2 (M
+-Cl). high resolution mass spectrum (EI): theoretical value C
6H
7F
2N (M
+-HCl): 147.04957; Experimental value 147.05016.
Embodiment 6
The preparation method is identical with embodiment 1 and 2.Compound 3f characterization data is as follows: white solid. and fusing point 112-114 ℃. specific rotation [α]
D 25=-25.0 (c=0.8, CHCl
3). infrared spectra (film): 2965,1584,1449,1337,1164cm
-1. nucleus magnetic resonance:
1H NMR: δ 7.96 (d, J=7.8Hz, 2H), 7.76 (t, J=7.5Hz, 1H), 7.62 (t, J=7.8Hz, 2H), 3.93-4.08 (m, 1H), 3.43 (d, J=8.7Hz, 1H), 2.17-2.28 (m, 1H), 1.76-1.92 (m, 1H), 1.26 (s, 9H), 1.17 (t, J=7.2Hz, 3H).
19F NMR: δ-103.93 (dd, J=231.5,10.1Hz, 1F), 105.00 (dd, J=231.5,12.0Hz, 1F).
13C NMR: δ 135.35,133.57,130.46,129.32,121.77 (t, J=292.5Hz), 60.69 (t, J=20.4Hz), 57.13,23.92 (d, J=3.4Hz), 22.58, the 10.27. mass spectrum (EI, m/z%): 354 (M
++ 1,4.3), 57 (100.0). high resolution mass spectrum (MALDI): theoretical value C
14H
22NO
3S
2(M
++ 1): 354.10037; Experimental value: 354.1007.
Compound 4f characterization data is as follows: white solid.Specific rotation: [α]
D 25=-19.7 (c=0.2, CH
3COCH
3). infrared spectra (KBr): 2887,1601,1525,1462,1106cm
-1. nucleus magnetic resonance:
1HNMR (CD
3OD): δ 6.22 (td, J=53.7,2.4Hz, 1H), 3.51-3.66 (m, 1H), 1.67-1.95 (m, 2H), 1.12 (t, J=7.5Hz, 3H).
19F NMR (CD
3OD): δ-127.84 (ddd, J=286.5,53.5,7.6Hz, 1F) ,-134.33 (ddd, J=286.5,54.7,16.4Hz, 1F).
13C NMR (CD
3OD): δ 115.74 (t, J=241.8Hz), 55.36 (t, J=20.6Hz), 22.00, the 9.90. mass spectrum (ESI, m/z): 110.3 (M
+-Cl). high resolution mass spectrum (EI): theoretical value C
4H
9F
2N (M
+-HCl): 109.07031; Experimental value 109.07066.
Embodiment 7
The preparation method is identical with embodiment 1 and 2.Compound 3g characterization data is as follows: white solid. and fusing point 120-121 ℃. specific rotation: [α]
D 25=-54.3 (c=0.9, CHCl
3). infrared spectra (film): 2964,1584,1475,1449,1345,1164cm
-1. nucleus magnetic resonance:
1H NMR: δ 7.96 (d, J=7.5Hz, 2H), 7.76 (t, J=7.5Hz, 1H), 7.62 (t, J=7.5Hz, 2H), and 4.01-4.15 (m, 1H), 3.43 (d, J=9.9Hz, 1H), 2.56-2.63 (m, 1H), 1.27 (s, 9H), 1.22 (d, J=6.9Hz, 3H), 1.06 (d, J=6.9Hz, 3H).
19FNMR: δ-101.63 (dd, J=241.9,13.2Hz, 1F) ,-104.59 (dd, J=241.9,12.4Hz, 1F).
13C NMR: δ 135.26,133.43,130.44,129.24,122.29 (t, J=291.2Hz), 62.53 (t, J=20.0Hz), 57.21,28.12,22.54,20.48, the 16.65. mass spectrum: (EI, m/z, %): 311 (M
+-57,21.01), 57 (100.0). ultimate analysis: theoretical value C
15H
23F
2NO
3S
2: C, 49.03; H, 6.31; N, 3.81; Experimental value: C, 49.20; H, 6.29; N, 3.63.
Compound 4g characterization data is as follows: white solid.Specific rotation: [α]
D 25=-26.3 (c=0.3, CH
3COCH
3). infrared (KBr): 2948,1683,1594,1515,1040cm
-1. nucleus magnetic resonance:
1H NMR (CD
3OD): δ 6.33 (td, J=54.0,1.8Hz, 1H), 3.40-3.53 (m, 1H), 2.05-2.17 (m, 1H), 1.13 (dd, J=6.6,2.1Hz, 6H).
19F NMR (CD
3OD): δ-125.38 (ddd, J=288.2,51.8,6.4Hz, 1F) ,-133.42 (ddd, J=288.2,55.5,11.8Hz, 1F).
13C NMR (CD
3OD, 500M): δ 115.46 (t, J=241.8Hz), 59.13 (t, J=19.2Hz), 28.77 (d, J=4.8Hz), the 18.89. mass spectrum (ESI, m/z): 124.3 (M
+-Cl). high resolution mass spectrum (EI): theoretical value C
5H
11F
2N (M
+-HCl): 123.08596; Experimental value 123.08658.
Embodiment 8
The preparation method is identical with embodiment 1 and 2.Compound 3h characterization data is as follows: white solid. and fusing point 105-106 ℃. specific rotation: [α]
D 25=-9.7 (c=1.0, CHCl
3). infrared (film): 1584,1475,1449,1347,1160,1080cm
-1. nucleus magnetic resonance:
1H NMR: δ 7.91 (d, J=7.5Hz, 2H), 7.70-7.76 (m, 1H), 7.59 (td, J=7.5,1.2Hz, 2H), 3.89-4.01 (m, 1H), 3.78 (d, J=9.9Hz, 1H), 1.31 (s, 9H), 1.20 (s, 9H).
19F NMR: δ-90.86 (d, J=236.0Hz, 1F) ,-104.33 (dd, J=2360,16.1Hz, 1F).
13C NMR: δ 135.06,133.81,130.36,129.14,122.84 (t, J=291.0Hz), 65.94 (t, J=21.2Hz), 57.58,35.33,27.88 (t, J=2.2Hz), the 22.79. mass spectrum (EI, m/z, %): 382 (M
++ 1,10.8), 57 (100.0). ultimate analysis: theoretical value C
16H
25F
2NO
3S
2: C, 50.37; H, 6.61; N, 3.67; Experimental value: C, 50.50; H, 6.55; N, 3.52.
Compound 4h characterization data is as follows: white solid.Specific rotation: [α]
D 25=-17.6 (c=0.2, CH
3COCH
3). infrared (KBr): 2943,1596,1526,1482,1076cm
-1. nucleus magnetic resonance:
1H NMR (CD
3OD): δ 6.39 (td, J=52.0,1.5Hz, 1H), 3.41-3.52 (m, 1H), 1.12 (s, 9H).
19FNMR (CD
3OD): δ-121.05 (dd, J=290.4,51.6Hz, 1F) ,-129.62 (ddd, J=290.4,52.7,3.9Hz, 1F).
13C NMR (CD
3OD, 400M): δ 115.51 (t, J=241.1Hz), 62.40 (t, J=18.1Hz), 33.39 (d, J=5.4Hz), 27.12 (d, J=1.3Hz). mass spectrum MS:(EI, m/z, %): 138.1 (M
+-Cl). high distribution mass spectrum (EI): theoretical value C
5H
10F
2N (M
+-HCl-CH
3) 122.07813; Experimental value: 122.07835.
Embodiment 9
The preparation of compound 5: under the nitrogen protection condition, difluoromethyl ammonium salt 4a (19mg, 0.1mmol), Benzoyl chloride (0.2mmol), triethylamine (0.3mmol) be dissolved in the 2mL dioxane, and stirred 3 hours at 40 ℃.Go down to desolventize and obtain compound 5 (26g), productive rate 100% in vacuum with silica gel column chromatography.Characterization data is as follows:
White solid, fusing point 153-155 ℃.Chiral high performance liquid chromatography: (Diacel Chiralpak AD-H post, 80: 20 hexane/2-propyl alcohol; 0.7mL/min; 254nm; (S)-9, r
t=9.1min, (R)-9, r
t=14.8min); Specific rotation: [α]
D 25=-10.8. (c=0.45, CHCl
3); IR (film): 3314,3066,1640,1580,1533,1490cm
-1. nucleus magnetic resonance:
1H NMR: δ 7.80-7.84 (m, 2H), 7.37-7.57 (m, 8H), 6.74 (d, J=7.5Hz, 1H), 6.14 (td, J=55.2,2.1Hz, 1H), 5.55-5.68 (m, 1H).
19F NMR: δ-125.26 (ddd, J=282.1,56.5,16.4Hz, 1F) ,-128.50 (ddd, J=282.1,53.6,13.8Hz, 1F).
13C NMR (CDCl
3): δ 167.20,134.11 (d, J=4.0Hz), 133.66,132.05,129.00,128.84,128.72,127.86,127.53,114.77 (t, J=244.0Hz), 55.18 (t, J=21.6Hz). mass spectrum (EI, m/z, %): 262 (M
++ 1,0.6), 105 (100.0). ultimate analysis: theoretical value C
15H
13F
2NO:C, 68.96; H, 5.02; N, 5.36; Experimental value: C, 69.25; H, 5.14; N, 5.30.
Claims (6)
1
2, optical purity alpha-difluoromethyl amine as claimed in claim 1 and derivative thereof is characterized in that having following structural formula:
3, the preparation method of a kind of optical purity alpha-difluoromethyl amine as claimed in claim 1 and derivative thereof is characterized in that adopting following (1), the three kinds of method preparations in (1) and (2) and (1)～(3)
(1), in organic solvent, during-78 ℃～room temperature and in the presence of the alkali, with difluoromethyl phenyl sulfone, (R) or (S)-reaction of tertiary butyl sulfoxide group aldimine O.1～1 hour, obtain structural formula and be
Compound; The mol ratio of described difluoromethyl phenyl sulfone, (R) or (S)-tertiary butyl sulfoxide group aldimine and alkali is 1: 0.8～1: 1～5; Described alkali is hmds lithium (LHMDS), butyllithium, potassium tert.-butoxide, diisobutyl amine lithium (LDA) or sodium hydroxide; Or/and
(2), with structural formula be
Compound in organic solvent, 0 ℃～room temperature and the time, C
1～4Pure and mild monovalence metal exists down, and reaction generated optical purity alpha-difluoromethyl amine in 0.1～1 hour
Described monovalence metal is potassium or sodium; Or/and
(3), reaction product is at C
1～4Alcoholic solution and excessive in hydrochloric acid reaction 0.1～1 hour generates the hydrochloride of optically pure alpha-difluoromethyl amine.
4, the preparation method of optical purity alpha-difluoromethyl amine as claimed in claim 1 and derivative thereof is characterized in that described organic solvent is ether, toluene, methylene dichloride, acetonitrile or tetrahydrofuran (THF).
5, the purposes of optical purity alpha-difluoromethyl amine as claimed in claim 1 and derivative thereof, it is synthetic to it is characterized in that being used for chiral drug.
6, the purposes of optical purity alpha-difluoromethyl amine as claimed in claim 1 and derivative thereof is characterized in that described optical purity alpha-difluoromethyl amine is used for synthetic fluorinated amino acids, polypeptide or enzyme inhibitors.
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