CN109867686A - A method of preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives - Google Patents
A method of preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives Download PDFInfo
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Abstract
The present invention relates to a kind of methods for preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives, using alkynyl amide and substituted isoxazole and water as raw material, under the conditions of acid is existing, construct to obtain by [5+2] cycloaddition.Alkynyl amide can synthesize to obtain by simple alkynes, paratoluensulfonyl chloride and benzylamine, and subsequent cycloaddition reaction is easy to operate, is swift in response, and not need to carry out multistep reaction.
Description
Technical field
The present invention relates to a kind of methods for preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives.
Background technique
Explore the important topic (document 1:a) that effectively practical synthesis bridge heptatomic ring always is Synthetic Organic Chemistry
M.H.Filippini,J.Rodriguez,Chem.Rev.1999,99,27；b)W.Y.Zhao,Chem.Rev.2010,110,
1706；c)M.Ruiz,P.Lopez-Alvarado,G.Giorgi,J.C.Menendez,Chem.Soc.Rev.2011,40,
3445；d)M.Presset,Y.Coquerel,J.Rodriguez,Chem.Rev.2013,113,525.).Cycloaddition reaction because
Simple and Atom economy is considered as current synthesizing heterocyclic or carbocyclic compound most efficient method.Two ring of oxazole [3,2,
1] octane is widely present in many natural products and drug molecule.(document 2:a) T.Sekine, N.Fukasawa,
Y.Kashiwagi,N.Ruangrungsi,I.Murakoshi,Chem.Pharm.Bull.1994,42,1360；b)
R.Innocenti,E.Lenci,G.Menchi,A.Pupi,A.Trabocchi,Bioorg.Med.Chem.2017,25,5077；
c)A.Trabocchi,C.Mannino,F.Machetti,F.De Bernardis,S.Arancia,R.Cauda,
A.Cassone,A.Guarna,J.Med.Chem.2010,53,2502.).Currently, for this kind of compound there is also some
Effective synthetic method, but be mostly by intramolecular cyclization, it is seldom for intermolecular cycloaddition reaction.(document 3:a)
M.Flores,D.Diez,Synlett 2014,25,1643；For examples,see:b)P.Szolcsanyi,
T.Gracza,Chem.Commun.2005,3948；c)F.Machetti,I.Bucelli,G.Indiani,C.O.Kappe,
A.Guarna,J.Comb.Chem.2007,9,454；d)A.Dieguez-Vazquez,C.C.Tzschucke,W.Y.Lam,
S.V.Ley,Angew.Chem.Int.Ed.2008,47,209；e)E.M.Beccalli,G.Broggini,S.Gazzola,
A.Mazza, Org.Biomol.Chem.2014,12,6767.) this patent provides and a kind of prepares 6,8- dioxy -2- azabicyclic
[3,2,1] method of oct-2-ene derivatives.
Summary of the invention
The present invention provides a kind of methods for preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives.
To achieve the above object, technical scheme is as follows:
A kind of method preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives,
With water form cycloaddition reaction can occur for alkynyl amide (1) and substituted isoxazole (2) under the action of an acid, obtain
To 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives (3), reaction equation is as follows:
Wherein R, R1、R2、R3、R4、R5Respectively C1-C8 alkyl, C1-C8 alkoxyl, naphthalene, furyl, phenyl, benzyl or
The phenyl or benzyl replaced by 1-5 following radicals, following radicals be C1-C8 alkyl, C1-C8 alkoxyl ,-F ,-Cl ,-Br or-
NO2。
Specific steps are as follows: sequentially adding alkynyl amide (1) under inert gas argon gas or nitrogen atmosphere, being substituted
Isoxazole (2), water and solvent, acid is added at a certain temperature, contact plate monitors reaction system, after reaction, with volume point
The pentane solution of several 10% triethylamines is quenched, and with Rotary Evaporators solvent evaporated, obtained solid is 6,8- dioxy -2- azepine
Two rings [3,2,1] oct-2-ene derivatives (3).
Acid is trifluoromethanesulfonic acid (TfOH), bis trifluoromethyl sulfimide (Tf2NH), Trimethylsilyl trifluoromethanesulfonate
(TMSOTf), dibenzenesulfonimide, trifluoromethanesulfanhydride anhydride (Tf2O), acetic acid (HOAc), trifluoroacetic acid (TFA), benzene sulfonic acid, to first
One or more of base benzene sulfonic acid or benzoic acid.
The dosage of acid is the 1-50mol% of substrate alkynyl amide (1).
Solvent is acetonitrile, methylene chloride, dichloroethanes, chloroform, N,N-dimethylformamide, toluene, ether, four chlorinations
One of carbon, 1,4- dioxane or two kinds or more.
The molar concentration of alkynyl amide (1) is 0.1-20mol/L, and reaction temperature is -30-40 DEG C, reaction time 2-48h.
The molar ratio of substituted isoxazole (2) and alkynyl amide (1) is 0.5-2, and water and the molar ratio of alkynyl amide (1) are
0.5-2。
After reaction, with Rotary Evaporators solvent evaporated, 25-40 DEG C of temperature, obtained solid dissolves in methylene chloride, on
Sample carries out silica gel column chromatography, obtains product.
The present invention has the following advantages:
Used catalyst is acid, transition-metal catalyst expensive, that separation is difficult is not needed, in bioactive molecule
There is potential purposes in synthesis；
Oxygen bridge heptatomic ring is constructed with the cycloaddition reaction of intermolecular three component for the first time；Isoxazole is for the first time with pentaatomic shape
Formula participates in acid catalyzed cycloaddition reaction；
In the presence of water, hydrolysis generation amide generally can all occur for alkynyl amide, and for the first time with the shape of oxygen bridge in the system
Formula participates in reaction；
The operation of 6,8- dioxy -2- azabicyclic [3,2, the 1] oct-2-ene derivatives (3) generated is simple, only passes through
Product just can be obtained in simple single step reaction, does not need to carry out multistep reaction.
Detailed description of the invention
Fig. 1 is the nucleus magnetic hydrogen spectrum of 1 product 3a of embodiment；
The nuclear-magnetism carbon that Fig. 2 is 1 product 3a of embodiment is composed；
Fig. 3 is the nucleus magnetic hydrogen spectrum of 2 product 3b of embodiment；
The nuclear-magnetism carbon that Fig. 4 is 2 product 3b of embodiment is composed；
Fig. 5 is the nucleus magnetic hydrogen spectrum of 3 product 3c of embodiment；
The nuclear-magnetism carbon that Fig. 6 is 3 product 3c of embodiment is composed；
Fig. 7 is the nucleus magnetic hydrogen spectrum of 4 product 3d of embodiment；
The nuclear-magnetism carbon that Fig. 8 is 4 product 3d of embodiment is composed；
Fig. 9 is the nucleus magnetic hydrogen spectrum of 5 product 3e of embodiment；
The nuclear-magnetism carbon that Figure 10 is 5 product 3e of embodiment is composed；
Figure 11 is the nucleus magnetic hydrogen spectrum of 6 product 3f of embodiment；
The nuclear-magnetism carbon that Figure 12 is 6 product 3f of embodiment is composed；
Figure 13 is the nucleus magnetic hydrogen spectrum of 7 product 3g of embodiment；
The nuclear-magnetism carbon that Figure 14 is 7 product 3g of embodiment is composed；
Figure 15 is the nucleus magnetic hydrogen spectrum of 8 product 3h of embodiment；
The nuclear-magnetism carbon that Figure 16 is 8 product 3h of embodiment is composed；
Figure 17 is the nucleus magnetic hydrogen spectrum of 9 product 3i of embodiment；
The nuclear-magnetism carbon that Figure 18 is 9 product 3i of embodiment is composed；
Figure 19 is the nucleus magnetic hydrogen spectrum of 10 product 3j of embodiment；
The nuclear-magnetism carbon that Figure 20 is 10 product 3j of embodiment is composed；
Figure 21 is the nucleus magnetic hydrogen spectrum of 11 product 3k of embodiment；
The nuclear-magnetism carbon that Figure 22 is 11 product 3k of embodiment is composed；
Figure 23 is the nucleus magnetic hydrogen spectrum of 12 product 3l of embodiment；
The nuclear-magnetism carbon that Figure 24 is 12 product 3l of embodiment is composed；
Figure 25 is the monocrystalline spectrogram of 5 product 3e of embodiment.
Specific embodiment
(1) reference literature (Zhang, Y.S.；Hsung,R.P.；Tracey,M.R.；Kurtz,K.M.Org.Lett.,
2004,6,1151-1154.), synthesize alkynyl amide (formula 1) through three steps: the first step, benzene sulfonyl chloride and benzylamine are anti-in methylene chloride
Secondary amine should be generated；In acetone, silver nitrate is catalyst, obtains alkynes bromine by second step, alkynes and NBS；Third step, alkynes bromine and second level
Amine makees catalyst in cupric sulfate pentahydrate, and toluene makees solvent, and Anhydrous potassium carbonate obtains ynamine under conditions of doing alkali.
Reaction equation 1
Reaction equation 2
Reaction equation 3
The synthesis step of 1. alkynyl amide of formula
(2) isoxazole replaced is commercially available.
(3) 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives (3) are prepared
The synthesis step of 2. oxygen bridge heptatomic ring product of formula
Reaction equation is shown in formula 2, and in argon atmosphere glove box, the alkynyl amide of 0.3mmol is added into 10mL reaction tube
(1), 2mL solvent is then added in the substituted isoxazole (2) of 0.2mmol, and acid is added, reacts 6-24h at -20-0 DEG C.Reaction
After rotate solvent after, solid carry out silica gel column chromatography, obtain 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene and spread out
Biological (3).
(4) nuclear magnetic data is designated as TMS both from Bruker 400MHz nuclear-magnetism in nucleus magnetic hydrogen spectrum, and hydrogen composes CDCl3For
7.26ppm, carbon compose CDCl3For 77.16ppm, hydrogen composes DMSO-d6For 2.50ppm, carbon composes DMSO-d6For 39.52ppm, hydrogen spectrum
Acetone-d6For 2.05ppm, carbon composes Acetone-d6For 206.26ppm.
Embodiment 1
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1a (0.3mmol, 108.3mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -10 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3a (66.5mg, 70%).
The characterize data of 3a is as follows:
1H NMR(400MHz,CDCl3) δ 7.65 (d, J=8.0Hz, 2H), 7.28-7.12 (m, 12H), 6.06 (s, 1H),
4.87-4.66 (m, 2H), 2.52 (d, J=18.0Hz, 1H), 2.42-2.32 (m, 4H), 1.75 (s, 3H), 1.57 (s, 3H)
(spectrogram is shown in Fig. 1)
13C NMR(100MHz,CDCl3)δ168.9,143.0,139.1,135.9,129.9,128.8,128.6,128.4,
127.90,127.87,127.6,126.8,126.3,103.9,103.8,85.4,49.7,44 .1,25.4,23.6,21.6. (spectrum
Figure is shown in Fig. 2)
Embodiment 2
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1b (0.3mmol, 112.5mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -10 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3b (63.2mg, 64%).
The characterization number of 3b is as follows:
1H NMR(400MHz,CDCl3) δ 7.62 (d, J=8.2Hz, 2H), 7.27-7.24 (m, 2H), 7.18-7.15 (m,
3H), 7.12 (d, J=8.1Hz, 2H), 7.08-7.01 (m, 4H), 5.99 (s, 1H), 4.83-4.70 (m, 2H), 2.52 (d, J=
18.0Hz, 1H), 2.41-2.31 (m, 4H), 2.31 (s, 3H), 1.77 (s, 3H), 1.57 (s, 3H) (spectrogram is shown in Fig. 3)
13C NMR(100MHz,CDCl3)δ168.8,142.9,139.3,139.2,137.3,132.7,128.8,128.7,
128.5,128.4,127.9,126.8,126.3,103.9,103.7,85.5,49.7,44.1,25.5,23.7,21.6,21.3.
(spectrogram is shown in Fig. 4)
Embodiment 3
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1c (0.3mmol, 117.3mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -10 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3c (45.0mg, 45%).
The characterization number of 3c is as follows:
1H NMR(400MHz,Acetone-d6) δ 7.76 (d, J=8.1Hz, 2H), 7.36-7.27 (m, 4H), 7.24-
7.11 (m, 5H), 6.80 (d, J=8.6Hz, 2H), 6.01 (s, 1H), 4.74 (d, J=16.2Hz, 1H), 4.65 (d, J=
16.2Hz, 1H), 3.77 (s, 3H), 2.60 (d, J=18.2Hz, 1H), 2.49 (d, J=18.3Hz, 1H), 2.40 (s, 3H),
1.78 (s, 3H), 1.49 (s, 3H) (spectrogram is shown in Fig. 5)
13C NMR(100MHz,Acetone-d6)δ170.8,160.3,144.1,140.8,140.3,129.8,129.6,
129.2,129.1,128.7,128.6,127.5,114.0,104.8,104.7,85.7,55.6,50.6,44.4,25.6,
(23.8,21.6. spectrogram is shown in Fig. 6)
Embodiment 4
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1d (0.3mmol, 118.5mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -10 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3d (67.7mg, 66%).
The characterization number of 3d is as follows:
1H NMR(400MHz,CDCl3) δ 7.68 (d, J=8.3Hz, 2H), 7.31-7.23 (m, 2H), 7.22-7.12 (m,
7H), 7.10 (d, J=8.4Hz, 2H), 6.03 (s, 1H), 4.80-4.65 (m, 2H), 2.52 (d, J=18.0Hz, 1H), 2.38
(s, 3H), 2.33 (d, J=18.0Hz, 1H), 1.76 (s, 3H), 1.56 (s, 3H) (spectrogram is shown in Fig. 7)
13C NMR(100MHz,CDCl3)δ169.1,143.2,139.0,138.9,134.4,133.3,128.9,128.6,
128.04,127.97,127.6,127.0,104.0,103.7,84.7,49.8,44.0,25. (spectrogram is shown in figure to 5,23.6,21.7.
8)
Embodiment 5
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1e (0.3mmol, 110.1mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -20 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3e (70.7mg, 73%).
The characterization number of 3e is as follows
1H NMR(400MHz,DMSO-d6) δ 7.71 (d, J=8.4Hz, 2H), 7.44 (dd, J=4.9,1.4Hz, 1H),
7.37-7.28 (m, 4H), 7.27-7.18 (m, 3H), 6.96-6.86 (m, 2H), 5.96 (s, 1H), 4.69 (d, J=16.7Hz,
1H), 4.58 (d, J=16.7Hz, 1H), 2.62 (d, J=18.4Hz, 1H), 2.42-2.32 (m, 4H), 1.81 (s, 3H), 1.38
(s, 3H) (spectrogram is shown in Fig. 9)
13C NMR(100MHz,DMSO-d6)δ171.5,143.3,139.4,138.2,138.0,129.1,128.0,
127.7,127.5,127.1,126.7,126.6,126.2,103.9,102.4,81.4,49.4,43.2,25.4,23.0,
21.0. (spectrogram is shown in Figure 10)
Embodiment 6
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1f (0.3mmol, 87.3mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -20 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3f (43.7mg, 54%).
The characterization number of 3f is as follows
1H NMR(400MHz,Acetone-d6)δ7.40–7.34(m,3H),7.28–7.17(m,3H),6.93–6.88(m,
2H), 6.01 (s, 1H), 4.81-4.68 (m, 2H), 3.08 (s, 3H), 2.78 (d, J=18.3Hz, 1H), 2.52 (d, J=
18.3Hz, 1H), 2.00 (s, 3H), 1.53 (s, 3H) (spectrogram is shown in Figure 11)
13C NMR(100MHz,Acetone-d6)δ172.3,140.3,139.5,128.8,128.7,127.60,
127.58,126.9,126.7,104.9,103.7,82.8,49.6,44.3,43.4,26.0 23.7. (spectrogram is shown in 12)
Embodiment 7
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1g (0.3mmol, 105.9mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -20 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3g (70.1mg, 75%).
The characterization number of 3g is as follows
1H NMR(400MHz,Acetone-d6) δ 7.87 (d, J=7.4Hz, 2H), 7.60 (t, J=7.4Hz, 1H), 7.50
(t, J=7.7Hz, 2H), 7.41-7.31 (m, 3H), 7.25-7.16 (m, 3H), 6.96-6.87 (m, 2H), 6.11 (s, 1H),
4.85 (d, J=16.4Hz, 1H), 4.72 (d, J=16.4Hz, 1H), 2.60 (d, J=18.3,1H), 2.40 (d, J=
18.3Hz, 1H), 1.86 (s, 3H), 1.43 (s, 3H) (spectrogram is shown in Figure 13)
13C NMR(100MHz,Acetone-d6)δ172.0,143.1,140.6,139.6,133.4,129.3,129.1,
128.9,128.6,127.9,127.6,127.0,126.8,105.0,104.0,83.3,50. 6,44.3,25.9,23.6. (spectrum
Figure is shown in Figure 14)
Embodiment 8
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1h (0.3mmol, 114.3mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -20 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3h (71.7mg, 72%).
The characterization number of 3h is as follows
1H NMR(400MHz,Acetone-d6) δ 7.83 (d, J=8.4Hz, 2H), 7.48 (d, J=6.8Hz, 1H),
7.38-7.31 (m, 3H), 7.07-7.00 (m, 3H), 6.95-6.88 (m, 2H), 6.05 (s, 1H), 4.76 (d, J=17.4Hz,
1H), 4.60 (d, J=17.4Hz, 1H), 2.59 (d, J=18.2Hz, 1H), 2.42 (s, 3H), 2.37 (d, J=18.2Hz,
1H), 2.17 (s, 3H), 1.80 (s, 3H), 1.46 (s, 3H) (spectrogram is shown in 15)
13C NMR(100MHz,Acetone-d6)δ171.9,144.3,139.8,139.4,138.6,134.8,130.2,
129.8,129.4,128.33,128.32,127.1,127.0,126.8,126.3,105.1,103.8,83.4,48.3,44.1,
(25.9,23.7,21.5,19.2. spectrogram is shown in 16)
Embodiment 9
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1i (0.3mmol, 114.3mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -20 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3i (65.1mg, 66%).
The characterization number of 3i is as follows
1H NMR(400MHz,Acetone-d6) δ 7.74 (d, J=8.3Hz, 2H), 7.34-7.27 (m, 3H), 7.25 (d, J
=7.9Hz, 2H), 7.02 (d, J=7.9Hz, 2H), 6.94-6.88 (m, 2H), 6.12 (s, 1H), 4.76 (d, J=16.3Hz,
1H), 4.64 (d, J=16.3Hz, 1H), 2.60 (d, J=18.3Hz, 1H), 2.43-2.36 (m, 4H), 2.28 (s, 3H), 1.88
(s, 3H), 1.44 (s, 3H) (spectrogram is shown in Figure 17)
13C NMR(100MHz,Acetone-d6)δ171.8,144.1,140.3,139.7,137.7,136.8,129.8,
129.27,129.25,129.0,127.9,126.9,126.7,105.0,104.0,83.3,50.3,44.3,25.9,23.7,
(21.5,21.2. spectrogram is shown in Figure 18)
Embodiment 10
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1j (0.3mmol, 133.5mg), the different evil of 3,5- dimethyl
Azoles 2a (0.2mmol, 20 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) is eventually adding bis-trifluoromethylsulfoandimide
(15mol%, 8.4mg) reacts 6h at -20 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction,
After 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3j (80.5mg, 72%).
The characterization number of 3j is as follows
1H NMR(400MHz,Acetone-d6) δ 7.83 (d, J=7.8Hz, 2H), 7.38-7.32 (m, 5H), 7.32-
7.26 (m, 2H), 7.02-6.97 (m, 1H), 6.95-6.90 (m, 1H), 6.22 (s, 1H), 4.72 (d, J=16.4Hz, 1H),
4.57 (d, J=16.5Hz, 1H), 2.60 (d, J=18.3Hz, 1H), 2.46-2.38 (m, 4H), 1.88 (s, 3H), 1.44 (s,
3H) (spectrogram is shown in Figure 19)
13C NMR(100MHz,Acetone-d6)δ172.3,144.4,140.1,139.5,139.4,131.4,130.9,
129.9,129.2,127.8,126.9,126.74,120.70,104.9,103.8,83.1,50.0,44.1,25.9,23.5,
21.4. (spectrogram is shown in Figure 20)
Embodiment 11
Under an argon atmosphere, it is sequentially added into 10mL reaction tube 1e (0.3mmol, 110.1mg), chloromethyl isoxazole 2b
(0.2mmol, 27 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL), be eventually adding bis-trifluoromethylsulfoandimide (15mol%,
8.4mg), 6h is reacted at -20 DEG C.It is quenched after reaction with the pentane solution of 10% triethylamine of volume fraction, 30 DEG C of revolvings
After falling solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3k (41.6mg, 40%).
The characterization number of 3k is as follows
1H NMR(400MHz,Acetone-d6) δ 7.78 (d, J=8.4Hz, 2H), 7.45-7.28 (m, 5H), 7.26-
7.11 (m, 3H), 7.02-6.92 (m, 1H), 6.94-6.82 (m, 1H), 6.19 (s, 1H), 4.81 (d, J=16.5Hz, 1H),
4.63 (d, J=16.5Hz, 1H), 4.12 (d, J=12.9Hz, 1H), 4.05 (d, J=12.9Hz, 1H), 2.77 (d, J=
18.4Hz, 1H), 2.64 (d, J=18.4Hz, 1H), 2.41 (s, 3H), 1.51 (s, 3H) (spectrogram is shown in Figure 21)
13C NMR(100MHz,Acetone-d6)δ169.6,144.4,140.3,139.7,138.6,129.9,129.2,
128.8,128.6,127.9,127.5,127.0,126.8,105.2,104.0,83.3,50.8,47.4,40.7,23.5,21.4
(spectrogram is shown in Figure 22)
Embodiment 12
Under an argon atmosphere, 1e (0.3mmol, 110.1mg), 4- chloromethyl -3,5- are sequentially added into 10mL reaction tube
Dimethyl isoxazole 2c (0.2mmol, 29 μ L), water (0.2mmol, 3.6 μ L), DCE (2mL) are eventually adding double trifluoro methylsulfonyls
Imines (15mol%, 8.4mg) reacts 6h at -20 DEG C.The pentane solution of 10% triethylamine of volume fraction is used after reaction
It is quenched, after 30 DEG C rotate solvent, solid carries out silica gel column chromatography, obtains oxygen bridge heptatomic ring product 3l (58.1mg, 59%).
The characterization number of 3l is as follows
1H NMR(400MHz,Acetone-d6) δ 7.74 (d, J=8.3Hz, 2H), 7.43-7.27 (m, 5H), 7.27-
7.13 (m, 3H), 6.95-6.84 (m, 2H), 6.21 (s, 1H), 5.70 (s, 1H), 5.65 (s, 1H), 4.84 (d, J=16.4Hz,
1H), 4.71 (d, J=16.4Hz, 1H), 2.40 (s, 3H), 2.06 (s, 3H), 1.64 (s, 3H) (spectrogram is shown in Figure 23).
13C NMR(100MHz,Acetone-d6)δ166.9,144.2,141.3,140.5,140.0,139.2,129.8,
129.1,128.8,128.6,128.0,127.5,127.0,126.9,115.8,105.1,104.2,82.2,50.7,21.4,
20.1. (spectrogram is shown in Figure 24).
Claims (8)
1. a kind of method for preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives, it is characterised in that:
With water form cycloaddition reaction occurs for alkynyl amide (1) and substituted isoxazole (2) under the action of an acid, obtains 6,8- bis-
Oxygen -2- azabicyclic [3,2,1] oct-2-ene derivatives (3), reaction equation is as follows:
Wherein R, R1、R2、R3、R4、R5Respectively C1-C8 alkyl, C1-C8 alkoxyl, naphthalene, furyl, phenyl, benzyl or by 1-
The phenyl or benzyl that 5 following radicals replace, following radicals are C1-C8 alkyl, C1-C8 alkoxyl ,-F ,-Cl ,-Br or-NO2。
2. the method for preparation 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives described in accordance with the claim 1,
It is characterized in that: specific steps are as follows:
Under inert gas argon gas or nitrogen atmosphere, alkynyl amide (1), substituted isoxazole (2), water and solvent are sequentially added,
It is eventually adding acid, contact plate monitoring reaction system is quenched with the pentane solution of 10% triethylamine of volume fraction after reaction,
With Rotary Evaporators solvent evaporated, obtained solid is 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives (3).
3. 6 are prepared according to claim 2, the method for 8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives,
It is characterized in that:
Acid is trifluoromethanesulfonic acid (TfOH), bis trifluoromethyl sulfimide (Tf2NH), Trimethylsilyl trifluoromethanesulfonate
(TMSOTf), dibenzenesulfonimide, trifluoromethanesulfanhydride anhydride (Tf2O), acetic acid (HOAc), trifluoroacetic acid (TFA), benzene sulfonic acid, to first
One or more of base benzene sulfonic acid or benzoic acid.
4. according to the side described in claim 2 or 3 for preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives
Method, it is characterised in that:
The dosage of acid is the 1-50mol% of substrate alkynyl amide (1).
5. the side according to claim 1 or 2 for preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives
Method, it is characterised in that:
The solvent is acetonitrile, methylene chloride, dichloroethanes, chloroform, N,N-dimethylformamide, toluene, ether, carbon tetrachloride
Or one of 1,4- dioxane or two kinds or more.
6. the side according to claim 1 or 2 for preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives
Method, it is characterised in that:
The molar concentration of the alkynyl amide (1) is 0.1-20mol/L, and reaction temperature is -30-40 DEG C, reaction time 2-48h.
7. the side according to claim 1 or 2 for preparing 6,8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives
Method, it is characterised in that:
The molar ratio of substituted isoxazole (2) and alkynyl amide (1) is 0.5-2, and water and the molar ratio of alkynyl amide (1) are 0.5-2.
8. 6 are prepared according to claim 2, the method for 8- dioxy -2- azabicyclic [3,2,1] oct-2-ene derivatives,
It is characterized in that:
After reaction, with Rotary Evaporators solvent evaporated, 25-40 DEG C of temperature, obtained solid is dissolved in methylene chloride, and loading carries out
Silica gel column chromatography obtains product.
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Non-Patent Citations (3)
| Title |
|---|
| ANDREA TRABOCCHI, ET AL: "Identification of Inhibitors of Drug-Resistant Candida albicans Strains from a Library of Bicyclic Peptidomimetic Compounds", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| RICCARDO INNOCENTI, ET AL: "Design and synthesis of bicyclic acetals as Beta Secretase (BACE1) inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 宋志光等: "光活性内酯(+)-2,8,8-三甲基-6-氧代-7-氧-二环[3,2,1]-辛-2-烯的水解及产物的氧化", 《中国化学会第四届有机化学学术会议》 * |
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