CN103102329A - Synthetic method of 2,3-dihydro-[1,4]-benzothiazine compound - Google Patents
Synthetic method of 2,3-dihydro-[1,4]-benzothiazine compound Download PDFInfo
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Abstract
The invention discloses a synthetic method of 2,3-dihydro-[1,4]-benzothiazine compound. The method comprises the steps of: by taking 2-iodine-N-(2-iodoethyl) aniline derivant as a reaction material and taking Na2S2O3 as a vulcanization reagent, reacting in a reaction solvent in the presence of a metal palladium catalyst to obtain multisubstituted 2,3-dihydro-[1,4]-benzothiazine compound. The synthetic method is mild in reaction condition, available in material, cheap in material, simple to react and operate and high in yield, provides a key skeleton structure for synthesis of a plurality of natural products and medicines, and can be widely applied to industrial mass production.
Description
Technical field
The present invention is specifically related to a kind of synthetic method for preparing 2,3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds, belongs to organic compound process application technical field.
Background technology
2,3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is an extremely important pharmaceutical-chemical intermediate of class, has very high using value.At a lot of medicines and bioactive molecules, as rufloxacin, DHBT-NE-1, MX-68, HeronamycinA etc. have the skeleton of 2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine, and are as follows:
It is synthetic that 2,3-dihydro-traditional method of [Isosorbide-5-Nitrae]-benzo thiazides compounds is mainly to prepare by the near amino thiophenols compounds.But in this method, the near amino thiophenols of replacement preparation is more difficult, and the adaptability of substrate is extensive not, and not only taste is larger, and is seriously polluted, and is easy to oxidizedly, and the application of this method is restricted.
Summary of the invention
The present invention overcomes the above defective of prior art, has proposed to innovation first the novel method of a kind of simple efficient preparation 2,3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds, by using metal palladium catalyst, with Na
2S
2O
3Be sulfuration reagent, the conversion of realization response efficiently.
As with as shown in following formula (I), the present invention utilizes 2-iodo-N-(2-iodine ethyl) aniline (substrate 1) and Na
2S
2O
3(substrate 2), reacts in reaction solvent under the effect of metal palladium catalyst as starting raw material, synthetic 2,3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds.
In the present invention, R is hydrogen, halogen, heteroatoms, alkyl or heterocycle; X is NTs, NNs or C; Y is I, Br, Cl, OMs or OTs.Preferably, R is F,, Cl, Br, alkane, aromatic hydrocarbons.X is NTs, C.Y is Cl, Br, I.In the present invention, R, X, Y include but are not limited to above-mentioned group, and for example, R can also be multi-substituent, the aromatic ring of replacement and heterocycle, all kinds of side chain.
In the present invention, described starting raw material 2-iodo-N-(2-iodine ethyl) amino benzenes derivates and sulfuration reagent N a
2S
2O
3Usage ratio be 1: 1-1: 5.Preferably, both usage ratio are 1: 5.
In the present invention, with Na
2S
2O
3Be sulfuration reagent.
In the present invention, described palladium catalyst is Pd (OAc)
2, PdCl
2, Pd (TFA)
2, Pd (dba)
2, Pd
2(dba)
3, PdCl
2(PPh
3)
2, PdCl
2(dppf) or PdCl
2(dppp).Preferably, described palladium catalyst is PdCl
2(dppf).The consumption of described catalyzer is the 1-10mol% of raw material 2-iodo-N-(2-iodine ethyl) aniline (substrate 1).Preferably, described catalyst levels is 10mol%.
In the present invention, described part is PPh3, PtBu3, tricyclohexyl phosphine, three furyl phosphines, dppm (1, two (diphenylphosphine) methane of 1-), dppe[1, two (diphenylphosphine) ethane of 2-], dppp[1, two (diphenylphosphine) propane of 3-], dppb[1, two (diphenyl phosphine) butane of 4-], dppf[1,1 '-two (diphenylphosphine) ferrocene] or binap[2,2 '-two diphenyl phosphines-1,1 '-dinaphthalene].Preferably, described part is dppf[1,1 '-two (diphenylphosphine) ferrocene].Described part consumption is the 1-5mol% of 2-iodo-N-(2-iodine ethyl) aniline (substrate 1).Preferably, described part consumption is 5mol%.
In the present invention, described additive is TBAC (tetrabutylammonium chloride), TBAB (Tetrabutyl amonium bromide) or TBAI (tetrabutylammonium iodide).Preferably, described additive is TBAB (Tetrabutyl amonium bromide).Described additive comprises but is not limited to abovely, can also be 18-hat-6,15-hat-5.
In the present invention, described alkali is K
2CO
3, Cs
2CO
3, K
3PO
4, TEA (triethylamine) or DMAP (4, DMAP).Preferably, described alkali is Cs
2CO
3Described alkali including, but not limited to more than, can also be NaOH, KOH, Na
2CO
3, DBU (bicyclic amidine).
In the present invention, described reaction solvent is toluene, DMA, 1,2-ethylene dichloride, THF or acetonitrile.Described reaction solvent including, but not limited to more than, can also be chlorobenzene, Isosorbide-5-Nitrae-dioxane, DMF, DMSO.
In the present invention, described building-up reactions is to carry out at 80-150 ℃ of temperature.Preferably, be to react at 150 ℃ of temperature.
Particularly, building-up reactions of the present invention is in reaction flask A, and 2-iodo-N-(2-iodine ethyl) aniline (substrate 1, X mmol) is dissolved in Z mL reaction solvent, under room temperature, adds successively sulfuration reagent N a
2S
2O
3(Y mmol), catalyst P dCl
2(dppf) (W mmol%), part dppf (V mmol%), additive TBAB (U mol%), alkali Cs
2CO
3(s mol%).Reaction was reacted 6 hours under 80-150 ℃.With TLC detection reaction process.React complete after, directly add silica gel, be spin-dried for column chromatography, separate to obtain target product 2.
The advantage of building-up reactions of the present invention comprises: each raw material that synthetic method of the present invention is used is very simple, is the industrialization commodity, be simple and easy to, wide material sources, and performance is highly stable, does not need special preservation condition.The various metal catalysts that the present invention is used and part are all also the commercialization reagent of commonly using, and be highly stable.Use the Sulfothiorine of colorless and odorless as sulfuration reagent, have the characteristic that cost is low, productive rate is high, technique is simple, pollution is few, fully applicable to scale operation.Traditional method of synthetic 2,3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is generally to realize with the near amino thiophenols that replaces.But because the near amino thiophenols preparation that replaces is more difficult, and taste is larger, and easily oxidized, aftertreatment is difficult, and is seriously polluted, and suitability for industrialized production is caused very large restriction.The present invention is take 2-iodo-N-(the 2-iodine ethyl) amino benzenes derivates of easy preparation as reaction raw materials, with the Na of colorless and odorless
2S
2O
3Salt is as sulfuration reagent, and under the metal palladium catalyst effect, reaction obtains polysubstituted 2,3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds.Operation is fairly simple, and reaction conditions is gentle, and productive rate is higher, is fit to large-scale industrial production.The present invention synthesize 2,3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is the core skeleton of a lot of natural products and active drug molecule, the reaction scheme of innovative design of the present invention provides an extensively applicable preparation method for synthetic this compounds.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope that do not deviate from inventive concept, variation and advantage that those skilled in the art can expect all are included in the present invention, and take appending claims as protection domain.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content of mentioning specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.The given data of following examples comprise concrete operations and reaction conditions and product.Product purity is identified by nuclear-magnetism.
Embodiment 1
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) under nitrogen atmosphere.Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a (10%).R
f=0.7 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.39 (s, 3H), 2.86 (t, J=5.6Hz, 2H), 3.97 (t, J=6.0Hz, 2H), 7.03-7.10 (m, 2H), 7.19 (d, J=8.4Hz, 2H), 7.46 (d, J=8.4Hz, 2H), 7.65-7.68 (m, 1H);
13C NMR (100MHz, CDCl
3): δ 143.9,137.2, and 134.2,129.7,128.0,127.9,127.0,126.7,126.4,124.5,44.5,25.6,21.6; IR (neat) 3005,1714,1422,1360,1221,1164,1092,1068,913,836,814,762,729,686,670,651cm
-1.MS (EI) m/z305 (M
+); The HRMS calculated value is C
15H
15NO
2S
2305.0544 actual value is 305.0545.
Embodiment 2
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 15%.Analytical data is with embodiment 1.
Embodiment 3
4-tosyl group-2,3-dihydro-11,4]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 39%.Analytical data is with embodiment 1.
Embodiment 4
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAI (0.03mmol, 11.1mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 8%.Analytical data is with embodiment 1.
Embodiment 5
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAC (0.03mmol, 8.3mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 10%.Analytical data is with embodiment 1.
Embodiment 6
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dpPf) (0.01mmol, 7.3mg), dppf (0.005mmol, 2.8mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 78%.Analytical data is with embodiment 1.
Embodiment 7
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), Pd (OAc)
2(0.01mmol, 2.2mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 55%.Analytical data is with embodiment 1.
Embodiment 8
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), Pd (dba)
2(0.01mmol, 5.7mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 63%.Analytical data is with embodiment 1.
Embodiment 9
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(PPh
3)
2(0.01mmol, 7.0mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 50%.Analytical data is with embodiment 1.
Embodiment 10
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), TFP (0.01mmol, 2.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 25%.Analytical data is with embodiment 1.
Embodiment 11
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Sphos (0.01mmol, 4.1mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 21%.Analytical data is with embodiment 1.
Embodiment 12
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), PCy
3(0.01mmol, 4.1mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (200 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 11%.Analytical data is with embodiment 1.
Embodiment 13
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (100 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 95%.Analytical data is with embodiment 1.
Embodiment 14
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (100 μ L).Reaction system is heated to 80 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 55%.Analytical data is with embodiment 1.
Embodiment 15
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1aa (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (100 μ L).Reaction system is heated to 110 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate 75%.Analytical data is with embodiment 1.
Embodiment 16
4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1ab-1ae (0.1mmol, 52.8mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (100 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2a, productive rate is respectively 99%, 94%, and 76%, 53%.Analytical data is with embodiment 1.
Embodiment 17
7-fluoro-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
In the test-tube reaction device of 25mL, use nitrogen exchange of air 3 times.With substrate 1b (0.1mmol, 54.5mg), PdCl
2(dppf) (0.01mmol, 7.3mg), Cs
2CO
3(0.3mmol, 98mg), Na
2S
2O
3(0.5mmol, 124mg), TBAB (0.03mmol, 9.7mg) is weighed into reaction tubes successively, finds time to change nitrogen, and adds MeCN (2mL) and H under nitrogen atmosphere
2O (100 μ L).Reaction system is heated to 150 ℃, reacted 8 hours.The TCL detection reaction is cooled to room temperature with system after finishing.Directly add silica gel, be spin-dried for column chromatography, obtain white solid 2b, productive rate is 94%.R
f=0.6 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.40 (s, 3H), 2.82 (t, J=5.6Hz, 2H), 3.95 (t, J=6.0Hz, 2H), 7.76-6.83 (m, 2H), 7.21 (d, J=8.0Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.64 (dd, J=9.2Hz, 5.6Hz, 1H);
19F NMR (400MHz, CDCl
3): δ-114.7;
13C NMR (100MHz, CDCl
3): δ 161.7,159.2, and 144.1,136.9,129.8,127.0,113.0,112.8,111.9,111.7,44.4,25.0,21.6; IR (neat) 3005,1714,1422,1363,1221,1093,904,785cm
-1.MS (EI) m/z323 (M
+); The HRMS calculated value is C
15H
14FNO
2S
2323,0450, actual value is 323.0451.
Embodiment 18
7-chloro-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 90%.R
f=0.5 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.40 (s, 3H), 2.81 (t, J=5.6Hz, 2H), 3.95 (t, J=5.6Hz, 2H), 7.03-7.06 (m, 2H), 7.2 (d, J=8.0Hz, 2H), 7.46 (d, J=8.4Hz, 2H), 7.60-7.62 (m, 1H);
13C NMR (100MHz, CDCl
3): δ 144.2,136.9, and 132.6,131.9,129.9,129.7,129.1,127.0,126.1,124.6,44.3,25.2,21.6; IR (neat) 3004,2886,2838,2363,1713,1472,1422,1362,1222,1166,1091,1064,1019,903,815,781,687,663,611cm
-1.MS (EI) m/z339 (M
+); The HRMS calculated value is C
15H
14 35ClNO
2S
2339.0155 actual value is 339.0157.
Embodiment 19
7-bromo-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 46%.R
f=0.5 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.41 (s, 3H), 2.81 (t, J=5.2Hz, 2H), 3.95 (t, J=5.6Hz, 2H), 7.18-7.24 (m, 4H), 7.46 (d, J=8.4Hz, 2H), 7.54 (d, J=9.6Hz, 2H);
13C-NMR (100MHz, CDCl
3): δ 144.2,136.9, and 133.2,130.1,129.9,129.4,127.5,127.0,119.7,44.3,25.3,21.6; IR (neat) 3005,2361,1714,1421,1361,1222,1165,1092,1014,902cm
-1.MS (EI) m/z383 (M
+); The HRMS calculated value is C
15H
14 79BrNO
2S
2382.9649 actual value is 382.9651.
Embodiment 20
7-methyl-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 87%.R
f=0.6 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.27 (s, 3H), 2.39 (s, 3H), (2.82 t, J=5.6Hz, 2H), 3.96 (t, J=6.0Hz, 2H), 6.86-6.91 (m, 2H), (7.20 d, J=8.0Hz, 2H), (7.46 d, J=8.0Hz, 2H), (7.55 d, J=8.4Hz, 2H);
13C-NMR (100MHz, CDCl
3): δ 143.8,137.3, and 136.4,131.5,129.7,127.9,127.4,127.1,126.8,125.5,44.6,25.3,21.6,20.8; IR (neat) 3006,2360,1714,1421,1362,1222,1165,1092,903,678cm
-1.MS (EI) m/z319 (M
+); The HRMS calculated value is C
16H
17NO
2S
2319.0701 actual value is 319.0703.
Embodiment 21
The 7-tertiary butyl-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 88%.R
f=0.7 (ethyl acetate: sherwood oil=10: 1);
1H NMR (400MHz, CDCl
3): δ 1.28 (s, 9H), 2.40 (s, 3H), (2.83 t, J=5.6Hz, 2H), 3.95 (t, J=5.6Hz, 2H), 7.04 (d, J=2.0Hz, H), 7.10-7.13 (m, 1H), 7.21 (d, J=8.4Hz, 2H), 7.48 (d, J=8.4Hz, 2H), 7.56 (d, J=8.4Hz, 2H);
13C-NMR (100MHz, CDCl
3): δ 149.5,143.8, and 137.4,131.5,129.7,127.5,127.1,126.8,123.3,122.1,44.6,34.5,31.1,25.6,21.6; IR (neat) 3006,1715,1421,1362,1222,1092,904,836cm
-1.MS (EI) m/z361 (M
+); The HRMS calculated value is C
19H
23NO
2S
2361.1170 actual value is 361,1172.
Embodiment 22
7-cyano group-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 72%.R
f=0.4 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.35 (s, 3H), 2.80 (t, J=5.2Hz, 2H), 3.91 (t, J=5.6Hz, 2H), 7.18-7.20 (m, 2H), 7.26-7.28 (m, 2H), (7.42 d, J=8.4Hz, 2H), 7.71 (d, J=8.4Hz, 2H);
13C-NMR (100MHz, CDCl
3): δ 144.7,138.1, and 136.6,130.4,130.1,129.2,127.7,127.6,126.9,118.0,109.7,44.1,25.1,21.6; IR (neat) 3006,1714,1421,1362,1222,1092,903,785cm
-1.MS (EI) m/z330 (M
+); The HRMS calculated value is C
16H
14N
2O
2S
2330.0497 actual value is 330.0495.
Embodiment 23
7-nitro-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 45%.R
f=0.4 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.42 (s, 3H), 2.91 (t, J=5.6Hz, 2H), 4.0 (t, J=5.6Hz, 2H), (2.27 d, J=6.8Hz, 2H), 2.52 (d, J=8.8Hz, 2H), 7.84-7.86 (m, 1H), 7.90-7.92 (m, 1H), (7.98 d, J=2.4Hz, 1H);
13C-NMR (100MHz, CDCl
3): δ 145.0,144.8, and 139.7,136.5,130.2,129.0,127.5,127.0,122.2,119.2,44.2,25.5,21.6; IR (neat) 3004,2884,2836,1714,1421,1362,1222,1093,902,806cm
-1.MS (EI) m/z350 (M
+); The HRMS calculated value is C
15H
14N
2O
4S
2350.0395 actual value is 350.0396.
Embodiment 24
7-ethanoyl-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 50%.R
f=0.6 (ethyl acetate: sherwood oil=3: 1);
1H NMR (400MHz, CDCl
3): δ 2.40 (s, 3H), 2.56 (s, 3H), (2.87 t, J=6.4Hz, 2H), 4.00 (t, J=5.2Hz, 2H), 7.23 (d, J=8.0Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.63-7.68 (m, 2H), (7.78 d, J=8.4Hz, 2H);
13C-NMR (100MHz, CDCl
3): δ 196.8,144.4, and 138.3,136.9,134.5,130.0,127.9,127.3,127.1,127.0,124.4,44.4,26.5,25.6,21.6; IR (neat) 3005,2253,1750,1714,1421,1362,1222,1092,918,734,647cm
-1.MS (EI) m/z347 (M
+); The HRMS calculated value is C
17H
17NO
3S
2347.0650 actual value is 347.0647.
Embodiment 25
7-(1-ethanol based)-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 75%.R
f=0.3 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 1.47 (d, J=6.4Hz, 3H), 2.40 (s, 3H), (2.84 t, J=5.6Hz, 2H), 3.96 (t, J=6.0Hz, 2H), 4.83 (t, J=6.4Hz, 1H), 7.06-7.09 (m, 2H), 7.21 (d, J=8.0Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 7.63 (d, J=8.4Hz, 2H);
13C-NMR (100MHz, CDCl
3): δ 144.1,144.0, and 137.3,133.3,129.8,128.1,127.8,127.1,123.5,121.8,69.7,44.6,25.6,25.2,21.6; IR (neat) 3008,2361,1761,1705,1486,1421,1362,1260,1228,1163,1091,1018,916,855,804,708,679,649cm
-1.MS (EI) m/z349 (M
+); The HRMS calculated value is C
17H
19NO
3S
2349.0806 actual value is 349.0807.
Embodiment 26
7-(2-methyl-1,3-dithiolan-2-yl]-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 62%.R
f=0.4 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.11 (s, 3H), 2.40 (s, 3H), (2.83 t, J=5.2Hz, 2H), 3.34-3.39 (m, 4H), 3.95 (t, J=5.6Hz, 2H), (7.22 d, J=8.0Hz, 2H), 7.42-7.46 (m, 2H), 7.49 (d, J=8.0Hz, 2H), (7.58 d, J=8.4Hz, 2H);
13C-NMR (100MHz, CDCl
3): δ 144.3,144.0, and 137.4,133.1,129.9,127.4,127.1,127.0,125.0,123.5,67.8,44.5,40.5,33.6,25.6,21.7; IR (neat) 3003,2362,1750,1712,1597,1482,1421,1360,1221,1163,1090,920,816,710,686,654cm
-1.MS (EI) m/z423 (M
+); The HRMS calculated value is C
19H
21NO
2S
4423.0455 actual value is 423.0452.
Embodiment 27
8-(methoxyl group)-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 82%.R
f=0.6 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.39 (s, 3H), 2.83 (t, J=6.0Hz, 2H), 3.80 (s, 3H), 3.97 (t, J=5.6Hz, 2H), 6.71-6.74 (m, 1H), (6.94 d, J=8.8Hz, 1H), 7.21 (d, J=8.0Hz, 2H), 7.29 (d, J=2.8Hz, 1H), 7.48 (d, J=8.4Hz, 2H)
13C NMR (100MHz, CDCl
3): δ 156.8,143.9, and 137.1,135.0,129.7,127.4,127.0,118.7,114.2,112.8,55.5,45.1,25.6,21.6; IR (neat) 2926,2852,1713,1600,1568,1484,1440,1353,1289,1236,1199,1161,1091,1067,1033,922,853,811,784,751,708,688,659cm
-1.MS (EI) m/z335 (M
+); The HRMS calculated value is C
16H
17NO
3S
2335.0650 actual value is 335.0649.
Embodiment 28
7-fluoro-8-methyl-4-tosyl group-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 72%.R
f=0.4 (ethyl acetate: sherwood oil=5: 1);
1H NMR (400MHz, CDCl
3): δ 2.42 (s, 3H), 2.51 (s, 3H), 2.82 (ddd, J=1.2Hz, 5.2Hz, 12.0Hz, 1H), 2.98 (td, J=6.8Hz, 11.6Hz, 1H), 3.21 (ddd, J=14.4Hz, 11.2Hz, 5.2Hz, 1H), 4.53 (ddd, J=14.8Hz, 6.8Hz, 2.8Hz, 1H), 6.66 (dd, J=8.4Hz, 2.8Hz, 1H), 6.78 (dd, J=9.2Hz, 2.8Hz, 1H), (7.20 d, J=8.4Hz, 2H), (7.51 d, J=8.4Hz, 2H);
19F NMR (400MHz, CDCl
3): δ 114.2;
13C NMR (100MHz, CDCl
3): δ 161.9,159.4,144.0,142.0 (d, J=36.0Hz), 137.2,134.0 (d, J=38.4Hz), 129.5,127.7,114.7 (d, J=87.6Hz), 111.6 (d, J=98.8Hz), 46.0,26.6,21.6,19.9; IR (neat) 3004,2360,2254,1714,1420,1363,1223,1164,1092,916,734,648cm
-1.MS (EI) m/z337 (M
+); The HRMS calculated value is C
16H
16FNO
2S
2337.0607 actual value is 337.0604.
Embodiment 29
4-nitro alkylsulfonyl-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 66%.R
f=0.3 (ethyl acetate: sherwood oil=5: 1);
1HNMR (400MHz, CDCl
3): δ 2.93 (t, J=5.6Hz, 2H), 4.05 (t, J=6.0Hz, 2H), (7.07-7.09 m, 1H), 7.15-7.18 (m, 2H), 7.67-7.69 (m, 1H), (7.72 d, J=8.8Hz, 2H), 8.24 (d, J=8.8Hz, 2H);
13C-NMR (100MHz, CDCl
3): δ 150.2,145.7, and 133.4,129.2,128.3,127.4,127.3,125.3,124.3,45.5,26.6; IR (neat) 2930,1715,1535,1438,1363,1277,1223,1171,1090,1011,838,742,616cm
-1.MS (EI) m/z336 (M
+); The HRMS calculated value is C
14H
12N
2O
4S
2336.0239 actual value is 336.0241.
Embodiment 30
4-nitro alkylsulfonyl-2,3-dihydro-[Isosorbide-5-Nitrae]-benzothiazine synthetic:
Operation is with embodiment 13, and productive rate is 50%.R
f=0.6 (ethyl acetate: sherwood oil=10: 1);
1H NMR (400MHz, CDCl
3): δ 2.39 (s, 3H), 2.67 (t, J=5.2Hz, 2H), 3.76 (s, 2H), 4.60 (s, 2H), 7.20-7.22 (m, 3H), 7.26-7.31 (m, 1H), 7.47-7.50 (m, 2H), 7.53 (d, J=8.4Hz, 2H);
13C-NMR (100MHz, CDCl
3): δ 142.3,141.0, and 135.9,135.0,131.9,129.4,128.6,127.2,127.1,126.0,52.9,51.3,32.8,20.5; IR (neat) 3005,1715,1421,1363,1261,1222,1093,904,805em
-1.MS (EI) m/z319 (M
+); The HRMS calculated value is C
16H
17NO
2S
2319.0701 actual value is 319.0703.
Embodiment 31
Synthesizing of 2,3-dihydrobenzo thiophene:
Operation is with embodiment 13, and productive rate is 70%.R
f=0.6 (sherwood oil);
1H NMR (400MHz, CDCl
3): δ 3.26-3.30 (m, 2H), 3.34-3.38 (m, 2H), 7.00-7.03 (m, 1H), 7.12 (t, J=7.2Hz, 1H), 7.18-7.26 (m, 2H);
13CNMR (100MHz, CDCl
3): δ 141.4,140.0, and 127.3,124.4,124.0,122.1,36.2,33.3; IR (neat) 3727,3704,3628,3003,2946,1717,1686,1600,1440,1361,1220,1165,1109,1066,1007,867,697,615cm
-1.MS (EI) m/z136 (M
+); The HRMS calculated value is C
8H
8S136.0347, actual value is 136.0348.
Embodiment 32
Synthesizing of sulfo-chroman:
Operation is with embodiment 13, and productive rate is 65%.R
f=0.6 (sherwood oil);
1H NMR (400MHz, CDCl
3): δ 1.43 (s, 3H), 2.09-2.15 (m, 2H), 2.81 (t, J=6.0Hz, 2H), 3.03 (t, J=6.0Hz, 2H), 6.97-7.10 (m, 4H);
13CNMR (100MHz, CDCl
3): δ 133.8,130.0, and 126.5,126.4,125.5,123.9,30.28,27.6,22.8; IR (neat) 3633,3062,2926,2854,1478,1439,1296,1263,1157,1076,1049,1018,912,862,801,744cm
-1.MS (EI) m/z150 (M
+); The HRMS calculated value is C
9H
10S150.0503, actual value is 150.0502.
Claims (9)
1. one kind 2, the synthetic method of 3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is characterized in that, take 2-iodo-N-(2-iodine ethyl) amino benzenes derivates as reaction raw materials, with Na
2S
2O
3For sulfuration reagent, under the palladium catalyst effect, reaction obtains 2,3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds in reaction solvent; Reaction process is suc as formula shown in (I);
Wherein, R is hydrogen, halogen, heteroatoms, alkyl, heterocycle; X is NTs, NNs, C; Y is I, Br, Cl, OMs, OTs.
2. as claimed in claim 12, the synthetic method of 3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is characterized in that, described palladium catalyst is Pd (OAc)
2, PdCl
2, Pd (TFA)
2, Pd (dba)
2, Pd
2(dba)
3, PdCl
2(dppf) or PdCl
2(dppp); The consumption of described catalyzer is 1-10%.
3. as claimed in claim 12, the synthetic method of 3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is characterized in that described part is PPh
3, PtBu
3, tricyclohexyl phosphine, three furyl phosphines, 1, two (diphenylphosphine) methane, 1 of 1-, two (diphenylphosphine) ethane, 1 of 2-, two (diphenylphosphine) propane, 1 of 3-, two (diphenyl phosphine) butane, 1 of 4-, 1 '-two (diphenylphosphine) ferrocene or 2,2 '-two diphenyl phosphines-1,1 '-dinaphthalene; Described part consumption is 1-5%.
4. as claimed in claim 12, the synthetic method of 3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is characterized in that, described additive is tetrabutylammonium chloride, Tetrabutyl amonium bromide or tetrabutylammonium iodide.
5. as claimed in claim 12, the synthetic method of 3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is characterized in that, described alkali is K
2CO
3, Cs
2CO
3, K
3PO
4, triethylamine or 4, DMAP.
6. as claimed in claim 12, the synthetic method of 3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is characterized in that, described reaction solvent is toluene, DMA, 1,2-ethylene dichloride, THF or acetonitrile.
7. as claimed in claim 12, the synthetic method of 3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is characterized in that described building-up reactions is carried out at 80-150 ℃.
8. as claimed in claim 12, the synthetic method of 3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds is characterized in that, described reaction raw materials 2-iodo-N-(2-iodine ethyl) amino benzenes derivates and described sulfuration reagent N a
2S
2O
3Ratio be 1: 1-1: 5.
As claim 1 synthetic method prepare 2,3-dihydro-[Isosorbide-5-Nitrae]-benzo thiazides compounds.
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