CN106146388A - A kind of 3 phenylpiperidine derivative synthesizing process - Google Patents
A kind of 3 phenylpiperidine derivative synthesizing process Download PDFInfo
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- CN106146388A CN106146388A CN201610518448.1A CN201610518448A CN106146388A CN 106146388 A CN106146388 A CN 106146388A CN 201610518448 A CN201610518448 A CN 201610518448A CN 106146388 A CN106146388 A CN 106146388A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
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Abstract
The invention discloses a kind of 3 phenylpiperidine derivative synthesizing process, it is in reaction dissolvent, with N pi-allyl 4 methoxyl group N vinylbenzenesulfonamide compound and substituted iodophenyl compounds as reaction raw materials, under metal palladium catalyst effect, reaction obtains polysubstituted 3 Phenylpiperidine analog derivatives.Reaction condition of the present invention is gentle, raw material is easy to get inexpensive, operation is simple, productivity is higher, and the route of synthesis substrate is ripe, does not has particular/special requirement, method is simple, workable, provide the framing structure of key for multiclass drug molecule and efficiently synthesizing of natural product, and industrial-scale production can be widely used in.
Description
Technical field
Present invention relates particularly to a kind of synthetic method preparing 3-phenyl-piperidines analog derivative, belong to organic compound work
Skill applied technical field.
Background technology
3-phenyl-piperidines compounds is an extremely important pharmaceutical-chemical intermediate of class, has the highest using value.
At a lot of medicines and bioactive molecule, such as preclamol, mesulegine, dexetimide etc., all there is 3-phenyl-piperazine
The skeleton of pyridine, as follows:
Fig. 1 contains medicine and the bioactive molecule of 3-phenyl-piperidines skeleton.
Summary of the invention
The present invention overcomes the upper vacancy of technology in the past, the most innovatively proposes a kind of simple efficiently preparation 3-phenyl-piperazine
The method of pyridine compounds, by using metal palladium catalyst, can realize the conversion of reaction efficiently.
Fig. 2 formula (I)
As shown in above formula (I), the present invention utilize iodobenzene derivant (substrate 1) as initiation material, at metal palladium catalyst
Under effect, react in reaction dissolvent, synthesize 3-phenyl-piperidines compounds compounds.
In the present invention, R1It is hydrogen, halogen, hetero atom, acyl group；PG is Ts.Preferably, R1It is F, Cl, nitro, acetyl group.PG
It is Ts.In the present invention, R1, R2Include but are not limited to above-mentioned group, such as, R1, R2Can also is that multi-substituent, all kinds of
Side chain.
In the present invention, described palladium catalyst is PdCl2(dppf)、Pd (PPh3)4、PdCl2(PPh3)2.Preferably, described
Palladium catalyst is Pd (PPh3)4.The consumption of described catalyst is the 1-10 mol% of raw material 1.Preferably, the use of described catalyst
Amount is 10 mol%.
In the present invention, described part is dppf(1,1 '-bis-(diphenylphosphine) ferrocene), PPh3.The consumption of described part
20-30 mol% for raw material 1.Preferably, described part consumption is 20 mol%.
In the present invention, described alkali is Cy2NMe(N-methyldicyclohexylamine), Et3N(triethylamine), DIPEA(N, N-diisopropyl
Base ethamine).Preferably, described alkali is Cy2NMe。
In the present invention, described reaction dissolvent is toluene, dimethylbenzene or dioxane.Preferably, it is to enter in dioxane
Row reaction.Described reaction dissolvent including, but not limited to more than, it is also possible to be dimethylbenzene, Isosorbide-5-Nitrae-dioxane, DMF, DMSO.
In the present invention, described synthetic reaction is at 50-100oCarry out at a temperature of C.Preferably, it is 80oEnter at a temperature of C
Row reaction.
Specifically, synthetic reaction of the present invention is in reaction bulb A, iodobenzene derivant (substrate 1, X mmol) is dissolved in
In Z mL reaction dissolvent, under room temperature, it is sequentially added into N-pi-allyl-4-methoxyl group-N-vinylbenzenesulfonamide compound (substrate 2
, Y mmol), catalyst Pd (PPh3)4(W mol%), part dppf (V mol%), alkali Cy2NMe (2.0 equiv).Reaction
At 50-100o4-10 hour is reacted under C inert gas shielding.Reaction process is detected with TLC.After completion of the reaction, silicon is directly added
Glue, is spin-dried for column chromatography, isolated target product 3.
The advantage of synthetic reaction of the present invention includes: the reaction substrate that synthetic method of the present invention is used is the most simple and easy to get, institute
The raw material needed is business-like product, wide material sources, and stable performance, it addition, synthetic route is the most all ripe classics
Synthetic reaction.Various metallic catalysts used by the present invention are the most all conventional commercial reagents, highly stable, and have product
Rate is high, technique is simple, pollute few characteristic, is applicable to industrialized production completely.The 3-phenyl-piperidines class of present invention synthesis is spread out
Biological species compound is a kind of very important natural product and the core skeleton of modern medicines, the reaction of innovative design of the present invention
Route is to synthesize this compounds to provide a generally applicable preparation method.Synthesis 3-phenyl-piperidines analog derivative class
Traditional method of compound typically difficulty operates, productivity is the lowest, and industrial applications causes the biggest restriction.
Detailed description of the invention:
In conjunction with specific examples below, the present invention is described in further detail, the protection content of the present invention be not limited to
Lower embodiment.Under the spirit and scope without departing substantially from inventive concept, those skilled in the art it is conceivable that change and advantage all
It is included in the present invention, and with appending claims as protection domain.Implement the process of the present invention, condition, reagent,
Experimental techniques etc., outside the lower content mentioned specially, are universal knowledege and the common knowledge of this area, and the present invention does not has
Limit content especially.Data given by following example include concrete operations and reaction condition and product.Product purity is passed through
Nuclear-magnetism is identified.
Embodiment 1
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Fig. 3 embodiment 1
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), Pd (PPh3)4(0.01 mmol, 23 mg), potassium carbonate (0.40mmol, 55.0mg), depend on
The secondary reaction tube that is weighed into, evacuates and changes nitrogen, and add dioxane (2 mL) under nitrogen atmosphere.Reaction system is heated to
80oC, reacts 10 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain
Brown solid 3a (50%).1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.4 Hz, 2H), 7.27-7.25
(m, 4H), 7.06 (t, J = 2.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 4.94 (dd, J =
12.8,1.2 Hz, 2H), 3.93 (s, 2H), 3.81 (s, 3H), 3.02 (d, J = 1.6 Hz, 2H), 2.40
(s, 3H). 13C-NMR (100 MHz, CDCl3): δ 158.8, 143.8, 134.8, 129.7, 125.8, 118.9,
114.0, 113.1, 55.4, 49.5, 32.4, 21.6. MS (EI) m/z 355 (M+);HRMS value of calculation is
C20H21NO3S 355.1242, actual value is 355.1239.
Embodiment 2
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Fig. 4 embodiment 2
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), Pd(OAc)2 (0.02 mmol, 4.5 mg), triphenylphosphine (0.05mmol, 13.1mg),
Potassium carbonate (0.40mmol, 55.0mg), is weighed into reaction tube successively, and evacuation changes nitrogen, and adds dioxy six under nitrogen atmosphere
Ring (2 mL).Reaction system is heated to 100oC, reacts 10 hours.After TLC detection reaction terminates, system is cooled to room
Temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid 3a (45%).Analytical data is with embodiment 1.
Embodiment 3
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Fig. 5 embodiment 3
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), Pd(OAc)2 (0.02 mmol, 4.5 mg), 2 '-two tertiary fourth phosphino--2 '-4 '-6 '-three are different
Pentylbiphenyl (0.05mmol, 21.2mg), potassium carbonate (0.40mmol, 55.0mg), it is weighed into reaction tube successively, evacuates and change nitrogen,
And add dioxane (2 mL) under nitrogen atmosphere.Reaction system is heated to 80oC, reacts 5 hours.TLC detects reaction
After end, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid 3a (37%).Analytical data is same
Embodiment 1.
Embodiment 4
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Fig. 6 embodiment 4
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), PdCl2(dppf)2 (0.02 mmol, 14.6mg), potassium carbonate (0.40mmol,
55.0mg), it is weighed into reaction tube successively, evacuates and change nitrogen, and add dioxane (2 mL) under nitrogen atmosphere.By reactant
System is heated to 80oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for post
Chromatography, obtains brown solid 3a (34%).Analytical data is with embodiment 1.
Embodiment 5
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Fig. 7 embodiment 5
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), Pd(OAc)2 (0.02 mmol, 4.5 mg) potassium carbonate (0.40mmol, 55.0mg), three rings
Hexyl phosphine borofluoride (0.05mmol, 18.4mg), is weighed into reaction tube successively, evacuates and changes nitrogen, and adds under nitrogen atmosphere
Dioxane (2 mL).Reaction system is heated to 80oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled down
To room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid 3a (27%).Analytical data is with embodiment 1.
Embodiment 6
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Fig. 8 embodiment 6
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),Pd(OAc)2 (0.02 mmol, 4.5 mg) potassium carbonate (0.40mmol, 55.0mg), three (2,
4-Dimethoxyphenyl) phosphine (0.05mmol, 17.6mg), it is weighed into reaction tube successively, evacuation changes nitrogen, and under nitrogen atmosphere
Add dioxane (2 mL).Reaction system is heated to 80oC, reacts 5 hours.After TLC detection reaction terminates, by system
It is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid 3a (25%).Analytical data is with embodiment 1.
Embodiment 7
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Fig. 9 embodiment 7
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),Pd(OAc)2 (0.02 mmol, 4.5 mg), potassium carbonate (0.40mmol, 55.0mg), 1,1'-
Double (diphenylphosphine) ferrocene (0.03mmol, 16.6mg), is weighed into reaction tube successively, evacuates and changes nitrogen, and under nitrogen atmosphere
Add dioxane (2 mL).Reaction system is heated to 80oC, reacts 5 hours.After TLC detection reaction terminates, by system
It is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid 3a (30%).Analytical data is with embodiment 1.
Embodiment 8
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 10 embodiment 8
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), Pd (PPh3)4(0.01 mmol, 23 mg), cesium carbonate (0.40mmol, 55.0mg), depend on
The secondary reaction tube that is weighed into, evacuates and changes nitrogen, and add dioxane (2 mL) under nitrogen atmosphere.Reaction system is heated to 80oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain palm fibre
Color solid 3a (44%).Analytical data is with embodiment 1.
Embodiment 9
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 11 embodiment 9
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), PdCl2(PPh3)2(0.02mol 14.0mg), potassium carbonate (0.40mmol, 55.0mg), depend on
The secondary reaction tube that is weighed into, evacuates and changes nitrogen, and add dioxane (2 mL) under nitrogen atmosphere.Reaction system is heated to 80oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain palm fibre
Color solid 3a (39%).Analytical data is with embodiment 1.
Embodiment 10
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 12 embodiment 10
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),PdCl2(PPh3)2(0.02mol 14.0mg), cesium carbonate (0.40mmol, 55.0mg), successively
It is weighed into reaction tube, evacuates and change nitrogen, and add dioxane (2 mL) under nitrogen atmosphere.Reaction system is heated to 80oC,
React 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid
Body 3a (25%).Analytical data is with embodiment 1.
Embodiment 11
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 13 embodiment 11
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),PdCl2(PPh3)2 (0.02mol 14.0mg), potassium carbonate (0.40mmol, 55.0mg), depend on
The secondary reaction tube that is weighed into, evacuates and changes nitrogen, and add DMF (2 mL) under nitrogen atmosphere.Reaction system is heated to 80oC, instead
Answer 8 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid
3aa(25%).Analytical data is with embodiment 1.
Embodiment 12
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 14 embodiment 12
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),PdCl2(PPh3)2(0.02mol 14.0mg), potassium carbonate (0.40mmol, 55.0mg), successively
It is weighed into reaction tube, evacuates and change nitrogen, and add acetonitrile (2 mL) under nitrogen atmosphere.Reaction system is heated to 80oC, instead
Answer 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid
3a (38%).Analytical data is with embodiment 1.
Embodiment 13
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 15 embodiment 13
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),Pd(dba)2(0.02mol, 11.5mg), PPh3(0.05mmol, 13.1 mg), potassium carbonate
(0.40mmol, 55.0mg), is weighed into reaction tube successively, evacuates and changes nitrogen, and adds dioxane (2 under nitrogen atmosphere
mL).Reaction system is heated to 80oC, reacts 6 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add
Silica gel, is spin-dried for column chromatography, obtains brown solid 3a (25%).Analytical data is with embodiment 1.
Embodiment 14
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 16 embodiment 14
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), Pd (PPh3)4(0.01 mmol, 23 mg), are weighed into reaction tube successively, evacuate and change nitrogen, and
Add dioxane (2 mL) under nitrogen atmosphere, use liquid-transfering gun to add triethylamine (56 μ L).Reaction system is heated to
80 oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain
Brown solid 3a (48%).Analytical data is with embodiment 1.
Embodiment 15
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 17 embodiment 15
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), Pd (PPh3)4(0.01 mmol, 23 mg), are weighed into reaction tube successively, evacuate and change nitrogen,
And add dioxane (2 mL) under nitrogen atmosphere, then use liquid-transfering gun add N-methyldicyclohexylamine (2.0 equivalents, 86
μL),.Reaction system is heated to 80oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add
Silica gel, is spin-dried for column chromatography, obtains brown solid 3a (60%).Analytical data is with embodiment 1.
Embodiment 16
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 18 embodiment 16
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), Pd (PPh3)4(0.01 mmol, 23 mg), potassium phosphate (2.0 equivalents, 84.9mg), depend on
The secondary reaction tube that is weighed into, evacuates and changes nitrogen, and add dioxane (2 mL) under nitrogen atmosphere.Reaction system is heated to 80oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain palm fibre
Color solid 3a (45%).Analytical data is with embodiment 1.
Embodiment 17
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 19 embodiment 17
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), Pd (PPh3)4 (0.01 mmol, 23 mg), sodium acetate (2.0 equivalents, 23.1mg),
It is weighed into reaction tube successively, evacuates and change nitrogen, and add dioxane (2 mL) under nitrogen atmosphere.Reaction system is heated to
80 oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain
Brown solid 3a (33%).Analytical data is with embodiment 1.
Embodiment 18
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 20 embodiment 18
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),Pd(dba)2(0.02mol, 11.5mg), dppf (0.03mmol, 16.6 mg), carbonic acid
Potassium (0.40mmol, 55.0mg), is weighed into reaction tube successively, evacuates and changes nitrogen, and adds dioxane (2 under nitrogen atmosphere
mL).Reaction system is heated to 100oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly
Add silica gel, be spin-dried for column chromatography, obtain brown solid 3a (35%).Analytical data is with embodiment 1.
Embodiment 19
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 21 embodiment 19
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),PdCl2(PPh3)2(0.02mol 14.0mg), is weighed into reaction tube successively, evacuates and changes nitrogen, and
Add dioxane (2 mL) under nitrogen atmosphere, use liquid-transfering gun to add triethylamine (2.0 equivalents, 56 μ L).By reaction system
It is heated to 80oC, reacts 5 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silica gel, be spin-dried for post layer
Analysis, obtains brown solid 3a (30%).Analytical data is with embodiment 1.
Embodiment 20
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 22 embodiment 20
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),PdCl2(PPh3)2(0.02mol 14.0mg), is weighed into reaction tube successively, evacuates and changes nitrogen, and
Add dioxane (2 mL) under nitrogen atmosphere, use liquid-transfering gun to add N-methyldicyclohexyl amine (2.0 equivalents, 86 μ L).
Reaction system is heated to 100oC, reacts 7 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly add silicon
Glue, is spin-dried for column chromatography, obtains brown solid 3a (31%).Analytical data is with embodiment 1.
Embodiment 21
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 23 embodiment 21
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),PdCl2(PPh3)2(0.02mol 14.0mg), dppf (0.03mmol, 16.6mg), successively
It is weighed into reaction tube, evacuates and change nitrogen, and add dioxane (2 mL) under nitrogen atmosphere, use liquid-transfering gun to add N-methyl two
Cyclo-hexylamine (2.0 equivalents, 86 μ L).Reaction system is heated to 110oC, reacts 6 hours.After TLC detection reaction terminates, will
System is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid 3a (21%).Analytical data is with embodiment 1.
Embodiment 22
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 24 embodiment 22
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg),Pd(OAc)2 (0.02 mmol, 4.5 mg), and triphenylphosphine (0.05 mmol, 13.1
Mg), it is weighed into reaction tube successively, evacuates and change nitrogen, and add dioxane (2 mL) under nitrogen atmosphere, use liquid-transfering gun
Add N-methyldicyclohexyl amine (2.0 equivalents, 86 μ L).Reaction system is heated to 80oC, reacts 5 hours.TLC detection is anti-
After should terminating, system is cooled to room temperature.Directly add silica gel, be spin-dried for column chromatography, obtain brown solid 3a (42%).Analytical data
With embodiment 1.
Embodiment 23
The synthesis of 5-(4-anisyl)-3-methylene-1-p-toluenesulfonyl tetrahydropyridine:
Figure 25 embodiment 23
In the test tube reactor of 25 mL, by nitrogen exchange of air 3 times.By substrate 1a (0.24 mmol, 56.2mg), 2a
(0.20mmol, 49.7 mg), PdCl2(dppf) (0.02 mmol, 14.6 mg), are weighed into reaction tube successively, evacuate and change nitrogen
Gas, and add dioxane (2 mL) under nitrogen atmosphere, use liquid-transfering gun addition N-methyldicyclohexyl amine (2.0 equivalents,
86 μ L).Reaction system is heated to 110oC, reacts 7 hours.After TLC detection reaction terminates, system is cooled to room temperature.Directly
Connect and add silica gel, be spin-dried for column chromatography, obtain brown solid 3a (18%).Analytical data is with embodiment 1.
Embodiment 24
3-methylene-5-(4-nitrobenzophenone) synthesis of-1-tosyl tetrahydropyridine:
Figure 26 embodiment 24
Operation is with embodiment 15, and productivity is 32%.1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.8 Hz,
2H), 7.69 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 7.40 (t, J = 1.6 Hz,
1H), 7.32 (d, J = 8.4 Hz, 2H), 5.05 (d, J = 1.4 Hz, 2H), 3.97 (s, 2H), 3.09
(d, J = 1.6 Hz, 2H), 2.42 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ 145.3, 144.4,
135.2, 134.6, 130.0,127.2,125.7, 124.5, 124.0, 115.5, 114.1, 100.0, 49.2,
31.8, 21.6. MS (EI) m/z 370 (M+);HRMS value of calculation is C19H18N2O4S 370.0987, actual value is
370.0990。
Embodiment 25
3-methylene-5-(4-nitrobenzophenone) synthesis of-1-tosyl tetrahydropyridine:
Figure 27 embodiment 25
Operation is with embodiment 15, and productivity is 32%.1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.8 Hz,
2H), 7.69 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 7.40 (t, J = 1.6 Hz,
1H), 7.32 (d, J = 8.4 Hz, 2H), 5.05 (d, J = 1.4 Hz, 2H), 3.97 (s, 2H), 3.09
(d, J = 1.6 Hz, 2H), 2.42 (s, 3H), 13C-NMR (100 MHz, CDCl3): δ 145.3, 144.4,
135.2, 134.6, 130.0,127.2,125.7, 124.5, 124.0, 115.5, 114.1, 100.0, 49.2,
31.8, 21.6. MS (EI) m/z 370 (M+);HRMS value of calculation is C19H18N2O4S 370.0987, actual value is
370.0988。
Embodiment 26
5-(4-chlorphenyl) synthesis of-3-methyl isophthalic acid-tosyl tetrahydropyridine:
Figure 28 embodiment 26
Operation is with embodiment 15, and productivity is 34%.1H NMR (400 MHz, CDCl3): δ 7.67(d, J = 8.0Hz,
2H), 7.29 (dd, J = 10.4 Hz, 4H), 7.15 (t, J = 1.6 Hz 1H), 7.15 (t, J = 1.6 Hz
1H), 3.93 (s, 2H), 3.02 (d, J = 1.2 Hz, 2H), 2.41 (s, 3H). 13C-NMR (100 MHz,
CDCl3): δ144.0, 137.1, 135.9, 134.7, 132.5, 129.8,128.7,127.1, 125.8, 122.7,
117.5, 113.5, 49.4, 32.1, 21.6. MS (EI) m/z 359 (M+);HRMS value of calculation is
C19H18ClNO2S 359.0747, actual value is 359.0745.
Embodiment 27
1-(4-(5-methyl isophthalic acid-tosyl-1,4,5,6-tetrahydropyridine-3-base) phenyl) synthesis of ethyl ketone:
Figure 29 embodiment 27
Operation is with embodiment 15, and productivity is 34%.1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.4 Hz,
2H), 7.68 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 1.6 Hz,
1H), 7.30 (d, J = 8.0 Hz, 2H), 5.02 (dd, J = 15.2,1.2 Hz, 2H), 3.96 (s, 2H),
3.09 (d, J = 1.2 Hz, 2H), 2.60 (s, 3H), 2.41 (s, 3H), 13C-NMR (100 MHz,
CDCl3): δ 197.5, 144.2, 135.7, 135.3, 134.7,129.9,128.8, 127.2, 124.3, 124.2,
116.9, 113.7, 111.8, 49.3, 31.9, 26.5, 21.6. MS (EI) m/z 367 (M+);HRMS calculates
Value is C21H21NO3S 367.1242, actual value is 367.1244.
Embodiment 28
3-methylene-5-(o-tolyl) synthesis of-1-tosyl tetrahydropyridine:
Figure 30 embodiment 28
Operation is with embodiment 15, and productivity is 35%.1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz,
2H), 7.31 (d, J = 8.0 Hz, 2H), 7.19-7.13 (m, 3H), 7.08-7.06 (m, 1H), 6.62-
6.61 (m, 1H), 4.93 (dd, J = 6.4,1.2 Hz, 2H), 3.97 (s, 2H), 2.86 (d, J = 8.4
Hz,1.6H), 2.44 (s, 3H), 2.23 (s, 3H). 13C-NMR (100 MHz, CDCl3): δ 143.8,
143.6, 139.5, 136.3, 135.8, 134.8, 130.3, 129.7, 127.3 125.8, 123.6, 121.1,
112.8, 49.5, 34.9, 27.9, 21.6. MS (EI) m/z 339 (M+);HRMS value of calculation is C20H21NO2S
339.1293, actual value is 339.1294.
Embodiment 29
3-methylene-5-(o-tolyl) synthesis of-1-tosyl tetrahydropyridine:
Figure 31 embodiment 29
Operation is with embodiment 15, and productivity is 53%1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.0Hz,
2H), 7.30-7.27 (m, 4H), 7.09 (t, J = 1.6 Hz, 1H), 7.01 (t, J = 8.8 Hz, 2H),
4.97 (d, J = 10.8Hz, 2H), 3.93 (s, 2H), 3.02 (d, J = 3.0 Hz 2H), 2.41 (s,
3H). 13C-NMR (100 MHz, CDCl3): δ 143.9, 136.0, 134.8, 129.8, 127.2, 126.2,
126.1,122.2, 117.9, 115.5, 115.3, 113.4, 49.4, 32.4, 21.6. MS (EI) m/z 343 (M+);HRMS value of calculation is C19H18FNO2S 343.1042, actual value is 343.1040.
Embodiment 30
5-(3-fluorophenyl) synthesis of-3-methyl isophthalic acid-tosyl tetrahydropyridine:
Figure 32 embodiment 30
Operation is with embodiment 15, and productivity is 35%.1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz,
2H), 7.30 (d, J = 2.8 Hz, 3H), 7.20 (t, J = 2.0 Hz, 1H), 7.13-7.10 (m, 1H),
7.00 (dt, J = 10.8, 2.0Hz ,1H), 6.95-6.90 (m, 1H), 4.99 (dd, J = 13.6,4.0 Hz,
2H), 3.94 (s, 2H), 3.03 (d, J = 1.6Hz, 2H), 2.41 (s, 3H). 13C-NMR (100 MHz,
CDCl3): δ 143.8, 138.7, 138.1, 136.3, 134.9, 129.8,128.5,127.7, 127.2, 125.4,
122.1, 121.7, 118.9, 113.1, 49.5, 32.3, 21.6, 21.5. MS (EI) m/z 343 (M+);
HRMS value of calculation is C19H18FNO2S 343.1042, actual value is 343,1044.
Embodiment 31
Tolyl between 3-methylene-5-() synthesis of-1-tosyl tetrahydropyridine:
Figure 33 embodiment 31
Operation is with embodiment 15, and productivity is 45%.1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.4 Hz,
2H), 7.28 (d, J = 8.4 Hz, 2H), 7.21 (d,J = 7.6Hz, 1H), 7.17-7.16 (m,2H), 7.13
(d, J = 8.0Hz, 1H), 7.06 (d, J = 6.4 Hz, 1H), 4.96 (dd, J = 14.0, 1.6 Hz,
2H), 3.94 (s, 2H), 3.05 (d, J = 1.6Hz, 2H), 2.41 (s, 3H), 2.36 (s, 3H). 13C-
NMR (100 MHz, CDCl3): δ 143.8, 138.7, 138.2, 136.3, 130.1, 127.7, 127.2,
125.4, 122.1, 121.7, 118.9, 113.1, 49.5, 32.3,21.5 (d, J = 4.0 Hz). MS (EI)
m/z 339 (M+);HRMS value of calculation is C20H21NO2S 339.1293, actual value is 339.1294.
Embodiment 32
3-methylene-5-(p-methylphenyl) synthesis of-1-tosyl tetrahydropyridine:
Figure 34 embodiment 32
Operation is with embodiment 15, and productivity is 50%.1H NMR (400 MHz, CDCl3): δ 7.68(d, J = 8.4 Hz,
2H), 7.27 (d, J = 9.2 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.14 (s, 1H), 7.13
(d, J = 2.0 Hz, 2H), 4.95 (d, J = 12.8 Hz, 2H), 3.93 (s, 2H), 3.03 (d, J =
1.2 Hz, 2H), 2.40 (s, 3H), 2.34 (s, 3H). 13C-NMR (100 MHz, CDCl3): δ 143.8,
136.7, 136.4, 135.8, 134.9, 129.7, 129.2, 127.2, 124.5, 121.6, 119.0, 113.1,
49.5, 32.3, 21.6, 21.1. MS (EI) m/z 339 (M+);HRMS value of calculation is C20H21NO2S
339.1293, actual value is 339.1295.
Embodiment 33
5-(3,4-fluorophenyl) synthesis of-3-methyl isophthalic acid-tosyl tetrahydropyridine:
Figure 35 embodiment 33
Operation is with embodiment 15, and productivity is 38%. δ1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.4 Hz,
2H), 7.34 (d, J = 8.0 Hz, 0H), 7.13-7.02 (m, 4H), 4.99 (d, J = 11.2 Hz, 2H),
3.93 (s, 2H), 2.99 (d, J = 1.2 Hz, 2H), 2.42 (s, 3H). 13C-NMR (100 MHz,
CDCl3): δ 144.1, 135.6, 134.7, 129.9, 127.2, 123.1,120.4,117.4, 117.2, 116.6,
113.6, 113.5, 113.4, 49.3, 32.2, 21.6. MS (EI) m/z 361 (M+);HRMS value of calculation is
C19H17F2NO2S 361.0948, actual value is 361.0950.
Embodiment 34
5-(2,3-3,5-dimethylphenyl) synthesis of-3-methyl isophthalic acid-tosyl tetrahydropyridine:
Figure 36 embodiment 34
Operation is with embodiment 15, and productivity is 59%. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz,
2H), 7.34 (d, J = 8.0 Hz, 2H), 9.091 (dd, J = 7.6 Hz ,1.6, 1H), 7.06 (d, J =
7.6 Hz, 1H), 6.923 (dd, J = 7.2,1.2 Hz, 1H), 6.59 (t, J = 2.0 Hz, 1H), 4.92
(dd, J = 7.6,1.2 Hz, 2H), 3.96 (s, 2H), 2.82 (d, J = 1.6 Hz, 1H), 2.44 (s,
3H), 2.28 (s, 3H), 2.11 (s, 3H).13C-NMR (100 MHz, CDCl3): δ 143.7, 139.8,
137.2, 136.4, 134.8, 134.5,129.6, 129.0, 127.4, 127.0, 125.4, 123.4, 122.0,
112.7, 49.6, 35.4, 21.6, 20.5, 16.5. MS (EI) m/z 353 (M+);HRMS value of calculation is
C21H23NO2S 353.1449, actual value is 353.1446.
Embodiment 35
5-(2-fluorophenyl) synthesis of-3-methyl isophthalic acid-tosyl tetrahydropyridine:
Figure 37 embodiment 35
Operation is with embodiment 15, and productivity is 58%. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz,
2H), 7.53-7.44 (m, 4H), 7.30 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 2.0 Hz, 1H),
5.01 (dd, J = 15.6,1.2 Hz,2 H), 3.96 (s, 2H), 3.07 (d, J = 1.2 Hz, 2H), 2.42
(s, 3H).13C-NMR (100 MHz, CDCl3): δ 144.1, 139.6, 135.6, 139.6, 135.6,134.7,
126.9, 129.0, 127.7, 127.2,123.6, 123.4, 121.2, 117.1, 113.7, 49.5, 32.1,
21.6. MS (EI) m/z 343 (M+);HRMS value of calculation is C19H18FNO2S 343.1042, actual value is
343.1044。
Embodiment 36
The synthesis of 4-(5-methyl isophthalic acid-tosyl tetrahydropyridine:
Figure 38 embodiment 36
Operation is with embodiment 15, and productivity is 48%. 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 7.83
(d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.38
(t, J = 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 5.03 (dd, J = 15.2,0.8 Hz,
2H), 3.96 (s, 2H), 3.10 (d, J = 1.6Hz, 2H), 2.42 (s, 3H). 13C-NMR (100 MHz,
CDCl3): δ 191.6, 144.8, 1144.2, 135.5, 134.7,134.6,130.1, 130.0, 127.2,
124.9,124.6, 116.6, 113.8, 49.3, 31.8, 21.6. MS (EI) m/z 353 (M+);HRMS calculates
Value is C20H19NO3S 353.1086, actual value is 353.1088.
Embodiment 37
2-(5-methylene-1-tolysulfonyl-1,4,5,6-tetrahydropyridine-3-base) synthesis of essence of Niobe:
Figure 39 embodiment 37
Operation is with embodiment 15, and productivity is 58%. 1H NMR (400 MHz, CDCl3): δ 7.79 (dd, J = 7.6,1.2
Hz 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.47-7.43 (m, 1H), 7.35 (dd, J = 8.0,4.0,
1H), 7.31 (d, J = 8.0 Hz, 3H), 7.20 (dd, J = 7.6,1.2 Hz, 1H), 6.62 (t, J =
1.6 Hz, 1H), 4.94 (d, J = 4.4 Hz, 2H), 4.19 (d, J = 7.2 Hz, 1H), 4.18 (d, J =
7.2Hz, 1H), 3.95 (s, 2H), 2.95 (d, J = 1.6 Hz, 2H), 2.43 (s, 3H), 1.21 (t, J
= 7.2 Hz, 3H).13C-NMR (100 MHz, CDCl3): δ 167.9, 143.7, 140.5, 136.4, 135.1,
131.5,131.1, 130.3, 130.1, 129.7,127.3, 122.6, 121.3, 112.7, 61.1, 49.4,
35.0, 21.6,14.1. MS (EI) m/z 397 (M+);HRMS value of calculation is C22H23NO4S 397.1048, actual
Value is 397.1051.
Claims (8)
1. this 3-phenyl-piperidines analog derivative synthetic method, it is characterised in that with N-pi-allyl-4-methoxyl group-N-vinyl benzene
Sulfonamide compounds and substituted iodobenzene derivant are reaction raw materials, under the effect of metal palladium catalyst, in reaction dissolvent
Reaction obtains 3-phenyl-piperidines analog derivative compounds；Course of reaction is as shown in the formula (I)；
Formula (I)；
Wherein, R1, it is hydrogen, halogen, hetero atom, alkyl;PG is Ts.
2. the synthetic method of 3-phenyl-piperidines analog derivative as claimed in claim 1, it is characterised in that described palladium catalyst
It is Pd (OAc)2、PdCl2 、Pd(PPh3)4、Pd(TFA)2、PdCl2Or PdCl (dppf)2(PPh3)2；The consumption of described catalyst
For 1-10%.
3. the synthetic method of 3-phenyl-piperidines analog derivative as claimed in claim 1, it is characterised in that described part is
DPPF,PPh3, described part consumption is 1-30%.
4. the synthetic method of 3-phenyl-piperidines analog derivative as claimed in claim 1, it is characterised in that described alkali is Et3N、
K3PO4、Cy2NMe、K2CO3、Cs2CO3。
5. the synthetic method of 3-phenyl-piperidines analog derivative as claimed in claim 1, it is characterised in that described solvent is second
Nitrile, DMF, dioxane.
6. the synthetic method of 3-phenyl-piperidines analog derivative as claimed in claim 1, it is characterised in that described synthetic reaction
At 50-100oC is carried out.
7. the synthetic method of 3-phenyl-piperidines analog derivative as claimed in claim 1, it is characterised in that described response time
For 4-10h.
8. prepare 3-phenyl-piperidines analog derivative such as claim 1 synthetic method.
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