CN106397317B - 1,2,3,4- 3,4-tetrahydroquinoline compounds and its synthetic method and application - Google Patents
1,2,3,4- 3,4-tetrahydroquinoline compounds and its synthetic method and application Download PDFInfo
- Publication number
- CN106397317B CN106397317B CN201610845979.1A CN201610845979A CN106397317B CN 106397317 B CN106397317 B CN 106397317B CN 201610845979 A CN201610845979 A CN 201610845979A CN 106397317 B CN106397317 B CN 106397317B
- Authority
- CN
- China
- Prior art keywords
- methyl
- tetrahydroquinoline
- nitro
- formate
- har
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention relates to a kind of 1,2,3,4- 3,4-tetrahydroquinoline compounds and its synthetic method and applications.R1 is nitro, trifluoromethyl, 3- nitrobenzenesulfonyl or cyano in the structural formula of such compound；R2 is hydrogen or methyl；R3 is methyl formate base or butyl formate base；R4 is methyl.Aromatic ring contains serial electron-withdrawing group in 1,2,3,4- 3,4-tetrahydroquinoline compounds of the invention.Synthetic method of the invention is simple, economic and environment-friendly, easy to operate, easy to control, and product purity and yield are higher, is a kind of novel method for synthesizing of atom economy, there is good development prospect in the industrial production.1,2,3,4- 3,4-tetrahydroquinoline compounds therein can be used as intermediate and be used to prepare antagonist pharmaceuticals.
Description
Of the invention subsidizes to Tianjin Natural Science Fund In The Light (No. 16JCYBJC19700).
Technical field
The invention belongs to synthetic organic chemical arts, are related to 1,2,3,4- 3,4-tetrahydroquinoline compounds of one kind and its synthetic method
With application.
Background technique
1,2,3,4- 3,4-tetrahydroquinoline compounds are a kind of very important N- heterocyclic aromatic compounds, in organic compound bone
Play important role in the building of frame structure, be constitute many natural products (for example, tetrahydroquinoline Alkaloid) and
(see reference the important structural unit of extensive bioactive molecule document: Rakotoson, J. H.et al.Planta Med,
1998,64, 762).Tetrahydroquinoline derivative with structure complicated and changeable is the important component and new drug development of modern medicines
Source.Itself has multiple biological activities, and can be used for preventing and treating anti-arrhythmia, antitumor etc., (see reference text
It offers: Rano, T. A. et al.Bioorg Med Chem. Lett, 2009, 19, 2456;Wallace, O. B. et
al. Bioorg Med Chem. Lett, 2003,13, 1907).In addition, 1,2,3,4- 3,4-tetrahydroquinoline compounds or one kind
Chromophore with good electron supplying capacity can be used as synthesis of the intermediate for disperse dyes, as electron donor
Disperse dyes have many advantages, such as good hyperchromic effect and biggish molar extinction coefficient.Therefore, related 1,2,3,4- tetrahydro quinolines
The research of quinoline compound has been a concern.
Earliest, scientists be 1,2,3,4- 3,4-tetrahydroquinoline compounds are synthesized by the reduction reaction of quinoline, but by
Hydrogen source in this method usually using hydrogen as reaction, operation is more inconvenient, and there is certain risks, and hydrogenates anti-
The raw material answered can only be quinolines, and the scope of application of substrate is not extensive, therefore limits the party to a certain extent
The application of method.
Since there is certain deficiencies for the method using hydrogenation 1,2,3,4- 3,4-tetrahydroquinoline compounds of synthesis, in recent years
Come, non-hydrogenated method tetrahydrobiopterin synthesis quinoline compound attracts attention.In acid condition, using palladium, rhodium, ruthenium is golden,
The Diels-Alder of the metal catalytics such as copper anil and aldehyde compound reaction synthesis 1,2,3,4- tetrahydroquinoline chemical combination
Object is exactly current a kind of more common method of non-hydrogenated tetrahydrobiopterin synthesis quinoline compound.This method can be to avoid hydrogenation
The use of hazardous gas in reaction, but the adaptability of its substrate is not but extensive.
Recently, domestic and international scientist has invented multistep reaction synthetic method, multi-component reaction synthetic method and more meters successively again
A series of synthetic method of 1,2,3,4- 3,4-tetrahydroquinoline compounds such as promise reaction synthesis method.However, these method and steps are cumbersome, and
Require to use the anil of functionalization as raw material.And anil itself is then by nitrotoleune or derivatives thereof
It is obtained under conditions of harsh with unsaturated carbonyls.So, find one kind can directly by nitrotoleune or its spread out
Biology is used as raw material, and under conditions of comparatively safe mild, efficiently, the method that a step obtains target product is exactly that have very much must
It wants.
Summary of the invention
One of the objects of the present invention is to provide a kind of 1,2,3,4- 3,4-tetrahydroquinoline compounds.
The second object of the present invention is to provide the synthetic method of such compound.
The third object of the present invention is that providing such compound as pharmaceutical intermediate is being used to prepare antagonist pharmaceuticals
The application of aspect.Experimental result is shown, can be used as complete male rat appendicle using compound prepared by the intermediate
Official's growth inhibitor.
In order to achieve the above objectives, the invention discloses following technology contents:
1,2,3,4- 3,4-tetrahydroquinoline compounds, structural formula are as follows:
In formula: R1 is nitro, trifluoromethyl, 3- nitrobenzenesulfonyl or cyano；R2 is hydrogen or methyl；R3 is formic acid first
Ester group or butyl formate base；R4 is methyl.
Of the present invention 1,2,3,4- 3,4-tetrahydroquinoline compounds, typical compound are as follows:
2- methyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2- methyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate；
2,4- dimethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2,4- dimethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate；
2- methyl -5- trifluoromethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2- methyl -5- trifluoromethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate；
2- methyl -7- (3- nitrobenzenesulfonyl) -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2- methyl -7- (3- nitrobenzenesulfonyl) -1,2,3,4- tetrahydroquinoline -2- butyl formate；
2- methyl -7- cyano -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2- methyl -7- cyano -1,2,3,4- tetrahydroquinoline -2- butyl formate.
The present invention further discloses the synthetic methods of 2,3,4- 3,4-tetrahydroquinoline compounds, it is characterised in that by following
Step carries out:
(1) in nitrogen atmosphere, by the ortho-nitrophenyl derivative containing electron-withdrawing group, alkene derivatives, cesium carbonate presses 1:
The molar ratio of 3:2 is added in tetrahydrofuran solution, and 65oUnder conditions of C, flow back 8-12 hours；
(2) after reaction, rotary evaporation removes solvent and extra alkene, remaining solid are washed with enough methylene chloride
It washs, filters, filtrate is spin-dried for, and crosses silicagel column purification, obtains 1,2,3,4- 3,4-tetrahydroquinoline compounds of target product；
The ortho-nitrophenyl derivant structure containing electron-withdrawing group are as follows:The alkene is derivative
Object structure are as follows:R1 is nitro, trifluoromethyl, 3- nitrobenzenesulfonyl or cyano；R2 is hydrogen or methyl；R3 is first
Sour carbomethoxy or butyl formate base；R4 is methyl.
The present invention further discloses 1,2,3,4- 3,4-tetrahydroquinoline compounds as intermediate in terms of preparing antagonist
Application.Experimental result shows that 1,2,3,4- 3,4-tetrahydroquinoline compounds (such as embodiment 11) may be used as preparing in antagonist
Mesosome.
Disclosed by the invention 1,2,3,4- 3,4-tetrahydroquinoline compounds and its synthetic method and application compared with the existing technology, have
It has the advantage that
(a) raw material is simple and easy to get, and method is easy to operate, quick.
(b) yield with higher, wide application range of substrates are general.
(c) catalyst cesium carbonate can be recycled and reused by straightforward procedure.
(d) meet the theory of atom economy, environmentally protective, environmental pollution is small.
Detailed description of the invention:
Fig. 1 is the structural formula of 1,2,3,4- 3,4-tetrahydroquinoline compounds.
Specific embodiment
The present invention is described below by specific embodiment.Unless stated otherwise, technological means used in the present invention
It is method known in those skilled in the art.In addition, embodiment is interpreted as illustrative, it is not intended to limit the present invention
Range, the spirit and scope of the invention are limited only by the claims that follow.To those skilled in the art, without departing substantially from this
Under the premise of invention spirit and scope, to the various changes or change of material component and dosage progress in these embodiments
It belongs to the scope of protection of the present invention.Wherein raw materials used: 2,4-DNT, methyl methacrylate, cesium carbonate etc. are equal
It is commercially available.
Embodiment 1
The synthesis of 2- methyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- methyl formate:
The 10 mL round-bottomed flasks for being connected with reflux condensing tube are taken, are added 2,4- dinitrotoluene (DNT) (182 mg, 1 mmol), first
Base methyl acrylate (294 mg, 3 mmol) and cesium carbonate (652 mg, 2 mmol) vacuumize logical nitrogen, inject anhydrous
THF (5 mL), is heated to 65oC flows back 12 hours.After reaction, rotary evaporation removes solvent and extra alkene, remains
Remaining solid is washed with enough methylene chloride, filtering, and enough water dissolution is added in filter residue, adds active carbon decoloring, filters off solid back spin
Dry solvent, vacuum drying, the cesium carbonate recycled.Filtrate containing product is spin-dried for, and crosses silicagel column purification, solvent is dichloro
Methane, obtaining target product is yellow solid, 213 mg of yield, 85 % of yield.
Product ir data: IR (KBr): 3362 cm-1, 2925 cm-1, 1724 cm-1, 1618 cm-1,
1527 cm-1, 1454 cm-1, 1348 cm-1, 1176 cm-1。
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 8.2, 1.7
Hz, 1H, HAr), 7.42 (d, J = 1.6 Hz, 1H, HAr), 7.07 (d, J = 8.2 Hz, 1H, HAr),
4.66 (s, 1H, NH), 3.75 (s, 3H, CH3), 2.95-2.65 (m, 2H, CH2), 2.41-2.28 (m, 1H,
CH2), 1.97-1.80 (m, 1H, CH2), 1.51 (s, 3H, CH3) ppm。
Product structure formula:
Embodiment 2
The synthesis of 2- methyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate:
Reaction raw materials are 2,4- dinitrotoluene (DNT) (182 mg, 1 mmol), and butyl methacrylate (420 mg, 3
Mmol), the reaction time is 12 hours, and other concrete operations are the same as embodiment 1.Product is yellow solid, 237 mg of yield, yield 81
%。
Product ir data: IR (KBr): 3382 cm-1, 2933 cm-1, 1728 cm-1, 1616 cm-1,
1523 cm-1, 1454 cm-1, 1346cm-1, 1180 cm-1.
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 8.2, 2.1
Hz, 1H, HAr), 7.42 (d, J = 2.1 Hz, 1H, HAr), 7.07 (d, J = 8.3 Hz, 1H, HAr),
4.66 (s, 1H, NH), 4.14 (t, J = 6.6 Hz, 2H, CH2), 2.93-2.68 (m, 2H, CH2), 2.34
(dt, J = 13.0, 5.2 Hz, 1H, CH2), 1.90 (ddd, J = 13.2, 10.3, 5.9 Hz, 1H, CH2),
1.61 (dd, J = 13.3, 5.5 Hz, 2H, CH2), 1.50 (s, 3H, CH3), 1.33 (dd, J = 15.1,
7.5 Hz, 2H, CH3), 0.92 (t, J = 7.4 Hz, 3H, CH3) ppm。
Product structure formula:
Embodiment 3
The synthesis of 2,4- dimethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- methyl formate:
Reaction raw materials are 2,4- dinitro ethylbenzene (194 mg, 1 mmol), and methyl methacrylate (294 mg, 3
Mmol), the reaction time is 12 hours, and other concrete operations are the same as embodiment 1.Product is yellow solid, 191 mg of yield, yield
73 %。
Product ir data: IR (KBr): 3383 cm-1, 2932 cm-1, 1732 cm-1, 1603 cm-1,
1535 cm-1, 1485 cm-1, 1345 cm-1, 1181 cm-1.
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 2.3 Hz,
1H, HAr), 7.47 (s, 1H, HAr), 7.03 (d, J = 2.2 Hz, 1H, HAr), 4.96 (s, 1H, NH),
3.77(s, 3H, CH3), 3.00 (ddd, J = 16.1, 14.6, 9.5 Hz, 1H, CH2), 2.88 (d, J =
8.4 Hz, 3H, CH3), 2.81 (d, J = 26.5 Hz, 1H, CH2), 2.32-1.87 (m, 1H, CH2), 1.60
(s, 3H, CH3) ppm。
Product structure formula:
Embodiment 4
The synthesis of 2,4- dimethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate:
Reaction raw materials are 2,4- dinitro ethylbenzene (194 mg, 1 mmol), and butyl methacrylate (420 mg, 3
Mmol), the reaction time is 12 hours, and other concrete operations are the same as embodiment 1.Product is yellow solid, 210 mg of yield, yield
69 %。
Product ir data: IR (KBr): 3385 cm-1, 2932 cm-1, 1731 cm-1, 1609 cm-1,
1537 cm-1, 1488 cm-1, 1355 cm-1, 1188 cm-1。
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 2.3 Hz,
1H, HAr), 7.46(s, 1H, HAr), 7.02 (d, J = 10.2 Hz, 1H, HAr), 4.96 (s, 1H, NH),
4.39 (q, J = 7.1 Hz, 2H, CH2), 2.88 (s, 3H, CH3), 3.00 (ddd, J = 16.1, 14.6,
9.5 Hz, 1H, CH2), 2.81 (d, J = 26.5 Hz, 1H, CH2), 2.32-1.87 (m, 1H, CH2), 1.61
(dd, J = 13.3, 5.5 Hz, 2H, CH2), 1.60 (s, 3H, CH3), 1.33 (dd, J = 15.1, 7.5
Hz, 2H, CH2), 0.92 (t, J = 7.4 Hz, 3H, CH3) ppm。
Product structure formula:
Embodiment 5
The synthesis of 2- methyl -5- trifluoromethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- methyl formate:
Reaction raw materials are 2,4- dinitro -6- trifluoromethyl toluene (251 mg, 1 mmol), methyl methacrylate
(294 mg, 3 mmol), reaction time are 12 hours, and other concrete operations are the same as embodiment 1.Product is yellow solid, yield
207 mg, 65 % of yield.
Product ir data: IR (KBr): 3389 cm-1, 2932 cm-1, 1731 cm-1, 1602 cm-1,
1533 cm-1, 1469 cm-1, 1346 cm-1, 1127 cm-1。
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H, HAr), 7.58
(s, 1H, HAr), 4.93 (s, 1H, NH), 3.78 (s, 3H, CH3), 3.17-2.97 (m, 1H, CH2),
2.92-2.77 (m, 1H, CH2), 2.37 (dt, J = 11.0, 7.8 Hz, 1H, CH2), 1.93-1.83 (m,
1H, CH2), 1.53 (s, 3H, CH3) ppm。
Product structure formula:
Embodiment 6
The synthesis of 2- methyl -5- trifluoromethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate:
Reaction raw materials are 2,4- dinitro -6- trifluoromethyl toluene (251 mg, 1 mmol), butyl methacrylate
(420 mg, 3 mmol), reaction time are 12 hours, and other concrete operations are the same as embodiment 1.Product is yellow solid, yield
188 mg, 52 % of yield.
Product ir data: IR (KBr): 3380 cm-1, 2934 cm-1, 1731 cm-1, 1602 cm-1,
1535 cm-1, 1468 cm-1, 1357 cm-1, 1130 cm-1。
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 1.7 Hz,
1H, HAr), 7.59 (d, J = 1.8 Hz, 1H, HAr), 4.91 (s, 1H, NH), 4.17 (t, J = 6.5
Hz, 2H, CH2), 3.11-2.99 (m, 1H, CH2), 2.87 (ddd, J = 18.6, 10.6, 5.1 Hz, 1H,
CH2), 2.40-2.28 (m, 1H, CH2), 1.92 (ddd, J = 13.4, 10.7, 5.2 Hz, 1H, CH2),
1.68-1.56 (m, 2H, CH2), 1.52 (s, 3H, CH3), 1.40 – 1.30 (m, 2H, CH2), 0.93 (t,J = 7.4 Hz, 3H, CH3) ppm。
Product structure formula:
Embodiment 7
The synthesis of 2- methyl -7- (3- nitrobenzenesulfonyl) -1,2,3,4- tetrahydroquinoline -2- methyl formate:
Reaction raw materials are 2- nitro -4- (3- nitrobenzenesulfonyl) toluene (258 mg, 1 mmol), methyl methacrylate
Ester (294 mg, 3 mmol), reaction time are 12 hours, and other concrete operations are the same as embodiment 1.Product is faint yellow solid, is produced
Measure 246 mg, 63 % of yield.
Product ir data: IR (KBr): 3388 cm-1, 3084 cm-1, 2926 cm-1, 1637 cm-1,
1571 cm-1, 1413 cm-1, 1365 cm-1, 1117 cm-1。
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H, HAr), 8.41
(d, J = 8.2 Hz, 1H, HAr), 8.27 (d, J = 7.8 Hz, 1H, HAr), 7.72 (t, J = 8.0 Hz,
1H, HAr), 7.20 (d, J = 7.9 Hz, 1H, HAr), 7.14 (s, 1H, HAr), 7.10 (d, J = 7.9
Hz, 1H, HAr), 4.67 (s, 1H, NH), 3.73 (s, 3H, CH3), 2.84-2.70 (m, 2H, CH2),
2.36-2.24 (m, 1H, CH2), 1.84 (ddd, J = 13.5, 10.2, 5.8 Hz, 1H, CH2), 1.48 (s,
3H, CH3) ppm。
Product structure formula:
Embodiment 8
The synthesis of 2- methyl -7- (3- nitrobenzenesulfonyl) -1,2,3,4- tetrahydroquinoline -2- butyl formate
Reaction raw materials are 2- nitro -4- (3- nitrobenzenesulfonyl) toluene (258 mg, 1 mmol), methacrylic acid fourth
Ester (420 mg, 3 mmol), reaction time are 12 hours, and other concrete operations are the same as embodiment 1.Product is faint yellow solid, is produced
Measure 311 mg, 72 % of yield.
Product ir data: IR (KBr): 3388 cm-1, 3085 cm-1, 2926 cm-1, 1627 cm-1,
1577 cm-1, 1403 cm-1, 1366 cm-1, 1118 cm-1。
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H, HAr), 8.41
(d, J = 8.1 Hz, 1H, HAr), 8.26 (d, J = 7.8 Hz, 1H, HAr), 7.72 (t, J = 8.0 Hz,
1H, HAr), 7.20 (dd, J = 7.9, 1.5 Hz, 1H, HAr), 7.14 (d, J = 1.4 Hz, 1H, HAr),
7.10 (d, J = 7.9 Hz, 1H, HAr), 4.67 (s, 1H, NH), 4.12 (t, J = 6.6 Hz, 2H,
CH2), 2.87-2.69 (m, 2H, CH2), 2.37-2.20 (m, 1H, CH2), 1.85 (ddd, J = 13.3,
10.1, 5.8 Hz, 1H, CH2), 1.62-1.56 (m, 2H, CH2), 1.47 (s, 3H, CH3), 1.30 (dd, J
= 15.0, 7.5 Hz, 2H, CH2), 0.89 (t, J = 7.4 Hz, 3H, CH3) ppm。
Product structure formula:
Embodiment 9
The synthesis of 2- methyl -7- cyano -1,2,3,4- tetrahydroquinoline -2- methyl formate
Reaction raw materials be 2- nitro -4- cyano toluene (162 mg, 1 mmol), methyl methacrylate (294 mg, 3
Mmol), the reaction time is 8 hours, and other concrete operations are the same as embodiment 1.Product is white solid, 164 mg of yield, yield 71
%。
Product ir data: IR (KBr): 3384 cm-1, 2927 cm-1, 2226 cm-1, 1731 cm-1,
1611 cm-1, 1488 cm-1, 1196 cm-1。
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 7.7 Hz,
1H, HAr), 6.91 (d, J = 7.6 Hz, 1H, HAr), 6.81 (s, 1H, HAr), 4.52 (s, 1H, NH),
3.75 (s, 3H, CH3), 2.82-2.61 (m, 2H, CH2), 2.40-2.24 (m, 1H, CH2), 1.87 (ddd,J = 13.2, 10.1, 6.1 Hz, 1H, CH2), 1.49 (s, 3H, CH3) ppm。
Product structure formula:
Embodiment 10
The synthesis of 2- methyl -7- cyano -1,2,3,4- tetrahydroquinoline -2- butyl formate
Reaction raw materials be 2- nitro -4- cyano toluene (162 mg, 1 mmol), butyl methacrylate (430 mg, 3
Mmol), the reaction time is 8 hours, and other concrete operations are the same as embodiment 1.Product is white solid, 158 mg of yield, yield 58
%。
Product ir data: IR (KBr): 3385 cm-1, 2932 cm-1, 22244 cm-1, 1733 cm-1,
1605 cm-1, 1466 cm-1, 1180 cm-1。
Product hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 7.7 Hz,
1H, HAr), 6.91 (d, J = 7.7 Hz, 1H, HAr), 6.82 (s, 1H, HAr), 4.53 (s, 1H, NH),
4.13 (t, J = 5.8 Hz, 2H, CH2), 2.88-2.63 (m, 2H, CH2), 2.31 (dt, J = 13.0, 5.2
Hz, 1H, CH2), 1.88 (ddd, J = 13.2, 10.1, 6.1 Hz, 1H, CH2), 1.60 (dd, J = 14.5,
6.9 Hz, 2H, CH2), 1.48 (s, 3H, CH3), 1.31 (dd, J = 16.0, 8.8 Hz, 2H, CH2),
0.92 (t, J = 7.4 Hz, 3H, CH3) ppm。
Product structure formula:
Embodiment 11
The application of 1,2,3,4- 3,4-tetrahydroquinoline compounds:
2- methyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate can be used as pharmaceutical intermediate use.With 2- first
Base -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate is raw material through a series of synthesis step (specific synthetic route
It is as follows) drug (compound VII) of antagonistic activity can be synthesized
The synthesis of compound VII:
In the round-bottomed flask of 100 mL, compound III(250 mg, 1 mmol is added), 10% NaOH aqueous solution (8
ML), methanol (24 mL) flows back 1.5 hours.After being cooled to room temperature, with the hydrochloric acid tune pH value of 1M to 5-6, CH is then used2Cl2
(3 x, 20 mL) extraction, organic layer is dry with anhydrous sodium sulfate, is spin-dried for, obtains solid product IV, yield 90%.
By compound IV(200 mg, 0.85 mmol obtained above), SnCl2∙H2O(588 mg, 2.6 mmol), TBAB
(547 mg, 1.7 mmol) and 10 mL of ionic liquid are added in 50 mL round-bottomed flasks, and reaction is heated to 90 °C, react 20 points
Clock, filtering purification, obtains compound V, yield 97%.
Compound the V(103 mg, 0.5 mmol that will be obtained again) it is added in 25 mL flasks, logical nitrogen is vacuumized repeatedly.
By B (C6F5)3(26 mg, 0.05 mmol) is dissolved in the anhydrous CH of 5 mL2Cl2In, above-mentioned 25 mL flask is injected, is stirred at room temperature 10
Minute.Then normal-butyl silane (88 mg, 1 mmol) is added, is stirred to react 12 hours.After reaction, pillar purification is crossed, is obtained
To pure compound VI, yield 80%.
VI hydrogen nuclear magnetic resonance modal data of compound:1H NMR (400 MHz, CDCl3) δ 6.77 (d, 1H, J =
7.9 Hz, HAr), 6.00 (dd, 1H, J=7.9,2.2 Hz, HAr), 5.81 (d, 1H,J = 2.2 Hz,
HAr), 3.47 (s, 1H, NH), 3.40 (s, 2H, NH), 2.66 (dd, 2H, J = 6.7, 6.6 Hz,
CH2), 1.65 (dd, 2H, J = 6.7, 6.6 Hz, CH2), 1.18 (s, 6H, CH3) ppm。
By compound VI(102 mg, 0.58 mmol), trifluoroacetic ethyl acetoacetate (85.4 μ L, 0.58 mmol) is absolute
50 mL round-bottomed flasks are added in ethyl alcohol (2.5 mL), and after stirring a few minutes, ZnCl is added2(110 mg, 0.81 mmol), is heated back
Stream 3 hours.It after being cooled to room temperature, is extracted with ethyl acetate (40 mL), is saturated NH4Cl aqueous solution is washed, organic layer anhydrous slufuric acid
Sodium is dry, is spin-dried for, and crosses pillar purification, obtains yellow needles solid, yield 52%.
Compound VII hydrogen nuclear magnetic resonance modal data:1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H,
NH), 7.18 (s, 1H, HAr), 6.85 (s, 1H, HAr), 6.35 (s, 1H, HAr), 2.65 (dd, 2H, J
= 6.6, 6.6 Hz, CH2), 1.61 (dd, 2H, J = 6.6, 6.6 Hz, CH2), 1.17 (s, 6H, CH3)
ppm。
According to pertinent literature (Hamann, L. G. et al.J. Med. Chem. 1998, 41, 623), to chemical combination
The antagonistic activity test that object VII is carried out shows that the compound can be used as complete male rat accessory organ growth inhibition
Agent.
Claims (3)
1.1,2,3,4- 3,4-tetrahydroquinoline compounds, typical compound are as follows:
2- methyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2- methyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate；
2,4- dimethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2,4- dimethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate；
2- methyl -5- trifluoromethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2- methyl -5- trifluoromethyl -7- nitro -1,2,3,4- tetrahydroquinoline -2- butyl formate；
2- methyl -7- (3- nitrobenzenesulfonyl) -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2- methyl -7- (3- nitrobenzenesulfonyl) -1,2,3,4- tetrahydroquinoline -2- butyl formate；
2- methyl -7- cyano -1,2,3,4- tetrahydroquinoline -2- methyl formate；
2- methyl -7- cyano -1,2,3,4- tetrahydroquinoline -2- butyl formate.
2. the synthetic method of 1,2,3,4- 3,4-tetrahydroquinoline compounds described in claim 1, it is characterised in that by following step into
Row:
(1) in nitrogen atmosphere, by the ortho-nitrophenyl derivative containing electron-withdrawing group, alkene derivatives, cesium carbonate is by 1:3:2's
Molar ratio is added in tetrahydrofuran solution, and 65oUnder conditions of C, flow back 8-12 hours；
(2) after reaction, rotary evaporation removes solvent and extra alkene, remaining solid are washed with enough methylene chloride, mistake
Filter, filtrate are spin-dried for, and cross silicagel column purification, obtain 1,2,3,4- 3,4-tetrahydroquinoline compounds of target product；
The ortho-nitrophenyl derivant structure containing electron-withdrawing group are as follows:The alkene derivatives knot
Structure are as follows:R1 is nitro, trifluoromethyl, 3- nitrobenzenesulfonyl or cyano；R2 is hydrogen or methyl；R3 is methyl formate
Base or butyl formate base；R4 is methyl.
3. 1,2,3,4- 3,4-tetrahydroquinoline compounds described in claim 1 are as pharmaceutical intermediate in terms of preparing antagonist pharmaceuticals
Application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610845979.1A CN106397317B (en) | 2016-09-26 | 2016-09-26 | 1,2,3,4- 3,4-tetrahydroquinoline compounds and its synthetic method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610845979.1A CN106397317B (en) | 2016-09-26 | 2016-09-26 | 1,2,3,4- 3,4-tetrahydroquinoline compounds and its synthetic method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106397317A CN106397317A (en) | 2017-02-15 |
| CN106397317B true CN106397317B (en) | 2019-03-22 |
Family
ID=57997919
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610845979.1A Expired - Fee Related CN106397317B (en) | 2016-09-26 | 2016-09-26 | 1,2,3,4- 3,4-tetrahydroquinoline compounds and its synthetic method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106397317B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382858B (en) * | 2017-07-06 | 2020-02-21 | 天津师范大学 | Series of 1,2,3, 4-tetrahydroisoquinoline-4-ketone compounds, and synthetic method and application thereof |
| CN110372589B (en) * | 2019-08-13 | 2020-12-25 | 聊城大学 | Preparation method of 4- (4-tert-butylphenyl) -2-phenyl-1, 2,3, 4-tetrahydroquinoline-8-methyl formate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1175247A (en) * | 1994-12-22 | 1998-03-04 | 配位体药物股份有限公司 | Steroid receptor modulator compounds and methods |
| CN1230885A (en) * | 1996-09-18 | 1999-10-06 | 史密丝克莱恩比彻姆有限公司 | Use of benzopyranols to treat neurological disorders |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000513362A (en) * | 1996-06-27 | 2000-10-10 | リガンド・ファーマスーティカルス・インコーポレーテッド | Androgen receptor modulator compounds and methods |
| WO2004096210A1 (en) * | 2003-05-01 | 2004-11-11 | Glaxo Group Limited | Acylated indoline and tetrahydroquinoline derivatives as hcv inhibitors |
-
2016
- 2016-09-26 CN CN201610845979.1A patent/CN106397317B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1175247A (en) * | 1994-12-22 | 1998-03-04 | 配位体药物股份有限公司 | Steroid receptor modulator compounds and methods |
| CN1230885A (en) * | 1996-09-18 | 1999-10-06 | 史密丝克莱恩比彻姆有限公司 | Use of benzopyranols to treat neurological disorders |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis and Biological Activity of a Novel Series of Nonsteroidal,Peripherally Selective Androgen Receptor Antagonists Derived from 1,2-Dihydropyridono[5,6-g]quinolines;Lawrence G. Hamann，et al.;《J. Med. Chem.》;19981231;第41卷;第623-639页 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106397317A (en) | 2017-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104892672B (en) | Chiral spiro phosphine-nitrogen-sulphur tridentate ligand and its preparation method and application | |
| Rajawinslin et al. | Iron/acetic acid mediated intermolecular tandem C–C and C–N bond formation: an easy access to acridinone and quinoline derivatives | |
| CN106397317B (en) | 1,2,3,4- 3,4-tetrahydroquinoline compounds and its synthetic method and application | |
| CN105017259A (en) | Trifluoromethyl containing quinazoline derivative and preparation method and application thereof | |
| CN107892654B (en) | Isolongifolane-based fluorescent acid-base indicator and synthetic method and application thereof | |
| CN106146334B (en) | 2,3- diaryl -2- alkynes propionamido- -3- arylamino methyl propionate derivative and its preparation method and application | |
| CN102898385A (en) | Synthesis of 4(3H)-quinazolone through catalysis of recyclable copper oxide | |
| CN102942511B (en) | Preparation method of cyclopentadiene | |
| CN105237491B (en) | Isoxazole compounds and its synthetic method | |
| CN104610267A (en) | Method for efficiently synthetizing 6-alkylpyrazol-[1,5-c]-quinazoline skeleton compounds under no catalytic condition | |
| Xu et al. | Total synthesis of hirsutellide A | |
| CN104030994A (en) | Synthetic method for 1,2,3-triazole compounds | |
| Dargó et al. | Application of Proline-Derived (Thio) squaramide Organocatalysts in Asymmetric Diels–Alder and Conjugate Addition Reactions | |
| CN103694182A (en) | Preparation method of quinoxaline compound | |
| CN103923058A (en) | Method for synthesizing vilanterol intermediate and salt thereof | |
| CN108558758A (en) | A kind of synthetic method of 4- fluorine isoquinolin -5- amine | |
| CN104402813B (en) | Novel method for synthesizing sorafenib | |
| CN107353256A (en) | The method of the triazole compounds of 4 acetyl group of one pot process 1,2,3 | |
| CN109705014B (en) | Novel chiral amine oxide ligand and preparation method thereof | |
| CN104402910B (en) | Thiazole pyridine compound and preparation method thereof | |
| CN105884673B (en) | A kind of synthetic method of indole derivatives | |
| CN104059075A (en) | 8, 9-mono and/or di-substituted imidazo[1, 2-c]quinazolin-3(2H)-one fused heterocyclic compound and preparation method thereof | |
| CN104788431B (en) | Synthetic method for chiral marine natural product with high optical activity | |
| CN105566202B (en) | A kind of 1,2,3,4- tetrahydro cyclopentyl base indole derivatives and its synthetic method | |
| CN106866489A (en) | A kind of synthetic method of nitrogenous pharmaceutical intermediate indole derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190322 Termination date: 20210926 |