CN103626767A - Azaindole with regionselectivity and synthetic method thereof - Google Patents
Azaindole with regionselectivity and synthetic method thereof Download PDFInfo
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- CN103626767A CN103626767A CN201310641083.8A CN201310641083A CN103626767A CN 103626767 A CN103626767 A CN 103626767A CN 201310641083 A CN201310641083 A CN 201310641083A CN 103626767 A CN103626767 A CN 103626767A
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- azaindole
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- 0 C*1C(CCCC2)=C2C2*=C(C(F)(F)F)C=CC12 Chemical compound C*1C(CCCC2)=C2C2*=C(C(F)(F)F)C=CC12 0.000 description 1
Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to azaindole with regioselectivity and a synthetic method thereof, and mainly solves the technical problems that no document reports the synthesis of azaindole with regioselectivity, and the structure-function relationship of the pharmaceutical activity of the azaindole is screened. The structure general formula is as follows (as shown in the specification), R1 and R2 are substituent groups on the pentabasic pyrrole ring of the azaindole, and can be hydrogen, straight chains, side chains or ring-shaped alkyl groups, R3 is an alkyl group on the hexahydric n-heterocyclic of the azaindole, a halogen substituent group or a hydrogen atom without substitution, and A is one of carbon atom or nitrogen heteroatom.
Description
Technical field
The present invention relates to a kind of azaindole and synthetic method thereof, azaindole and synthetic method thereof that particularly a kind of regioselectivity is very high.
Background technology
Benzazole compounds is the important medicine intermediate of a class.Indoles is natural amino acid---tryptophane, and the integral part of important neurotransmitter serotonin.In a lot of natural products and synthetic Medicine small molecule, all comprise indolyl radical.
Azaindole, as the bioisostere of indoles, is more and more subject to extensive concern.
The summary that relevant azaindole is synthetic, mainly contain Beno t Joseph and in 2007, be published in the < < 4 of tetrahedron (Tetrahedron) 8689-8707 page, 5, synthetic and the reaction > > of 6-azaindole, and M é rour Jean-Yves is published in modern organic chemistry (Current Organic Chemistry) in calendar year 2001, synthetic and the reaction > > of the < < 7-azaindole of 471-506 page.The synthetic of azaindole of organo-metallic mediation is the synthesis method of the important azaindole of a class, sees the summary of Jinhua J. Song, is published in chemical social comment (Chem. Soc. Rev), 1120-1132 page in 2007.
In addition, Wang Tao has delivered in 2002 and has been entitled as mono-kind of < < and prepares 4, the article of the simple method > > of 6-azaindole, its core content is that Bartili indole synthesis is applied to the synthetic of azaindole, is published in organic chemistry magazine (J. Org. Chem.) 2345-2347 page.More novel is that Mattieu Desroses was published in the microwave of tetrahedron magazine (Tetrahedron Letters) 4417-4420 page introduction and the azaindole one-pot synthesis of propyl group phosphoric anhydride T3P mediation in 2011.
PCT patent No. WO2011128455A1 has introduced the cyclohexyl hydrazone of the bromo-2-hydrazine of 6-pyridine in solvent two polyoxyethylene glycol, under 250 ℃ of microwave conditions, reacts 0.5 hour, can obtain 2 of 51% yield, the dibasic 6-bromo-7-azaindole of 3-.When we are according to said method synthetic, find that two polyoxyethylene glycol are very low as solvent reaction yield.When optimizing reaction, when substituting two polyoxyethylene glycol as solvent with thermal oil (mixture of phenyl ether/biphenyl), 250 ℃ of reactions of microwave 10 minutes, can obtain product by high yield (approximately 70%).By that analogy, we have synthesized other azaindole in this way, have found interesting regioselectivity.When the hydrazone of the bromo-3-hydrazine of 6-indoles is closing ring, the pass of energy highly selective, at the ortho position of pyridine nitrogen, obtains single 4-azaindole, rather than the contraposition of closing in pyridine nitrogen obtains 6-azaindole.In addition, when the hydrazone of 3-hydrazine quinoline closes indole ring, be optionally what to close in the 4-position of quinoline.
Summary of the invention
The object of the present invention is to provide the synthesis method of the azaindole that a kind of regioselectivity of novelty is very high.Mainly solve in azaindole synthesis method optionally technical matters of domain of dependence.
Technical scheme of the present invention: the azaindole of regioselectivity, is characterized in that: general structure is shown in following formula:
Formula
i
R wherein
1, R
2for substituting group on five yuan of pyrrole rings on azaindole, can be hydrogen, straight chain, side chain or cyclic alkyl substituting group, preferred hydrogen, straight chain, side chain or cyclic alkyl substituting group are selected from: R
1for hydrogen, R
2for sec.-propyl; R
1for methyl, R
2for methyl or R
1and R
2ring ethyl for ring-type.R
3for the alkyl on six-membered heterocycle on azaindole or halogenic substituent or be without the hydrogen atom replacing.A is a kind of in carbon or nitrogen heteroatom, is preferably nitrogen-atoms.
Synthesizing of preferred regioselectivity azaindole is following compounds:
1-a:2-is bromo-6,7,8,9-tetrahydrochysene-5H-pyrido [3,2, b] indoles,
1-b:5-is bromo-2,3-dimethyl-1H-pyrrolo-[3,2, b] pyridine,
1-c:5-bromo-3-sec.-propyl-1H-pyrrolo-[3,2, b] pyridine,
1-d:6,7,8,9-tetrahydrochysene-5H-pyrido [3,2, b] indoles,
1-e:2-is bromo-6,7,8,9-tetrahydrochysene-5H-pyrido [2,3, b] indoles,
1-f:6-is bromo-2,3-dimethyl-1H-pyrrolo-[2,3, b] pyridine,
1-g:the bromo-1-of 3-methyl-6,7,8,9-tetrahydrochysene-5H-pyrido [3,4, b] indoles,
1-h:6,7,8,9-tetrahydrochysene-5H-pyrido [4,3, b] indoles,
1-i:6,7,8,9-tetrahydrochysene-5H-pyrazine is [2,3, b] indoles also,
1-j:8,9,10,11-tetrahydrochysene-7H-indoles is [2,3, c] quinoline also.
When A is formula
iin 4 nitrogen-atoms, be formula
iIshown in 4-azaindole:
Formula
iI
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group, R
3for hydrogen or halogen.
When A is formula
iin 7 nitrogen-atoms, be formula
iIIshown in 7-azaindole:
Formula
iII
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group, R
3for hydrogen or halogen.
When A is formula
iin 6 nitrogen-atoms, be formula
iVshown in 6-azaindole:
Formula
iV
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group, R
3for replacing halogen or alkane, R
4for hydrogen, halogen or alkane substitute.
When A is formula
iin 5 nitrogen-atoms, be formula
vshown in 5-azaindole:
Formula
v
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group.
When A is formula
iin 4,7 nitrogen-atoms, be formula
vIshown in 4, the two azaindoles of 7-:
Formula
vI
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group.
When A is formula
iin the quinoline ring of 7 nitrogen-atoms, be formula
vIIshown in 7-azepine quino-indoles:
Formula
vII
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group.
Formula
iIcompounds process for production thereof, step is as follows: the 6-replacement-3-hydrazine pyridine of take is raw material, refluxes and prepares the hydrazone of pyridine under ethanol condition with aldehyde, ketone, then uses thermal oil as solvent, reaction at lower 250 ℃ of microwave, obtains the 5-replacement-4-azaindole of single regioselectivity.Reaction formula is as follows:
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group, R
3for hydrogen or halogen.
Work as R
3during for hydrogen, can also use the method dehalogenation of hydrogenation, reaction formula is as follows:
。
Formula
iIIcompounds process for production thereof, step is as follows: the 6-replacement-1-hydrazine pyridine of take is raw material, refluxes and prepares the hydrazone of pyridine under ethanol condition with aldehyde, ketone, then uses thermal oil as solvent, and at lower 250 ℃ of microwave, reaction, obtains 6-replacement-7-azaindole.Reaction formula is as follows:
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group, R
3for hydrogen or halogen.
Formula
iVcompounds process for production thereof, step is as follows: with 2,6-, bis-replacement-3-hydrazine pyridines, for raw material, reflux and prepare the hydrazone of pyridine under ethanol condition with aldehyde, ketone, then use thermal oil as solvent, at lower 250 ℃ of microwave, reaction, obtains 5,7-, bis-replacement-6-azaindoles.Reaction formula is as follows:
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group, R
3for replacing halogen or alkane, R
4for hydrogen, halogen or alkane substitute.
Formula
vcompounds process for production thereof, step is as follows: the 4-hydrazine pyridine of take is raw material, refluxes and prepares the hydrazone of pyridine under ethanol condition with aldehyde, ketone, then uses thermal oil as solvent, and at lower 250 ℃ of microwave, reaction, obtains 5-azaindole.Reaction formula is as follows:
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group.
Formula
vIcompounds process for production thereof, step is as follows: the 1-hydrazine pyrazine of take is raw material, refluxes and prepares the hydrazone of pyridine under ethanol condition with aldehyde, ketone, then uses thermal oil as solvent, and reaction at lower 250 ℃ of microwave obtains the two azaindoles of 4,7-.Reaction formula is as follows:
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group.
Formula
vIIcompounds process for production thereof, step is as follows: the 3-hydrazine quinoline of take is raw material, refluxes and prepares the hydrazone of pyridine under ethanol condition with aldehyde, ketone, then uses thermal oil as solvent, reaction at lower 250 ℃ of microwave, obtains the 6-azepine quino-indoles of single regioselectivity.Reaction formula is as follows:
R
1, R
2for hydrogen, straight chain, side chain or cyclic alkyl substituting group.
Embodiment
Enumerate embodiment so that the present invention is described in detail, but the present invention is not limited to these embodiment.
embodiment 1:
2-is bromo-6,7,8,9-tetrahydrochysene-5H-pyrido [3,2, b] indolespreparation
Operation steps:
The bromo-5-fluorine of 2-pyridine (4 grams, 23 mmoles) and 10 milliliters of hydrazine hydrates are reacted 1 hour with 110 ℃, microwave, will in reaction solution impouring 60 ml waters, separate out solid after cooling, filter, after filtration cakes torrefaction the 2 grams of bromo-5-hydrazine of 2-pyridines, yield 47%.
1H?NMR?(400MHz,?CDCl
3)?
d:?7.99?(br.?s.,?1H),?7.30?(s,?1H),?7.11?(d,?
J=8.0?Hz,?1H),?5.28?(s,?1H),?3.64?(s,?2H)。
By the bromo-5-hydrazine of 2-pyridine (2 grams, 11 mmoles) and cyclohexyl ketone (1.15 grams, 12 mmoles) 15 milliliters of ethanol than water four to one in room temperature reaction 1 hour, filter out solid and obtain the 0.77 gram of bromo-5-cyclohexyl of 2-hydrazone pyridine, yield 28%.
1H?NMR?(400MHz,?CDCl
3)?
d：8.07?(s,?1H),?7.39?-?7.33?(m,?1H),?7.33?-?7.29?(m,?1H),?7.07?(s,?1H),?2.37?-?2.31?(m,?4H),?1.91?–?1.99?(m,?2H),?1.80?-?1.72?(m,?4H)。
By (0.77 gram of the bromo-5-cyclohexyl of 2-hydrazone pyridine, 2.9 mmoles) in 3 milliliters of thermal oils, in 250 ℃ of microwave reactions 10 minutes, the cooling rear silicagel column of directly going up of reaction solution, sherwood oil is eluent than ethyl acetate approximately ten to, collect component concentrating under reduced pressure and obtain 0.52 gram of 2-bromo-6,7,8,9-tetrahydrochysene-5H-pyrido [3,2, b] indoles, yield 72%.
1H?NMR?(400MHz,?CDCl
3)?
δ：7.85?(s,?1H),?7.40?(d,?J=8.3?Hz,?1H),?7.15?(d,?
J=8.3?Hz,?1H),?2.82?(t,?
J=6.0?Hz,?2H),?2.77?(t,?
J=6.1?Hz,?2H),?1.97?-?1.91?(m,?2H),?1.90?-?1.83?(m,?2H)。
embodiment 2:
5-is bromo-2,3-dimethyl-1H-pyrrolo-[3,2, b] pyridinepreparation
Operation steps:
By the bromo-5-hydrazine of 2-pyridine (8 grams, 46.2 mmoles) and fourth-2 ketone (5 grams, 69.4 mmoles) in 65 milliliters of ethanol in room temperature reaction 18 hours, reaction solution pressurization is concentrated to obtain the 4.34 grams of bromo-5-(2-(fourth-2-of 2-hydrazones) pyridine crude product.
By the 4.34 grams of bromo-5-(2-(fourth-2-of crude product 2-hydrazones) pyridine is in 15 milliliters of thermal oils, in 250 ℃ of microwave reactions 10 minutes, the cooling rear silicagel column of directly going up of reaction solution, sherwood oil is eluent than ethyl acetate approximately 20 to, collecting component concentrating under reduced pressure, to obtain 2.8 grams of 5-bromo-2,3-dimethyl-1H-pyrrolo-[3,2, b] pyridine, yield 69%.
1H?NMR?(400MHz,?CDCl
3)?
δ：7.37（d,?
J=8.1?Hz,?1H）,?7.14?（d,?
J=8.1?Hz,?1H）,?2.42(s,?3H),?2.37(s,?3H)。
embodiment 3:
5-bromo-3-sec.-propyl-1H-pyrrolo-[3,2, b] pyridinepreparation
Operation steps:
By the bromo-5-hydrazine of 2-pyridine (5 grams, 26.6 mmoles) and 3-methyl butyraldehyde (3.44 grams, 39.9 mmoles) in 50 milliliters of ethanol in room temperature reaction 18 hours, reaction solution pressurization is concentrated to obtain the 3.8 grams of bromo-5-(2-(3-methyl butyl of 2-hydrazones) pyridine crude product.
By the 3.8 grams of bromo-5-(2-(3-methyl butyl of crude product 2-hydrazones) pyridine is in 15 milliliters of thermal oils, in 250 ℃ of microwave reactions 10 minutes, the cooling rear silicagel column of directly going up of reaction solution, sherwood oil is eluent than ethyl acetate approximately 20 to, collect component concentrating under reduced pressure and obtain the 1.7 grams of bromo-3-sec.-propyl-1H-of 5-pyrrolo-es [3,2, b] pyridine, yield 49%.
1H?NMR?(400MHz,?CDCl
3)?
δ：7.48（d,?
J=8.1?Hz,?1H）,?7.22?(s,?1H),?7.19?（d,?
J=8.1?Hz,?1H）,?3.40(m,?1H),?1.36(d,
?J=6.8?Hz,?6H)。
embodiment 4:
6,7,8,9-tetrahydrochysene-5H-pyrido [3,2, b] indolespreparation
Operation steps:
By (2.0 grams of 3-cyclohexyl hydrazone pyridines, 10.6 mmoles) in 10 milliliters of thermal oils, in 250 ℃ of microwave reactions 10 minutes, the cooling rear silicagel column of directly going up of reaction solution, sherwood oil is eluent than ethyl acetate approximately ten to, collect component concentrating under reduced pressure and obtain 0.52 gram 6,7,8,9-tetrahydrochysene-5H-pyrido [3,2, b] indoles, yield 11%.
In addition, with the way yield of hydrogenation dehalogenation, can reach 95%.
Operation steps:
2-is bromo-6,7,8, (0.2 gram of 9-tetrahydrochysene-5H-pyrido [3,2, b] indoles, 0.8 mmole) and 0.1 gram, palladium carbon in 5 milliliters of ethanol, under hydrogen, stir 1 hour, filtering palladium carbon, mother liquor concentrating under reduced pressure obtains 0.13 gram 6,7,8,9-tetrahydrochysene-5H-pyrido [3,2, b] indoles, yield 95%.
1H?NMR?(400MHz,?CD
3OD-
d4)?
δ：8.36?（m,?2H）,?7.52?(t,1H),?2.97?(t,?2H),?2.83?(t,?2H),?1.99-1.94?(m,?4H)。
embodiment 5:
2-is bromo-6,7,8,9-tetrahydrochysene-5H-pyrido [2,3, b] indolespreparation
Operation steps:
By 2,6-dibromo pyridine (5.0 grams, 21.1 mmoles) and 10 milliliters of hydrazine hydrates, 50 milliliters of ethanol are heated to reflux, and react 16 hours.Reaction solution concentrating under reduced pressure, washing, obtains the 2.8 grams of bromo-6-hydrazine of 2-pyridines, yield 71%.
By the bromo-6 hydrazine pyridines of 2-(2.8 grams, 14.9 mmoles) and cyclohexyl ketone (2.2 grams, 22.3 mmoles) in 25 milliliters of ethanol, room temperature reaction 18 hours, reacting liquid filtering, obtains the 2.6 grams of bromo-6-cyclohexyl of 2-hydrazone pyridines, yield 65%.
1H?NMR?(400MHz,?CDCl
3)?
d：7.45?(t,?1H),?7.01?(d,?
J=8.3?Hz,1H),?6.82?(d,?
J=8.3?Hz,1H),?2.40?(m,?2H),?2.18?(m,?2H),?1.55?(m,?6H)
By 0.77 gram of the bromo-6-cyclohexyl of 2-hydrazone pyridine, 2.9 mmoles) in 3 milliliters of thermal oils, in 250 ℃ of microwave reactions 10 minutes, the cooling rear silicagel column of directly going up of reaction solution, sherwood oil is eluent than ethyl acetate approximately ten to, collect component concentrating under reduced pressure and obtain 0.51 gram of 2-bromo-6,7,8,9-tetrahydrochysene-5H-pyrido [2,3, b] indoles, yield 72%.
1H?NMR?(400MHz,?CDCl
3)?
δ：8.80?(br,?1H),?7.59?(d,?
J=8.2?Hz,?1H),?7.16?(d,?
J=8.2?Hz,?1H),?2.79?(t,?
J=6.1?Hz,?2H),?2.66?(t,
?J=6.1?Hz,?2H),?1.96-1.85?(m,?4H)。
embodiment 6:6-is bromo-2,3-dimethyl-1H-pyrrolo-[2,3, b] pyridinepreparation
Operation steps:
By the bromo-6-hydrazine of 2-pyridine (4 grams, 21.3 mmoles) and fourth-2 ketone (2.3 grams, 31.9 mmoles) in 40 milliliters of ethanol in room temperature reaction 18 hours, reaction solution pressurization is concentrated to obtain the 3.1 grams of bromo-6-(2-(fourth-2-of 2-hydrazones) pyridine crude product.
By the 0.8 gram of bromo-5-(2-(fourth-2-of crude product 2-hydrazone) pyridine is in 15 milliliters of thermal oils, in 250 ℃ of microwave reactions 10 minutes, the cooling rear silicagel column of directly going up of reaction solution, sherwood oil is eluent than ethyl acetate approximately 20 to, collecting component concentrating under reduced pressure, to obtain 0.5 gram of 6-bromo-2,3-dimethyl-1H-pyrrolo-[2,3, b] pyridine, yield 67%.
1H?NMR?(400MHz,?CDCl
3)?
δ：8.78?(br,?1H),?7.63（d,?
J=8.1?Hz,?1H）,?7.20?（d,?
J=8.1?Hz,?1H）,?2.42(s,?3H),?2.22(s,?3H)。
the bromo-1-of embodiment 7:3-methyl-6,7,8,9-tetrahydrochysene-5H-pyrido [3,4, b] indolespreparation
Operation steps:
By (0.37 gram of Sodium Nitrite, 5.3 mmoles) be dissolved in 1 ml water, under ice bath, be slowly added dropwise to (1 gram of the bromo-2-methyl-3-of 6-amido pyridine, 5.3 mmoles) in 10 milliliter of 6 mole hydrochloride, react 20 minutes, add 2 milliliters of concentrated hydrochloric acid solutions of tindichloride monohydrate (2.18 grams, 9.65 mmoles), remove ice bath, room temperature reaction 3 hours.Reacting liquid filtering,, mother liquor is adjusted to pH value 5 with sodium hydroxide, ethyl acetate extraction, the crude product of dry concentrated the 1.1 grams of bromo-2-methyl-3-of the 6-hydrazine pyridines of organic phase.
The crude product of the 1.1 grams of bromo-2-methyl-3-of 6-hydrazine pyridines is dissolved in to 10 milliliters of ethanol, adds cyclohexyl ketone (0.53 gram, 5.4 mmoles), room temperature reaction 18 hours, reacting liquid filtering obtains the 1 gram of bromo-6-methyl-5-of 2-cyclohexyl hydrazone pyridine, yield 65%.
By (0.5 gram of the bromo-6-methyl-5-of 2-cyclohexyl hydrazone pyridine, 1.8 mmoles) in 3 milliliters of thermal oils, in 200 ℃ of microwave reactions 10 minutes, the cooling rear silicagel column of directly going up of reaction solution, sherwood oil is eluent than ethyl acetate approximately 20 to, collect component concentrating under reduced pressure and obtain the 0.32 gram of bromo-1-of 3-methyl-6,7,8,9-tetrahydrochysene-5H-pyrido [3,4, b] indoles, yield 68%.
1H?NMR?(400MHz,?CDCl
3)?
δ：7.34?(s,?1H),?2.42(s,?3H),?2.81(m,?2H),?2.64(m,?2H),?2.60?(s,?3H),?1.94-1.85?(m,?4H)。
embodiment 8:6,7,8,9-tetrahydrochysene-5H-pyrido [4,3, b] indolespreparation
Operation steps:
By adding 8 milliliters of ethanol than the mixed solution of water four to one in 4-hydrazine pyridine hydrochloride (0.8 gram, 5.5 mmoles) and cyclohexyl ketone (1.1 grams, 11 mmoles), react 2 hours, reaction solution is adjusted to pH value 6, filters to obtain 0.58 gram of 3-cyclohexyl hydrazone pyridine.
1H?NMR?(400MHz,?CDCl
3)?
δ：8.07?(d,?
J=8.0?Hz?,?2H),?6.97?(d,?
J=8.0?Hz?,?2H),?2.44?(m,?2H),?2.36?(m,?2H),?1.71?(m,?6H)。
By (0.58 gram of 3-cyclohexyl hydrazone pyridine, 1.8 mmoles) in 3 milliliters of thermal oils, in 250 ℃ of microwave reactions 10 minutes, the cooling rear silicagel column of directly going up of reaction solution, sherwood oil is eluent than ethyl acetate approximately 20 to, collect component concentrating under reduced pressure and obtain 0.31 gram 6,7,8,9-tetrahydrochysene-5H-pyrido [4,3, b] indoles, yield 59%.
1H?NMR?(400MHz,?CDCl
3)?
δ：8.55?(s,?1H),?8.03?(d,?
J=8.0?Hz?,?2H),?7.26?(d,
?J=8.0?Hz?,?2H),?2.75?(m,?4H),?2.36?(m,?2H),?1.92?(m,?4H)。
embodiment 9:6,7,8,9-tetrahydrochysene-5H-pyrazine is [2,3, b] indoles alsopreparation
Operation steps:
By adding 10 milliliters of ethanol than the mixed solution of water four to one in 2-hydrazine pyrazine (1.5 grams, 13.6 mmoles) and cyclohexyl ketone (2.0 grams, 21.4 mmoles), react 2 hours, filter to obtain 1.5 grams of 2-cyclohexyl hydrazone pyrazines, yield 58%
1H?NMR?(CDCl
3)?
δ：8.63?(s,?2H),?7.99?(m,?2H),?7.75?(m,?1H),?2.40?(m,?2H),?2.35?(m,?2H),?1.75?(m,?6H)
By 2-cyclohexyl hydrazone pyrazine (0.2 gram, 1.1 mmoles) in 2 milliliters of thermal oils, in 250
oc microwave reaction 10 minutes, the cooling rear silicagel column of directly going up of reaction solution, sherwood oil is eluent than ethyl acetate approximately 20 to, collects component concentrating under reduced pressure and obtains 0.12 gram 6,7,8,9-tetrahydrochysene-5H-pyrazine is [2,3, b] indoles also, yield 66%.
1H?NMR?(400MHz,?CDCl
3)?
δ：8.20?(d,?
J=3.0Hz,?1H),?8.08?(d,?
J=3.0?Hz?,?1H),?2.86?(m,?4H),?2.78?(m,?2H),?1.98-1.89?(m,?4H)。
embodiment 10:8,9,10,11-tetrahydrochysene-7H-indoles is [2,3, c] quinoline alsopreparation
Operation steps:
By (0.48 gram of Sodium Nitrite, 7.28 mmoles) be dissolved in 1 ml water, under ice bath, be slowly added dropwise to (1 gram, the bromo-quinoline of 3-, 6.93 mmoles) in 10 milliliter of 6 mole hydrochloride, react 20 minutes, add 2 milliliters of concentrated hydrochloric acid solutions of tindichloride monohydrate (2.8 grams, 12.4 mmoles), remove ice bath, room temperature reaction 18 hours.Reacting liquid filtering obtains 0.92 gram of 3-hydrazine quinoline, yield 68%.
By 3-hydrazine quinoline (0.82 gram, 5.2 mmoles) and cyclohexyl ketone (0.76 gram, 7.7 mmoles), in 10 milliliters of ethanol, room temperature reaction 2 hours, reacting liquid filtering obtains 0.67 gram of 3-cyclohexyl hydrazone quinoline, yield 72%.
1H?NMR?(400MHz,?CDCl
3)?
δ：8.65?(d,?
J=3.0Hz,?1H),?7.99?(m,?1H),?7.76?(s,?1H),?7.72?(m,?1H),?7.47?(m,?2H),?7.24?(s,?1H),?2.46?(m,?4H),?1.79?(m,?6H)
By 3-cyclohexyl hydrazone quinoline (0.38 gram, 1.6 mmoles), in 3 milliliters of thermal oils, in 250 ℃ of microwave reactions 10 minutes, reaction solution was cooling, in 50 milliliters of sherwood oils of impouring, separate out solid, filter to obtain 0.22 gram 8,9,10,11-tetrahydrochysene-7H-indoles is [2,3, c] quinoline also, yield 62%.
1H?NMR?(400MHz,?DMSO-
d6)?
δ：11.75?(br,?1H),?8.87(s,?1H),?8.22(m,?1H),?8.00(m,?1H),?7.52(m,?2H),?3.05?(m,?2H),?2.83?(m,?2H),?1.89?(m,?4H)。
embodiment 11: compound
1a-kto the pharmacological evaluation to the rat model of (R)-Alpha-Methyl histamine induction dipsogenia
reagent and compound are prepared:
1. male, (280-330 gram, Glaxo) closes respectively in 12 cages Lister Hooded rats, allows free diet, wherein has separately one in experiment, within first 18 hours, forbid drinking-water but can take food.All test operations carried out between at 14 o'clock in afternoon in the morning 10.Medicine is taked single-dose vein or subcutaneous every 1 milliliter of every kg body weight dosage, or twice administration rat abdomen two lateral vein or subcutaneous every 0.5 milliliter of every kg body weight; After administration, rat is closed in cage, gives with food but to drinking-water 30 minutes.Mouse is separately raised in independent cage, given with 20 milliliters of droppers but to food.After 10 minutes, the drinking-water volume of metering rat;
Preparation damping fluid: by 20ml substrate (1M) add 1L(1 *) damping fluid, be stored in 4 ℃.;
3. prepare dyestuff storage liquid: 100ml damping fluid is added in one bottle of dye powder, fully mix until dissolving is completely stored in-40 ℃;
4. preparation 250mM storage liquid: 1ml damping fluid is added in the powder that a dye reagent box provides, fully mix until dissolve completely, be stored in-40 ℃;
5. 0.1% substrate solution: take 1g substrate, dissolve completely with 1L damping fluid, be stored in-40 ℃;
6. prepare hMTLR (human stomach power element) agonist solution: 1mg substrate is dissolved in 1492ul damping fluid, is mixed with 200uM storage liquid, 20ul packing, is stored in-40 ℃;
7. prepare testing compound solution: testing compound is dissolved in DMSO, is mixed with 20mM storage liquid;
8. HEK-hMTLR(human stomach power element) cell cultures stores with substratum.
cell is prepared:
1. the day before yesterday of testing, with the HEK-hMTLR(human stomach power element in trysinization culture dish) cell, and with substratum by cell suspension;
2. pair cell is counted, and is 5 * 10 by cell density dilution
5individual/ml, plants cell in 384 coated orifice plates of polylysine, 25000, every hole cell;
3. 384 orifice plates are put in to (37 ℃, the carbonic acid gas of 5% concentration expressed in percentage by volume) in cell culture incubator, overnight incubation (8-16 hour).
active by FLIPR detection compound:
1. the same day was prepared dyestuff working fluid in experiment: 200ul 250mM substrate is added in 20ml dyestuff storage liquid, mix;
2. from incubator, take out Tissue Culture Plate, detect under the microscope cell density.Cell is through overnight growth, and density should be greater than 90%;
3. after the cell culture medium in centrifugal removal plate, in every hole, add 40ul dyestuff working fluid;
4. Tissue Culture Plate is put back in 37 ℃ of incubators and hatched 30 minutes, be then put in equilibrium at room temperature 30 minutes;
5. prepare compound test plate;
6. programming and reading:
The specified location of compound plate and cell plate being put into instrument, setting program is transferred to 10ul compound in cell plate 40ul dye liquor.Compound concentration is diluted 5 times, and the final quality percentage concentration of solution is 0.5%, positive control [concentration be 100nM;
7. data analysis: derive raw data after reading, by following calculation formula, the resulting signal value of each mass percentage concentration of testing compound is converted to percent value.
100% * (compound signal value-negative control signal value)/(positive control signal value-negative control signal value)
With related software, to data analysis, and matching compound concentration-signal value curve, draws EC50 value and the IA of testing compound.
Synthetic compound azaindole is to HEK-hMTLR(human stomach power element) cell EC50 value is 5681nM, maximum activation value is 35%;
Experiment conclusion: this experiment shows that this compounds is to HEK-hMTLR(human stomach power element) cell has certain agonism, likely develops into the new medicine with gastric motility element.
Claims (7)
1. an azaindole for regioselectivity, is characterized in that: general structure is shown in following formula:
Formula
1
R wherein
1, R
2for hydrogen, straight chain, a kind of in side chain or cyclic alkyl substituting group, R
3for alkyl or halogenic substituent or be without the hydrogen atom replacing, A is a kind of in carbon or nitrogen heteroatom.
2. the azaindole of regioselectivity according to claim 1, is characterized in that: R
1, R
2be chosen as one of following three kinds of modes: R
1for hydrogen, R
2for sec.-propyl; R
1for methyl, R
2for methyl; Or R
1and R
2ring ethyl for ring-type.
3. the azaindole of regioselectivity according to claim 1, is characterized in that: A is at least one nitrogen-atoms.
4. the azaindole of regioselectivity according to claim 1, is characterized in that:
The azaindole compound of described regioselectivity is a kind of in following compound:
1-a:2-is bromo-6,7,8,9-tetrahydrochysene-5H-pyrido [3,2, b] indoles,
1-b:5-is bromo-2,3-dimethyl-1H-pyrrolo-[3,2, b] pyridine,
1-c:5-bromo-3-sec.-propyl-1H-pyrrolo-[3,2, b] pyridine,
1-d:6,7,8,9-tetrahydrochysene-5H-pyrido [3,2, b] indoles,
1-e:2-is bromo-6,7,8,9-tetrahydrochysene-5H-pyrido [2,3, b] indoles,
1-f:6-is bromo-2,3-dimethyl-1H-pyrrolo-[2,3, b] pyridine,
1-g:the bromo-1-of 3-methyl-6,7,8,9-tetrahydrochysene-5H-pyrido [3,4, b] indoles,
1-h:6,7,8,9-tetrahydrochysene-5H-pyrido [4,3, b] indoles,
1-i:6,7,8,9-tetrahydrochysene-5H-pyrazine is [2,3, b] indoles also,
1-j:8,9,10,11-tetrahydrochysene-7H-indoles is [2,3, c] quinoline also.
5. a synthetic method of preparing the azaindole of regioselectivity claimed in claim 1, it is characterized in that preparation process is as follows: a kind of in the bromo-5-hydrazine of the 2-of take pyridine, the bromo-6-hydrazine of 2-pyridine, 6-methyl-2-bromo-5-hydrazine pyridine or 4-hydrazine pyridine is raw material, under ethanol condition, reflux and prepare the hydrazone of pyridine with aldehyde, ketone, then use thermal oil as solvent, reaction at lower 250 ℃ of microwave, obtains respectively the bromo-4-azaindole of 5-, 7-azaindole, 5-bromine-7-methyl-6-azaindole and the 5-azaindole of the single regioselectivity corresponding with raw material.
6. a synthetic method of preparing the azaindole of regioselectivity claimed in claim 1, it is characterized in that preparation process is as follows: the 3-hydrazine quinoline of take is raw material, prepare corresponding hydrazone, then use thermal oil as solvent, reaction at lower 250 ℃ of microwave, obtains the 6-pyridine diindyl of single regioselectivity.
7. a synthetic method of preparing the azaindole of regioselectivity claimed in claim 1, is characterized in that preparation process is as follows: the 2-hydrazine pyrazine of take is raw material, prepares corresponding hydrazone, then use thermal oil as solvent, at lower 250 ℃ of microwave, reaction, obtains 4,7-diaza indoles.
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