CN106928222A - A kind of preparation method of 3 alkyl Indoli zine derivatives - Google Patents
A kind of preparation method of 3 alkyl Indoli zine derivatives Download PDFInfo
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- 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
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Abstract
The invention discloses a kind of preparation method of 3 alkyl Indoli zine derivatives, by what is directly produced by pyridine derivate and primary halogenated alkaneNFixanol, in alkali and 2,2,6,6 tetramethyl piperidine nitrogen oxides（TEMPO）Under existence condition, with Electron-poor olefin hydrocarbon reaction, it is prepared into 3 alkyl Indoli zine derivatives, present invention aim at the preparing raw material by developing 3 brand-new alkyl Indoli zine derivatives, and corresponding process, realize under loose reaction condition, with relatively low production cost, 3 alkyl Indoli zine derivatives are synthesized simple and easy to apply and environmentally friendlyly.
Description
Technical field
The present invention relates to Synthetic Organic Chemistry technology, the more particularly to preparation method of Indoli zine derivatives, and in particular to one
Plant the preparation method of 3- alkyl Indoli zine derivatives.
Background technology
Indoli zine derivatives are widely used in biology, agricultural chemicals, medicine and field of light emitting materials, be production medicine, dyestuff and
The necessity of luminous organic material.For example：It is pigment, herbicide, latent property inhibitor of phospholipase enzymes, anti-Leishmania and antiviral
Active principle in medicine；In addition, it has also showed that antimycobacterial activity；It is that synthesis has important physiologically active biological
The key intermediate of alkali.Research is confirmed again in the last few years, the bioactivity of Indoli zine derivatives, be the mankind antitumor, antibacterial,
The aspects such as antiviral, mite killing worm, anti-inflammatory, anti-arrhythmia, anti-hypertension are also played positive role.Wherein, nitrogen in 3- alkyl
Indene derivative is a kind of important synthetic in Indoli zine derivatives, with various properties, and is used for multiple fields.So
And, there is certain difficulty in 3- alkyl Indoli zine derivatives synthesis in the prior art, not only course of reaction is long, step is more, also needs
In most cases to also need to meet the harsh reaction condition of anhydrous and oxygen-free environment, while former using expensive metal and part
Material price is high and majority cannot directly be bought from the market, has thus resulted in its high preparation cost.Therefore, using in the market
Cheap, the large chemical products that can directly buy are raw material, using organic reagent as oxidant, are directly synthesized 3- alkyl indolizine
Method there is the extensive market demand.
The content of the invention
The present invention proposes a kind of simple method for preparing of 3- alkyl Indoli zine derivatives.Purpose is brand-new by developing
3- alkyl Indoli zine derivatives preparing raw material, and corresponding process realized under loose reaction condition, with relatively low
Production cost, 3- alkyl Indoli zine derivatives are synthesized simple and easy to apply and environmentally friendlyly.
The present invention is achieved through the following technical solutions：
A kind of preparation method of 3- alkyl Indoli zine derivatives, by what is directly produced by pyridine derivate and primary halogenated alkaneN- alkane
Yl pyridines salt, in alkali and 2,2,6,6- tetramethyl piperidine nitrogen oxides（TEMPO）It is anti-with electron deficient olefins under existence condition
Should, it is prepared into 3- alkyl Indoli zine derivatives, it is characterised in that：The preparation method foundation
Chemical equation, is obtained by following processing step：
1）By required starting components：Pyridine, primary halogenated alkane, electron deficient olefins, alkali and TEMPO press 1:1:0.2~5.0:1.0
~2.0:0.80~5.0 proportionality principle configuration；
2）The pyridine that will replace（1）And the primary halogenated alkane of substitution（2）, in molar ratio 1：1 with inserting in reaction vessels, adds few
Amount solvent 1 or not solubilizer, in 60~120 degree of temperature conditionss heating stirring, after 0.5~4.0 hour heating stirring time, instead
Answer in vessel is synthesisN- Fixanol（3）；
3）Then by electron deficient olefins, alkali and TEMPO addition reaction vessels, solvent 2 is added, 100~1600Add under C
Thermal agitation to reaction terminates, and reacted mixture is poured into water, and is recrystallized after filtering, extracting, wash, dry or post layer
Analysis is separated, the solids or grease for obtaining as target product 3- alkyl Indoli zine derivatives（5）.
The Technological improvement plan that further solves of the invention is：
The preparation process is further arranged to：
1）Substituted pyridine（1）It is 0.60 mM, the primary halogenated alkane of substitution（2）It is 0.60 mM, it is same to insert reactor
In ware, 0.20 milliliter of solvent 1 or not solubilizer are added, in 60~120 degree of temperature conditionss heating stirring, heating stirring
0.5~4.0 hour, be synthesis in reaction vesselsN- Fixanol（3）；
2）0.80 mM of alkali, 0.20 mM of electron deficient olefins and 0.80 mM of TEMPO are sequentially added into reaction
In vessel, 0.80~3.0 milliliter of solvent 2 is added, 100~1600Heating stirring to reaction terminates under C；
3）The reacted mixture of step 2 is poured into water, is filtered, extraction, washing, recrystallization or column chromatography for separation after drying,
The solids for obtaining as target product 3- alkyl Indoli zine derivatives（5）.
The Technological improvement plan that further solves of the invention is：
The substituted pyridine（1）The selection of component：Or be quinoline, or be isoquinolin or R1=hydrogen, or 2- methyl, or 3- first
Base, or 4- methyl, or 4- phosphinylidyne carbomethoxies, or 4- phenyl, or 3- phenyl, or 2- phenyl, or 4- benzoyls, or be 3,5- bis-
Methyl, or be 3,5- diphenyl.
The Technological improvement plan that further solves of the invention is：
The substituted primary halogenated hydrocarbons（2）The selection of component：Or be bromoethane, or be N-Propyl Bromide, or be NBB, or be bromine penta
Alkane, or be bromohexane, or be 3- methoxyl group -1- N-Propyl Bromides, or be 3- phenoxy group -1- N-Propyl Bromides, or be chloro- 2, the 2- diphenyl of 4-
Butyronitrile, or be the bromo- 3- phenyl-propanes of 1-, or be the chloro- 2- diphenylphosphino ethanes of 1-, or be 6- bromocaproic acid methyl esters, or be 4- bromo-butyric acid second
Ester, or be chloromethyl cyclopropane, or be 2- ethyls-hexyl bromide 1 bromohexane, or be 2- bromomethyls-DOX, or be 2- (2- bromines
Ethyl)-DOX, or be 2- (3- bromines propoxyl group) tetrahydrochysene -2H- pyrans.
The Technological improvement plan that further solves of the invention is：
The selection of the alkali：Or tert-butyl alcohol lithium, or potassium phosphate, or cesium carbonate, or potassium hydroxide, or sodium hydride, or lithium hydroxide,
Or cesium hydroxide.
The Technological improvement plan that further solves of the invention is：
The selection of the solvent 1：OrN,N- dimethylformamide, or glycol dimethyl ether, or Isosorbide-5-Nitrae-dioxane, or acetonitrile.
The Technological improvement plan that further solves of the invention is：
The selection of the solvent 2：OrN,N- dimethylformamide, orN,N- dimethylacetylamide,N- methyl pyrrolidone, or two
First sulfoxide, or HMPA.
The Technological improvement plan that further solves of the invention is：
The preparation process is entered a more step and is set to：
1）Substituted pyridine（1）It is 0.60 mM, the primary halogenated alkane of substitution（2）It is 0.60 mM, it is same to insert reactor
In ware, 0.20 milliliter is addedN,N- dimethylformamide, in 100 degree of temperature conditionss heating stirring, heating stirring 4.0
Hour；
2）By 0.80 mM of lithium hydroxide, 0.20 mM of electron deficient olefins and 0.80 mM of TEMPO add successively
Enter in reaction vessels, add 2.8 milliliters of dimethyl sulfoxides；1400Heating stirring to reaction terminates under C；
3）The reacted mixture of step 2 is poured into water, filter, extract, washing, dry after recrystallization or column chromatography for separation,
The solids for obtaining as target product 3- alkyl Indoli zine derivatives（5）.
The present invention compared with prior art, with following obvious advantage：
The present invention takes what is directly produced by primary halogenated hydrocarbons and pyridine derivateN- Fixanol, in the presence of alkali and TEMPO,
With Electron-poor olefin hydrocarbon reaction, the 3- alkyl Indoli zine derivatives prepared, greatly reduce prior art prepare 3- alkyl in nitrogen
The production cost of indene derivative；All raw materials can directly be bought, and price is relatively cheap is easy to get；Need not be used in technological process
Any noble metal catalyst and part, technological process is also simpler, and cost is substantially reduced；There is not yet mistake in target product
Cross the exceeded problem of metal；Whole flow process is all insensitive for air and moisture, can make routine operation in loose reaction condition,
It is environmentally safe；It can be that biological, agricultural chemicals and field of medicaments prepare Related product, there is provided the relatively low 3- alkyl of the abundant price in source
Indoli zine derivatives.
Brief description of the drawings
Accompanying drawing 1 is the inventive method process flow diagram：
Accompanying drawing 2 is the nucleus magnetic hydrogen spectrum figure of the gained target product 3- alkyl Indoli zine derivatives of the embodiment of the present invention one；
Accompanying drawing 3 is the nuclear-magnetism carbon spectrogram of the gained target product 3- alkyl Indoli zine derivatives of the embodiment of the present invention one；
Accompanying drawing 4 is the nucleus magnetic hydrogen spectrum figure of the gained target product 3- alkyl Indoli zine derivatives of the embodiment of the present invention five；
Accompanying drawing 5 is the nuclear-magnetism carbon spectrogram of the gained target product 3- alkyl Indoli zine derivatives of the embodiment of the present invention five.
Additionally, the nucleus magnetic hydrogen spectrum figure and nuclear-magnetism carbon spectrogram of the embodiment of the present invention two, three, four, six, seven, eight, nine are limited to a piece
Width, in excluding accompanying drawing.
Specific embodiment
Section Example given below simultaneously combines relevant drawings, and the invention will be further described.
Embodiment one：
Such as the technological process of accompanying drawing 1, pyridine is taken for 48 microlitres (equivalent to 0.60 mM), 1- NBBs are 65 microlitres（Quite
In 0.60 mM）, with inserting in reaction vessels, add 0.20 milliliterN,N- dimethylformamide, in 80 degree of temperature strip
Part heating stirring 2.0 hours, is subsequently added 19.2 milligrams of lithium hydroxide（Equivalent to 0.80 mM）, 125.0 milligrams of TEMPO
（Equivalent to 0.80 mM）,N,N21 microlitres of-DMAA（Equivalent to 0.20 mM）With 2.8 milliliters of diformazan Asias
In sulfone to reaction vessels, terminate to reaction within 24 hours in 140 degrees Celsius of lower heating stirrings, reacted mixture is poured into water
In, filtering, washing separates to obtain 32.7 milligrams of the present embodiment target product（Yield is 71%）.
The target product of the present embodiment one, through nuclear magnetic resonance chemical analyser（Model：AVANCE 400MHz, manufacturer：Switzerland
Brooker）Analysis, obtains the nucleus magnetic hydrogen spectrum shown in Fig. 2 and the nuclear-magnetism carbon spectrum shown in Fig. 3.The former its parameter be 7.91 (d,J
= 9.1 Hz, 1H), 7.77 (d, J = 7.0 Hz, 1H), 6.90 – 6.86 (m, 1H), 6.73 (s, 1H),
6.65 (td, J = 6.8, 1.4 Hz, 1H), 3.18 (s, 6H), 2.78 (t, J = 7.5 Hz, 2H), 1.80
– 1.75 (m, 2H), 1.04 (t, J= 7.3 Hz, 3H);The latter its parameter is13C NMR (CDCl3, 100MHz):
168.1, 134.2, 124.0, 122.0, 120.0, 119.0, 112.6, 111.5, 105.8, 27.8, 20.4,
14.1.It is confirmed that：The target product 3- alkyl Indoli zine derivatives for implementing one comply fully with quality requirements.
Embodiment two：
Such as the technological process of accompanying drawing 1,4- phenylpyridines are taken for 93.1 milligrams (equivalent to 0.60 mM), the bromo- 3- methoxyl groups of 1-
Propane is 91.8 milligrams（Equivalent to 0.60 mM）, with inserting in reaction vessels, without solvent 1, in 90 degree of temperature
Condition heating stirring 1.0 hours, is subsequently added 180 milligrams of cesium hydroxide（Equivalent to 1.20 mMs）, 156 milligrams of TEMPO
（Equivalent to 1.0 mMs）, 13 microlitres of acrylonitrile（Equivalent to 0.20 mM）With 2.0 millilitersN,N- dimethylformamide is to anti-
Answer in vessel, terminate to reaction within 24 hours in 150 degrees Celsius of lower heating stirrings, reacted mixture is poured into water, filter,
Washing, separates to obtain 47.5 milligrams of the present embodiment target product（Yield is 86%）.
Embodiment three：
Such as the technological process of accompanying drawing 1,3,5- lutidines is taken for 64.3 milligrams (equivalent to 0.60 mM), 2- bromomethyls-
1,3- dioxolanes is 100 milligrams（Equivalent to 0.60 mM）, with inserting in reaction vessels, add 0.2 milliliter of Isosorbide-5-Nitrae-dioxy
Six rings, in 100 degree of temperature conditionss heating stirring 3.0 hours, are subsequently added 80 milligrams of tert-butyl alcohol lithium（Equivalent to 1.00 millis
Mole）, 313 milligrams of TEMPO（Equivalent to 2.0 mMs）, 43.2 milligrams of dimethyl maleate（Equivalent to 0.30 mM）With
3.0 millilitersNIn-methyl pyrrolidone to reaction vessels, terminate in the extremely reaction in 36 hours of 130 degrees Celsius of lower heating stirrings, will be anti-
Mixture after answering is poured into water, and filters, and washing separates to obtain 72.0 milligrams of the present embodiment target product（Yield is 72%）.
Example IV：
Such as the technological process of accompanying drawing 1,2- picolines are taken for 55.9 milligrams (equivalent to 0.60 mM), 2- (2- bromoethyls)-
1,3- dioxolanes is 108.6 milligrams（Equivalent to 0.60 mM）, with inserting in reaction vessels, add glycol dimethyl ether
0.2 milliliter, in 80 degree of temperature conditionss heating stirring 10 hours, it is subsequently added 24 milligrams of NaOH（Equivalent to 0.60 milli
Mole）, 188 milligrams of TEMPO（Equivalent to 1.2 mMs）, 41.7 milligrams of chalcone（Equivalent to 0.20 mM）With 1.8 milliliters
In 6-methyl phosphonic triamide to reaction vessels, terminate to reaction within 24 hours in 150 degrees Celsius of lower heating stirrings, reacted will mix
Compound is poured into water, filtering, and washing separates to obtain 73.1 milligrams of the present embodiment target product（Yield is 92%）.
Embodiment five：
Such as the technological process of accompanying drawing 1,3,5- lutidines is taken for 64.3 milligrams (equivalent to 0.60 mM), the bromo- 3- first of 1-
Epoxide propane is 91.8 milligrams（Equivalent to 0.60 mM）, with inserting in reaction vessels, addN,N- dimethylformamide
0.20 milliliter, in 100 degree of temperature conditionss heating stirring 4.0 hours, it is subsequently added 293 milligrams of cesium carbonate（Equivalent to 0.90
MM）, 156 milligrams of TEMPO（Equivalent to 1.0 mMs）, 13 microlitres of acrylonitrile（Equivalent to 0.20 mM）With 2.6 milliliters
In dimethyl sulfoxide to reaction vessels, terminate to reaction within 24 hours in 150 degrees Celsius of lower heating stirrings, reacted mixture is fallen
Enter in water, filtering, washing separates to obtain 43.8 milligrams of the present embodiment target product（Yield is 96%）.
Five target products of the present embodiment, through nuclear magnetic resonance chemical analyser（Model：AVANCE 400MHz, manufacturer：Switzerland
Brooker）Analysis, obtains the nucleus magnetic hydrogen spectrum shown in Fig. 4 and the nuclear-magnetism carbon spectrum shown in Fig. 5.The former is at its parameter1H NMR
(CDCl3, 400MHz): 7.63 (s, 1H), 6.80 (s, 1H), 6.64 (s, 1H), 3.73 (t, J = 6.6
Hz, 2H), 3.40 (s, 3H), 3.05 (t, J= 6.5 Hz, 2H), 2.68 (s, 3H), 2.29 (s, 3H)；
The latter its parameter is13C NMR (CDCl3, 100MHz): 13C NMR (101 MHz, CDCl3) δ 136.0, 128.3,
124.9, 123.0, 122.4, 119.2, 115.5, 79.8, 70.4, 58.8, 26.5, 18.4, 18.3.Thus demonstrate,prove
It is real：The target product 3- alkyl Indoli zine derivatives for implementing five comply fully with quality requirements.
Embodiment six：
Such as the technological process of accompanying drawing 1, quinoline is taken for 77.5 milligrams (equivalent to 0.60 mM), chloro- 2, the 2- diphenylbutanenitriles of 4-
It is 153.5 milligrams（Equivalent to 0.60 mM）, same to insert in reaction vessels, 0.20 milliliter of acetonitrile, in 90 degree of temperature strip
Part heating stirring 3.0 hours, is subsequently added 64 milligrams of tert-butyl lithium（Equivalent to 1.00 mMs）, 156 milligrams of TEMPO（Quite
In 1.0 mMs）, 25.6 milligrams of tert-butyl acrylate（Equivalent to 0.20 mM）With 2.5 millilitersN,N- dimethylacetylamide
Into reaction vessels, terminate to reaction within 24 hours in 140 degrees Celsius of lower heating stirrings, reacted mixture be poured into water,
Filtering, washing, separates to obtain 83.2 milligrams of the present embodiment target product（Yield is 88%）.
Embodiment seven：
Such as the technological process of accompanying drawing 1,4- phenylpyridines are taken for 93.1 milligrams (equivalent to 0.60 mM), 2- (3- bromines propoxyl group)
Tetrahydrochysene -2H- pyrans is 133.9 milligrams（Equivalent to 0.60 mM）, with inserting in reaction vessels, add glycol dimethyl ether
0.20 milliliter, in 80 degree of temperature conditionss heating stirring 6.0 hours, it is subsequently added 112 milligrams of potassium tert-butoxide（Equivalent to
1.00 mMs）, 125 milligrams of TEMPO（Equivalent to 0.80 mM）, 29.9 milligrams of 4- nitrostyrolenes（Equivalent to 0.20 milli
Mole）In 2.8 milliliters of 6-methyl phosphonic triamide to reaction vessels, tied in the extremely reaction in 24 hours of 140 degrees Celsius of lower heating stirrings
Beam, reacted mixture is poured into water, filtering, and washing separates to obtain 74.9 milligrams of the present embodiment target product（Yield is
82%）.
Embodiment eight：
Such as the technological process of accompanying drawing 1,3- phenylpyridines are taken for 93.1 milligrams (equivalent to 0.60 mM), the chloro- 2- phenyl second of 1-
Alkane is 84.4 milligrams（Equivalent to 0.60 mM）, with inserting in reaction vessels, addN,N0.20 milliliter of-dimethylformamide,
In 90 degree of temperature conditionss heating stirring 2.0 hours, 24 milligrams of lithium hydroxide is subsequently added（Equivalent to 1.00 mMs）,
156 milligrams of TEMPO（Equivalent to 1.0 mMs）, 13 microlitres of acrylonitrile（Equivalent to 0.20 mM）With 2.0 milliliters of dimethyl sulfoxides
Into reaction vessels, terminate to reaction within 24 hours in 140 degrees Celsius of lower heating stirrings, reacted mixture be poured into water,
Filtering, washing, separates to obtain 50.0 milligrams of the present embodiment target product（Yield is 81%）, two kinds of ratios of isomers are 2 to 1.
By above-described embodiment and the nucleus magnetic hydrogen spectrum figure for being given and nuclear-magnetism carbon spectrogram susceptible of proof：Mesh prepared by the present invention
Mark product 3- alkyl Indoli zine derivatives meet quality requirements, and it has enough selections on the compatibility of component raw material
Space, simply the difference that when reaction condition is present of the amount between component raw material, the different change of yield is brought to target product.
It should be noted that above-described embodiment is only presently preferred embodiments of the present invention, it is not of the invention for limiting
Protection domain, the equivalent or replacement made on the basis of above-mentioned technical proposal, belongs to protection scope of the present invention,
Protection scope of the present invention is defined by claims.
Claims (6)
1. a kind of preparation method of 3- alkyl Indoli zine derivatives, by what is directly produced by pyridine derivate and primary halogenated alkaneN-
Fixanol, in alkali and 2,2,6,6- tetramethyl piperidine nitrogen oxides（TEMPO）It is anti-with electron deficient olefins under existence condition
Should, it is prepared into 3- alkyl Indoli zine derivatives, it is characterised in that：The preparation method foundation
Chemical equation, is obtained by following processing step：
1）By required starting components：Pyridine, primary halogenated alkane, electron deficient olefins, alkali and TEMPO press 1:1:0.2~5.0:1.0
~2.0:0.80~5.0 proportionality principle configuration；
2）The pyridine that will replace（1）And the primary halogenated alkane of substitution（2）, in molar ratio 1：1 with inserting in reaction vessels, adds few
Amount solvent 1 or not solubilizer, in 60~120 degree of temperature conditionss heating stirring, after 0.5~4.0 hour heating stirring time, instead
Answer in vessel is synthesisN- Fixanol（3）；
3）Then by electron deficient olefins, alkali and TEMPO addition reaction vessels, solvent 2 is added, 100~1600Add under C
Thermal agitation to reaction terminates, and reacted mixture is poured into water, and is recrystallized after filtering, extracting, wash, dry or post layer
Analysis is separated, the solids or grease for obtaining as target product 3- alkyl Indoli zine derivatives（5）；
The substituted pyridine（1）The selection of component：Or be quinoline, or be isoquinolin or R1=hydrogen, or 2- methyl, or 3- first
Base, or 4- methyl, or 4- phosphinylidyne carbomethoxies, or 4- phenyl, or 3- phenyl, or 2- phenyl, or 4- benzoyls, or be 3,5- bis-
Methyl, or be 3,5- diphenyl；
The substituted primary halogenated hydrocarbons（2）The selection of component：Or be bromoethane, or be N-Propyl Bromide, or be NBB, or be bromine penta
Alkane, or be bromohexane, or be 3- methoxyl group -1- N-Propyl Bromides, or be 3- phenoxy group -1- N-Propyl Bromides, or be chloro- 2, the 2- diphenyl of 4-
Butyronitrile, or be the bromo- 3- phenyl-propanes of 1-, or be the chloro- 2- diphenylphosphino ethanes of 1-, or be 6- bromocaproic acid methyl esters, or be 4- bromo-butyric acid second
Ester, or be chloromethyl cyclopropane, or be 2- ethyls-hexyl bromide 1 bromohexane, or be 2- bromomethyls-DOX, or be 2- (2- bromines
Ethyl)-DOX, or be 2- (3- bromines propoxyl group) tetrahydrochysene -2H- pyrans.
2. the preparation method of a kind of 3- alkyl Indoli zine derivatives according to claim 1, it is characterised in that：The preparation
Step is further arranged to：
1）Substituted pyridine（1）It is 0.60 mM, the primary halogenated alkane of substitution（2）It is 0.60 mM, it is same to insert reactor
In ware, 0.20 milliliter of solvent 1 or not solubilizer are added, in 60~120 degree of temperature conditionss heating stirring, heating stirring
0.5~4.0 hour, be synthesis in reaction vesselsN- Fixanol（3）；
2）0.80 mM of alkali, 0.20 mM of electron deficient olefins and 0.80 mM of TEMPO are sequentially added into reaction
In vessel, 0.80~3.0 milliliter of solvent 2 is added, 100~1600Heating stirring to reaction terminates under C；
3）The reacted mixture of step 2 is poured into water, is filtered, extraction, washing, recrystallization or column chromatography for separation after drying,
The solids for obtaining as target product 3- alkyl Indoli zine derivatives（5）.
3. the preparation method of a kind of 3- alkyl Indoli zine derivatives according to claim 1 and 2, it is characterised in that：It is described
The selection of alkali：Or tert-butyl alcohol lithium, or potassium phosphate, or cesium carbonate, or potassium hydroxide, or sodium hydride, or lithium hydroxide, or hydroxide
Caesium.
4. the preparation method of a kind of 3- alkyl Indoli zine derivatives according to claim 1 and 2, it is characterised in that：It is described
The selection of solvent 1：OrN,N- dimethylformamide, or glycol dimethyl ether, or Isosorbide-5-Nitrae-dioxane, or acetonitrile.
5. the preparation method of a kind of 3- alkyl Indoli zine derivatives according to claim 1 and 2, it is characterised in that：It is described
The selection of solvent 2：OrN,N- dimethylformamide, orN,N- dimethylacetylamide,N- methyl pyrrolidone, or dimethyl sulfoxide,
Or HMPA.
6. the preparation method of a kind of 3- alkyl Indoli zine derivatives according to claim 1 and 2, it is characterised in that：It is described
The preparation process is entered a more step and is set to：
1）Substituted pyridine（1）It is 0.60 mM, the primary halogenated alkane of substitution（2）It is 0.60 mM, it is same to insert reactor
In ware, 0.20 milliliter is addedN,N- dimethylformamide, in 100 degree of temperature conditionss heating stirring, heating stirring 4.0
Hour；
2）By 0.80 mM of lithium hydroxide, 0.20 mM of electron deficient olefins and 0.80 mM of TEMPO add successively
Enter in reaction vessels, add 2.8 milliliters of dimethyl sulfoxides；1400Heating stirring to reaction terminates under C；
3）The reacted mixture of step 2 is poured into water, filter, extract, washing, dry after recrystallization or column chromatography for separation,
The solids for obtaining as target product 3- alkyl Indoli zine derivatives（5）.
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| US11001588B2 (en) | 2018-09-19 | 2021-05-11 | Forma Therapeutics, Inc. | Activating pyruvate kinase R and mutants thereof |
| US11014927B2 (en) | 2017-03-20 | 2021-05-25 | Forma Therapeutics, Inc. | Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators |
| US11071725B2 (en) | 2018-09-19 | 2021-07-27 | Forma Therapeutics, Inc. | Activating pyruvate kinase R |
| CN114014858A (en) * | 2021-12-03 | 2022-02-08 | 淮阴师范学院 | Process for preparing polysubstituted indolizine derivatives |
| US12128035B2 (en) | 2021-03-19 | 2024-10-29 | Novo Nordisk Health Care Ag | Activating pyruvate kinase R |
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| US11014927B2 (en) | 2017-03-20 | 2021-05-25 | Forma Therapeutics, Inc. | Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators |
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| US12071440B2 (en) | 2017-03-20 | 2024-08-27 | Novo Nordisk Health Care Ag | Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators |
| US11001588B2 (en) | 2018-09-19 | 2021-05-11 | Forma Therapeutics, Inc. | Activating pyruvate kinase R and mutants thereof |
| US11071725B2 (en) | 2018-09-19 | 2021-07-27 | Forma Therapeutics, Inc. | Activating pyruvate kinase R |
| US11844787B2 (en) | 2018-09-19 | 2023-12-19 | Novo Nordisk Health Care Ag | Activating pyruvate kinase R |
| US11980611B2 (en) | 2018-09-19 | 2024-05-14 | Novo Nordisk Health Care Ag | Treating sickle cell disease with a pyruvate kinase R activating compound |
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| US12128035B2 (en) | 2021-03-19 | 2024-10-29 | Novo Nordisk Health Care Ag | Activating pyruvate kinase R |
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