CN108117552A - The method for preparing bromo pyrrolin and pyridine hydrochloride - Google Patents
The method for preparing bromo pyrrolin and pyridine hydrochloride Download PDFInfo
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- CN108117552A CN108117552A CN201611074580.4A CN201611074580A CN108117552A CN 108117552 A CN108117552 A CN 108117552A CN 201611074580 A CN201611074580 A CN 201611074580A CN 108117552 A CN108117552 A CN 108117552A
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- bromo
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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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Abstract
The invention discloses a kind of preparation method of bromo pyrrolin simultaneously [3,4 c] pyridine hydrochloride, with 7 bromine furans simultaneously [3,4 c] pyridine 1,3 diketone are starting material, and by lactamizing, reducing, obtaining target product into salt, which is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of bromo pyrrolin simultaneously [3,
4-c] pyridine hydrochloride a kind of preparation method.
Technical background
Simultaneously [3,4-c] pyridine hydrochloride, structural formula are compound bromo pyrrolin：
Antimicrobial agents are the current clinical practice a kind of drugs larger compared with wide, dosage, in control and treatment disease side
Face plays an important role.The antimicrobial agents kind of Clinical practice is numerous at present, but a large amount of with antimicrobial agents
And widely use, irrational use or even abuse particularly clinically finally result in multidrug resistant.Therefore, how to overcome
Multidrug resistant becomes the important topic of antimicrobial agents research both at home and abroad at present.The method for solving drug resistance is numerous, wherein newly
The research and development of type structure antimicrobial agents are one of important channels for solving drug resistance, it has also become current pharmaceutical chemistry is very active
Field.
Pyrrolopyridine ring is that common one kind basic group, small toxicity easily form multiple hydrogen in pharmaceutical chemistry research
Key or ionic bond often can effectively adjust the lipid of drug and acid-base balance constant.Molecule is introduced into, it can be effective
Ground increases the alkaline and water-soluble of molecule, so as to enhance the activity of molecule.Therefore, to a certain extent, piperazine group is one
Synergist groups often introduce in the design and exploitation of many drugs.Research shows that the compound of the ring containing pyrrolopyridine is often shown
Go out extensive bioactivity, such as antimicrobial, anti-hypertension, anticancer, anti-inflammatory and analgesic, especially as antimicrobial agents,
It is studied active and quickly grows, and shows broad development potentiality.
Compound bromo pyrrolin of the present invention simultaneously [3,4-c] pyridine hydrochloride for new drug development have it is important
Effect.
The content of the invention
The invention discloses a kind of preparation method of bromo pyrrolin simultaneously [3,4-c] pyridine hydrochloride, it is characterized in that with
Simultaneously [3,4-c] pyridine -1,3- diketone is starting material to 7- bromines furans, by lactamizing, reducing, target product 4 being obtained into salt,
Synthesis step is as follows：
(1) with 7- bromines furans, simultaneously for starting material, 2 are obtained through lactamization reaction for [3,4-c] pyridine -1,3- diketone；
(2) 2 and reducing agent are reacted, obtains 3；
(3) 4 are obtained by the reaction with hydrochloric acid 3；
In a preferred embodiment, the lactamization reaction prepare bromo- 2H- pyrrolo-es [3, the 4-c] pyridines of 7--
Lactamization reagent used in 1,3- diketone is selected from urea；The reduction reaction prepare the bromo- 2,3- dihydros -1H- pyrrolo-es of 7- [3,
4-c] reducing agent used in pyridine is selected from Lithium Aluminium Hydride；Salt-forming reagent used in the salt-forming reaction is selected from hydrogen chloride.
In a preferred embodiment, the lactamization reaction prepare bromo- 2H- pyrrolo-es [3, the 4-c] pyridines of 7--
Solvent used in 1,3- diketone is selected from ortho-xylene；The reduction reaction prepares the bromo- 2,3- dihydros -1H- pyrrolo-es [3,4- of 7-
C] solvent used in pyridine is selected from tetrahydrofuran；Solvent used in the salt-forming reaction is selected from methanol.
In a preferred embodiment, the lactamization reaction prepare bromo- 2H- pyrrolo-es [3, the 4-c] pyridines of 7--
Reaction temperature used in 1,3- diketone is the reflux temperature of solvent, and the reduction reaction prepares bromo- 2, the 3- dihydros -1H- pyrroles of 7-
It is 0 DEG C~room temperature to cough up the temperature simultaneously used in [3,4-c] pyridine；Temperature used in the salt-forming reaction is 0 DEG C.
The present invention relates to a kind of preparation method of bromo pyrrolin simultaneously [3,4-c] pyridine hydrochloride, currently without other
Patents documents are reported.
The present invention is further described by the following embodiment, these descriptions are not present invention to be made into one
The restriction of step.It should be understood by those skilled in the art that the equivalent substitution made of technical characteristic to the present invention or changing accordingly
Into still falling within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of bromo- 2H- pyrrolo-es [3,4-c] pyridine -1,3- diketone of 7-
30g 7- bromines furans, simultaneously [3,4-c] pyridine -1,3- diketone is added in 180ml ortho-xylenes, adds in 25g ureas,
It when heating stirring reflux 6 is small, is cooled to room temperature, filters, add water and ethyl acetate is extracted, liquid separation, drying, concentration are
Crude product is obtained, crude product crosses column and obtains being recrystallized to give bromo- 2H- pyrrolo-es [3,4-c] pyridine -1, the 3- diketone of 16g 7-.
(2) synthesis of bromo- 2,3- dihydros -1H- pyrrolo-es [3,4-c] pyridines of 7-
Bromo- 2H- pyrrolo-es [3,4-c] pyridine -1, the 3- diketone of 15g 7- is added in 150ml tetrahydrofurans, is cooled to 0
DEG C, 6.5g Lithium Aluminium Hydrides are added portionwise in a nitrogen atmosphere, after adding, when reaction 1 is small at 0 DEG C, then are slowly increased to be stirred at room temperature
Overnight, 1N hydrochloric acid is added in, adds ethyl acetate, extracts liquid separation, collects organic phase, liquid separation, drying, concentration, silicon on residue
Rubber column gel column separates to obtain bromo- 2,3- dihydros -1H- pyrrolo-es [3,4-c] pyridines of 8.2g 7-.
(3) synthesis of bromo- 2,3- dihydros -1H- pyrrolo-es [3,4-c] pyridine hydrochlorides of 7-
Bromo- 2,3- dihydros -1H- pyrrolo-es [3, the 4-c] pyridines of 8g 7- are added in 120ml methanol, are cooled to 0 DEG C, are led to
Enter dry hydrogen chloride until saturation, be stirred at room temperature 12 it is small when, reaction solution is concentrated to give 10.4g bromos pyrrolin simultaneously [3,4-c]
Pyridine hydrochloride.
Claims (6)
1. prepare the method for bromo pyrrolin simultaneously [3,4-c] pyridine hydrochloride, it is characterized in that with 7- bromines furans simultaneously [3,4-c] pyrrole
Pyridine -1,3- diketone is starting material, and by lactamizing, reducing, target product 4 being obtained into salt, synthetic route is as follows,
2. the method according to claim 1, it is characterized in that the 3 steps reaction is,
(1) with 7- bromines furans, simultaneously for starting material, 2 are obtained through lactamization reaction for [3,4-c] pyridine -1,3- diketone；
(2) 2 and reducing agent are reacted, obtains 3；
(3) 4 are obtained by the reaction with hydrochloric acid 3；
3. the method according to claim 1, which is characterized in that the lactamization reaction prepare the bromo- 2H- pyrrolo-es of 7- [3,
4-c] the lactamization reagent used in pyridine -1,3- diketone is selected from the mixture of one or more of acetamide, ammonia, urea；Institute
The reducing agent that the reduction reaction stated prepares used in bromo- 2,3- dihydros -1H- pyrrolo-es [3,4-c] pyridines of 7- is selected from lithium borohydride, boron
The mixing of one or more of sodium hydride, potassium borohydride, Lithium Aluminium Hydride, sodium cyanoborohydride, sodium triacetoxy borohydride
Object；Salt-forming reagent used in the salt-forming reaction is selected from the mixture of one or more of hydrochloric acid, hydrogen chloride.
4. the method according to claim 1, which is characterized in that the lactamization reaction prepare the bromo- 2H- pyrrolo-es of 7- [3,
4-c] solvent used in pyridine -1,3- diketone is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, tetrahydrofuran, toluene, adjacent diformazan
The mixture of one or more of benzene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide；
The reduction reaction prepare solvent used in bromo- 2,3- dihydros -1H- pyrrolo-es [3,4-c] pyridines of 7- be selected from methanol, ethyl alcohol,
Isopropanol, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, toluene, tetrahydrofuran, toluene, ortho-xylene, to diformazan
The mixture of one or more of benzene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide；It is described into
Solvent used in reactant salt is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, chloroform, acetic acid second
One kind in ester, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide
Or several mixture.
5. the method according to claim 1, which is characterized in that the lactamization reaction prepare the bromo- 2H- pyrrolo-es of 7- [3,
4-c] reaction temperature used in pyridine -1,3- diketone be 0 DEG C~solvent reflux temperature；It is bromo- that the reduction reaction prepares 7-
Temperature used in 2,3- dihydro -1H- pyrrolo-es [3,4-c] pyridine is the reflux temperature of 0 DEG C~solvent；The salt-forming reaction institute
Temperature is the reflux temperature of 0 DEG C-solvent.
6. the method according to claim 1, which is characterized in that the lactamization reaction prepare the bromo- 2H- pyrrolo-es of 7- [3,
4-c] reaction temperature used in pyridine -1,3- diketone be solvent reflux temperature, the reduction reaction prepares bromo- 2, the 3- bis- of 7-
Temperature used in hydrogen -1H- pyrrolo-es [3,4-c] pyridine is 0 DEG C~room temperature；Temperature used in the salt-forming reaction is 0 DEG C.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230923A (en) * | 2014-07-05 | 2014-12-24 | 湖南华腾制药有限公司 | Method for preparing 2,3-dihydro-1H-pyrrolo pyridine hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104230923A (en) * | 2014-07-05 | 2014-12-24 | 湖南华腾制药有限公司 | Method for preparing 2,3-dihydro-1H-pyrrolo pyridine hydrochloride |
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Application publication date: 20180605 |