CN107200744A - A kind of method for preparing Pyrrolopyrimidin thiamine hydrochloride - Google Patents
A kind of method for preparing Pyrrolopyrimidin thiamine hydrochloride Download PDFInfo
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- CN107200744A CN107200744A CN201710400898.5A CN201710400898A CN107200744A CN 107200744 A CN107200744 A CN 107200744A CN 201710400898 A CN201710400898 A CN 201710400898A CN 107200744 A CN107200744 A CN 107200744A
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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 discloses a kind of Pyrrolopyrimidin thiamine hydrochloride 6,7 dihydro 5H pyrrolo-es [3,4 d] pyrimidine hydrochloride synthesis technique, with furans simultaneously [3,4 d] pyrimidine 5,7 diketone are initiation material, obtain target product by lactamize, reduction, into salt, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to Pyrrolopyrimidin thiamine hydrochloride 6,7- bis-
A kind of preparation method of hydrogen -5H- pyrrolo-es [3,4-d] pyrimidine hydrochloride.
Technical background
Compound Pyrrolopyrimidin thiamine hydrochloride 6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine hydrochloride, structural formula is：
Antimicrobial agents are a current clinical practice relatively wide, class medicines of large usage quantity, in control and treatment disease side
Face is played an important role.The antimicrobial agents kind of current Clinical practice is numerous, but a large amount of with antimicrobial agents
And widely use, irrational use particularly clinically, or even abuse, finally result in multidrug resistant.Therefore, how to overcome
Multidrug resistant turns into 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 to solve one of important channel of drug resistance, it has also become current pharmaceutical chemistry is very active
Field.
Pyrrolopyridine ring is the class basic group commonly used in pharmaceutical chemistry research, and its small toxicity easily forms multiple hydrogen
Key or ionic bond, often can the effectively lipid of regulating drug and acid-base balance constant.Molecule is introduced into, can be effective
Ground increases the alkaline and water solubility of molecule, so as to strengthen the activity of molecule.Therefore, to a certain extent, piperazine group is one
Synergist groups, are often introduced in the design and exploitation of many medicines.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 grown, and shows the development potentiality of broadness.
Compound Pyrrolopyrimidin thiamine hydrochloride 6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine hydrochloride of the present invention
Play an important roll for new drug development.
The content of the invention
The invention discloses a kind of Pyrrolopyrimidin thiamine hydrochloride 6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine hydrochloride
Preparation method, it is characterized in that with furans simultaneously [3,4-d] pyrimidine -5,7- diketone be initiation material, by lactamize, reduction, into
Salt obtains target product 4, and synthesis step is as follows：
(1) with furans, simultaneously [3,4-d] pyrimidine -5,7- diketone, for initiation material, 2 is obtained through lactamization reaction；
(2) reacted 2 with reducing agent, obtain 3；
(3) 4 are obtained with hydrochloric acid reaction 3；
In a preferred embodiment, the lactamize reagent used in described lactamization reaction prepare compound 1
Selected from urea；Reducing agent used in described reduction reaction prepare compound 2 is selected from Lithium Aluminium Hydride；Used in described salt-forming reaction
Salt-forming reagent is selected from hydrogen chloride.
In a preferred embodiment, the solvent used in described lactamization reaction prepare compound 1 is selected from neighbour two
Toluene；Solvent used in described reduction reaction prepare compound 2 is selected from tetrahydrofuran；Solvent used in described salt-forming reaction
Selected from methanol.
In a preferred embodiment, the reaction temperature used in described lactamization reaction prepare compound 1 is molten
The reflux temperature of agent, the temperature used in described reduction reaction prepare compound 2 is 0 DEG C~room temperature；Described salt-forming reaction institute
Temperature is 0 DEG C.
The present invention relates to a kind of Pyrrolopyrimidin thiamine hydrochloride 6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine hydrochloride hydrochloric acid
The preparation method of salt, is reported currently without other Patents documents.
The present invention is further described by the following embodiment, and 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 to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of compound 2
Furans, simultaneously [3,4-d] pyrimidine -5,7- diketone is added in 180ml ortho-xylenes, adds 25g ureas, heating stirring
Backflow 6 hours, is cooled to room temperature, filters, adds water and ethyl acetate is extracted, and point liquid, drying, concentration obtain thick
Product, crude product crosses post and obtains being recrystallized to give 16g compounds 2 6H- pyrrolo-es [3,4-d] pyrimidine -5,7- diketone.
(2) synthesis of compound 3
15g 6H- pyrrolo-es [3,4-d] pyrimidine -5,7- diketone is added in 150ml tetrahydrofurans, 0 DEG C is cooled to,
6.5g Lithium Aluminium Hydrides are added portionwise under nitrogen atmosphere, after adding, are reacted 1 hour at 0 DEG C, then are slowly increased to be stirred overnight at room temperature,
1N hydrochloric acid is added, ethyl acetate is added, extraction point liquid collects organic phase, point liquid, drying, concentration, silicagel column point on residue
From 8.2g compounds 3 6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine.
(3) synthesis of Pyrrolopyrimidin thiamine hydrochloride 6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine hydrochloride
8g Pyrrolopyrimidin thiamine hydrochloride 6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine hydrochloride is added to 120ml first
In alcohol, 0 DEG C is cooled to, dry hydrogen chloride is passed through until saturation, is stirred at room temperature 12 hours, reaction solution is concentrated to give 10.4g pyrroles
And pyrimidine hydrochloride 6,7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine hydrochloride.
Claims (6)
1. Pyrrolopyrimidin thiamine hydrochloride 6 is prepared, the method for 7- dihydro -5H- pyrrolo-es [3,4-d] pyrimidine hydrochloride, it is characterized in that
With furans, simultaneously [3,4-d] pyrimidine -5,7- diketone, for initiation material, by lactamize, reduction, obtains target product 4 into salt, closes
It is as follows into route,
2. method according to claim 1, it is characterized in that described 3 steps reaction is,
(1) with furans, simultaneously [3,4-c] pyridine -1,3- diketone, for initiation material, 2 is obtained through lactamization reaction；
(2) reacted 2 with reducing agent, obtain 3；
(3) 4 are obtained with hydrochloric acid reaction 3；
3. method according to claim 1, it is characterised in that the interior acyl used in described lactamization reaction prepare compound 1
One or more of mixtures of the amination reagent in acetamide, ammonia, urea；Used in described reduction reaction prepare compound 2
Reducing agent be selected from lithium borohydride, sodium borohydride, potassium borohydride, Lithium Aluminium Hydride, sodium cyanoborohydride, triacetoxy boron hydride
One or more of mixtures in sodium；The one kind of salt-forming reagent in hydrochloric acid, hydrogen chloride used in described salt-forming reaction
Or several mixtures.
4. method according to claim 1, it is characterised in that the solvent used in described lactamization reaction prepare compound 1
Selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- diformazans
One or more of mixtures in base formamide, DMAC N,N' dimethyl acetamide；Used in described reduction reaction prepare compound 2
Solvent be selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, toluene, tetrahydrofuran,
One kind or several in toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide
The mixture planted；Solvent used in described salt-forming reaction is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloro
Methane, chloroform, ethyl acetate, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N-
One or more of mixtures in dimethyl acetamide.
5. method according to claim 1, it is characterised in that the reaction used in described lactamization reaction prepare compound 1
Temperature is the reflux temperature of 0 DEG C~solvent；Temperature used in described reduction reaction prepare compound 2 is returning for 0 DEG C~solvent
Flow temperature；Temperature used in described salt-forming reaction is the reflux temperature of 0 DEG C-solvent.
6. method according to claim 1, it is characterised in that the reaction used in described lactamization reaction prepare compound 1
Temperature is the reflux temperature of solvent, and the temperature used in described reduction reaction prepare compound 2 is 0 DEG C~room temperature；It is described into
Temperature used in reactant salt is 0 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710400898.5A CN107200744A (en) | 2017-05-31 | 2017-05-31 | A kind of method for preparing Pyrrolopyrimidin thiamine hydrochloride |
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| CN201710400898.5A CN107200744A (en) | 2017-05-31 | 2017-05-31 | A kind of method for preparing Pyrrolopyrimidin thiamine hydrochloride |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006127530A2 (en) * | 2005-05-25 | 2006-11-30 | Merck & Co., Inc. | Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| CN102372706A (en) * | 2010-08-09 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | Phthalazinone derivative, its preparation method and application in medicament |
| 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 |
| WO2016044641A2 (en) * | 2014-09-17 | 2016-03-24 | Epizyme, Inc. | Carm1 inhibitors and uses thereof |
-
2017
- 2017-05-31 CN CN201710400898.5A patent/CN107200744A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006127530A2 (en) * | 2005-05-25 | 2006-11-30 | Merck & Co., Inc. | Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| CN102372706A (en) * | 2010-08-09 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | Phthalazinone derivative, its preparation method and application in medicament |
| 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 |
| WO2016044641A2 (en) * | 2014-09-17 | 2016-03-24 | Epizyme, Inc. | Carm1 inhibitors and uses thereof |
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Application publication date: 20170926 |