CN104829620A - Method for preparing aminopyrrolo[2,3-d]pyrimidine derivatives - Google Patents
Method for preparing aminopyrrolo[2,3-d]pyrimidine derivatives Download PDFInfo
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- CN104829620A CN104829620A CN201510163913.XA CN201510163913A CN104829620A CN 104829620 A CN104829620 A CN 104829620A CN 201510163913 A CN201510163913 A CN 201510163913A CN 104829620 A CN104829620 A CN 104829620A
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- pyrroles
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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 provides a method for preparing aminopyrrolo[2,3-d]pyrimidine derivatives. In the presence of ammonium hydroxide, halogenated pyrrolo[2,3-d]pyrimidine and ammonium hydroxide undergo a replacement reaction to produce the aminopyrrolo[2,3-d]pyrimidine derivatives. The method has a high yield, solves the problem that the prior art produces environmental pollution and has a high cost, has simple, effective and eco-friendly processes, and is conducive to large scale production. The method has a yield of 90% or more. The prepared aminopyrrolo[2,3-d]pyrimidine derivative has content of 95% or more.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly one prepares the method for amino-pyrroles [2,3-d] pyrimidine derivatives.
Background technology
Pyrroles [2,3-d] pyridine derivatives is a kind of effective proteinase inhibitor, effectively, optionally can suppress JAK3, and the genetic expression of cytokine signaling and cytokine induction can be blocked, and restraining effect is not had to the JAK enzyme family member relevant with receptor phosphorylation with other cytokines, can be used for organ transplantation and the various autoimmune disorder for the treatment of.This kind of disease comprises: lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriatic, type i diabetes and diabetic complication, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, clone disease (Crohn's disease), Alzheimer (Alzheimer's disease) and leukemia.Pyrroles [2,3-d] pyrimidines is the important source material of the many antimicrobial drugs of synthesis, antitumour drug, antitrypanosomal, in field of medicaments application widely.
Document " organic and biological chemistry " 2013,11 volumes, 31 pages of 5189-5193# describe halogenated pyrrole [2,3-d] pyridine derivatives and ammonia is 1, in 4-dioxane, water mixed liquid, in 130 DEG C of reaction under high pressures 19 hours, obtain amino-pyrroles [2,3-d] pyrimidine derivatives, yield 91%.Document " pharmaceutical chemistry magazine " 2009,52 volume, 19 pages of 5974-5989# describe halogenated pyrrole [2,3-d] pyridine derivatives and ammonia in Isosorbide-5-Nitrae-dioxane, in 110 DEG C of reactions 16 hours, obtain amino-pyrroles [2,3-d] pyrimidine derivatives, yield 87%.
In above preparation method, due to an organic solvent, post-processing operation is complicated, and cost is relatively high; Temperature of reaction is high, has to use special reaction device--high pressure vessel, safety in production can not be accomplished; Production efficiency is low, not environmentally, is not suitable with industrial production.
Summary of the invention
In view of this, the object of the invention is to the preparation method of a kind of amino-pyrroles [2,3-d] pyrimidine derivatives, this method avoid reaction and carry out under high pressure or hot conditions.
For achieving the above object, technical scheme of the present invention is:
Prepare amino-pyrroles [2,3-d] method of pyrimidine derivatives, described amino-pyrroles [2,3-d] molecular formula of pyrimidine derivatives as shown in I, by starting halo pyrroles [2,3-d] pyrimidine (shown in II) and ammoniacal liquor generation substitution reaction, obtain amino-pyrroles [2,3-d] pyrimidine derivatives, its productive rate is up to 90%, and content is by percentage to the quality up to 95%;
In formula I, R1, R2, R3 and R4 tetra-substituting groups have one at least for amino, and when the quantity that substituting group is amino is less than 4, remaining substituting group can be any one or more in hydrogen, methyl, ethyl, halogeno-group and nitro; The group of substituting group in formula I before being replaced by amino is halogeno-group, namely such as formula the material shown in II.
Such as, material shown in formula I can be 4-amino-7H-pyrroles [2,3-d] pyrimidine, 2.4-diamines-5.6-dimethyl-7H-pyrroles [2,3-d] pyrimidine, 4-amine-6-ethyl-7H-pyrroles [2,3-d] pyrimidine, 4-methyl-6-amine-7H-pyrroles [2,3-d] pyrimidine, 2-amine-5-nitro-7H-pyrroles [2,3-d] pyrimidine, 2-nitro-5-amine-7H-pyrroles [2,3-d] pyrimidine and 2-methyl-4-amine-6-ethyl-7H-pyrroles [2,3-d] pyrimidine.
As preferred method, the mol ratio of described ammoniacal liquor and formula starting halo pyrroles [2,3-d] pyrimidine is 2 ~ 20:1.
As preferred method, the concentration expressed in percentage by volume of described ammoniacal liquor is 5 ~ 30%.
As preferred method, the temperature of reaction of described substitution reaction is not less than 0 DEG C, and the reaction times of described substitution reaction is not less than 5 hours.
As preferred method, the temperature of reaction of described substitution reaction is 0 DEG C ~ 70 DEG C, and such temperature of reaction makes reaction conditions not harsh, and has saved a large amount of heat energy.From the angle of production cost, compared with the existing technology, the heat energy of about 40% can be saved.
As preferred method, the reaction times of described substitution reaction is 5 ~ 20 hours.
Two of object of the present invention is a kind of method providing suitability for industrialized production amino-pyrroles [2,3-d] pyrimidine derivatives, the method safety.
For achieving the above object, technical scheme of the present invention is:
The method of suitability for industrialized production amino-pyrroles [2,3-d] pyrimidine derivatives, on the basis of " preparing the method for amino-pyrroles [2,3-d] pyrimidine derivatives ", selects the aminating reaction still not containing high-tension unit as reacting environment.In the prior art, high pressure reaction assembly produces the indispensable condition of amino-pyrroles [2,3-d] pyrimidine derivatives often, but high-tension unit is dangerous in suitability for industrialized production, and cost is high.Can be breakthrough carry out the innovative point that suitability for industrialized production is this programme in atmospheric conditions.
As preferred method, described aminating reaction still comprises reactor main body and is arranged on the input channel of reactor main body, and described input channel is for passing into ammonia or ammoniacal liquor.Aminating reaction still main body is reactor that is conventional, that be convenient to the realized ammonification function bought on the market.
As preferred scheme, described reactor main body is also provided with Ammonia recovery pipeline.
As preferred scheme, described aminating reaction still is not containing heating device.Temperature of reaction due to present method is 0 DEG C ~ 70 DEG C, and reaction conditions is not harsh, without the need to carrying out realization response by possessing the heat riser making reaction be warming up to boiling point, from safety in production and the angle of energy-conserving and environment-protective, possesses significant progressive.
Beneficial effect
Present method yield is high, overcomes in prior art and there is environmental pollution, problem that cost is high, and simple to operate, effectively and environmental protection, be conducive to large-scale production.Yield more than 90%, content reaches more than 95%.
Embodiment
In order to make the object, technical solutions and advantages of the present invention clearly, below the preferred embodiments of the present invention are described in detail.
Yield in following embodiment all by concrete each step feed intake substrate as calculating denominator.
Starting halo pyrroles [2,3-d] pyrimidine derivatives (formula II) used in following examples, its preparation method is
In formula III, R1 ", R2 ", R3 " and R4 " four substituting groups have one at least for hydroxyl, remaining substituting group can be any one or more in hydrogen, methyl, ethyl, halogeno-group and nitro.
HPLC instrument involved in following examples and testing conditions as follows:
Instrument: LC-10ATVP
Chromatographic column: SHIMDZU VP-ODS 250mm × 4.6mm, 5 μm
Determined wavelength: 254nm
Moving phase: tetrahydrofuran (THF)-methyl alcohol (5:90)
Flow velocity: 2.0ml/min
Sample size: 20 μ L
Temperature: 25 DEG C
The preparation of embodiment 1 4-amino-7H-pyrroles [2,3-d] pyrimidine
In reactor, add the chloro-7H-pyrroles of 4-[2,3-d] pyrimidine 153g (1mol) and water 300ml, be cooled to 0 ~ 10 DEG C, add 25.0% ammoniacal liquor 500ml (7.4mol), be warming up to 40 ~ 50 DEG C of reactions 12 hours; Be cooled to 0 ~ 5 DEG C, stir filtration in 1 hour, vacuum-drying obtains 4-amino-7H-pyrroles [2,3-d] pyrimidine 125.0g.Yield 93.2%, content 98.5%.Chemical reaction is as follows.
As industrialized production, send out large X times by production, carry out in aminating reaction still in production, described aminating reaction still comprises reactor main body, and described reactor main body is provided with input channel, and described input channel is for passing into ammonia or ammoniacal liquor.Described reactor main body is also provided with Ammonia recovery pipeline.Compare with existing production technology, saving heat energy 190%.
The preparation of embodiment 2 2.4-diamines-5.6-dimethyl-7H-pyrroles [2,3-d] pyrimidine
The chloro-5.6-dimethyl of 2.4-bis--7H-pyrroles [2 is added in reactor, 3-d] pyrimidine 215g (1mol) and water 300ml, be cooled to 0 ~ 10 DEG C, add 30.0% ammoniacal liquor 1133ml (20.0mol), 20 ~ 30 DEG C of reactions 10 hours; Be cooled to 0 ~ 5 DEG C, stir filtration in 1 hour; Vacuum-drying obtains 2.4-diamines-5.6-dimethyl-7H-pyrroles [2,3-d] pyrimidine 175.6g.Yield 91.6%, content 97.8%.Chemical reaction is as follows.
The preparation of embodiment 3 4-amine-6-ethyl-7H-pyrroles [2,3-d] pyrimidine
In reactor, add the iodo-6-ethyl of 4--7H-pyrroles [2,3-d] pyrimidine 273g (1mol) and water 300ml, be cooled to 0 ~ 10 DEG C, add 15.0% ammoniacal liquor 1133ml (10.0mol), 30 ~ 40 DEG C of reactions 12 hours; Be cooled to 0 ~ 5 DEG C, stir filtration in 1 hour; Vacuum-drying obtains 4-amine-6-ethyl-7H-pyrroles [2,3-d] pyrimidine 147.0g.Yield 90.7%, content 96.4%.Chemical reaction is as follows.
The preparation of embodiment 4 4-methyl-6-amine-7H-pyrroles [2,3-d] pyrimidine
The chloro-7H-pyrroles [2 of 4-methyl-6-is added in reactor, 3-d] pyrimidine 167g (1mol) and water 300ml, be cooled to 0 ~ 10 DEG C, add 10.0% ammoniacal liquor 140ml (2.0mol), be warming up to 50 ~ 60 DEG C of reactions, 20 hours (react after 12 hours, slowly pass into ammonia 8 hours); Be cooled to 0 ~ 5 DEG C, stir and filter for empty 1 hour; Very dry 4-methyl-6-amine-7H-pyrroles [2,3-d] pyrimidine 133.9g.Yield 90.4%, content 96.2%.Chemical reaction is as follows.
The preparation of embodiment 5 2-amine-5-nitro-7H-pyrroles [2,3-d] pyrimidine
The chloro-5-nitro of 2--7H-pyrroles [2 is added in reactor, 3-d] pyrimidine 198g (1mol) and water 300ml, be cooled to 0 ~ 10 DEG C, add 5.0% ammoniacal liquor 1700ml (5.0mol), be warming up to 60 ~ 70 DEG C of reactions, 5 hours (react after 3.5 hours, slowly pass into ammonia 1.5 hours); Be cooled to 0 ~ 5 DEG C, stir filtration in 1 hour; Vacuum-drying obtains 2-amine-5-nitro-7H-pyrroles [2,3-d] pyrimidine 166.8g.Yield 93.2%, content 95.5%.Chemical reaction is as follows.
As industrialized production, send out large X times by production, carry out in aminating reaction still in production, described aminating reaction still comprises reactor main body, and described reactor main body is provided with input channel, and described input channel is for passing into ammonia or ammoniacal liquor.Described reactor main body is also provided with Ammonia recovery pipeline.Compare with existing XXX technology, saving heat energy 180%.
The preparation of embodiment 6 2-nitro-5-amine-7H-pyrroles [2,3-d] pyrimidine
In reactor, add 2-nitro-5-bromo-7H-pyrroles [2,3-d] pyrimidine 241.9g (1mol) and water 300ml, be cooled to 0 ~ 10 DEG C, add 15.0% ammoniacal liquor 1700ml (15.0mol), be warming up to 40 ~ 50 DEG C of reactions 10 hours; Be cooled to 0 ~ 5 DEG C, stir 1 hour filtering vacuum dry 2-nitro-5-amine-7H-pyrroles [2,3-d] pyrimidine 162.4g.Yield 90.7%, content 95.9%.Chemical reaction is as follows.
The preparation of embodiment 7 2-methyl-4-amine-6-ethyl-7H-pyrroles [2,3-d] pyrimidine
In reactor, add 2-methyl-4-chloro-6-ethyl-7H-pyrroles [2,3-d] pyrimidine 195.1g (1mol) and water 300ml, be cooled to 0 ~ 10 DEG C, add 25.0% ammoniacal liquor 816ml (12.0mol), 0 ~ 10 DEG C of reaction 20 hours; Filter, vacuum-drying obtains 2-methyl-4-amine-6-ethyl-7H-pyrroles [2,3-d] pyrimidine 60.4g.Yield 91.1%, content 95.4%.Chemical reaction is as follows.
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to technical scheme of the present invention or equivalent replacement, and not departing from aim and the scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.
Claims (10)
1. prepare amino-pyrroles [2,3-d] method of pyrimidine derivatives, the molecular formula of described amino-pyrroles [2,3-d] pyrimidine derivatives, as shown in I, is characterized in that, by starting halo pyrroles [2,3-d] pyrimidine and ammoniacal liquor generation substitution reaction, obtain amino-pyrroles [2,3-d] pyrimidine derivatives, the molecular formula of described halogenated pyrrole [2,3-d] pyrimidine is as shown in II;
In formula I, R1, R2, R3 and R4 tetra-substituting groups have one at least for amino, and when the quantity that substituting group is amino is less than 4, remaining substituting group can be any one or more in hydrogen, methyl, ethyl, halogeno-group and nitro; The group of substituting group in formula I before being replaced by amino is halogeno-group.
2. method according to claim 1, is characterized in that, the mol ratio of described ammoniacal liquor and formula starting halo pyrroles [2,3-d] pyrimidine is 2 ~ 20:1.
3. method according to claim 2, is characterized in that, the concentration expressed in percentage by volume of described ammoniacal liquor is 5 ~ 30%.
4. method according to claim 1, is characterized in that, the temperature of reaction of described substitution reaction is not less than 0 DEG C, and the reaction times of described substitution reaction is not less than 5 hours.
5. method according to claim 1, is characterized in that, the temperature of reaction of described substitution reaction is 0 DEG C ~ 70 DEG C.
6. method according to claim 1, is characterized in that, the reaction times of described substitution reaction is 5 ~ 20 hours.
7. the method for suitability for industrialized production amino-pyrroles [2,3-d] pyrimidine derivatives, is characterized in that: use the method described in any one of Claims 1 to 4, and the reacting environment of the method does not carry out containing in the aminating reaction still of high-tension unit.
8. method according to claim 7, is characterized in that, described aminating reaction still comprises reactor main body, and described reactor main body is provided with input channel, and described input channel is for passing into ammonia or ammoniacal liquor.
9. method according to claim 8, is characterized in that, described reactor main body is also provided with Ammonia recovery pipeline.
10. method according to claim 7, is characterized in that, described aminating reaction still is not containing heating device.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001044258A1 (en) * | 1999-12-17 | 2001-06-21 | Ariad Pharmaceuticals, Inc. | Novel heterocycles |
| WO2010015643A1 (en) * | 2008-08-06 | 2010-02-11 | Novartis Ag | New antiviral modified nucleosides |
| CN102526087A (en) * | 2010-12-30 | 2012-07-04 | 南开大学 | Application of nucleoside compound to preparation of medicament for treating enterovirus 71 (EV71) infectious disease |
-
2015
- 2015-04-08 CN CN201510163913.XA patent/CN104829620A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001044258A1 (en) * | 1999-12-17 | 2001-06-21 | Ariad Pharmaceuticals, Inc. | Novel heterocycles |
| WO2010015643A1 (en) * | 2008-08-06 | 2010-02-11 | Novartis Ag | New antiviral modified nucleosides |
| CN102526087A (en) * | 2010-12-30 | 2012-07-04 | 南开大学 | Application of nucleoside compound to preparation of medicament for treating enterovirus 71 (EV71) infectious disease |
Non-Patent Citations (3)
| Title |
|---|
| ALEEM GANGJEE, 等: "Design, Synthesis and Biological Evaluation of 2,4-Diamino-6-methyl-5-substitutedpyrrolo[2,3-d]pyrimidines as Dihydrofolate Reductase Inhibitors", 《J. HETEROCYCLIC CHEM.》 * |
| MARTIN KLEčKA, 等: "Direct C–H sulfenylation of purines and deazapurines", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
| XIAOHUA PENG, 等: "pH-Dependent mismatch discrimination of oligonucleotide duplexes containing 2’-deoxytubercidin and 2- or 7-substituted derivatives: protonated base pairs formed between 7-deazapurines and cytosine", 《NUCLEIC ACIDS RESEARCH》 * |
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Application publication date: 20150812 |