CN110343112A - A kind of preparation method preparing chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 4- - Google Patents
A kind of preparation method preparing chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 4- Download PDFInfo
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- CN110343112A CN110343112A CN201910617449.5A CN201910617449A CN110343112A CN 110343112 A CN110343112 A CN 110343112A CN 201910617449 A CN201910617449 A CN 201910617449A CN 110343112 A CN110343112 A CN 110343112A
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- pyrrolo
- pyrimidine
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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
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Abstract
The present invention provides a kind of preparation method of chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 4-, including the following steps: (1) formula (I) compound is reacted with ammonia water the formula of being converted into (II) in dichloromethane solvent；(2) formula (II) compound reacts to obtain formula (III) compound under sodium metaperiodate and the catalysis of transition metal ruthenium；(3) formula (III) compound in acid condition, itself occurs ring-closure reaction and generates chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of ideal product 4-.This method preparation chloro- 7H- pyrrolo- [2,3-d] pyrimidine initial feed of 4- easily obtains, and waste liquid is easier to handle in reaction process, and each step reaction condition is mild, and purifying is easier to, and operation is simple and feasible, and yield is higher.
Description
Technical field
The invention belongs to chemicals synthesis technical field, a kind of system preparing chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of 4-
Preparation Method.
Background technique
Also about there is the influence of 1% adult by rheumatoid arthritis (RA) in the whole world.
JAK/STAT is a kind of important cytokine signaling conduction path, related to rheumatoid arthritis.In recent years
Come, the drug about treatment rheumatoid arthritis (RA) obtains rapid development.Pyrrolopyrimidine structural compounds are that have
Preferable physiological activity and pharmacological activity, chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of intermediate 4- are synthesis treatment rheumatoid joints
Scorching one Luso of JAK inhibitor is for Buddhist nun, the important intermediate of tropsch imatinib.There is starting material prices for known related methods of synthesis
High, the problems such as yield is low.These problems are needed to be optimized to reach market needs.As tropsch imatinib, Luso are for Buddhist nun's
Listing in succession, both at home and abroad to tropsch imatinib, bulk pharmaceutical chemicals (API) and its chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of key intermediate 4-
Demand it is increasing, design and exploitation efficiently, it is economical, green meet industrialized production synthetic route, there is larger economy
Value and significance.
Has pertinent literature report about the synthesis of chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine intermediate of 4- at present.
Niwas et al. is rebuked using adjacent amino coughs up formic acid esters and n,N-Dimethylformamide oxalic acid aldehyde reaction obtains schiff bases
Intermediate reacts to obtain to rebuke with amine again coughs up hepyramine, and chloro obtains target product.
Fumeaux et al. reacts to obtain pyrrolopyridinone compound, assimilation with carbonamidine using o-aminopyridine formic acid esters
It closes the further chlorination of object and obtains chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of final product 4-.
It is that starting material is obtained by bromo, coupling and cyclization that Philip et al., which rebukes pyridine using one 4- hydroxyl of 6- amino,
Target product.
Bromination yield is less than 50% in the reaction, and total recovery is lower, is not suitable for industrialized production.
Preparation method of the country about 4- chloro- 7H- pyrrolo- [2,3-d] pyrimidine uses original identical with us in document
Expect (4,6- bis- chloro- 5- allyl yl pyrimidines), pass first into ammonia and carry out ammonification, then passes to ozone and alkene aoxidize also
Acid is added in original reaction, final step, and intramolecular cyclization obtains target product.Although ultimate yield is up to 70%, in the reaction
Ammonia is more toxic, and the redox reaction of ozone is not easy to operate, is unfavorable for industrial mass production.Its reaction process is as follows:
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of synthesis step is shorter, raw material is easy to get, each step reaction item
Part is mild, and purification is easier to, easy to operate, the preparation method of chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of the higher 4- of yield.
In order to reach the purpose of the present invention, by lot of experiments, it is finally obtained following technical solution:
Specific embodiment
In order to more clearly understand the present invention, we are further illustrated association reaction example:
1, the synthesis of (II): under nitrogen protection, taking 50g (I), 200ml ammonium hydroxide, 38gN- methyl-N- morpholine oxide, and two
Chloromethanes 200ml is added in reaction flask.And reaction is placed in stirring in oil bath and is warming up to 35-40 DEG C of degree stirring for 24 hours.TLC tracking
Reaction process disappears when raw material point or not in variation, stops reaction, and removal solvent obtains compound II40.5g, yield
90%.
2, the synthesis of (III): under nitrogen protection, taking 10g (II), 2g transition metal ruthenium, 38g sodium metaperiodate, 50ml without
Water-acetonitrile is added in reaction flask, and oil bath is warming up to 60 DEG C and is stirred to react.TLC detection, when disappearing when raw material point or no longer changing,
We carry out experiment post-processing: water 100ml is added dropwise and is quenched, repeatedly with EA extraction (50 × 3), merges organic phase, is saturated with 100mL
Brine It × 2, anhydrous sodium sulfate dry, filter vacuum rotary steam, mix silica gel column chromatography (petroleum ether: ethyl acetate=10: 1)
Obtain compound III 8g, yield 79.1%.
3, the synthesis of (IV): taking 5g compound III to be dissolved in 20ml methanol, and the hydrochloric acid of 10ml 3M-5M is added, is warming up to
50-60 DEG C of reaction 3h.TLC following response process merges organic phase, with 100mL saturated common salt with EA extraction (a small amount of multiple)
Water washing is multiple, and anhydrous sodium sulfate dries, filters vacuum rotary steam solvent and obtains the chloro- 7H- pyrrolo- [2,3-d] of final product 4-
Pyrimidine 3.67g, yield 82%.
1H NMR (400MHz, DMSO) δ 12.54 (s, 1H), 8.58 (s, 1H), 7.67 (d, 1H), 6.6 (d, 1H)
That has been described as specific optimization experimental implementations of the invention, It should be understood by those skilled in the art that the present invention is not
It is restricted to the described embodiments, the above embodiments and description only describe specific experiment of the invention operation,
Without departing from the spirit of the invention, the present invention can make appropriate modification.The claimed scope of the invention is by appended
Claims and its equivalent thereof.
Claims (7)
1. a kind of method for preparing chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of 4-, it is characterised in that include the following steps:
(1) formula (I) compound is reacted with ammonia water into the formula of being converted into (II) under alkaline condition:
(2) formula (II) compound redox reaction occurs under the conditions of transition metal ruthenium obtains formula (III) compound:
(3) itself cyclization generates compound (IV) to formula (III) compound in acid condition:
Gained formula (IV) compound is chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of final product 4-.
2. the preparation method of chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of 4- according to claim 1, it is characterised in that: step (1)
In, reaction temperature is 30-60 DEG C, and the reaction time about 24 hours, reaction dissolvent was selected from methylene chloride, methanol, ethyl alcohol or isopropanol
One of.
3. the preparation method of chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of 4- according to claim 1, it is characterised in that: step (1)
In, the molar ratio of the compound I and N- methyl-N- morpholine oxide is 1.2: 1-1.5: 1.
4. the preparation method of chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of 4- according to claim 1, it is characterised in that: step (2)
In, transition metal ruthenium used is as catalyst, and sodium metaperiodate is as oxidant, reaction time 1-3h.
5. the preparation method of chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of 4- according to claim 1, it is characterised in that: step (2)
In, compound II is dissolved in methanol, ethyl alcohol or isopropanol, and the molar ratio of sodium metaperiodate and compound II are 6: 1, transition metal ruthenium
It can suitably add.
6. the preparation method of chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of 4- according to claim 1, it is characterised in that: step (3)
In, reaction dissolvent is methylene chloride, methanol, ethyl alcohol, isopropanol, and acid condition is the hydrochloric acid solution or acetic acid that concentration is 2M-4M,
Reaction temperature is generally 25-50 DEG C, reaction time 1-3h.
7. the preparation method of chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of the 4- according to claim 1, it is characterised in that: step
Suddenly in (3), post-processing: removing organic solvent, extracts, washing, and final product is precipitated in recrystallization, and crystallization organic solvent used is first
Alcohol, ethyl alcohol or acetonitrile.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910617449.5A CN110343112A (en) | 2019-07-05 | 2019-07-05 | A kind of preparation method preparing chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 4- |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910617449.5A CN110343112A (en) | 2019-07-05 | 2019-07-05 | A kind of preparation method preparing chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 4- |
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| CN110343112A true CN110343112A (en) | 2019-10-18 |
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| CN201910617449.5A Pending CN110343112A (en) | 2019-07-05 | 2019-07-05 | A kind of preparation method preparing chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 4- |
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2019
- 2019-07-05 CN CN201910617449.5A patent/CN110343112A/en active Pending
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Application publication date: 20191018 |
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