CN109970631A - A kind of synthetic method of the iodo- 2- pyridylacetic acid of 5- - Google Patents
A kind of synthetic method of the iodo- 2- pyridylacetic acid of 5- Download PDFInfo
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- CN109970631A CN109970631A CN201910231401.0A CN201910231401A CN109970631A CN 109970631 A CN109970631 A CN 109970631A CN 201910231401 A CN201910231401 A CN 201910231401A CN 109970631 A CN109970631 A CN 109970631A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention relates to a kind of synthetic methods of the iodo- 2- pyridylacetic acid of 5-.Mainly solve the technical issues of iodo- 2- pyridylacetic acid of 5- can not be using the preparation of silica gel chromatograph column purification be closed.Synthetic method of the present invention is the following steps are included: the cyanoacetic acid tert-butyl ester is in dimethyl sulphoxide solution and sodium hydride reaction, the bromo- 5- iodine pyridine reaction of the intermediate and 2- of generation generate compound 1；Compound 1 heats decarboxylation, cyan-hydrolysis in hydrochloric acid solution, generates target compound 2；As expensive medicine intermediate, the iodo- 2- pyridylacetic acid of 5- has wide practical use in chemical pharmacy field, can be used for synthesizing KX2-391, a kind of highly selective Src kinase inhibitor.
Description
Technical field
The present invention relates to the synthetic methods of the iodo- 2- pyridylacetic acid (CAS:1234616-74-0) of 5-.
Background technique
As expensive medicine intermediate, the iodo- 2- pyridylacetic acid of 5- is before chemical pharmacy field is widely used
Scape can be used for synthesizing KX2-391, a kind of highly selective Src kinase inhibitor.
KX2-391 is a kind of non ATP competitiveness Src inhibitor and the first targeting Src kinase substrate binding site
Inhibitor, is reported in US Patent 7 earliest, and 300,931, synthetic method is as follows:
5- bromo-2-pyridyl acetic acid is reported out in the form of patent as a kind of medicine intermediate, synthetic method and application
Come, common synthetic method is the bromo- 2- iodine pyridine of 5- and the reaction of malonic acid rouge, is obtained by hydrolysis, decarboxylation；As reactivity
The iodo- 2- pyridylacetic acid of bigger 5- is easy decarboxylation because its activity is big, is not suitable for silica gel chromatograph column purification, can not use the method
Synthesis.
Summary of the invention
The object of the present invention is to provide a kind of synthetic methods of the iodo- 2- pyridylacetic acid of 5-, mainly solve the iodo- 2- pyridine second of 5-
The technical issues of acid can not be using the preparation of silica gel chromatograph column purification be closed.
Technical solution of the present invention are as follows: a kind of synthetic method of the iodo- 2- pyridylacetic acid of 5-, it is characterized in that the following steps are included:
The first step, the cyanoacetic acid tert-butyl ester react in dimethyl sulphoxide solution with sodium hydride, the bromo- 5- iodine pyrrole of the intermediate and 2- of generation
Pyridine reaction, generates compound 1；Second step, compound 1 heat decarboxylation, cyan-hydrolysis in hydrochloric acid solution, generate target chemical combination
Object 2.Synthetic line is as follows:
。
The first step reacts 125 DEG C, and the reaction time is 6 hours；Second step reaction is reacted in 6 M hydrochloric acid, and reaction temperature is
100 DEG C, the reaction time is 3 hours.With sodium hydrate aqueous solution tune pH=9-10 of 2 M after reaction, extracted；Again with 2 M
Hydrochloride tune pH=4 carry out suction filtration drying.
The beneficial effects of the present invention are: the present invention has reported the synthetic method of the iodo- 2- pyridylacetic acid of 5-, compound 1 for the first time
By decarboxylation, hydrolysis, the target compound 2 of high-purity can be obtained.Reaction route of the invention is unique, and raw material is cheap, is not necessarily to
Chromatography is suitable for amplification production.
Specific embodiment
Step 1:
Into 1 liter of three-necked flask be added dimethyl sulfoxide (500 mL), in room temperature be added sodium hydride (60%, 27.7 g,
692 mmol), it is added dropwise the cyanoacetic acid tert-butyl ester (100.7 g, 713 mmol), drips off within about 1 hour, be stirred at room temperature half an hour, then plus
The bromo- 5- iodine pyridine of 2- (76.7 g, 270 mmol) is heated to 125 DEG C, reacts 6 hours, stops heating, after being cooled to room temperature, stirs
Mix it is lower reaction solution is slowly poured into ammonium chloride solution (150 g ammonium chlorides are dissolved in 1.5 L water), be precipitated solid, filter, washing,
Solid is dissolved in about ethyl acetate (2 L), saturated common salt water washing, organic phase is dry, is spin-dried for, mixed with ethyl acetate and petroleum ether
Liquid (volume ratio 1:10,200 mL) mashing is closed, solid is filtered out, is transferred to paper disc and dries overnight, obtain yellow solid, target chemical combination
Object 1(54 g, 157 mmol, 58%)；
Step 2:
Water (300 mL) is added into 1 liter of three-necked flask, concentrated hydrochloric acid (300 mL) and target compound 1(54 g, 157
Mmol), 100 DEG C are heated to, is reacted 3 hours.Yellow solid disappears, and reaction solution becomes light brown.Reaction solution is gone into 1 liter of single port
Bottle is cooled to room temperature in 70 DEG C of revolvings to paste, then plus trash ice (100 g) on a small quantity, in ice bath, slowly plus the sodium hydroxide of 2 M
About 400 mL of aqueous solution tune pH=9-10(), it is extracted twice with methyl tertiary butyl ether(MTBE) (200 mL), discards organic phase, water phase is taken out
After filter, with hydrochloride tune pH=4 of 2 M, khaki solid is precipitated, is stirred for filtering after ten minutes, with a small amount of washing, solid
It is transferred to vacuum oven, 40 DEG C are dried in vacuo 2 hours, obtain khaki solid, target compound 2(30 g, 114 mmol,
73%).1H NMR (400 MHz, DMSO-d6): 12.89 (s, 1 H), 8.69 (d, J=1.6 Hz, 1 H),
8.10-8.08 (m, 1 H), 7.20 (d, J = 1.6 Hz, 1 H), 3.69 (s, 2 H)。
Claims (6)
1. a kind of synthetic method of the iodo- 2- pyridylacetic acid of 5-, it is characterized in that: the following steps are included: the first step, the tertiary fourth of cyanoacetic acid
Ester is in dimethyl sulphoxide solution and sodium hydride reaction, the bromo- 5- iodine pyridine reaction of the intermediate and 2- of generation generate compound
1；Second step, compound 1 heat decarboxylation, cyan-hydrolysis in hydrochloric acid solution, generate target compound 2；Synthetic line is as follows:
。
2. the synthetic method of the iodo- 2- pyridylacetic acid of a kind of 5- according to claim 1, it is characterized in that: first step reaction temperature
125 DEG C of degree, reaction time are 6 hours.
3. the synthetic method of the iodo- 2- pyridylacetic acid of a kind of 5- according to claim 1, it is characterized in that: second step is in 6 M
It is reacted in hydrochloric acid.
4. the synthetic method of the iodo- 2- pyridylacetic acid of a kind of 5- according to claim 1, it is characterized in that: second step reaction temperature
When degree is 100 DEG C, react 3 hours.
5. the synthetic method of the iodo- 2- pyridylacetic acid of a kind of 5- according to claim 4, it is characterized in that: after second step reaction
It is extracted with sodium hydrate aqueous solution tune pH=9-10 of 2 M.
6. the synthetic method of the iodo- 2- pyridylacetic acid of a kind of 5- according to claim 5, it is characterized in that: with 2 M after extraction
Hydrochloric acid tune pH=4 carry out suction filtration drying.
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| CN201910231401.0A CN109970631A (en) | 2019-03-26 | 2019-03-26 | A kind of synthetic method of the iodo- 2- pyridylacetic acid of 5- |
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| CN201910231401.0A CN109970631A (en) | 2019-03-26 | 2019-03-26 | A kind of synthetic method of the iodo- 2- pyridylacetic acid of 5- |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102939290A (en) * | 2010-03-19 | 2013-02-20 | 辉瑞大药厂 | 2,3 dihydro-1h-inden-1-yl- 2,7-diazaspiro [3.6] nonane derivatives and their use as antagonists or inverse agonists of the ghrelin receptor |
| WO2015092610A1 (en) * | 2013-12-20 | 2015-06-25 | Pfizer Limited | N-acylpiperidine ether tropomyosin-related kinase inhibitors |
| CN108026045A (en) * | 2015-05-15 | 2018-05-11 | 奥瑞基尼探索技术有限公司 | The tetrahydroquinoline ketone compound by substitution as ROR gamma modulators |
-
2019
- 2019-03-26 CN CN201910231401.0A patent/CN109970631A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102939290A (en) * | 2010-03-19 | 2013-02-20 | 辉瑞大药厂 | 2,3 dihydro-1h-inden-1-yl- 2,7-diazaspiro [3.6] nonane derivatives and their use as antagonists or inverse agonists of the ghrelin receptor |
| WO2015092610A1 (en) * | 2013-12-20 | 2015-06-25 | Pfizer Limited | N-acylpiperidine ether tropomyosin-related kinase inhibitors |
| CN108026045A (en) * | 2015-05-15 | 2018-05-11 | 奥瑞基尼探索技术有限公司 | The tetrahydroquinoline ketone compound by substitution as ROR gamma modulators |
Non-Patent Citations (1)
| Title |
|---|
| SUBOTA, ANDRII I. 等: "Scalable synthesis and properties of 7-methyl-4-azaindole", 《HETEROCYCLIC COMMUNICATIONS》 * |
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