CN107383076A - A kind of synthetic method of the chlorophenylboronic acid pinacol ester of 3 amino 4 - Google Patents
A kind of synthetic method of the chlorophenylboronic acid pinacol ester of 3 amino 4 Download PDFInfo
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- CN107383076A CN107383076A CN201710514048.8A CN201710514048A CN107383076A CN 107383076 A CN107383076 A CN 107383076A CN 201710514048 A CN201710514048 A CN 201710514048A CN 107383076 A CN107383076 A CN 107383076A
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- CN
- China
- Prior art keywords
- amino
- synthetic method
- chlorophenylboronic acid
- acid pinacol
- compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The present invention relates to a kind of synthetic method of the chlorophenylboronic acid pinacol ester of 3 amino 4.Mainly solves the technical problem for improving its yield.Synthetic method of the present invention comprises the following steps：Under the catalytic action of [1,1' double (diphenylphosphino) ferrocene] palladium chloride, the chloronitrobenzene of 5 bromine 2 reacts in Isosorbide-5-Nitrae dioxane with duplex pinacol borate, obtains compound 1；Compound 1 is reduced into amino, generates target compound 2 in the mixed liquor of second alcohol and water with ammonium chloride, iron powder reaction, nitro.As expensive medicine intermediate, the chlorophenylboronic acid pinacol ester of 3 amino 4 is used widely in pharmaceutical industry.
Description
Technical field
The present invention relates to the synthesis of 3- amino -4- chlorophenylboronic acid pinacol esters.
Background technology
3- amino -4- chlorophenylboronic acid pinacol esters（CAS：850567-56-5）As very important medicine intermediate,
It is used widely in pharmaceutical industry.Di Qiu in 2014 etc. report compound 1 and targeted on J. Org. Chem.
The synthetic method of compound 2, yield are respectively 52% and 74%.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of 3- amino -4- chlorophenylboronic acid pinacol esters, mainly solve
Present synthetic method step is more, the relatively low technical problem of yield.
Technical solution of the present invention is：A kind of synthetic method of 3- amino -4- chlorophenylboronic acid pinacol esters, it is characterized in that bag
Include lower step：The first step, under the catalytic action of [1,1'- double (diphenylphosphino) ferrocene] palladium chloride, the bromo- 2- chlorine nitre of 5-
Base benzene is in Isosorbide-5-Nitrae-dioxane and duplex pinacol borate back flow reaction obtains compound 1, and second step, compound 1 is in second
In the mixed liquor of alcohol and water and ammonium chloride, iron powder back flow reaction, nitro are reduced into amino, generate target compound 2.
Synthetic line is as follows：
。
90-130 DEG C of first step reaction temperature, preferably 110 DEG C；The first step reaction time is 2-4 hours, preferably 3 hours,
Two 80-130 DEG C of step reaction temperatures, preferably 105 DEG C；The second step reaction time is 1-3 hours, preferably 2 hours.
The beneficial effects of the invention are as follows：The synthetic line of synthetic method design of the present invention is simple；In whole building-up process,
Raw material is cheap, and intermediate and target product purifying are simple, substantially increase the yield of reaction intermediate and target compound.
Under the catalytic action of [1,1'- double (diphenylphosphino) ferrocene] palladium chloride, the yield of compound 1 brings up to 92%；Compound
1 passes through ammonium chloride and iron powder reducing, obtains compound 2, yield brings up to 94%, and avoids urging using expensive palladium carbon
Agent.
Embodiment
Embodiment 1：
Step 1：
The bromo- 2- chloronitrobenzenes of 5- are added into three-necked flask（11.8 g, 50.0 mmol）, duplex pinacol borate（12.7
g, 50.0 mmol）, potassium acetate（9.8 g, 100.0 mmol）, Isosorbide-5-Nitrae-dioxane（,120 mL）[1,1'- double (two
Phenyl phosphino-) ferrocene] palladium chloride（1.8 g, 2.5 mmol）.It is small that lower 110 DEG C of reaction solution nitrogen protection is heated to reflux 3
When.Room temperature is cooled to, is evaporated under reduced pressure and removes solvent, residue with Ethyl acetate（200 mL）Dissolving, is filtered to remove solid impurity,
Filtrate water（60 mL）Saturated aqueous common salt（60 mL）Washing, sodium sulphate are dried, filtering.Filtrate is spin-dried for, crude product purified by silica gel post
Chromatographic isolation（Petroleum ether：Ethyl acetate volume ratio=10:1）, obtain yellow solid, compound 1（13.0 g, 45.9
mmol, 92%）.1H NMR (300 MHz, CDCl3)： 1.35 (s, 12 H), 7.54 (d,J = 6.0 Hz, 1 H),
7.89 (d, J= 6.0 Hz, 1 H), 8.10 (s, 1 H)；
Step 2：
Compound 1 is added into three-necked flask（55.0 g, 190 mmol）, ethanol（500 mL）, water（100 mL）And chlorination
Ammonium（20.4 g, 390 mmol）；It is stirred at room temperature down and is slowly added into iron powder（49 g, 880 mmol）.105 DEG C of reaction solution heats back
Stream 2 hours.Room temperature is cooled to, diatomite is filtered to remove unnecessary iron；It is evaporated under reduced pressure and removes ethanol, adds water（100 mL）With it is full
And sodium bicarbonate aqueous solution（150 mL）.Ethyl acetate extracts（200 mL x 3）;Organic phase merges, and uses saturated sodium bicarbonate
The aqueous solution（150 mL）And saturated aqueous common salt（150 mL）Washing, sodium sulphate are dried, filtering.Filtrate is spin-dried for obtaining yellow liquid
Body, compound 2（45.5 g, 179 mmol, 94 %）.1H NMR (300 MHz, CDCl3) 1.32 (s, 12 H),
3.98 (br, 2 H), 7.11 (d, J = 6.0 Hz, 1 H), 7.21 (d, J = 0.6 Hz, 1 H), 7.24
(s, 1 H)。
Embodiment 2：90 DEG C of first step reaction temperature, reaction time are 4 hours, 80 DEG C of second step reaction temperature, during reaction
Between be 3 hours；Remaining is the same as embodiment 1.
Embodiment 3：130 DEG C of first step reaction temperature, reaction time are 2 hours, 130 DEG C of second step reaction temperature, reaction
Time is 1 hour；Remaining is the same as embodiment 1.
Claims (4)
- A kind of 1. synthetic method of 3- amino -4- chlorophenylboronic acid pinacol esters, it is characterized in that comprising the following steps：The first step, Under the catalytic action of [1,1'- double (diphenylphosphino) ferrocene] palladium chloride, the bromo- 2- chloronitrobenzenes of 5- are in Isosorbide-5-Nitrae-dioxy six With duplex pinacol borate back flow reaction in ring, compound 1 is obtained；Second step, compound 1 is in the mixed liquor of second alcohol and water And ammonium chloride, iron powder back flow reaction, nitro are reduced into amino, generate target compound 2；Synthetic line is as follows：。
- 2. a kind of synthetic method of 3- amino -4- chlorophenylboronic acid pinacol esters according to claim 1, it is characterized in that First step reaction temperature is 90-130 DEG C.
- 3. a kind of synthetic method of 3- amino -4- chlorophenylboronic acid pinacol esters according to claim 1, it is characterized in that 2-4 hours in first step reaction time.
- 4. a kind of synthetic method of 3- amino -4- chlorophenylboronic acid pinacol esters according to claim 1, it is characterized in that 80-130 DEG C of reaction 1-3 hour of second step.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710514048.8A CN107383076A (en) | 2017-06-29 | 2017-06-29 | A kind of synthetic method of the chlorophenylboronic acid pinacol ester of 3 amino 4 |
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| CN201710514048.8A CN107383076A (en) | 2017-06-29 | 2017-06-29 | A kind of synthetic method of the chlorophenylboronic acid pinacol ester of 3 amino 4 |
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| CN201710514048.8A Withdrawn CN107383076A (en) | 2017-06-29 | 2017-06-29 | A kind of synthetic method of the chlorophenylboronic acid pinacol ester of 3 amino 4 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047258A (en) * | 2017-12-17 | 2018-05-18 | 沧州普瑞东方科技有限公司 | A kind of method of synthesizing amino pyridine boronic acid ester |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110301145A1 (en) * | 2008-11-12 | 2011-12-08 | Gilead Connecticut INc. | Pyridazinones, method of making, and method of use thereof |
| CN104530107A (en) * | 2014-12-31 | 2015-04-22 | 大连联化化学有限公司 | Synthetic method for 3-amino-4-fluorophenylboronic acid |
-
2017
- 2017-06-29 CN CN201710514048.8A patent/CN107383076A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110301145A1 (en) * | 2008-11-12 | 2011-12-08 | Gilead Connecticut INc. | Pyridazinones, method of making, and method of use thereof |
| CN104530107A (en) * | 2014-12-31 | 2015-04-22 | 大连联化化学有限公司 | Synthetic method for 3-amino-4-fluorophenylboronic acid |
Non-Patent Citations (2)
| Title |
|---|
| DI QIU等: "Synthesis of Trimethylstannyl Arylboronate Compounds by Sandmeyer-Type Transformations and Their Applications in Chemoselective Cross-Coupling Reactions", 《J. ORG. CHEM.》 * |
| HIROYUKI NAKAMURA等: "Development of hypoxia-inducible factor (HIF)-1ainhibitors: Effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047258A (en) * | 2017-12-17 | 2018-05-18 | 沧州普瑞东方科技有限公司 | A kind of method of synthesizing amino pyridine boronic acid ester |
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Application publication date: 20171124 |