CN102838627A - Synthesis of 2-amino benzoxazole-5-boric acid - Google Patents
Synthesis of 2-amino benzoxazole-5-boric acid Download PDFInfo
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- CN102838627A CN102838627A CN2012103311287A CN201210331128A CN102838627A CN 102838627 A CN102838627 A CN 102838627A CN 2012103311287 A CN2012103311287 A CN 2012103311287A CN 201210331128 A CN201210331128 A CN 201210331128A CN 102838627 A CN102838627 A CN 102838627A
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Abstract
The invention relates to synthesis of 2-amino benzoxazole-5-boric acid. The synthesis solves shortcomings that reaction yield is low, conditions are rigor, and the 2-amino benzoxazole-5-boric acid is not easy to purify in the previous synthetic methods of the 2-amino benzoxazole-5-boric acid. The invention provides a route that bromophenol serves as an initial raw material, and nitration, reduction, cyanogen bromide cyclization, coupling and hydrolysis are carried out on the bromophenol to obtain end products. The whole process is easy to operate, products are easy to purify, and the synthesis is suitable to industrialization, and the raw material cost is greatly reduced.
Description
Technical field
The present invention relates to the synthetic of the amino benzoxazoles of 2--5-boric acid, also relate to the synthetic of its midbody and use, belong to medicine, chemical technology field.
Background technology
2-is amino, and benzoxazoles-5-boric acid is important chemistry, and chemical intermediate is widely used in medicine and pesticide field; Especially aspect antineoplastic new drug INK128 synthetic; The analogue synthetic route that is seen in report at present seldom, and severe reaction conditions mostly, yield is low; Be difficult for purifying, be difficult to industriallization.
Summary of the invention
Benzoxazoles-5-boric acid compound method reaction yield in the past is low to the present invention is directed to 2-amino, and condition is harsh, is difficult for the deficiency of purifying; Invented described with the p bromophenol be starting raw material through nitrated, reduction, cyanogen bromide closes ring; Coupling, hydrolysis obtain the route of final product, make whole process easy handling; Product is easy to purifying, is fit to industriallization, and raw materials cost reduces greatly.
The amino benzoxazoles of described 2--5-boric acid is synthetic, is comprised by synthetic (4) the used alkali of midbody (3) reaction but is not limited to triethylamine, diisopropyl ethyl amine; Trimethylamine 99s etc., solvent comprise but are not limited to THF, methyl alcohol; Ethanol; Virahols etc., temperature of reaction are not limited to subzero 78 and spend to 100 degree, and the time is not limited to half a hour to 48 hour.
The amino benzoxazoles of described 2--5-boric acid is synthetic, and by midbody (4) reaction synthetic (5), used coupling reagent comprises but is not limited to tetramethyl ethylene ketone borine etc.; Catalyzer comprises but is not limited to Pd (dppf) Cl2, Pd (Ph3P) 4, Pddba etc.; Solvent comprises but is not limited to THF, dioxane, glycol dimethyl ether etc.; Temperature of reaction is not limited to 25 and spends to 150 degree, and the time is not limited to half a hour to 48 hour.
The amino benzoxazoles of described 2--5-boric acid is synthetic, is comprised by synthetic final product (6) hydrolysising condition of midbody (5) reaction but is not limited to the hydrochloric acid of 1N, the hydrochloric acid of 5N; The sulfuric acid of 1N; The sulfuric acid of 5N etc., temperature of reaction are not limited to 25 and spend to 100 degree, and the time is not limited to half a hour to 48 hour.
Above-mentioned is that the chemical reaction route of starting raw material is following with the p bromophenol:
Embodiment:
Preparation compound (2):
Starting raw material p bromophenol 346 grams (2 moles) are dissolved in 3 methylene dichloride, and the frozen water cooling splashes into 95% nitrosonitric acid 160 grams (2.4 moles) down, adds the back room temperature reaction 24 hours; Pour into and continue in 5 liters of frozen water to stir half a hour, layering extraction, organic phase washing; The saturated salt washing, anhydrous sodium sulfate drying filters; Revolve driedly, re-crystallizing in ethyl acetate obtains beige solid 231 gram (yield 53%).
Preparation compound (3):
Compound (2) 218 gram (1 mole) is dissolved in 2 liters of anhydrous tetrahydro furans, adds Raney's nickel 20 grams of new system, and reaction 24 hours under 1 atmospheric hydrogen environment is filtered behind the hydrogen exchange 3 times, revolves the dried pink solid 188 that obtains and restrains (yield 100%).
Preparation compound (4):
Compound (3) 188 grams (1 mole) after the reduction are dissolved in 2 liters of THFs, add triethylamine 101 grams (1 mole), and cooling adds cyanogen bromide 127.2 grams (1.2 moles) down in batches and added the back back flow reaction 24 hours; Residual solution is poured in 1 liter of frozen water after steaming solvent, and methylene dichloride extracts three times for 500 milliliters, merges organic phase; Washing, saturated salt washing, anhydrous sodium sulfate drying; Filter, revolve the dried off-white color solid that obtains, get 161.9 gram products (yield 76%) with re-crystallizing in ethyl acetate.
Preparation compound (5):
Compound (4) 106 grams (0.5 mole) of Guan Huan are dissolved in 1 liter of dioxane solution, add tetramethyl ethylene ketone borine 152.4 grams (0.6 mole), potassium acetate 245 grams (2.5 moles); Pd (dppf) Cl2 10.6 grams (catalytic amount) add back nitrogen protection refluxed reaction 24 hours, and residual solution was poured in 1 liter of frozen water after solvent was fallen in steaming, and methylene dichloride extracts three times for 500 milliliters; Merge organic phase, washing, saturated salt washing; Anhydrous sodium sulfate drying; Filter, revolve dried petroleum ether, obtain pale solid 108 grams (yield 83%).
The amino benzoxazoles of preparation 2--5-boric acid:
Compound (5) 26 grams (0.1 mole) are dissolved in 130 ml methanol, 50 milliliters of the hydrochloric acid of adding 5N, and reaction is 24 hours under the room temperature; Revolve most of solvent, pour in 100 ml waters, PH is transferred to 3; Solid is separated out, and filters, and vacuum-drying gets pale solid 16.9 grams (yield 95%).
Claims (4)
1. described with the p bromophenol be starting raw material through nitrated, reduction, cyanogen bromide closes ring, coupling, hydrolysis obtain the route of final product, make whole process easy handling, product is easy to purifying, is fit to industriallization, raw materials cost reduces greatly.
2. the amino benzoxazoles of described 2--5-boric acid is synthetic, is comprised by synthetic (4) the used alkali of midbody (3) reaction but is not limited to triethylamine, diisopropyl ethyl amine; Trimethylamine 99s etc., solvent comprise but are not limited to THF, methyl alcohol; Ethanol; Virahols etc., temperature of reaction are not limited to subzero 78 and spend to 100 degree, and the time is not limited to half a hour to 48 hour.
3. the amino benzoxazoles of described 2--5-boric acid is synthetic, and by midbody (4) reaction synthetic (5), used coupling reagent comprises but is not limited to tetramethyl ethylene ketone borine etc.; Catalyzer comprises but is not limited to Pd (dppf) Cl2, Pd (Ph3P) 4, Pddba etc.; Solvent comprises but is not limited to THF, dioxane, glycol dimethyl ether etc.; Temperature of reaction is not limited to 25 and spends to 150 degree, and the time is not limited to half a hour to 48 hour.
4. the amino benzoxazoles of described 2--5-boric acid is synthetic, is comprised by synthetic final product (6) hydrolysising condition of midbody (5) reaction but is not limited to the hydrochloric acid of 1N, the hydrochloric acid of 5N; The sulfuric acid of 1N; The sulfuric acid of 5N etc., temperature of reaction are not limited to 25 and spend to 100 degree, and the time is not limited to half a hour to 48 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103311287A CN102838627A (en) | 2012-09-10 | 2012-09-10 | Synthesis of 2-amino benzoxazole-5-boric acid |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012103311287A CN102838627A (en) | 2012-09-10 | 2012-09-10 | Synthesis of 2-amino benzoxazole-5-boric acid |
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| CN102838627A true CN102838627A (en) | 2012-12-26 |
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| CN2012103311287A Pending CN102838627A (en) | 2012-09-10 | 2012-09-10 | Synthesis of 2-amino benzoxazole-5-boric acid |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102271513A (en) * | 2008-11-03 | 2011-12-07 | 英特利凯恩股份有限公司 | Benzoxazole kinase inhibitors and methods of use |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102271513A (en) * | 2008-11-03 | 2011-12-07 | 英特利凯恩股份有限公司 | Benzoxazole kinase inhibitors and methods of use |
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Application publication date: 20121226 |