CN103965232B - A kind of method of synthesis 3-(2,5-dihydro) furan boronic acid ester - Google Patents
A kind of method of synthesis 3-(2,5-dihydro) furan boronic acid ester Download PDFInfo
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Abstract
The present invention's open a kind of synthesis 3-(2,5-dihydro) method of furan boronic acid ester, relate to a kind of boric acid ester new synthetic method of medical intermediate, belong to organic chemical synthesis field.It is characterized in that: comprise 3-(2,5 dihydros) preparation of furane sulfonic acid ester and 3-(2,5-dihydro) synthesis of furan boronic acid ester.Its beneficial effect is: cost of material is cheaply easy to get, and reactions steps is simple, the gentle easily operation of processing condition, and technology stability is good, is easy to realize suitability for industrialized production, and aftertreatment is simple, and productive rate is high, and purity is good, and product cost is low.
Description
Technical field
The present invention relates to a kind of boric acid ester new synthetic method of medical intermediate, belong to organic chemical synthesis field, refer to a kind of synthesis 3-(2,5-dihydro especially) method of furan boronic acid ester.
Background technology
3-(2,5-dihydro) furan boronic acid ester as a kind of fine chemical material, be extensively used as medicine intermediate.Its synthetic method seldom reported by existing document, only have one section of article report its synthesis (its synthetic route is as follows for J.Am.Chem.Soc, 1998,120,7995 – 7996:
This synthetic route relates to three steps, as long as the productive rate of the first step 20%, the productive rate of second step is 15%, three step overall yields less than 20%, and use active high tert-butyl lithium, severe reaction conditions, not easy to operate, reaction reagent Grubbs ' catalyst wherein expensive ($ 250/g) is also not easy to have bought, and use this synthetic route can only synthesize the product of several milligrams in laboratory, and the cost of product is very high.In addition, the finished product of gained should be colourless liquids, but are all can not remove by column chromatography or underpressure distillation purifying the trace metal catalysts contained, and the product of gained is auburn liquid, product purity not high (94%).In a word, no matter this synthetic route is from reaction conditions and the chemical reagent used, and not only consume energy but also expensive, production cost is high, all can not realize amplifying preparation, more can not realize suitability for industrialized production.Between this situation, we are badly in need of the novel process will researching and developing this compou nd synthesis, shorten synthetic route, change reaction conditions, thus good product purity (98%), raw material is easy to get and low price, easily amplifies synthesis, realizes suitability for industrialized production.
Summary of the invention
The object of the invention is to overcome above-mentioned not enough problem, provide 3-(2,5-dihydro) new synthetic process of furan boronic acid ester, synthetic method is simple, and raw material is easy to get and low price, good product purity, stable performance, and production cost is low, easily realizes suitability for industrialized production.
The present invention for achieving the above object, one synthesis 3-(2,5-dihydro of the present invention) method of furan boronic acid ester, comprise 3-(2,5 dihydros) preparation of furane sulfonic acid ester and 3-(2,5-dihydro) synthesis of furan boronic acid ester, reaction formula is as follows:
One, 3-(2; 5 dihydros) preparation of furane sulfonic acid ester: under nitrogen protection; 50g is added, 0.58mol3-(2,5 dihydros in 1L reaction flask) furanone and the anhydrous THF of 200mL; be chilled to-78 DEG C; then 376mL is dripped, the anhydrous THF diisopropylamine lithium of 0.64mol, 1.7N in; reaction reacts 2h at-78 DEG C; be added dropwise to 163.9g again, 0.58mol tri-fluorosulfonic anhydride, dropwises; reaction solution is allowed slowly to rise to room temperature; whole process need 12h, with 10% sodium hydroxide cancellation reaction, adds 1L ether dilute reaction solution; be separated organic phase, use anhydrous MgSO
4drying, underpressure distillation, except desolventizing, under the vacuum condition of 12mmHg, is collected 45 ~ 50 DEG C of cuts, is namely obtained the 3-(2.5 dihydro of 98% purity) furane sulfonic acid ester;
Two, 3-(2; 5-dihydro) synthesis of furan boronic acid ester: under nitrogen protection; 64g is added, 0.29mol3-(2,5 dihydros in 1L reaction flask) furane sulfonic acid ester; 74.5g; 0.29mol joins boric acid ester, 73.1g, 0.87mol salt of wormwood; and 6.43g, 0.09mol catalyst P d (dppf) Cl
2, and solvent 500mL1,4-dioxane, in reaction solution, blast nitrogen 10min, then slow under a nitrogen reaction system is warming up to 80 DEG C, allow system react 16h at this temperature, be chilled to room temperature, filter, removal of solvent under reduced pressure, residue dress on a silica gel column, with normal hexane: ethyl acetate=10:1 eluted product, distillation, except desolventizing, obtains colourless oil liquid, obtains product.
Described whole reaction is carried out in inert nitrogen gas.
In described step one, 3-(2,5-dihydro) mol ratio of furanone and diisopropylamine lithium and three fluorosulfonic anhydride is: 1:1.1:1.
In described step 2,3-(2.5 dihydro) furane sulfonic acid ester with the mol ratio of connection boric acid ester and catalyzer is: 1:0.9:0.03.
In described step one, reaction end is monitored by GC, raw material and intermediate product 3-(2.5 dihydro) the GC content ratio of furane sulfonic acid ester is less than 1% judgement reaction end.
In described step 2, reaction end is monitored by GC, intermediate product 3-(2.5 dihydro) the GC content ratio of furane sulfonic acid ester and final product is less than 1% judgement reaction end.
The described 3-(2 prepared, 5-dihydro) furan boronic acid ester is a kind of medicine intermediate.
One synthesis 3-(2 of the present invention, 5-dihydro) method of furan boronic acid ester, its beneficial effect is: cost of material is cheaply easy to get, and reactions steps is simple, the gentle easily operation of processing condition, and technology stability is good, be easy to realize suitability for industrialized production, aftertreatment is simple, and productive rate is high, purity is good, and product cost is low.
Embodiment
Be clearly and completely described below in conjunction with the technical scheme in the embodiment of the present invention, obviously, described embodiment is only one of them embodiment of the present invention, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment 1
One, 3-(2,5 dihydros) preparation of furane sulfonic acid ester:
Under nitrogen protection, in 1L reaction flask, 50g is added, 0.58mol3-(2; 5 dihydros) furanone and the anhydrous THF of 200mL, be chilled to-78 DEG C, then drip 376mL; the anhydrous THF diisopropylamine lithium of 0.64mol, 1.7N in, reacts and react 2h at-78 DEG C; be added dropwise to 163.9g again, 0.58mol tri-fluorosulfonic anhydride, dropwises; reaction solution is allowed slowly to rise to room temperature, whole process need 12h, with 10% sodium hydroxide cancellation reaction; add 1L ether dilute reaction solution, be separated organic phase, use anhydrous MgSO
4drying, underpressure distillation, except desolventizing, under the vacuum condition of 12mmHg, is collected 45 ~ 50 DEG C of cuts, is obtained 3-(2,5 dihydros) furane sulfonic acid ester;
Two, 3-(2,5-dihydro) synthesis of furan boronic acid ester:
Under nitrogen protection, in 1L reaction flask, add 64g, 0.29mol3-(2,5 dihydros) furane sulfonic acid ester, 74.5g, 0.29mol join boric acid ester, 73.1g, 0.87mol salt of wormwood, and 6.43g, 0.09mol catalyst P d (dppf) Cl
2, and solvent 500mL1,4-dioxane, in reaction solution, blast nitrogen 10min, then slow under a nitrogen reaction system is warming up to 80 DEG C, allow system react 16h at this temperature, be chilled to room temperature, filter, removal of solvent under reduced pressure, residue dress on a silica gel column, with normal hexane: ethyl acetate=10:1 eluted product, distillation is except desolventizing, and obtaining colourless oil liquid is 3-(2,5-dihydro) furan boronic acid ester.
From embodiment 1, preparing 3-(2,5 dihydros) furane sulfonic acid ester weight is 100.08g, productive rate 80%, GC>98%, 1H NMR (CDCl3): 4.62ppm, bimodal (2H); 4.81ppm, bimodal (2H); 6.61ppm, unimodal (1H); Prepare 3-(2,5-dihydro) furan boronic acid ester 40.83g, yield 78%, GC>98%, 1HNMR (CDCl
3): 1.25ppm, unimodal (12H); 4.61ppm, bimodal (2H); 4.66ppm, bimodal (2H); 6.45ppm, unimodal (1H).
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (6)
1. synthesize a 3-(2,5-dihydro) method of furan boronic acid ester, comprise 3-(2,5-dihydro) preparation of furane sulfonic acid ester and 3-(2,5-dihydro) synthesis of furan boronic acid ester, it is characterized in that:
1. 3-(2; 5-dihydro) preparation of furane sulfonic acid ester: under nitrogen protection; 50g is added, 0.58mol 3-(2,5-dihydro in 1L reaction flask) furanone and the anhydrous THF of 200mL; be chilled to-78 DEG C; then drip 376mL, 0.64mol, 1.7N are at the diisopropylamine lithium of anhydrous THF; reaction reacts 2h at-78 DEG C; be added dropwise to 163.9g again, 0.58mol tri-fluorosulfonic anhydride, dropwises; reaction solution is allowed slowly to rise to room temperature; whole process need 12h, with 10% sodium hydroxide cancellation reaction, adds 1L ether dilute reaction solution; be separated organic phase, use anhydrous MgSO
4drying, underpressure distillation, except desolventizing, under the vacuum condition of 12mmHg, is collected 45 ~ 50 DEG C of cuts, is namely obtained 3-(2,5-dihydro) furane sulfonic acid ester;
2. 3-(2; 5-dihydro) synthesis of furan boronic acid ester: under nitrogen protection; 64g is added, 0.29mol 3-(2,5-dihydro in 1L reaction flask) furane sulfonic acid ester; 74.5g; purity is the 0.29mol connection boric acid ester of 98%, 73.1g, 0.87mol salt of wormwood; and 6.43g, 0.09mol catalyst P d (dppf) Cl
2, and solvent 500mL Isosorbide-5-Nitrae-dioxane, in reaction solution, blast nitrogen 10min, then slow under a nitrogen reaction system is warming up to 80 DEG C, allow system react 16h at this temperature, be chilled to room temperature, filter, removal of solvent under reduced pressure, residue dress on a silica gel column, with normal hexane: ethyl acetate=10:1 eluted product, distillation, except desolventizing, obtains colourless oil liquid, obtains product.
2. synthesis 3-(2,5-dihydro as claimed in claim 1 a kind of) method of furan boronic acid ester, it is characterized in that: described whole reaction is carried out in normal pressure inert nitrogen gas.
3. synthesis 3-(2,5-dihydro as claimed in claim 1 a kind of) method of furan boronic acid ester, it is characterized in that: described 1. in, 3-(2,5-dihydro) mol ratio of furanone and diisopropylamine lithium and three fluorosulfonic anhydride is: 1:1.1:1.
4. synthesis 3-(2,5-dihydro as claimed in claim 1 a kind of) method of furan boronic acid ester, it is characterized in that: described step 1. in, raw material and intermediate product 3-(2,5-dihydro) the GC content ratio of furane sulfonic acid ester is less than 1% judgement reaction end.
5. synthesis 3-(2,5-dihydro as claimed in claim 1 a kind of) method of furan boronic acid ester, it is characterized in that: described step 2. in, intermediate product 3-(2,5-dihydro) the GC content ratio of furane sulfonic acid ester and final product is less than 1% judgement reaction end.
6. synthesis 3-(2,5-dihydro as claimed in claim 1 a kind of) method of furan boronic acid ester, it is characterized in that: described in the 3-(2 for preparing, 5-dihydro) furan boronic acid ester is applied as medicine intermediate.
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| WO2011084402A1 (en) * | 2009-12-21 | 2011-07-14 | Merck Sharp & Dohme Corp. | Tyrosine kinase inhibitors |
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| WO2011084402A1 (en) * | 2009-12-21 | 2011-07-14 | Merck Sharp & Dohme Corp. | Tyrosine kinase inhibitors |
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| Title |
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| Novel Synthesis of Cyclic Alkenylboronates via Ring-Closing Metathesis;Johanne Renaud and Stephane G. Ouellet;《Journal of the American Chemical Society》;19980724;第120卷(第31期);7995-7996 * |
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