CN107540699A - A kind of synthetic method of the boric acid hydrochloride of 2 amino, 3 fluorine pyridine 4 - Google Patents
A kind of synthetic method of the boric acid hydrochloride of 2 amino, 3 fluorine pyridine 4 Download PDFInfo
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- CN107540699A CN107540699A CN201710958105.1A CN201710958105A CN107540699A CN 107540699 A CN107540699 A CN 107540699A CN 201710958105 A CN201710958105 A CN 201710958105A CN 107540699 A CN107540699 A CN 107540699A
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- fluorine pyridine
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Abstract
The present invention relates to a kind of synthetic method of the boric acid hydrochloride of 2 amino, 3 fluorine pyridine 4, mainly solves the technical problem of existing expensive starting materials during the compound synthesis, the present invention is from the cheap and easily-available fluorine pyridine of 2 amino of raw material 3, synthesis step：（1）After the fluorine pyridine of 2 amino 3 and butyl lithium reaction, the amine of 3 fluorine of generation, 4 iodine pyridine 2 is reacted with elemental iodine；（2）The amine of 3 fluorine, 4 iodine pyridine 2 and the pinacol borate of 3 fluorine pyridine of duplex boron coupling 2 amino of generation 4；（3）The pinacol borate of 2 amino, 3 fluorine pyridine 4 obtains the boric acid hydrochloride of 2 amino, 3 fluorine pyridine 4 through HCl treatment.
Description
Technical field
The present invention relates to a kind of synthetic method of 2- amino -3- fluorine pyridine -4- boric acid hydrochlorides.
Background technology
2- amino -3- fluorine pyridine -4- borates are a kind of important intermediates for being used to synthesize carbon-carbon bond, WO2015/
193846A1 is obtained by three-step reaction：The effect of the first step, the bromo- 4- chloro-3-fluoropyridines of 2- and t-butyl carbamate in palladium
Lower coupling generation 4- chloro-3-fluoropyridine -2- carboxylic acid tert-butyl esters；Second step, 4- chloro-3-fluoropyridine -2- carboxylic acid tert-butyl esters and duplex
Boron is coupled the generation 3- fluorine pyridine-2-carboxylic acids tert-butyl ester -4- pinacol borates in the presence of palladium；3rd step, carboxylic acid tert-butyl ester
Remove under the action of an acid.Though the bromo- 4- chloro-3-fluoropyridines in the markets of raw material 2- that this method uses have supply, expensive,
And do not supply largely, while first, second step reaction is required for using expensive palladium catalyst so that 2- amino -3-
Fluorine pyridine -4- borates and boric acid hold at high price.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of 2- amino -3- fluorine pyridine -4- boric acid hydrochlorides, mainly solve
The technical problem of existing expensive starting materials during the compound synthesis, technical support is provided for the marketization of the compound.
Technical solution of the present invention is as follows：A kind of synthetic method of 2- amino -3- fluorine pyridine -4- boric acid hydrochlorides, including with
Lower step：
（1）2- amino -3- fluorine pyridine and butyl lithium, the elemental iodine reaction generation fluoro- 4- iodine pyridines -2- amine of 3-：By 2- amino -3- fluorine
Pyridine is dissolved in tetrahydrofuran, -78 DEG C of dropwise addition 1M n-BuLi toluene solution, and -78 DEG C are stirred 30 minutes, are then added dropwise single
The tetrahydrofuran solution of matter iodine, continue to obtain the fluoro- 4- iodine pyridines -2- amine of 3- in -78 DEG C of stirrings post processing in 1 hour（a）；
（2）Iodide and duplex boron coupling generation 2- amino -3- fluorine pyridine -4- pinacol borates：By the fluoro- 4- iodine pyridines of 3--
2- amine（a）, duplex boron, potassium acetate and two（Triphenyl phosphorus）Palladium chloride is added sequentially to N, in N '-dimethyl acetamide, so
Stir 2 hours at 100 DEG C afterwards, reaction completes post processing and obtains 2- amino -3- fluorine pyridine -4- pinacol borates（b）；
（3）The deprotection of 2- amino -3- fluorine pyridine -4- pinacol borates：By 2- amino -3- fluorine pyridine -4- boric acid pinacols
Ester（b）It is added in the aqueous hydrochloric acid solution of mass percentage concentration 10%, is then refluxed for 3 hours, is spin-dried for solvent and obtains 2- amino -3- fluorine
Pyridine -4- boric acid hydrochlorides（c）.
Reaction equation is as follows：
。
The beneficial effects of the invention are as follows：（1）Cheap raw material can be chosen by this method and technique synthesizes 2- amino -3-
Fluorine pyridine -4- boric acid hydrochlorides；（2）This method technique is relatively easy, easy to operate.
Brief description of the drawings
Fig. 1 be product of the present invention nuclear magnetic spectrum (400MHz,D 2 O）.
Fig. 2 is the mass spectrogram of product of the present invention.
Embodiment
Embodiment 1：Prepare 2- amino -3- fluorine pyridine -4- boric acid hydrochlorides
（1）The preparation of the fluoro- 4- iodine pyridines -2- amine of 3-：
2- amino -3- fluorine pyridine 50g are weighed, are placed in tri- mouthfuls of reaction bulbs of 2L, add tetrahydrofuran 300mL.Nitrogen is protected, drop
2.5M n-BuLis-tetrahydrofuran solution is slowly added dropwise to -78 DEG C in temperature（450 mL）.Reaction is protected in nitrogen, is stirred at -78 DEG C
Mix 30min.Then elemental iodine 510g tetrahydrofuran solution is slowly added dropwise（300mL）, add continuation stirring reaction at -78 DEG C
30min, reaction 1h is stirred at room temperature.Reaction solution is slowly poured into frozen water（1kg）, add ethyl acetate extraction three times, close
And the ethyl acetate phase obtained by liquid separation three times, with saturated common salt washing and anhydrous sodium sulfate drying.Filtrate is concentrated after filtering, crosses post
Obtain the fluoro- 4- iodine pyridines -2- amine 61g of 3-.
（2）The preparation of 2- amino -3- fluorine pyridine -4- pinacol borates：
By the fluoro- 4- iodine pyridines -2- amine 3.1g of 3-, duplex boron 4g, potassium acetate 2.6g and two（Triphenyl phosphorus）Palladium chloride 0.6g
It is added sequentially to N, in N '-dimethyl acetamide 20mL, then stirs 3 hours at 100 DEG C.Reaction solution is then down to room
Temperature, water 100mL is added, is extracted with ethyl acetate three times.Combined ethyl acetate phase, with saturated common salt washing twice, then with nothing
Aqueous sodium persulfate is dried.Sodium sulphate is filtered off, crossing post after filtrate concentration obtains 2- amino -3- fluorine pyridine -4- pinacol borates 1.7g.
（3）The preparation of 2- amino -3- fluorine pyridine -4- boric acid hydrochlorides：
2- amino -3- fluorine pyridine -4- pinacol borates 1.7g is added to the aqueous hydrochloric acid solution 15mL of mass percentage concentration 10%
In, it is then refluxed for 3 hours.It is spin-dried for solvent and obtains 2- amino -3- fluorine pyridine -4- boric acid hydrochlorides 1.2g.Nuclear magnetic spectrum is shown in Fig. 1,
Mass spectrogram is shown in Fig. 2.
Claims (2)
- A kind of 1. synthetic method of 2- amino -3- fluorine pyridine -4- boric acid hydrochlorides, it is characterised in that：Comprise the following steps：2- ammonia Base -3- fluorine pyridine and butyl lithium and elemental iodine the reaction generation fluoro- 4- iodine pyridines -2- amine of 3-, iodide are then coupled with duplex boron 2- amino -3- fluorine pyridine -4- pinacol borates are generated, 2- amino -3- fluorine pyridine -4- borates are obtained through HCl treatment after Hydrochlorate.
- A kind of 2. synthetic method of 2- amino -3- fluorine pyridine -4- boric acid hydrochlorides according to right 1, it is characterised in that：Tool Precursor reactant step is as follows：（1）2- amino -3- fluorine pyridine and butyl lithium and elemental iodine the reaction generation fluoro- 4- iodine pyridines -2- amine of 3-：By 2- amino -3- Fluorine pyridine is dissolved in tetrahydrofuran, and 2.5M n-BuLi tetrahydrofuran solution is added dropwise at -78 DEG C, 30 points are stirred at -78 DEG C Clock, the tetrahydrofuran solution of iodine is then added dropwise, continues to stir 30 minutes at -78 DEG C, room temperature post processing in 1 hour obtains 3- Fluoro- 4- iodine pyridines -2- amine；（2）Iodide and duplex boron coupling generation 2- amino -3- fluorine pyridine -4- pinacol borates：By the fluoro- 4- iodine pyridines of 3-- 2- amine, duplex boron, potassium acetate and two（Triphenyl phosphorus）Palladium chloride is added sequentially to N, in N '-dimethyl acetamide, then Stirred 2 hours at 100 DEG C, reaction completes post processing and obtains 2- amino -3- fluorine pyridine -4- pinacol borates；（3）The deprotection of 2- amino -3- fluorine pyridine -4- pinacol borates：By 2- amino -3- fluorine pyridine -4- boric acid pinacols Ester is added in the aqueous hydrochloric acid solution of mass percentage concentration 10%, is then refluxed for 3 hours, is spin-dried for solvent and is obtained 2- amino -3- fluorine pyrroles Pyridine -4- boric acid hydrochlorides, reaction equation are as follows：。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896921A (en) * | 2009-08-28 | 2014-07-02 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| WO2017160569A1 (en) * | 2016-03-14 | 2017-09-21 | Afferent Pharmaceuticals Inc. | Pyrimidines and variants thereof, and uses therefor |
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2017
- 2017-10-16 CN CN201710958105.1A patent/CN107540699A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896921A (en) * | 2009-08-28 | 2014-07-02 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| WO2017160569A1 (en) * | 2016-03-14 | 2017-09-21 | Afferent Pharmaceuticals Inc. | Pyrimidines and variants thereof, and uses therefor |
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Application publication date: 20180105 |