CN108047258A - A kind of method of synthesizing amino pyridine boronic acid ester - Google Patents
A kind of method of synthesizing amino pyridine boronic acid ester Download PDFInfo
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- CN108047258A CN108047258A CN201711360278.XA CN201711360278A CN108047258A CN 108047258 A CN108047258 A CN 108047258A CN 201711360278 A CN201711360278 A CN 201711360278A CN 108047258 A CN108047258 A CN 108047258A
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- ester
- nitro
- boric acid
- boronic acid
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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
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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 invention discloses a kind of methods of synthesizing amino pyridine boronic acid ester.Using nitro haloperidid, after Suzuki couplings occur using Metal Palladium and connection boric acid diol ester, after simple filtration, product is obtained after being directly filled with hydrogen reducing.The method provided by method operates, and the other half for avoiding the connection boron ester removed when being coupled in product forms complex compound with aminopyridine, and obtained product purity is high, and yield is good.
Description
Technical field
The present invention relates to a kind of methods of synthesizing amino pyridine boronic acid ester, belong to medicine intermediate synthesis technical field.
Background technology
Aminopyridine borate is a kind of important medicine intermediate, can be used for further being condensed generation miaow with chloroacetaldehyde
Azoles and pyridine compounds can also pass through coupling and generate different types of pharmaceutical intermediate, to meet different clinical stage demands.
Mostly it is directly with being obtained after the directly coupling of connection boric acid diol ester using aminopyridine halides in current synthetic method
It arrives, however in actual coupling process, it has been found that there are problems, react the other half and amino formation complex compound removed, no
Easily remove, it is especially the most serious with 2-aminopyridine borate.Speculate that reason may be coupled for the amino on aminopyridine
Deprotonation under alkaline condition, with falling down another semi-direct be connected with amino after connection boric acid diol ester coupling.It attempted using methanol
The methods of reflux, addition acid-base accommodation pH, all effectively removes without obtaining, and according to the product that existing document method obtains, finds not
It is very not big with document poor yields, and after repeating document, it obtains product and is detected as sterling through GC, purity more than 98%,
Confirm also be simple spike by mass spectrum, molecular weight can coincide with product.However not be pure product after nuclear-magnetism confirms, but
Complex compound finds still have part that product is complexed after characterization after recrystallizing repeatedly after methanol eddy.It is and molten due to product
Agent degree is very poor, and post-processing operation is just more cumbersome.
The content of the invention
In order to overcome drawbacks described above, the invention discloses a kind of methods of synthesizing amino pyridine boronic acid ester.Using nitro halogen
For pyridine, after Suzuki couplings occur using Metal Palladium and connection boric acid diol ester, after simple filtration, hydrogen is directly filled with also
Product is obtained after original.
A kind of method of synthesizing amino pyridine boronic acid ester, which is characterized in that including following operation：Nitro haloperidid uses
After Suzuki couplings occur for palladium catalyst and connection boric acid diol ester, after simple filtration, obtained after being directly filled with hydrogen reducing
Aminopyridine borate.
In the above-mentioned technical solutions, the nitro haloperidid is selected from 2- nitro -3- halogen pyridine, 2- nitro -4- halogen pyrroles
Pyridine, 2- nitro -5- halogen pyridine, 3- nitro -5- halogen pyridine, 3- halogen -4- nitropyridines.Halogen is selected from chlorine, bromine or iodine.
In the above-mentioned technical solutions, the boric acid diol ester be selected from connection boric acid neopentyl glycol ester, connection boric acid pinacol ester,
Join boric acid pinane diol ester, connection boric acid catechol ester.
In the above-mentioned technical solutions, Suzuki coupling reactions condition is palladium catalyst, under the conditions of solvent, acetic anhydride potassium,
It is warming up to 80-120 DEG C of reaction.Solvent selection dioxane, glycol dimethyl ether, toluene, DMSO or DMF；Palladium catalyst uses
PdCl2dppf, PdCl2 dppf-CH2Cl2, Pd (PPh3) 4, dichloro [double (di-t-butyl phosphorus) ferrocene of 1,1'-] palladium.
In the above-mentioned technical solutions, the nitro haloperidid, palladium catalyst, connection boric acid diol ester molar ratio are 1:
0.005-0.01：1-1.1.
In the above-mentioned technical solutions, the hydrogen reducing is carried out using under 1-5atm, after reaction, it is molten to add in alcohols
It is recrystallized after agent hot melt.
The method provided by method operates, and avoids the other half and ammonia of the connection boron ester removed when being coupled in product
Yl pyridines form complex compound, and obtained product purity is high, and yield is good.
Specific embodiment
Embodiment 1
Nitrogen protection under, sequentially added in reaction bulb dioxane 550mL, 2- nitro -5- bromopyridines (20.3g,
0.10mol), connection boric acid pinacol ester (25.4g, 0.10mol), after potassium acetate (14.7g, 0.15mol), after stirring evenly, most
Catalyst PdCl2dppf (0.74g, 0.001mol) is added in afterwards, is to slowly warm up to 80-90 DEG C, is stirred to react 2-3h.GC is detected
After reaction, cooling stops reaction, and diatomite filtering reacting liquid obtains aterrimus reaction solution, is filled with 1atm hydrogen rear chambers
Overnight, after reaction, activated carbon decolorizing, filtrate decompression is distilled to not flow liquid for temperature reaction, adds in ethyl alcohol/heptane mixed solvent drop
Temperature mashing half an hour, filtering obtain light grey product 18.5g, and after being heated again using ethyl alcohol, cooling is precipitated, anhydrous with -20 DEG C
Ethanol rinse filter cake obtains 16.9g, yield 77%, HPLC purity 99.6%, H NMR (400MHz, DMSO-d6) after drying：
8.16(s,1H),7.54(d,1H),6.39(d,1H),6.30(s, 2H),1.25(s,12H).
Embodiment 2
Nitrogen protection under, sequentially added in reaction bulb dioxane 550mL, 3- nitro -5- bromopyridines (20.3g,
0.10mol), connection boric acid pinacol ester (25.4g, 0.10mol), after potassium acetate (14.7g, 0.15mol), after stirring evenly, most
Catalyst PdCl2dppf (0.74g, 0.001mol) is added in afterwards, is to slowly warm up to 80-90 DEG C, is stirred to react 2-3h.GC is detected
After reaction, cooling stops reaction, and diatomite filtering reacting liquid obtains aterrimus reaction solution, is filled with 1atm hydrogen rear chambers
Overnight, after reaction, activated carbon decolorizing, filtrate decompression is distilled to not flow liquid for temperature reaction, adds in ethyl alcohol/heptane mixed solvent drop
Temperature mashing half an hour, filtering obtain light grey crude product, and after being heated again using ethyl alcohol, cooling is precipitated, with -20 DEG C of absolute ethyl alcohols
Filter cake is eluted, obtains light yellow solid 15.6g after drying, yield 71%, HPLC purity 97.9%, H NMR (400MHz,
CDCl3)：8.04(s,1H),7.93(s,1H),7.24(s,1H),6.68(s, 2H),1.23(s,12H).
Embodiment 3
Under nitrogen protection, glycol dimethyl ether 450mL, 2- nitro -3- bromopyridines are sequentially added in reaction bulb
(20.3g, 0.10mol), connection boric acid pinacol ester (25.4g, 0.10mol), after potassium acetate (14.7g, 0.15mol), stirring is equal
After even, catalyst PdCl2dppf (0.74g, 0.001mol) is eventually adding, 80-90 DEG C is to slowly warm up to, is stirred to react 2-3h.
GC is detected after reaction, and cooling stops reaction, and diatomite filtering reacting liquid obtains aterrimus reaction solution, is filled with 1atm hydrogen
It is reacted at room temperature after gas overnight, after reaction, activated carbon decolorizing, filtrate decompression is distilled to not flow liquid, adds in ethyl alcohol/heptane mixing
Solvent cooling mashing half an hour, filtering obtains light yellow crude product, and after being heated again using ethyl alcohol, cooling is precipitated, with -20 DEG C of nothings
Water-ethanol elutes filter cake, and faint yellow solid 16.3g, yield 74%, HPLC purity 98.4%, H NMR are obtained after drying
(400MHz,CDCl3)：8.06(d,1H),7.34(d,1H),6.59(m, 1H),6.26(s,2H),1.23(s,12H).
Embodiment 4
Nitrogen protection under, sequentially added in reaction bulb DMSO 450mL, 2- nitro -3- bromopyridines (20.3g,
0.10mol), connection boric acid pinacol ester (25.4g, 0.10mol), after potassium acetate (14.7g, 0.15mol), after stirring evenly, most
Catalyst Pd (PPh3) 4 (1.16g, 0.001mol) is added in afterwards, is to slowly warm up to 80-90 DEG C, is stirred to react 2-3h.GC is detected
After reaction, cooling stops reaction, and diatomite filtering reacting liquid obtains aterrimus reaction solution, evaporated under reduced pressure solvent, again
220mL tetrahydrofurans are added in, are reacted at room temperature overnight after being filled with 3atm hydrogen, after reaction, activated carbon decolorizing, filtrate decompression is steamed
It evaporates to not flow liquid, adds in ethyl alcohol/heptane mixed solvent cooling mashing half an hour, filtering obtains light grey crude product, uses again
After ethyl alcohol heating, cooling is precipitated, and elutes filter cake with -20 DEG C of absolute ethyl alcohols, off-white powder 17.4g, yield are obtained after drying
79%, HPLC purity 98.2%, H NMR (400MHz, CDCl3)： 8.06(d,1H),7.34(d,1H),6.59(m,1H),
6.26(s,2H),1.23(s,12H)。
Embodiment 5
Nitrogen protection under, sequentially added in reaction bulb dioxane 550mL, 2- nitro -4- chloropyridines (15.8g,
0.10mol), connection boric acid pinacol ester (25.4g, 0.10mol), after potassium acetate (14.7g, 0.15mol), after stirring evenly, most
Catalyst PdCl2dppf (0.74g, 0.001mol) is added in afterwards, is to slowly warm up to 80-90 DEG C, is stirred to react 2-3h.GC is detected
After reaction, cooling stops reaction, and diatomite filtering reacting liquid obtains aterrimus reaction solution, is filled with 1atm hydrogen rear chambers
Overnight, after reaction, activated carbon decolorizing, filtrate decompression is distilled to not flow liquid for temperature reaction, adds in ethyl alcohol/heptane mixed solvent drop
Temperature mashing half an hour, filtering obtain light grey crude product, and after being heated again using ethyl alcohol, cooling is precipitated, with -20 DEG C of absolute ethyl alcohols
Filter cake is eluted, obtains off-white powder 16.5g after drying, yield 75%, HPLC purity 99.1%, HNMR (CDCl3,
400MHz):8.12(s,1H),7.01(s,1H),6.89(s,1H),4.40(s,2H), 1.35(s,12H)。
Embodiment 6
Under nitrogen protection, glycol dimethyl ether 550mL, 2- nitro -4- chloropyridines are sequentially added in reaction bulb
(15.8g, 0.10mol), connection boric acid neopentyl glycol ester (22.6g, 0.10mol), after potassium acetate (14.7g, 0.15mol), stirring
After uniformly, catalyst PdCl2dppf (0.74g, 0.001mol) is eventually adding, 80-90 DEG C is to slowly warm up to, is stirred to react 2-
3h.GC is detected after reaction, and cooling stops reaction, and diatomite filtering reacting liquid obtains aterrimus reaction solution, is filled with 1atm
It is reacted at room temperature after hydrogen overnight, after reaction, activated carbon decolorizing, filtrate decompression is distilled to not flow liquid, is added in ethyl alcohol/heptane and is mixed
Bonding solvent cooling mashing half an hour, filtering obtains light yellow crude product, and after being heated again using ethyl alcohol, cooling is precipitated, with -20 DEG C
Absolute ethyl alcohol elutes filter cake, and off-white powder 14.8g, yield 72%, HPLC purity 99.0%, HNMR are obtained after drying
(CDCl3,400MHz):8.12(s,1H),7.01(s,1H),6.89(s,1H), 4.40(s,2H),1.35(s,12H)。
Embodiment 7
Nitrogen protection under, sequentially added in reaction bulb dioxane 550mL, 2- nitro -5- chloropyridines (15.8g,
0.10mol), boric acid neopentyl glycol ester (22.6g, 0.10mol) is joined, after potassium acetate (14.7g, 0.15mol), after stirring evenly,
Catalyst PdCl2dppf (0.74g, 0.001mol) is eventually adding, 80-90 DEG C is to slowly warm up to, is stirred to react 2-3h.GC is examined
It surveys after reaction, cooling stops reaction, and diatomite filtering reacting liquid obtains aterrimus reaction solution, after being filled with 3atm hydrogen
Overnight, after reaction, activated carbon decolorizing, filtrate decompression is distilled to not flow liquid, adds in ethyl alcohol/heptane mixed solvent for room temperature reaction
Cooling mashing half an hour, filtering obtain off-white color product, and after being heated again using ethyl alcohol, cooling is precipitated, with -20 DEG C of anhydrous second
Alcohol elutes filter cake, obtains off-white powder 14.0g after drying, yield 68%, HPLC purity 98.9%, H NMR (400MHz,
DMSO-d6)：8.16(s,1H),7.54(d,1H),6.39 (d,1H),6.30(s,2H),3.78(s,4H),0.95(s,6H).
Embodiment 8
Nitrogen protection under, sequentially added in reaction bulb toluene 750mL, 3- nitro -5- chloropyridines (15.8g,
0.10mol), boric acid neopentyl glycol ester (22.6g, 0.10mol) is joined, after potassium acetate (24.5g, 0.25mol), after stirring evenly,
Catalyst PdCl2dppf (0.74g, 0.001mol) is eventually adding, 100-105 DEG C is to slowly warm up to, is stirred to react 8-10h.GC
After reaction, cooling stops reaction for detection, and diatomite filtering reacting liquid obtains aterrimus reaction solution, adds in 100mL ethyl alcohol
Afterwards, reacted at room temperature overnight after being filled with 3atm hydrogen, after reaction, activated carbon decolorizing, filtrate decompression is distilled to not flow liquid, is added in
Ethyl alcohol/heptane mixed solvent cooling mashing half an hour, filtering obtain light grey product, again using ethyl alcohol dissolubility after, cooling analysis
Go out, elute filter cake with -20 DEG C of absolute ethyl alcohols, light yellow solid 15.2g, yield 74%, HPLC purity are obtained after drying
98.1%, H NMR (400MHz, CDCl3)：8.04(s,1H),7.93(s,1H), 7.24(s,1H),6.68(s,2H),1.23
(s,12H)。
Claims (7)
- A kind of 1. method of synthesizing amino pyridine boronic acid ester, which is characterized in that including following operation：After using palladium catalyst and connection boric acid diol ester Suzuki couplings occur for nitro haloperidid, after simple filtration, directly It connects and obtains aminopyridine borate after being filled with hydrogen reducing.
- 2. according to a kind of method of synthesizing amino pyridine boronic acid ester of claim 1, it is characterised in that：The nitro haloperidid choosing From 2- nitro -3- halogen pyridine, 2- nitro -4- halogen pyridine, 2- nitro -5- halogen pyridine, 3- nitro -5- halogen pyridine, 3- halogen -4- nitros Pyridine.
- 3. according to a kind of method of synthesizing amino pyridine boronic acid ester of claim 2, it is characterised in that：The halogen is selected from chlorine, bromine Or iodine.
- 4. according to a kind of method of synthesizing amino pyridine boronic acid ester of claim 1, it is characterised in that：The boric acid diol ester choosing From connection boric acid neopentyl glycol ester, connection boric acid pinacol ester, connection boric acid pinane diol ester, connection boric acid catechol ester.
- 5. according to a kind of method of synthesizing amino pyridine boronic acid ester of claim 1, it is characterised in that：The palladium catalyst uses PdCl2dppf, PdCl2dppf-CH2Cl2, Pd (PPh3) 4 or dichloro [double (di-t-butyl phosphorus) ferrocene of 1,1'-] palladium.
- 6. according to a kind of method of synthesizing amino pyridine boronic acid ester of claim 1, it is characterised in that：The nitro haloperidid, Palladium catalyst, connection boric acid diol ester molar ratio are 1:0.005-0.01：1-1.1.
- 7. according to a kind of method of synthesizing amino pyridine boronic acid ester of claim 1, it is characterised in that：The hydrogen reducing uses It carries out under 1-5atm, after reaction, is recrystallized after adding in alcohols solvent hot melt.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109467569A (en) * | 2018-12-23 | 2019-03-15 | 沧州普瑞东方科技有限公司 | The synthetic method of 3- amino phenyl boric acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109467569A (en) * | 2018-12-23 | 2019-03-15 | 沧州普瑞东方科技有限公司 | The synthetic method of 3- amino phenyl boric acid |
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