CN108997224A - A kind of preparation method of the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2- - Google Patents
A kind of preparation method of the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2- Download PDFInfo
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- CN108997224A CN108997224A CN201810986909.7A CN201810986909A CN108997224A CN 108997224 A CN108997224 A CN 108997224A CN 201810986909 A CN201810986909 A CN 201810986909A CN 108997224 A CN108997224 A CN 108997224A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
Abstract
The present invention provides a kind of preparation methods of the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2-, the method includes using the nitrogenous 6-membered heterocyclic compound of 2- hydroxyl -5- bromine as raw material, in the presence of a catalyst, in CO gas atmosphere, methanol as solvent obtains 2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylate methyl ester after coupling reaction occurs, and then successively passes through ammonolysis reaction, chlorination reaction, oxidation reaction are carried out with phosphorus oxychloride, obtains the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of the 2-；The preparation method of the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2- provided by the invention, route is short, raw material is easy to get, especially post-processing approach is simple, and column Image processing is not necessarily to after every single step reaction, can purify reaction product only by the washing of solvent, extraction, amplification can be achieved, industrialized production is carried out, environmental requirement is met, there is important value for actual production.
Description
Technical field
The invention belongs to medicine intermediates to synthesize field, be related to a kind of chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2-
Preparation method.
Background technique
The chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2- is the important doctor of the new drugs such as a kind of preparation treatment diabetes, cancer
Medicine intermediate.Wherein, the chloro- 5- cyanopyrimidine of 2-, No. CAS is 1753-50-0, molecular weight 139.54248, current synthesis road
There are mainly two types of for line.
Route disclosed in WO2008110611A1 is as follows:
The expensive raw material price of this route, yield is very low, and reproducibility is very poor, uses diazotising, and safety is poor, generates a large amount of
Waste water, while CuCN is used, it generates a large amount of copper salt waste and post-processing is complicated, need to be purified by column chromatography, it can not
It is amplified to feather weight to be produced, therefore, greatly limits production efficiency, be unfavorable for industrializing.
Another kind route disclosed in US20111522952A1 is as follows:
Route disclosed in the method, the ring compound obtained after the reaction of 4 steps, there is still a need for the reactions of 5 steps to have come later
At reaction route is long, and using this high toxic material of phosgene is arrived in reaction process, so that the whole yield of route is low, dirty
Dye is big, can not be applied to industrialized production.
The synthetic method of the chloro- 5- cyanopyridine of 2- is currently that it is chloro- to obtain 2- by chlorination reaction using cyanopyridine as raw material
5- cyanopyridine inevitably generates the by-products such as the chloro- nicotinonitrile of 2- in chlorination process.Due to both substances
Physicochemical properties it is very close, subsequent separation is extremely difficult, so the purity of the chloro- 5- cyanopyridine of 2- is difficult to improve,
Very big restriction is received as medicinal raw material, it is at high cost.
CN104072414A discloses a kind of preparation method of cyanopyridine, and it is molten that picoline, ammonia and water are made into mixing
Progress catalytic ammoxidation in the fixed bed reactors for being filled with catalyst is sent into after liquid and preheating jointly with air to react, it will be from admittedly
The high-temperature steam flowed out in fixed bed reactor is passed through in cooling water, keeps reaction mass soluble in water, then extract reaction product, institute
Catalyst is made of vanadium, iron, molybdenum, chromium, bismuth, potassium, phosphorus and carrier.But the catalyst that the method prepares cyanopyridine is multiple
It is miscellaneous, higher cost, and if the subsequent cyanopyridine for being used to prepare chlorine substitution, it is not easy to the generation of by-product is controlled, it is unfavorable
It is produced in actual industrial metaplasia.
Therefore, a kind of preparation method of chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2- how is developed, to reach by-product
Object is few, is suitable for industrializing amplification, for this kind of compound production have important value, while for downstream product production with
And the production cost reduction of drug provides guarantee.
Summary of the invention
In view of the deficiencies of the prior art, the purpose of the present invention is to provide a kind of chloro- nitrogenous hexa-member heterocycles of 5- cyano of 2-
The preparation method of object is closed, in order to industrial amplification production.
To achieve this purpose, the present invention adopts the following technical scheme:
The present invention provides a kind of preparation method of the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2-, the method includes
Using the nitrogenous 6-membered heterocyclic compound of 2- hydroxyl -5- bromine as raw material, in the presence of a catalyst, under carbon monoxide atmosphere, methanol is made molten
Agent obtains 2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylate methyl ester after coupling reaction occurs, and then successively passes through ammonolysis reaction, with trichlorine
Oxygen phosphorus carries out chlorination reaction, oxidation reaction, obtains the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of the 2-；
Wherein, nitrogenous hexa-member heterocycle is pyridine or pyrimidine.
When nitrogenous hexa-member heterocycle is pyrimidine, specific reaction route is as follows:
When nitrogenous hexa-member heterocycle is pyridine, specific reaction route is as follows:
The preparation method of the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2- provided by the invention, route is short, and raw material is easy to get,
Especially post-processing approach is simple, column Image processing is not necessarily to after every single step reaction, only by the washing of solvent, extraction
Reaction product is purified, compared to existing method for synthetic method there are routes long, more (such as mantoquitas of waste material of such compound
Equal waste materials), using high toxic materials such as phosgene, need the defect of column chromatographic purifying, the present invention may be implemented to amplify, and carry out industry
Metaplasia produces, and the waste material generated in production process is few, meets environmental requirement, has important value for actual production.
Preparation method provided by the invention is provided not only for the compound synthesis strategy such as cyanopyrimidine, and anti-
The intermediate that should be generated in the process, such as carboxylate methyl ester, amide pyrimidine, while providing the synthetic strategy of this kind of compounds.
Preferably, the catalyst is [1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex.
Preferably, relative to the nitrogenous hexa-member heterocycle of 1g 2- hydroxyl -5- bromine, the dosage of the methanol is 8~12mL, such as
It can be 8mL, 8.5mL, 9mL, 9.5mL, 10mL, 10.5mL, 11mL, 11.5mL or 12mL etc..
Preferably, relative to the nitrogenous hexa-member heterocycle of 1g 2- hydroxyl -5- bromine, the dosage of the catalyst is 0.03~
0.08g, such as can be 0.03g, 0.04g, 0.05g, 0.06g, 0.07g or 0.08g etc..
Preferably, the coupling reaction further includes triethylamine.
Preferably, relative to the nitrogenous hexa-member heterocycle of 1g 2- hydroxyl -5- bromine, the dosage of the triethylamine is 1.1~1.3g,
Such as can be 1.1g, 1.15g, 1.16g, 1.18g, 1.19g, 1.2g, 1.25g, 1.26g, 1.28g, 1.29g or 1.3g etc..
In the present invention, after coupling reaction, it is only necessary to be washed, product 2- hydroxyl can be contained using diatomite filtering, methanol
Nitrogen hexa-member heterocycle -5- carboxylate methyl ester is purified, without complicated post-processing operation.
Preferably, the pressure of the coupling reaction be 0.5~0.8MPa, such as can be 0.5MPa, 0.55MPa,
0.6MPa, 0.65MPa, 0.7MPa, 0.75MPa or 0.8MPa etc..
Preferably, the temperature of the coupling reaction is 100~110 DEG C, such as can be 100 DEG C, 101 DEG C, 102 DEG C, 103
DEG C, 104 DEG C, 105 DEG C, 106 DEG C, 107 DEG C, 108 DEG C, 109 DEG C or 110 DEG C etc..
In the present invention, pressure and temperature controls within the above range simultaneously, it is ensured that reaction is gone on smoothly, yield
Reach highest.Pressure and temperature may generate security risk if excessively high；And pressure and temperature is if too low,
Reaction time is too long, and reaction yield reduces.
Preferably, the time of the coupling reaction be 90~100h, such as can be 90h, 91h, 92h, 93h, 94h,
95h, 96h, 97h, 98h, 99h or 100h etc..
Preferably, the ammonolysis reaction are as follows: 2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylate methyl ester carries out in methyl alcohol with ammonium hydroxide
Reaction.
In the present invention, after ammonolysis reaction, amides compound is produced.
Preferably, relative to 1g 2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylate methyl ester, the dosage of the ammonium hydroxide is 3.5~
5mL, such as can be 3.5mL, 3.7mL, 3.8mL, 3.9mL, 4mL, 4.2mL, 4.6mL, 4.8mL, 4.9mL or 5mL etc..
Preferably, the concentration of the ammonium hydroxide be 28wt.%~30wt.%, such as can be 28wt.%, 28.4wt.%,
28.6wt.%, 28.9wt.%, 29.4wt.%, 29.6wt.%, 29.8wt.% or 30wt.% etc..
Preferably, the temperature of the ammonolysis reaction is 30~35 DEG C, such as can be 30 DEG C, 31 DEG C, 32 DEG C, 33 DEG C, 34
DEG C or 35 DEG C etc..
Preferably, the time of the ammonolysis reaction be 90~100h, such as can be 90h, 91h, 92h, 93h, 94h,
95h, 96h, 97h, 98h, 99h or 100h etc..
Preferably, relative to 1g 2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylate methyl ester, the dosage of the phosphorus oxychloride is 5~
7mL, such as can be 5mL, 5.5mL, 6mL, 6.5mL or 7mL etc..
In the present invention, use phosphorus oxychloride as raw material, chlorination reaction and oxidation reaction can be made anti-in same step
Middle progress is answered, process flow is simplified, it is only necessary to appropriate adjustment reaction temperature；And in existing method, such as
Route disclosed in US20111522952A1,2 chlorinations are until final synthesis cyano, intermediate reaction route up to 4-5
Step, considerably increases production cost, in the reaction time of consumption, is unfavorable for industrialized production.
Preferably, the temperature of the chlorination reaction is 50~55 DEG C, such as can be 50 DEG C, 51 DEG C, 52 DEG C, 53 DEG C, 54
DEG C or 55 DEG C etc..
Preferably, the time of the chlorination reaction be 2~3h, such as can be 2h, 2.1h, 2.2h, 2.3h, 2.4h,
2.5h, 2.6h, 2.7h, 2.8h, 2.9h or 3h etc..
Preferably, acid binding agent after 2~3h chlorination reaction, is directly being added into reaction solution, is carrying out oxidation reaction.
In reaction process of the invention, chlorination reaction while, also carries out the oxidation reaction of fraction, but oxygen at this time
It is slow to change reaction process, when chlorination reaction substantially completely after, the progress that acid binding agent promotes oxidation reaction, at this time oxidation reaction is added
It is dominant.
Preferably, the acid binding agent is n,N-diisopropylethylamine.
In the present invention, additive amount those skilled in the art of acid binding agent can suitably be adjusted according to the case where real reaction
It is whole.
Preferably, the temperature of the oxidation reaction is 75~85 DEG C, such as can be 75 DEG C, 76 DEG C, 77 DEG C, 78 DEG C, 79
DEG C, 80 DEG C, 81 DEG C, 82 DEG C, 83 DEG C, 84 DEG C or 85 DEG C etc..
Preferably, the time of the oxidation reaction is 20~25h, such as can be 20h, 21h, 22h, 23h, for 24 hours or 25h
Deng.
It preferably, further include that reaction solution is cooled to room temperature after the oxidation reaction, concentration, extraction, washing obtain
The chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2-.
In the present invention, it is cooled to room temperature after reaction, generally carries out the suitable volumes for being concentrated under reduced pressure into reaction solution, makes
It is extracted with extractant, reuses the alkali liquid washing as sodium bicarbonate aqueous solution, final product can be obtained.
Preferably, described to be extracted as extracting using extractant.
Preferably, the extractant includes in methyl tertiary butyl ether(MTBE), petroleum ether, tetrahydrofuran or 2- methyltetrahydrofuran
Any one or at least two combination；Preferably methyl tertiary butyl ether(MTBE).
In the present invention, when methyl tertiary butyl ether(MTBE) is as extractant, the effect of extraction is optimal, and other extractants extract effect
Fruit is poor, and such as petroleum ether, dissolubility of the product in petroleum ether is too low, will cause product loss；And such as tetrahydrofuran, each original
Material and impurity dissolubility in such solvent are preferable, so that the impurity that final products contain is more.
As optimal technical scheme, preparation method provided by the invention includes the following steps:
(1) using the nitrogenous 6-membered heterocyclic compound of 2- hydroxyl -5- bromine as raw material, at [1,1'- bis- (diphenylphosphine) ferrocene]
In the presence of palladium chloride dichloromethane complex, in CO gas atmosphere, methanol as solvent, triethylamine make alkali in pressure and are
0.5~0.8MPa, temperature are after 90~100h of coupling reaction occurs at 100~110 DEG C, to obtain 2- hydroxy nitrogen-containing hexa-member heterocycle-
5- carboxylate methyl ester；
(2) 2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylate methyl ester is anti-by ammonolysis in 30~35 DEG C in methyl alcohol with ammonium hydroxide
90~100h is answered to obtain 2- hydroxy nitrogen-containing hexa-member heterocycle -5- formamide；Wherein ammonia concn is 28wt.%~30wt.%；
(3) by 2- hydroxy nitrogen-containing hexa-member heterocycle -5- formamide and phosphorus oxychloride in 50~55 DEG C of 2~3h of progress chlorination reaction
Afterwards, continue to add acid binding agent, adjustment temperature is 75~85 DEG C of progress 20~25h of oxidation reaction, and reaction solution is then cooled to room
Temperature, be concentrated under reduced pressure, extracted using extractant, wash to it is neutral be further concentrated after to obtain the chloro- 5- cyano of the 2- nitrogenous
6-membered heterocyclic compound.
The chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of the product 2- that preparation method provided by the invention is prepared, product
Purity is generally 99% or more, and the product purity that prior art method is prepared is generally only 97% or so.Compared to existing
There is method, method of the invention greatly promotes product purity.
Compared with the existing technology, the invention has the following advantages:
The preparation method of the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2- provided by the invention, route is short, and raw material is easy to get,
Especially post-processing approach is simple, column Image processing is not necessarily to after every single step reaction, only by the washing of solvent, extraction
Reaction product is purified, it is long for there are routes in the synthetic method of such compound compared in existing method, waste material is more (such as
The waste materials such as mantoquita), using high toxic materials such as phosgene, need the defect of column chromatographic purifying, the present invention may be implemented to amplify, and carry out
Industrialized production, the waste material generated in production process is few, meets environmental requirement.Particularly with cyanopyrimidine or cyanopyridine class
The amplification production for closing object has important reference value, provides new strategy for practical amplification production.
Specific embodiment
The technical scheme of the invention is further explained by means of specific implementation.Those skilled in the art should be bright
, the described embodiments are merely helpful in understanding the present invention, should not be regarded as a specific limitation of the invention.
Embodiment 1
The present embodiment prepares the chloro- 5- cyanopyrimidine of 2- by following steps, and reaction route is as follows:
(1) 26 kilograms of the 2- hydroxyl -5- Bromopyrimidine of addition into autoclave, 260 liters of methanol, 30 kilograms of triethylamine (TEA),
[bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex (Pd (dppf) Cl2) 1 kilogram, add rear substitution
For carbon monoxide (CO), 0.6 megapascal of pressure is warming up to 105 DEG C, reacts 95 hours, after raw material fully reacting, reaction solution is down to room
Temperature, filtering elute filter cake with a small amount of methanol, and filtrate is concentrated into 60 liters, is then added 18 kilograms of 29wt.% ammonium hydroxide, at room temperature
Stirring 4 hours, filtering elute filter cake with 14 liters of methanol, and it is public that filter cake is dried to obtain 2- hydroxy pyrimidine -5- carboxylate methyl ester 26 at 55 DEG C
Jin.
(2) 26 kilograms of 2- hydroxy pyrimidine -5- carboxylate methyl ester is added into reaction flask, 106 liters of 29wt.% ammonium hydroxide, sealing rises
Temperature is reacted 95 hours, raw material fully reacting to 32 DEG C, filtering, elutes filter cake with 14 liters of methanol, then filter cake is in 55 DEG C of baking materials 24
Hour, obtain 9 kilograms of 2- hydroxypyrimidine-5-carboxamides.
(3) 1 kilogram of 2- hydroxypyrimidine-5-carboxamides is added into reaction flask, is slowly added to 8 liters of phosphorus oxychloride, will react
Liquid is warming up to 53 DEG C, reacts 2.5 hours, is slowly added to 3 kilograms of n,N-diisopropylethylamine (DIPEA), small in 80 DEG C of reactions 23
When, after raw material fully reacting, reaction solution is down to room temperature, is concentrated under reduced pressure into 4.5 liters, is extracted with 5 liters of methyl tertiary butyl ether(MTBE), methyl- tert
The sodium bicarbonate aqueous solution of butyl ethereal solution saturation is washed till neutrality, is concentrated to get 0.6 kilogram of the chloro- 5- cyanopyrimidine of product 2-,
It is calculated by the input amount of raw material 2- hydroxyl -5- Bromopyrimidine, ultimate yield is about 26.06%.
1H NMR(300MHz,CDCl3):δ8.94(2H,s)。
MS (m/z)=139.0,141.0.
Embodiment 2
The present embodiment is prepared by the following method the chloro- 5- cyanopyridine of 2-, and reaction route is as follows:
(1) 26 kilograms of the 2- hydroxyl -5- bromopyridine of addition into autoclave, 208 liters of methanol, 28.6 kilograms of triethylamine, [1,
Bis- (diphenylphosphine) ferrocene of 1'-] 0.78 kilogram of palladium chloride dichloromethane complex, it adds postposition and is changed to carbon monoxide, press
0.5 megapascal of power is warming up to 100 DEG C, reacts 90 hours, and after raw material fully reacting, reaction solution is down to room temperature, filtering, with a small amount of first
Alcohol elutes filter cake, and filtrate is concentrated into 50 liters, is then added 18 kilograms of 28wt.% ammonium hydroxide, is stirred at room temperature 3 hours, filters, and uses
13 liters of methanol elute filter cake, and filter cake is dried to obtain 24 kilograms of 2 hydroxy pyrimidine -5- carboxylate methyl ester 50.
(2) 24 kilograms of 2 hydroxy pyrimidine -5- carboxylate methyl ester is added into reaction flask, 100 liters of 28wt.% ammonium hydroxide, sealing rises
Temperature is reacted 90 hours, raw material fully reacting to 30 DEG C, filtering, elutes filter cake with 13 liters of methanol, then filter cake is in 50 DEG C of baking materials 20
Hour, obtain 8.1 kilograms of 2 hydroxy pyrimidine -5- formamide.
(3) 1 kilogram of 2 hydroxy pyrimidine -5- formamide is added into reaction flask, is slowly added to 7.2 liters of phosphorus oxychloride, it will be anti-
It answers liquid to be warming up to 50 DEG C, reacts 2 hours, be slowly added to 3.2 kilograms of n,N-diisopropylethylamine, reacted 20 hours at 75 DEG C, it is former
After expecting fully reacting, reaction solution is down to room temperature, is concentrated under reduced pressure into 4 liters, is extracted with 5.3 liters of methyl tertiary butyl ether(MTBE), methyl tertbutyl
The sodium bicarbonate aqueous solution of ethereal solution saturation is washed till neutrality, is concentrated to get 0.52 kilogram of the chloro- 5- cyanopyridine of product 2-, by original
Expect that the input amount of 2- hydroxyl -5- bromopyridine calculates, ultimate yield is about 20.34%.
1H NMR(300MHz,CDCl3): δ 8.72 (1H, d, J=2.1Hz), δ 7.95 (1H, dd, J=8.4,2.4Hz), δ
7.51 (1H, d, J=8.4Hz).
MS (m/z)=138.0,140.0.
Embodiment 3
The present embodiment is prepared by the following method the chloro- 5- cyanopyrimidine of 2-, and reaction route is as follows:
(1) 26 kilograms of the 2- hydroxyl -5- Bromopyrimidine of addition into autoclave, 312 liters of methanol, 33.8 kilograms of triethylamine, [1,
Bis- (diphenylphosphine) ferrocene of 1'-] 2.08 kilograms of palladium chloride dichloromethane complex, it adds postposition and is changed to carbon monoxide, press
0.8 megapascal of power is warming up to 110 DEG C, reacts 100 hours, and after raw material fully reacting, reaction solution is down to room temperature, filtering, with a small amount of first
Alcohol elutes filter cake, and filtrate is concentrated into 70 liters, is then added 18 kilograms of 30wt.% ammonium hydroxide, is stirred at room temperature 5 hours, filters, and uses
15 liters of methanol elute filter cake, and filter cake is dried to obtain 25.5 kilograms of carboxylate methyl ester of 2- hydroxy pyrimidine -5- at 60 DEG C.
(2) 26 kilograms of 2- hydroxy pyrimidine -5- carboxylate methyl ester is added into reaction flask, 106 liters of 30wt.% ammonium hydroxide, sealing rises
Temperature is reacted 100 hours, raw material fully reacting to 35 DEG C, filtering, elutes filter cake with 15 liters of methanol, then filter cake is in 60 DEG C of baking materials
25 hours, obtain 8.8 kilograms of 2- hydroxypyrimidine-5-carboxamides.
(3) 1 kilogram of 2- hydroxypyrimidine-5-carboxamides is added into reaction flask, is slowly added to 13 liters of phosphorus oxychloride, will react
Liquid is warming up to 55 DEG C, reacts 3 hours, is slowly added to 3.3 kilograms of n,N-diisopropylethylamine, reacts 25 hours at 85 DEG C, raw material
After fully reacting, reaction solution is down to room temperature, is concentrated under reduced pressure into 5 liters, is extracted with 4.8 liters of methyl tertiary butyl ether(MTBE), methyl tertiary butyl ether(MTBE)
The sodium bicarbonate aqueous solution of solution saturation is washed till neutrality, 0.58 kilogram of the chloro- 5- cyanopyrimidine of product 2- is concentrated to get, by raw material
The input amount of 2- hydroxyl -5- Bromopyrimidine calculates, and ultimate yield is about 24.63%.
1H NMR(300MHz,CDCl3):δ8.94(2H,s)。
MS (m/z)=139.0,141.0.
Embodiment 4
The present embodiment and the difference of embodiment 1 are only that the pressure that step (1) carries out coupling reaction is 0.3MPa, temperature
It is 80 DEG C, remaining is same as Example 1, and 0.52 kilogram of the chloro- 5- cyanopyrimidine of 2- is finally prepared.
Embodiment 5
The present embodiment and the difference of embodiment 1 are only that step (3) after reaction, is extracted using tetrahydrofuran,
Remaining is same as Example 1, and 0.45 kilogram of the chloro- 5- cyanopyrimidine of product 2- is finally prepared.
By the comparison of embodiment 4 and embodiment 5 and embodiment 1 it is found that preparation method pressure provided by the invention is necessary
Control needs to extract using methyl tertiary butyl ether(MTBE) in reasonable range, and in the step of end reaction post-processes,
Otherwise can all cause the yield of product reduces.
The Applicant declares that the present invention is explained by the above embodiments the chloro- nitrogenous hexa-member heterocycle of 5- cyano of 2- of the invention
The preparation method of compound, but the invention is not limited to above-mentioned method detaileds, that is, it is above-mentioned not mean that the present invention must rely on
Method detailed could be implemented.It should be clear to those skilled in the art, any improvement in the present invention, produces to the present invention
The equivalence replacement of each raw material of product and addition, the selection of concrete mode of auxiliary element etc., all fall within protection scope of the present invention and
Within the open scope.
Claims (10)
1. a kind of preparation method of the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of 2-, which is characterized in that the method includes with 2-
The nitrogenous 6-membered heterocyclic compound of hydroxyl -5- bromine is raw material, in the presence of a catalyst, in carbon monoxide atmosphere, methanol as solvent hair
2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylate methyl ester is obtained after raw coupling reaction, then successively passes through ammonolysis reaction, with phosphorus oxychloride
Chlorination reaction, oxidation reaction are carried out, the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of the 2- is obtained；
Wherein, nitrogenous hexa-member heterocycle is pyridine or pyrimidine.
2. preparation method according to claim 1, which is characterized in that the catalyst is [1,1'- bis- (diphenylphosphines) two
Luxuriant iron] palladium chloride dichloromethane complex.
3. preparation method according to claim 1 or 2, which is characterized in that nitrogenous hexa-atomic relative to 1g 2- hydroxyl -5- bromine
Heterocycle, the dosage of the methanol are 8~12mL；
Preferably, relative to the nitrogenous hexa-member heterocycle of 1g 2- hydroxyl -5- bromine, the dosage of the catalyst is 0.03~0.08g；
Preferably, the coupling reaction further includes triethylamine；
Preferably, relative to the nitrogenous hexa-member heterocycle of 1g 2- hydroxyl -5- bromine, the dosage of the triethylamine is 1.1~1.3g.
4. preparation method according to any one of claim 1-3, which is characterized in that the pressure of the coupling reaction is
0.5~0.8MPa；
Preferably, the temperature of the coupling reaction is 100~110 DEG C；
Preferably, the time of the coupling reaction is 90~100h.
5. preparation method described in any one of -4 according to claim 1, which is characterized in that the ammonolysis reaction are as follows: 2- hydroxyl
Nitrogenous hexa-member heterocycle -5- carboxylate methyl ester is reacted in methyl alcohol with ammonium hydroxide；
Preferably, relative to 1g 2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylate methyl ester, the dosage of the ammonium hydroxide is 3.5~5mL；
Preferably, the concentration of the ammonium hydroxide is 28wt.%~30wt.%；
Preferably, the temperature of the ammonolysis reaction is 30~35 DEG C；
Preferably, the time of the ammonolysis reaction is 90~100h.
6. preparation method according to any one of claims 1-5, which is characterized in that hexa-atomic relative to 1g2- hydroxy nitrogen-containing
Heterocycle -5- carboxylate methyl ester, the dosage of the phosphorus oxychloride are 5~7mL.
7. preparation method according to claim 1 to 6, which is characterized in that the temperature of the chlorination reaction is 50
~55 DEG C；
Preferably, the time of the chlorination reaction is 2~3h.
8. preparation method described in any one of -7 according to claim 1, which is characterized in that after 2~3h chlorination reaction,
Acid binding agent is directly added into reaction solution, carries out oxidation reaction；
Preferably, the acid binding agent is n,N-diisopropylethylamine；
Preferably, the temperature of the oxidation reaction is 75~85 DEG C；
Preferably, the time of the oxidation reaction is 20~25h.
9. preparation method according to claim 1 to 8, which is characterized in that after the oxidation reaction, also
Including reaction solution is cooled to room temperature, concentration, extraction, washing obtain the chloro- nitrogenous 6-membered heterocyclic compound of 5- cyano of the 2-；
Preferably, described to be extracted as extracting using extractant；
Preferably, the extractant includes any in methyl tertiary butyl ether(MTBE), petroleum ether, tetrahydrofuran or 2- methyltetrahydrofuran
It is a kind of or at least two combination；Preferably methyl tertiary butyl ether(MTBE).
10. preparation method according to claim 1 to 9, which is characterized in that the preparation method includes as follows
Step:
(1) using the nitrogenous 6-membered heterocyclic compound of 2- hydroxyl -5- bromine as raw material, in [1,1'- bis- (diphenylphosphine) ferrocene] dichloro
In the presence of changing palladium dichloromethane complex, in CO gas atmosphere, it is 0.5 that methanol as solvent, triethylamine, which make alkali in pressure,
~0.8MPa, temperature are after 90~100h of coupling reaction occurs at 100~110 DEG C, to obtain 2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylic
Sour methyl esters；
(2) 2- hydroxy nitrogen-containing hexa-member heterocycle -5- carboxylate methyl ester and ammonium hydroxide are passed through into ammonolysis reaction 90 in 30~35 DEG C in methyl alcohol
~100h obtains 2- hydroxy nitrogen-containing hexa-member heterocycle -5- formamide；Wherein ammonia concn is 28wt.%~30wt.%；
(3) by 2- hydroxy nitrogen-containing hexa-member heterocycle -5- formamide and phosphorus oxychloride after 50~55 DEG C of 2~3h of progress chlorination reaction,
Continuing to add acid binding agent, adjustment temperature is 75~85 DEG C of progress 20~25h of oxidation reaction, reaction solution is then cooled to room temperature,
Be concentrated under reduced pressure, extracted using extractant, wash to it is neutral be further concentrated after to obtain the chloro- 5- cyano of the 2- nitrogenous hexa-atomic
Heterocyclic compound.
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