CN106892902A - A kind of hydrochloric acid is for a pyrimidine and its synthetic method of the chloromethyluracil of intermediate 6 - Google Patents
A kind of hydrochloric acid is for a pyrimidine and its synthetic method of the chloromethyluracil of intermediate 6 Download PDFInfo
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- CN106892902A CN106892902A CN201710117569.XA CN201710117569A CN106892902A CN 106892902 A CN106892902 A CN 106892902A CN 201710117569 A CN201710117569 A CN 201710117569A CN 106892902 A CN106892902 A CN 106892902A
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
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Abstract
The invention provides a kind of synthetic method of 6 chloromethyluracil, including：6 methyluracils and cupric oxide are carried out into oxidation reaction in a solvent, 6 formoxyl uracils are obtained；6 formoxyl uracils are reduced, 6 methylol uracils are obtained；By 6 methylol uracils through chlorination, 6 chloromethyluracils, the purity ＞ 99.0% of the chloromethyluracil of gained 6 are obtained.Present invention optimizes the synthetic method of 6 chloromethyluracils, the oxidation technology that selenium dioxide realizes 6 methyluracils is instead of with the metal onidiges of hypotoxicity, increase environment friendly, while improve the yield and purity of 6 chloromethyluracils.Present invention also offers the synthetic method that a kind of hydrochloric acid replaces a pyrimidine, it is intermediate to use 6 chloromethyluracils of above-mentioned technique gained, hydrochloric acid is directly obtained through chloro, condensation, into salt three-step reaction and replaces a pyrimidine, without any purge process, purity is higher than 99.0% to gained bulk drug.
Description
Technical field
It is phonetic for a pyrimidine and its intermediate 6- chloromethyls urine the present invention relates to pharmaceutical technology field, more particularly to a kind of hydrochloric acid
The synthetic method of pyridine.
Background technology
Trifluridine hydrochloric acid replaces pyrimidine piece (TAS-102), is to be developed by roc medicine company (Taiho Pharma), in 2014
The approval of year Japan MHLW, the anti-tumor compound medicine of type or relapsing advanced colorectal cancer can not be cut off for treating.Wherein, salt
Acid is the main component of antineoplastic Trifluridine pyrimidine piece for a pyrimidine (or hydrochloric acid replaces pyrimidine).Hydrochloric acid is for a pyrimidine
Thymidine phosphorylase inhibitor, is effectively reduced the degraded of the Trifluridine in drug metabolism processes.
At present, hydrochloric acid includes for the main synthesis strategy of a pyrimidine：
1st, with the chloro- 6- methylpyrimidines of 5- as initiation material, the chlorine of methyl is carried out with NCS (N- chlorosuccinimides) first
Generation, then it is condensed to yield product with 2- amino pyrrolidine hydrochlorides；Reaction equation is as shown in Equation 1：
2nd, with 6- chloromethyluracils as initiation material, first pass around sulfonic acid chloride chloro, then with 2- amino-pyrroles heptane hydrochlorides
Salt is condensed, and finally obtains product into salt；Reaction equation by chloro, condensation is as shown in Equation 2：
The chloro yield of the first synthesis strategy is 10%, and condensation yield is 38%, and overall yield is relatively low, production process behaviour
Make difficult, it is relatively costly.Compared to the first synthesis strategy, the yield of second synthesis strategy is higher, and products obtained therefrom purity is higher,
To be currently used primarily in hydrochloric acid for a strategy for pyrimidine synthesis.
The starting material that second synthesis strategy is used is 6- chloromethyluracils, and prior art typically uses 6- methyl
Uracil is raw material, and oxidized successively, reduction, three processing steps of chloro are obtained.At present, the oxidation technology in the preparation process
Selected oxidant is generally selenium dioxide.But, selenium dioxide has toxicity higher, and the safety that increased medicine itself is hidden
Suffer from, be unfavorable for environment friendly.
Therefore, exploitation is more suitable for the synthetic method of the 6- chloromethyluracils that medical industry is used, and there is important practice to anticipate
Justice.
The content of the invention
In view of this, the application provides a kind of hydrochloric acid for a pyrimidine and its synthesis side of intermediate 6- chloromethyluracils
Method, the synthetic method of the 6- chloromethyluracils that the application is provided has environment friendly, and product yield and purity are high, are beneficial to
Hydrochloric acid is prepared for pyrimidine etc..
The present invention provides a kind of synthetic method of 6- chloromethyluracils, comprises the following steps：
6- methyluracils and cupric oxide are carried out into oxidation reaction in a solvent, 6- formoxyl uracils are obtained；
Reduction 6- formoxyl uracils, obtain 6- methylol uracils；
By 6- methylol uracils through chlorination, 6- chloromethyluracils are obtained.
Preferably, the cupric oxide and the molar ratio of 6- methyluracils are 1:60~70.
Preferably, the temperature of the oxidation reaction is 110~115 DEG C.
Preferably, the oxidation reaction is carried out in solvent acetic acid.
Preferably, the time of the oxidation reaction is 5h~8h.
Preferably, the mixture for oxidation reaction being obtained is under conditions of 55~65 DEG C and pressure are 0.09MPa in temperature,
Vacuum distillation, is then filtered with diatomite, obtains the filtrate of the uracil of formoxyl containing 6-.
Preferably, will the filtrate adjust pH value after refilter, take filter cake alcohol and wash, through 60 DEG C of dryings 7 hours~8 hours,
Obtain solid 6- formoxyl uracils.
Preferably, 6- formoxyl uracils are reduced under conditions of water presence using sodium borohydride, obtains 6- methylols urine
Pyrimidine.
Preferably, under conditions of dimethylformamide presence, it is anti-that 6- methylols uracil carries out chloro with thionyl chloride
Should, obtain 6- chloromethyluracils.
The present invention provides a kind of synthetic method of hydrochloric acid for a pyrimidine, comprises the following steps：
6- methyluracils and cupric oxide are carried out into oxidation reaction in a solvent, 6- formoxyl uracils are obtained；
Reduction 6- formoxyl uracils, obtain 6- methylol uracils；
By 6- methylol uracils through chlorination, 6- chloromethyluracils are obtained；
6- chloromethyluracils are sequentially passed through into chloro, condensation, into salt, obtain hydrochloric acid for a pyrimidine.
Compared with prior art, the present invention instead of the selenium dioxide that existing process is used using metal onidiges cupric oxide
As oxidant, realize 6- methyluracils oxidation, and after through reduction, chloro technique be prepared for 6- chloromethyluracils.Press
According to preparation method of the present invention, the purity ＞ 99.0% of gained 6- chloromethyluracils.Present invention optimizes hydrochloric acid for phonetic
The synthetic method of pyridine intermediate (6- chloromethyluracils), instead of selenium dioxide and realizes 6- first with the metal onidiges of hypotoxicity
The oxidation technology of base uracil, while environment friendly is increased, improves the yield and purity of 6- chloromethyluracils.
The present invention use above-mentioned technique obtained by 6- chloromethyluracils be intermediate, through chloro, condensation, into salt three-step reaction
Hydrochloric acid is directly obtained and replaces a pyrimidine, without any purge process, purity is higher than 99.0% to gained bulk drug.
Brief description of the drawings
Fig. 1 is the gained 6- formoxyl uracils of the embodiment of the present invention 11H NMR spectras；
Fig. 2 is the gained 6- methylol uracils of the embodiment of the present invention 21H NMR spectras；
Fig. 3 is the gained 6- chloromethyluracils of the embodiment of the present invention 31H NMR spectras；
Fig. 4 is the gained hydrochloric acid of the embodiment of the present invention 4 for a pyrimidine1H NMR spectras；
Fig. 5 is the gained hydrochloric acid of the embodiment of the present invention 4 for a pyrimidine13C NMR spectras；
Fig. 6 is infrared spectrum of the gained hydrochloric acid of the embodiment of the present invention 4 for a pyrimidine；
Fig. 7 is HPLC spectrogram of the gained hydrochloric acid of the embodiment of the present invention 4 for a pyrimidine.
Specific embodiment
The technical scheme in the embodiment of the present invention is clearly and completely described below, it is clear that described embodiment
Only a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, the common skill in this area
The every other embodiment that art personnel are obtained under the premise of creative work is not made, belongs to the model of present invention protection
Enclose.
The invention provides a kind of synthetic method of 6- chloromethyluracils, comprise the following steps：
6- methyluracils and cupric oxide are carried out into oxidation reaction in a solvent, 6- formoxyl uracils are obtained；
Reduction 6- formoxyl uracils, obtain 6- methylol uracils；
By 6- methylol uracils through chlorination, 6- chloromethyluracils are obtained.
The synthetic method of the 6- chloromethyluracils that the application is provided has environment friendly, and product yield and purity
Height, is more suitable for medical industry application.
The embodiment of the present application mixes 6- methyluracils, solvent and cupric oxide in a kettle., and normal pressure leads to in system
Enter air, heating carries out oxidation reaction, obtains 6- formoxyl uracils.
The application, with cupric oxide as oxidant, realizes methyl in 6- methyluracils with 6- methyluracils as raw material
Formoxyl is oxidized to, 6- formoxyl uracils are prepared.The present invention instead of titanium dioxide with the metal onidiges CuO of hypotoxicity
Selenium, realizes the oxidation technology of 6- methyluracils, can not only increase environment friendly, and can improve 6- chloromethyluracils
Yield and purity.
In an embodiment of the present invention, the cupric oxide and the molar ratio of 6- methyluracils are 1:60~70, preferably
It is 1:62~68, more preferably 1:63~65.The oxidation reaction is carried out preferably in solvent acetic acid；I.e. the embodiment of the present invention can
In a kettle., by 6- methyluracils addition acetic acid, stirring is lower to add cupric oxide, is heated to uniform temperature, is aoxidized
Reaction.
In an embodiment of the present invention, the temperature of the oxidation reaction is 110~115 DEG C；The time of the oxidation reaction
It is 5h~8h.The color of embodiment of the present invention gained reaction solution is changed into green turbid solution from white opacity, continues insulation reaction 5h
~8h, TLC tracking raw material point reaction are disappeared, and reaction is completed.Wherein, TLC uses dichloromethane：Methyl alcohol (volume ratio)=5:1.
After completion of the reaction, embodiment of the present invention evaporated under reduced pressure solvent, the mixture for preferably obtaining oxidation reaction is in temperature
Under conditions of being 0.09MPa for 55~65 DEG C and pressure, vacuum distillation.Then, the embodiment of the present invention is filtered with diatomite, is obtained
The filtrate of the uracil of formoxyl containing 6-.
The filtrate is cooled to room temperature, embodiment of the present invention acid for adjusting pH value, preferably with concentrated hydrochloric acid adjust pH value be 1~
2,8 hours~10 hours can be stood.The embodiment of the present invention is refiltered after the filtrate is adjusted into pH value, is taken filter cake alcohol and is washed, and is dried,
Obtain solid 6- formoxyl uracils.Wherein, the filtering can use suction filtration commonly used in the art.The filter cake that suction filtration is obtained can use
10L ethanol is washed, and through 60 DEG C of dryings 7 hours~8 hours, obtains faint yellow solid compound 6- formoxyl uracils.
After obtaining 6- formoxyl uracils using the synthesis of cupric oxide oxidizing process, the embodiment of the present application reduce anti-
Should, synthesis obtains 6- methylol uracils.In embodiments herein, reduced under conditions of water presence using sodium borohydride
6- formoxyl uracils, specially：
In a kettle., in 6- formoxyl uracils being added into solvent such as tetrahydrofuran (THF), stirring is opened, is added
Sodium borohydride (NaBH4), it is stirred at room temperature, add water (H2O reduction reaction) is carried out, 6- methylol uracils are obtained.
In embodiments herein, the sodium borohydride is 1 with the molar ratio of 6- formoxyl uracils：0.8~
1.2.The temperature of the reduction reaction can be 10~30 DEG C of room temperature；Time is 3 hours~5 hours, and TLC tracking 6- formoxyl urine is phonetic
The reaction of pyridine point is disappeared, and reaction is completed.Wherein, TLC uses dichloromethane：Methyl alcohol (volume ratio)=5:1.
The reaction solution that the embodiment of the present invention obtains reduction reaction adds water, removes solvent under reduced pressure；Reaction solution is clarified, cooling
To room temperature, with acid for adjusting pH value, it is 1~2 preferably to adjust pH value with concentrated hydrochloric acid, can stand 3 hours~4 hours, is centrifuged, and obtains filter cake
And filtrate.Be evaporated for filtrate decompression by the embodiment of the present invention, obtains solid, adds water stirring, and suction filtration, filter cake merges, and dries, and obtains
To off-white powder compound 6- methylol uracils.Wherein, the drying is preferably：In 60 DEG C of drying under reduced pressure 8 hours~10
Hour.
After synthesis obtains 6- methylol uracils, the embodiment of the present application is carried out chlorination, obtains 6- chloromethyls urine
Pyrimidine.In embodiments herein, under conditions of dimethylformamide presence, 6- methylols uracil enters with thionyl chloride
Row chlorination, specially：
In a kettle., in 6- methylol uracils being added into solvent such as dichloromethane (DCM), stirring, room temperature are opened
Lower addition thionyl chloride (SOCl2), keep room temperature to add dimethylformamide (DMF), chlorination is carried out, solution becomes clarification,
Reaction certain hour, obtains 6- chloromethyluracils.
In embodiments herein, the 6- methylols uracil is 1 with the molar ratio of thionyl chloride:10~25.
The temperature of the chlorination can be 10~30 DEG C of room temperature；Time is 3 hours~5 hours, has a large amount of white solids to separate out, TLC
The point reaction of tracking 6- methylols uracil is disappeared, and reaction is completed.Wherein, TLC uses dichloromethane：Methyl alcohol (volume ratio)=5:1.
The reaction solution centrifugation that the embodiment of the present invention obtains chlorination, takes filter cake small in 60 DEG C of forced air dryings 6 hours~8
When, obtain off-white powder 6- chloromethyluracils.
The reaction equation of some embodiments of the invention synthesis 6- chloromethyluracils is as shown in Equation 3：
In sum, the present invention instead of selenium dioxide with the metal onidiges cupric oxide of hypotoxicity, realize 6- methyl
The oxidation technology of uracil, and then optimize synthetic method of the hydrochloric acid for a pyrimidine intermediate (6- chloromethyluracils)；Gained
The purity ＞ 99.0% of 6- chloromethyluracils.The present invention improves 6- chloromethyls urine phonetic while environment friendly is increased
The yield and purity of pyridine, pyrimidine etc. is replaced beneficial to hydrochloric acid is prepared.
The invention provides a kind of hydrochloric acid for the synthetic method of a pyrimidine, comprise the following steps：
6- methyluracils and cupric oxide are carried out into oxidation reaction in a solvent, 6- formoxyl uracils are obtained；
Reduction 6- formoxyl uracils, obtain 6- methylol uracils；
By 6- methylol uracils through chlorination, 6- chloromethyluracils are obtained；
6- chloromethyluracils are sequentially passed through into chloro, condensation, into salt, obtain hydrochloric acid for a pyrimidine.
The hydrochloric acid that the present invention is provided can increase environment friendly for the synthetic method of a pyrimidine, and high income, products obtained therefrom is pure
Degree is high, safer.
The embodiment of the present application mixes 6- methyluracils, solvent and cupric oxide in a kettle., and normal pressure leads to in system
Enter air, heating carries out oxidation reaction, obtains 6- formoxyl uracils.
The present invention uses 6- methyluracils, with cupric oxide as oxidant, realizes methyl oxidation in 6- methyluracils
Into formoxyl, 6- formoxyl uracils are prepared；The contents such as concrete operation step are as mentioned before.The present invention is with hypotoxicity
Metal onidiges CuO instead of selenium dioxide, realize the oxidation technology of 6- methyluracils, increase the same of environment friendly
When, the yield and purity of 6- chloromethyluracils are improved, and then improve yield and purity of the hydrochloric acid for a pyrimidine.
After obtaining 6- formoxyl uracils, the embodiment of the present invention prepares 6- chloromethyls urine by reduction, chlorination
Pyrimidine.In the present invention, the content of the reduction, chlorination is as it was noted above, this is no longer going to repeat them.
After obtaining 6- chloromethyluracils, the embodiment of the present invention is carried out chlorination, obtains the chloro- 6- chloromethyls urine of 5-
Pyrimidine.
The present invention with above-mentioned technique gained 6- chloromethyluracils as intermediate, preferably through sulfonic acid chloride chloro, specially：
In reaction bulb, during 6- chloromethyluracils are added into solvent such as acetic acid, stirring is opened, ice bath adds sulfonic acid chloride
(SO2Cl2), finish and reaction is stirred at room temperature, obtain the reaction solution containing the chloro- 6- chloromethyluracils of 5-.
Wherein, the 6- chloromethyluracils and the usage ratio of sulfonic acid chloride are 1:0.8~1.2 (quality g/ volume mL).
The reaction is preferably carried out under conditions of 10~30 DEG C of room temperature, stirring；Stirring reaction 6 hours~8 hours, has a large amount of whites solid
Body is separated out.TLC tracking 6- chloromethyluracils point reaction disappearance (dichloromethane：Methyl alcohol (volume ratio)=10:1), reaction is completed.
Reaction solution suction filtration, gained solid can obtain the chloro- 6- chloromethyls urine of solid 5- phonetic in 60 DEG C of forced air dryings 12 hours~14 hours
Pyridine.
After obtaining the chloro- 6- chloromethyluracils of 5-, the embodiment of the present invention is preferably condensed with 2- amino pyrrolidine hydrochlorides again,
Obtain for a pyrimidine.
In an embodiment of the present invention, the chloro- 6- chloromethyluracils of 5- are added in DMF, open stirring, added at room temperature
Enter 2- amino pyrrolidine hydrochlorides, maintenance system temperature under water-bath, be preferably dividedly in some parts under caustic alcohol, stirring be condensed it is anti-
Should, obtain for a pyrimidine.
Wherein, the chloro- 6- chloromethyluracils of the 5- and the molar ratio of 2- amino pyrrolidine hydrochlorides are 1:2~2.5.
The temperature of the condensation reaction can be 10~30 DEG C of room temperature；Stirring reaction 10 hours~20 hours, there is a large amount of white solids.TLC
The chloro- 6- chloromethyluracils point reaction disappearance (dichloromethane of tracking 5-：Methyl alcohol (volume ratio)=10:1), reaction is completed.This hair
The bright preferred ice bath of embodiment, below 30 DEG C of temperature of control, to water is added in the reaction solution being condensed to yield, stirs, suction filtration.Gained is consolidated
Body can obtain off-white powder for a pyrimidine crude product in 60 DEG C of forced air dryings 6 hours~8 hours.
In reaction bulb, during the embodiment of the present invention will be for a pyrimidine crude product addition ethanol, stirring is opened, add water and hydrochloric acid
(HCl) backflow, is heated to, salt-forming reaction is carried out, hydrochloric acid is obtained for a pyrimidine.
In an embodiment of the present invention, the molar ratio for a pyrimidine and hydrochloric acid is 1:1~1.5.It is heated to backflow
Temperature be preferably 75~80 DEG C, solid all dissolves.The embodiment of the present invention is filtered while hot, takes filtrate room temperature stirring and crystallizing, is taken out
Filter, dries, and obtains white solid hydrochloric acid for a pyrimidine highly finished product.Wherein, the room temperature is generally 10~30 DEG C.Filtrate room temperature is stirred
Mix crystallization 10 hours~20 hours；Suction filtration gained solid can in 60 DEG C of forced air dryings 12 hours~14 hours, obtain hydrochloric acid for
Pyrimidine highly finished product.
Optimize content described in 6- chloromethyluracils based on preparing, the present invention replaces a pyrimidine intermediate using gained hydrochloric acid
(6- chloromethyluracils), can the hydrochloric acid of direct preparation of high-purity degree replace a pyrimidine, gained bulk drug is pure without any purge process
Degree is higher than 99.0%.
For a further understanding of the application, the hydrochloric acid provided the application with reference to embodiment replaces a pyrimidine and its centre
The synthetic method of body 6- chloromethyl pyrimidines is specifically described.
Embodiment 1
6- formoxyl uracils are synthesized using cupric oxide oxidizing process
In 500L reactors, by 6- methyluracils (20.0kg, 158.59mol) add 150L acetic acid in, under stirring
200g cupric oxide is added, normal pressure in system to being passed through air.110 DEG C are heated to, reaction solution color is changed into green from white opacity
Dirty solution, continues insulation reaction 5h, TLC tracking raw material point reaction disappearance (dichloromethane:Methyl alcohol=5:1), reaction is completed.
Depressurize (55 DEG C, 0.09MPa) solvent evaporated acetic acid after completion of the reaction, and diatomite filtering, filtrate is cooled to room temperature, uses
Concentrated hydrochloric acid regulation pH ≈ 1, stand 8 hours, and suction filtration, filter cake is washed with 10L ethanol, 60 DEG C of forced air dryings 7 hours, obtain faint yellow solid
(37%) 8.2kg, yield is to compound 1.
Gained faint yellow solid compound 11H NMR results are shown in that Fig. 1, Fig. 1 are the gained 6- formoxyls of the embodiment of the present invention 1
Uracil1H NMR spectras.Result shows that gained faint yellow solid compound 1 is 6- formoxyl uracils.
Comparative example 1
6- formoxyl uracils are synthesized using manganese dioxide method
In 5L reactors, by 6- methyluracils (200.0g, 1.59mol) addition 1.5L acetic acid, stirring is lower to be added
2.0g manganese dioxide, normal pressure in system to being passed through air.110~115 DEG C are heated to, reaction solution color is changed into green from white opacity
Color dirty solution, continues insulation reaction 24h, the TLC a large amount of residue (dichloromethane of tracking raw material point:Methyl alcohol=5:1), using column chromatography
Separate product (dichloromethane:Methyl alcohol=20:1).
Cut containing product is concentrated after merging, and (10%) 2.1g, yield is to obtain faint yellow solid compound 1.
Comparative example 2
6- formoxyl uracils are synthesized using selenium dioxide oxidizing process
In 5L reactors, by 6- methyluracils (200.0g, 1.59mol) addition 1.5L acetic acid, stirring is lower to be added
2.0g selenium dioxide, normal pressure in system to being passed through air.110~115 DEG C are heated to, reaction solution color is changed into green from white opacity
Color dirty solution, continues insulation reaction 5h, TLC tracking raw material point reaction disappearance (dichloromethane:Methyl alcohol=5:1), reaction is completed.
Depressurize (55 DEG C, 0.09MPa) solvent evaporated acetic acid after completion of the reaction, and diatomite filtering, filtrate is cooled to room temperature, uses
Concentrated hydrochloric acid regulation pH ≈ 1, stand 8 hours, and suction filtration, filter cake is washed with 100mL ethanol, 60 DEG C of forced air dryings 7 hours, obtain pale yellow colored solid
(20%) 4.2g, yield is to body compound 1.
From above content, according to preparation method of the present invention, the purity ＞ of gained 6- chloromethyluracils
99.0%.Present invention optimizes the synthetic method that hydrochloric acid replaces a pyrimidine intermediate (6- chloromethyluracils), with the gold of hypotoxicity
Belong to oxidizing copper and instead of selenium dioxide, realize the oxidation technology of 6- methyluracils, increase environment friendly, while
The yield and purity of 6- chloromethyluracils are improve, this has important practice significance for medical industry application.
Embodiment 2
The synthesis of 6- methylol uracils
In 500L reactors, compound 1 (8.2kg, 58.53mol) is added in 82L tetrahydrofurans, opens stirring,
Sodium borohydride (2.38kg, 64.38mol), (20 DEG C) stirring 20min of room temperature is added 100mL water to be slowly added dropwise, has bubble to produce,
(20 DEG C) of keeping temperature is stirred 3 hours, 1 point of reaction disappearance (dichloromethane of TLC tracking compound:Methyl alcohol=5:1), reacted
Into.
Reaction solution is slowly added into 42L water, removes tetrahydrofuran under reduced pressure, and reaction solution clarification is cooled to room temperature, is adjusted with concentrated hydrochloric acid
Section pH ≈ 1, stand 3 hours, and centrifugation obtains filter cake；Filtrate decompression is evaporated to obtain solid, adds 10L water stirring 30min, suction filtration, filter cake
Merge, 60 DEG C of drying under reduced pressure 8 hours, (96.20%) 8.0kg, yield is to obtain off-white powder compound 2.
Gained off-white powder compound 21H NMR results are shown in that Fig. 2, Fig. 2 are the gained 6- methylols of the embodiment of the present invention 2
Uracil1H NMR spectras.Result shows that gained off-white powder compound 2 is 6- methylol uracils, and purity is
98.8%.
Embodiment 3
The synthesis of 6- chloromethyluracils
In 500L reactors, compound 2 (8.0kg, 56.29mol) is added in 80L dichloromethane, opens stirring,
(20 DEG C) addition 8L thionyl chlorides, keep room temperature that 4L DMF are slowly added dropwise at room temperature, and solution becomes clarification, reacts 3h, there is a large amount of white
Color solid is separated out.2 points of reaction disappearance (dichloromethane of TLC tracking compound:Methyl alcohol=5:1), reaction is completed.Reaction solution is centrifuged,
The forced air drying 6 hours of 60 DEG C of filter cake, (55.56%) 5.0kg, yield is to obtain off-white powder SM1.
Gained off-white powder SM1's1H NMR results are shown in that Fig. 3, Fig. 3 are that the gained 6- chloromethyls of the embodiment of the present invention 3 urine is phonetic
Pyridine1H NMR spectras.Result shows that gained off-white powder SM1 is 6- chloromethyluracils, and purity is 99.2%.
Embodiment 4
Hydrochloric acid replaces the synthesis of a pyrimidine
In 20L reaction bulbs, compound SM1 (1000.0g, 6.23mol) is added in 5000mL acetic acid, opens machinery
Stirring, ice bath is added dropwise sulfonic acid chloride (1000mL, 12.37mol), keeps being added dropwise process temperature no more than 30 DEG C, finishes at room temperature
(20 DEG C) stirring reaction 6h, has a large amount of white solids to separate out.TLC tracking compound SM1 point reaction disappearance (dichloromethane:Methyl alcohol
=10:1), reaction is completed.Reaction solution suction filtration, gained solid obtained the chloro- 6- chloromethyls urine of 5- phonetic in 60 DEG C of forced air dryings 12 hours
Pyridine.
In 20L reaction bulbs, the chloro- 6- chloromethyluracils (950.0g, 4.87mol) of 5- are added in 9500mLDMF,
Mechanical agitation is opened, 2- amino pyrrolidine hydrochlorides (1175.0g, 9.74mol) is added under room temperature (20 DEG C), body is maintained under water-bath
It is that temperature is 20 DEG C, is dividedly in some parts caustic alcohol (994.6g, 14.61mol), stirring reaction 10h there are a large amount of white solids.TLC with
The chloro- 6- chloromethyluracils point reaction disappearance (dichloromethane of track 5-:Methyl alcohol=10:1), reaction is completed.Ice bath, controls temperature 30
Below DEG C, to 9500mL water is added in reaction solution, 30min, suction filtration are stirred.The forced air drying 6 hours of 60 DEG C of gained solid, obtains class white
Color solid replaces a pyrimidine crude product 685.6g.
In 20L reaction bulbs, will be added in 6800mL ethanol for a pyrimidine crude product (680.0g, 2.80mol), open machine
Tool is stirred, and adds 3400mL water, 1M HCl 2000mL to be heated to flowing back (75 DEG C), and solid all dissolves, and filters while hot, filtrate
Room temperature (20 DEG C) stirring and crystallizing 10 hours, suction filtration, 60 DEG C of gained solid forced air drying 12 hours obtains white solid hydrochloric acid for phonetic
Pyridine highly finished product 475.5g.
By nuclear magnetic resonance spectroscopy and infrared analysis, structure mirror is carried out for a pyrimidine highly finished product to gained white solid hydrochloric acid
It is fixed,1H NMR results are shown in that Fig. 4, Fig. 4 are that the gained hydrochloric acid of the embodiment of the present invention 4 replaces a pyrimidine1H NMR spectras；13C NMR results
See that Fig. 5, Fig. 5 are that the gained hydrochloric acid of the embodiment of the present invention 4 replaces a pyrimidine13C NMR spectras；Infrared results are shown in that Fig. 6, Fig. 6 are this hair
The gained hydrochloric acid of bright embodiment 4 replaces the infrared spectrum of a pyrimidine.
Using the conventional high performance liquid chromatography in this area, gained white solid hydrochloric acid is divided for a pyrimidine highly finished product
Analysis.Wherein, number of injections is 1, and sampling volume is 10 μ L, and run time is 40min；Acquisition method group is the relevant material sides of TPI
Method, processing method is TPI processing methods；Tunnel name is 2998Ch1 210nm@1.2nm.Fig. 7 is the gained of the embodiment of the present invention 4
Hydrochloric acid replaces the HPLC spectrograms of a pyrimidine, and table 1 is chromatographic peak result.Gained hydrochloric acid of the invention replaces a pyrimidine purity ＞ 99%, single miscellaneous
(see Fig. 7,99.959%) product purity is to ＜ 0.2%.
The chromatographic peak result of table 1
As seen from the above embodiment, the present invention use above-mentioned technique obtained by 6- chloromethyluracils be intermediate, through chloro,
It is condensed, hydrochloric acid is directly obtained into salt three-step reaction for a pyrimidine, gained bulk drug is higher than without any purge process, purity
99.0%.
The above is only the preferred embodiment of the present invention, it is noted that for making the professional technique of the art
Personnel, on the premise of the technology of the present invention principle is not departed from, are that by various modifications of these embodiments, and these
Modification also should be regarded as the scope that the present invention should be protected.
Claims (10)
1. a kind of synthetic method of 6- chloromethyluracils, comprises the following steps：
6- methyluracils and cupric oxide are carried out into oxidation reaction in a solvent, 6- formoxyl uracils are obtained；
Reduction 6- formoxyl uracils, obtain 6- methylol uracils；
By 6- methylol uracils through chlorination, 6- chloromethyluracils are obtained.
2. synthetic method according to claim 1, it is characterised in that the mol ratio of the cupric oxide and 6- methyluracils
Example is 1:60~70.
3. synthetic method according to claim 1, it is characterised in that the temperature of the oxidation reaction is 110~115 DEG C.
4. synthetic method according to claim 3, it is characterised in that the oxidation reaction is carried out in solvent acetic acid.
5. synthetic method according to claim 4, it is characterised in that the time of the oxidation reaction is 5h~8h.
6. synthetic method according to claim 4, it is characterised in that the mixture for obtaining oxidation reaction is 55 in temperature
Under conditions of~65 DEG C and pressure are 0.09MPa, then vacuum distillation is filtered with diatomite, obtains the uracil of formoxyl containing 6-
Filtrate.
7. synthetic method according to claim 6, it is characterised in that will the filtrate adjust pH value after refilter, take filter
Cake alcohol is washed, and through 60 DEG C of dryings 7 hours~8 hours, obtains solid 6- formoxyl uracils.
8. the synthetic method according to any one of claim 1~7, it is characterised in that existed in water using sodium borohydride
Under conditions of reduce 6- formoxyl uracils, obtain 6- methylol uracils.
9. synthetic method according to claim 8, it is characterised in that under conditions of dimethylformamide presence, 6- hydroxyls
Methyluracil carries out chlorination with thionyl chloride, obtains 6- chloromethyluracils.
10. a kind of hydrochloric acid is comprised the following steps for the synthetic method of a pyrimidine：
6- methyluracils and cupric oxide are carried out into oxidation reaction in a solvent, 6- formoxyl uracils are obtained；
Reduction 6- formoxyl uracils, obtain 6- methylol uracils；
By 6- methylol uracils through chlorination, 6- chloromethyluracils are obtained；
6- chloromethyluracils are sequentially passed through into chloro, condensation, into salt, obtain hydrochloric acid for a pyrimidine.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107216314A (en) * | 2017-08-02 | 2017-09-29 | 国药心制药有限公司 | A kind of hydrochloric acid is for crystal formation of a pyrimidine and preparation method thereof |
| CN109134385A (en) * | 2017-06-27 | 2019-01-04 | 尚科生物医药（上海）有限公司 | A kind of purification process of uracil compounds |
| EP3759082B1 (en) * | 2018-02-28 | 2022-04-20 | Procos S.p.A. | Process for the synthesis of 6-chloromethyluracil |
| US11465988B2 (en) * | 2018-12-15 | 2022-10-11 | Natco Pharma Limited | Process for the preparation of Tipiracil hydrochloride and intermediates thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6294535B1 (en) * | 1995-03-29 | 2001-09-25 | Taiho Pharmaceutical Co., Ltd. | Uracil derivatives and antitumor effect potentiator and antitumor agent containing the same |
| CN104725324A (en) * | 2015-03-23 | 2015-06-24 | 上海皓元生物医药科技有限公司 | Preparation method of 6-chloromethylpyrimidine-2,4-(1H, 3H)-diketone |
| CN104945384A (en) * | 2014-03-25 | 2015-09-30 | 江苏豪森药业股份有限公司 | Preparation method of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidine dione or salts thereof |
| CN105906573A (en) * | 2015-12-23 | 2016-08-31 | 嘉实（湖南）医药科技有限公司 | Preparation method of tipiracil intermediate |
| CN106317028A (en) * | 2015-11-03 | 2017-01-11 | 江苏悦兴药业有限公司 | Preparation method of anti-tumor medicine tipiracil hydrochloride and key intermediate thereof |
| CN106366073A (en) * | 2016-10-24 | 2017-02-01 | 扬子江药业集团南京海陵药业有限公司 | Method for preparing tipiracil hydrochloride |
-
2017
- 2017-03-01 CN CN201710117569.XA patent/CN106892902A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6294535B1 (en) * | 1995-03-29 | 2001-09-25 | Taiho Pharmaceutical Co., Ltd. | Uracil derivatives and antitumor effect potentiator and antitumor agent containing the same |
| CN104945384A (en) * | 2014-03-25 | 2015-09-30 | 江苏豪森药业股份有限公司 | Preparation method of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidine dione or salts thereof |
| CN104725324A (en) * | 2015-03-23 | 2015-06-24 | 上海皓元生物医药科技有限公司 | Preparation method of 6-chloromethylpyrimidine-2,4-(1H, 3H)-diketone |
| CN106317028A (en) * | 2015-11-03 | 2017-01-11 | 江苏悦兴药业有限公司 | Preparation method of anti-tumor medicine tipiracil hydrochloride and key intermediate thereof |
| CN105906573A (en) * | 2015-12-23 | 2016-08-31 | 嘉实（湖南）医药科技有限公司 | Preparation method of tipiracil intermediate |
| CN106366073A (en) * | 2016-10-24 | 2017-02-01 | 扬子江药业集团南京海陵药业有限公司 | Method for preparing tipiracil hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| K.M. PARIDA: "Structural properties and catalytic oxidation of benzene to", 《APPLIED CATALYSIS A: GENERAL》 * |
| LINGYI SUN: "Fragment-based approach to the design of 5-chlorouracil-linkedpyrazolo[1,5-a][1,3,5]triazines as thymidine phosphorylase inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134385A (en) * | 2017-06-27 | 2019-01-04 | 尚科生物医药（上海）有限公司 | A kind of purification process of uracil compounds |
| CN109134385B (en) * | 2017-06-27 | 2021-07-20 | 尚科生物医药（上海）有限公司 | Method for purifying uracil compounds |
| CN107216314A (en) * | 2017-08-02 | 2017-09-29 | 国药心制药有限公司 | A kind of hydrochloric acid is for crystal formation of a pyrimidine and preparation method thereof |
| EP3759082B1 (en) * | 2018-02-28 | 2022-04-20 | Procos S.p.A. | Process for the synthesis of 6-chloromethyluracil |
| US11465988B2 (en) * | 2018-12-15 | 2022-10-11 | Natco Pharma Limited | Process for the preparation of Tipiracil hydrochloride and intermediates thereof |
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Application publication date: 20170627 |