CN106749194B - A kind of preparation method for pyrimidine - Google Patents
A kind of preparation method for pyrimidine Download PDFInfo
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- CN106749194B CN106749194B CN201710058262.7A CN201710058262A CN106749194B CN 106749194 B CN106749194 B CN 106749194B CN 201710058262 A CN201710058262 A CN 201710058262A CN 106749194 B CN106749194 B CN 106749194B
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- chloromethyluracil
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Abstract
The invention discloses a kind of preparation methods for pyrimidine.This method first passes through chlorination and obtains intermediate A using 6- chloromethyluracil as starting material, then carries out condensation reaction with alpha-pyrrolidone in the presence of highly basic and improves the selectivity reacted, last intermediate B is obtained through ammonolysis reaction for pyrimidine.The preparation method is simple, and reaction condition is mild, the purity is high of product, high income, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, more specifically to a kind of preparation method for pyrimidine.
Background technique
It is one of the main component of fluorine glycosides pyrimidine piece that hydrochloric acid, which replaces a pyrimidine (TPI), and fluorine glycosides pyrimidine piece is Japanese roc medicine
A kind of compound preparation of product Industrial Co., Ltd exploitation, 03 month 2014 medicine are ratified to control for standard scheme by Japanese PMDA
Treat invalid unresectable advanced stage or recurrent colorectal cancer.Component in fluorine glycosides pyrimidine piece contains hydrochloric acid for pyrimidine
(TPI), hydrochloric acid is then able to suppress the thymidine phosphorylase for participating in degradation trifluorothymidine for pyrimidine, to maintain having for trifluorothymidine
Imitate blood concentration.It is able to suppress the adverse reaction of trifluorothymidine independent medication simultaneously, to enhance drug safety.Hydrochloric acid for
The structural formula of pyrimidine is as follows.
Currently, replacing the primary synthetic methods (such as EP1080726A1 patent) of a pyrimidine are as follows: be with 6- (chloromethyl) uracil
Starting material, first react with sulfonic acid chloride generation the chloro- 6- chloromethyluracil of 5-, then using sodium ethoxide as acid binding agent, in DMF and
2- imido grpup pyrrolidines reacts to obtain for pyrimidine.Chemical equation is as follows:
In above-mentioned synthetic method, impurity is more in reaction solution, and purification is relatively difficult, and the yield of product is not high, yield
About 35% or so.
Summary of the invention
For the problem that preparation is low for yield present in pyrimidine in existing industrial production, purity difference, the present invention is mentioned
A kind of preparation method for pyrimidine is supplied.This method first passes through chlorination and obtains using 6- chloromethyluracil as starting material
To intermediate A, condensation reaction then is carried out with alpha-pyrrolidone in the presence of highly basic and improves the selectivity reacted, it is last intermediate
Body B is obtained through ammonolysis reaction for pyrimidine.The preparation method is simple, and reaction condition is mild, the purity is high of product, high income, fits
Suitable industrialized production.
The technical scheme is that a kind of preparation method for pyrimidine, characterized in that
1) using 6- chloromethyluracil as starting material, it is chloro- that 5- is obtained with N- chlorosuccinimide progress chlorination
6- chloromethyluracil (intermediate A)；
2) then in the presence of highly basic, intermediate A and alpha-pyrrolidone carry out condensation reaction and obtain 5- chloro- 6- (2- carbonyl
Pyrrolidinyl -1- base) methyl -2,4- (1H, 3H) hybar X (intermediate B)；
3) intermediate B and ammonium hydroxide generation ammonolysis reaction obtain for pyrimidine.
Reaction equation is as follows.
Preferably, the reaction dissolvent of step 1) be dimethyl sulfoxide, acetonitrile, methanol or n,N-Dimethylformamide, it is more excellent
Select dimethyl sulfoxide；
Preferably, the molar ratio of step 1) 6- chloromethyluracil and N- chlorosuccinimide is 1:2.0~3.0.
Preferably, step 1) reaction temperature is 50~70 DEG C, and the reaction time is 2~4h.
Preferably, step 2) reaction dissolvent is tetrahydrofuran, methylene chloride, methanol, n,N-Dimethylformamide, preferably four
Hydrogen furans.
Preferably, highly basic used in step 2) is n-BuLi, sodium hydride or lithium diisopropyl amido, more preferable positive fourth
Base lithium.
Preferably, the molar ratio of step 2) intermediate A, alpha-pyrrolidone and highly basic is 1:1.4~1.6:1.4~1.6.
Preferably, step 2) reaction temperature is 0~10 DEG C, and the reaction time is 2~4h.
Preferably, the solvent of step 3) reaction is toluene, tetrahydrofuran or DMF, preferably DMF.
Preferably, step 3) intermediate B and concentrated ammonia liquor molar ratio are 1:1.4~1.6.
Preferably, step 3) reaction temperature is 80~90 DEG C, and the reaction time is 2~3h.
It is of the invention specific steps are as follows:
1) 6- chloromethyluracil is added in reaction dissolvent, adds N- chlorosuccinimide, then heats to 50
~70 DEG C of 2~4h of insulation reaction；After completion of the reaction, reaction solution is poured into water and yellow solid is precipitated, then filtered, dried
Obtain intermediate A；
2) alpha-pyrrolidone is slowly dropped in n-butyllithium solution, reacts at 0~5 DEG C of temperature control, is dripped after fully reacting
It is added in the solution of intermediate A and carries out 2~4h of reaction for 0~10 DEG C of temperature control；After being filtered after the reaction was completed, adding water mashing and drying
Obtain intermediate B；
3) intermediate B is added in organic solvent, concentrated ammonia liquor is then added and reacts 2~3h at 80~90 DEG C, has reacted
Cheng Houjia elutriation goes out solid, is filtered, dries to obtain for pyrimidine.
The beneficial effects of the present invention are:
1, the present invention avoids, labile sulphonyl strong using corrosivity using N- chlorosuccinimide as chlorinating agent
Chlorine reduces risk.Reactive intermediate first is generated with alpha-pyrrolidone using highly basic such as n-BuLis in condensation reaction simultaneously
Then it is reacted again with intermediate A, further improves the selectivity of condensation reaction, keep the yield 90% of condensation reaction left
It is right；
2, the preparation method is simple, and reaction condition is mild, the purity is high (>=99.8%) of product, high income (>=75%),
It is suitable for industrialized production.
Specific embodiment
Embodiment 1
1) 6- chloromethyluracil 10.0g is dissolved in 100ml dimethyl sulfoxide, is added under stirring condition at room temperature
17.0g chlorosuccinimide finishes and is warming up to 60 DEG C, and carries out insulation reaction 4h.The system of reaction is added to 400ml water
Middle precipitation light yellow solid filters, obtains 11.0g intermediate A, yield 90.7% after drying.
2) n-BuLi hexane solution (2mol/L) 33.6ml is added in reaction flask, 50ml tetrahydrofuran is added, it will
Alpha-pyrrolidone 5.9g is slowly dropped in reaction flask, is controlled 0-5 DEG C of temperature reaction, is added drop-wise among 9.0g after complete reaction
In the 50ml tetrahydrofuran solution of body A, then temperature control carries out reaction 3h to 5 DEG C, is warming up to room temperature after reaction, filters, Gu
Body object adds water mashing washing, filters, obtains 10.2g intermediate B, yield 90.2% after drying.
3) intermediate B 7.0g is weighed, 50ml DMF is added, is added 2.6g concentrated ammonia liquor (concentration 28%), is warming up to 85 DEG C instead
2h is answered, reaction terminates to be down to room temperature, and 100ml elutriation is added and goes out solid, filters, obtains solid 6.4g, yield 91.8% after drying；
Total yield of products is 75.1%, and the purity of product is 99.87%.
Embodiment 2
1) 6- chloromethyluracil 10.0g is dissolved in 100ml n,N-Dimethylformamide, at room temperature under stirring condition
16.5g chlorosuccinimide is added, finishes and is warming up to 60 DEG C, and carry out insulation reaction 3h.The system of reaction is added to
Light yellow solid is precipitated in 400ml water, filters, obtain 11.4g intermediate A, yield 94.0% after drying.
2) lithium diisopropyl amido THF solution (2.0mol/L) 37.5ml is added in reaction flask, 50ml methanol is added, it will
Alpha-pyrrolidone 6.6g is slowly dropped in reaction flask, is controlled 0-5 DEG C of temperature reaction, is added drop-wise among 10g after complete reaction
In the methanol solution of body A, then temperature control carries out reaction 3h to 0 DEG C, is warming up to room temperature after reaction, filters, and water is added to be beaten water
Wash, filter, dry after obtain 11.3g intermediate B, yield 90.0%.
3) intermediate B 7.0g is weighed, 50mlDMF is added, is added 2.7g concentrated ammonia liquor (28% concentration), is warming up to 85 DEG C of reactions
3h, reaction terminate to be down to room temperature, and 100ml elutriation is added and goes out solid, filters, solid 6.5g, yield 93.2% is obtained after drying；It produces
Product purity is 99.89%, total yield of products 78.8%.
Embodiment 3
1) 6- chloromethyluracil 10.0g is dissolved in 100mlN, in dinethylformamide, at room temperature under stirring condition plus
Enter 16.8g chlorosuccinimide, finishes and be warming up to 60 DEG C, and carry out insulation reaction 4h.The system of reaction is added to 400ml
Light yellow solid is precipitated in water, filters, obtain 11.2g intermediate A, yield 92.3% after drying.
2) n-BuLi hexane solution (2mol/L) 38.2ml is added in reaction flask, 50ml methanol is added, by α-pyrrole
Pyrrolidone 6.5g is slowly dropped in reaction flask, is controlled 0-5 DEG C of temperature reaction, is added drop-wise to 10g intermediate A after complete reaction
In methanol solution, then temperature control carries out reaction 2h to 0 DEG C, is warming up to room temperature after reaction, filters, and adds water mashing washing, takes out
11.2g intermediate B, yield 89.2% are obtained after filter, drying.
3) intermediate B 7.0g is weighed, 50ml DMF is added, is added 2.6g concentrated ammonia liquor (concentration 28%), is warming up to 85 DEG C instead
3h is answered, reaction terminates to be down to room temperature, and 100ml elutriation is added and goes out solid, filters, solid 6.6g, yield 94.6% is obtained after drying；
Product purity is 99.92%, total yield of products 77.8%.
Comparative example (referring to EP1080726A1 patent)
1) under room temperature by 12ml sulfonic acid chloride be slowly added dropwise acetic acid (50mL) 6- chloromethyluracil (16.3g) it is outstanding
In turbid, 3h is stirred at room temperature, reaction solution is added in ice water (50ml), stirring, crystallization, suction filtration obtain the chloro- 6- of solid 5-
Chloromethyluracil (18.2g), yield 92%；
2) the chloro- 6- chloromethyluracil (5.0g) of 5-, 2- imido grpup pyrrolidines (6.14g), sodium ethoxide (5.24g) are added to
In 50ml DMF solution, 14h is stirred under room temperature, is filtered, and solid is added in 30ml water, is carried out after being neutralized with acetic acid
Washing filters.Active carbon is added after the dissolving with hydrochloric acid that the solid being obtained by filtration passes through 1N, filters.Filtrate decompression obtains solid
2.68g, yield 38.2%；Total recovery is 35.1%；Purity is 98.7%.
Claims (7)
1. a kind of preparation method for pyrimidine, characterized in that the following steps are included:
1) using 6- chloromethyluracil as starting material, chlorination is carried out with N- chlorosuccinimide and obtains the chloro- 6- chlorine of 5-
Methyluracil；
2) then in the presence of highly basic, the chloro- 6- chloromethyluracil of 5- and alpha-pyrrolidone carry out condensation reaction and obtain the chloro- 6- of 5-
(2- carbonyl pyrrolidine alkyl -1- base) methyl -2,4- (1H, 3H) hybar X；Highly basic used be n-BuLi, sodium hydride or
Lithium diisopropyl amido；
3) then ammonolysis occurs for the chloro- 6- of 5- (2- carbonyl pyrrolidine alkyl -1- base) methyl -2,4- (1H, 3H) hybar X and ammonium hydroxide
Reaction obtains for pyrimidine.
2. a kind of preparation method for pyrimidine as described in claim 1, characterized in that highly basic used in step 2) is positive fourth
Base lithium.
3. a kind of preparation method for pyrimidine as claimed in claim 2, characterized in that the following steps are included:
1) 6- chloromethyluracil is added in reaction dissolvent, adds N- chlorosuccinimide, then heats to 50~70
DEG C 2~4h of insulation reaction；After completion of the reaction, reaction solution is poured into water and yellow solid is precipitated, then filtered, dry to obtain
The chloro- 6- chloromethyluracil of 5-；
2) alpha-pyrrolidone is added drop-wise in n-butyllithium solution, is reacted at 0~5 DEG C of temperature control, it is chloro- that 5- is added drop-wise to after fully reacting
2~4h of reaction is carried out for 0~10 DEG C of temperature control in the solution of 6- chloromethyluracil；It is filtered after the reaction was completed plus water is beaten and dries
The chloro- 6- of 5- (2- carbonyl pyrrolidine alkyl -1- base) methyl -2,4- (1H, 3H) hybar X is obtained after dry；
3) step 2) product is added in organic solvent, concentrated ammonia liquor is then added and reacts 2~3h at 80~90 DEG C, reaction is completed
Afterwards plus elutriation goes out solid, is filtered, dries to obtain for pyrimidine；The mass concentration of the concentrated ammonia liquor is 28%.
4. a kind of preparation method for pyrimidine as claimed in claim 3, characterized in that the reaction dissolvent of the step 1) is
Dimethyl sulfoxide, acetonitrile, methanol or N,N-dimethylformamide.
5. a kind of preparation method for pyrimidine as described in any one of claim 1-3, characterized in that 6- in step 1)
The molar ratio of chloromethyluracil and N- chlorosuccinimide is 1:2.0~3.0.
6. a kind of preparation method for pyrimidine as described in any one of claim 1-3, characterized in that 5- in step 2)
The molar ratio of chloro- 6- chloromethyluracil, alpha-pyrrolidone and highly basic is 1:1.4~1.6:1.4~1.6.
7. a kind of preparation method for pyrimidine as claimed in claim 3, characterized in that the chloro- 6- of 5- (2- carbonyl in step 3)
Pyrrolidinyl -1- base) methyl -2,4- (1H, 3H) hybar X and concentrated ammonia liquor molar ratio be 1:1.4~1.6.
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3681880A4 (en) * | 2017-09-14 | 2021-06-23 | Aurobindo Pharma Limited | Process for preparing crystalline tipiracil hydrochloride |
| US10866219B2 (en) * | 2017-12-22 | 2020-12-15 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine- and/or tipiracil-related substance |
| EP3730935A4 (en) | 2017-12-22 | 2022-02-23 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine- and/or tipiracil-derived analogs |
| US10816517B2 (en) | 2018-01-05 | 2020-10-27 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine-related substance by high-performance liquid chromatography |
| WO2019135405A1 (en) | 2018-01-05 | 2019-07-11 | 大鵬薬品工業株式会社 | Detection method for analog derived from trifluridine |
| CN109796441B (en) * | 2019-02-19 | 2020-10-16 | 北京民康百草医药科技有限公司 | Preparation method of impurity A of tipyrimidine hydrochloride |
| CN109776429A (en) * | 2019-03-11 | 2019-05-21 | 河南湾流生物科技有限公司 | A kind of Pyrimdinone molecule and its preparation method and application for promoting SOD vigor in cosmetics |
| CN112028837A (en) * | 2019-06-03 | 2020-12-04 | 鲁南制药集团股份有限公司 | Tilpyrimidine intermediate compound |
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| CN1407854A (en) * | 1999-12-03 | 2003-04-02 | 拜尔公司 | N-aryi-uracile-based herbicides |
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| CN1407854A (en) * | 1999-12-03 | 2003-04-02 | 拜尔公司 | N-aryi-uracile-based herbicides |
| CN105859691A (en) * | 2016-04-07 | 2016-08-17 | 扬子江药业集团南京海陵药业有限公司 | Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof |
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Effective date of registration: 20200226 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Patentee after: Shandong Anxin Pharmaceutical Co., Ltd Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |