CN108117523B - Preparation method of halogenated uracil compound - Google Patents
Preparation method of halogenated uracil compound Download PDFInfo
- Publication number
- CN108117523B CN108117523B CN201611073880.0A CN201611073880A CN108117523B CN 108117523 B CN108117523 B CN 108117523B CN 201611073880 A CN201611073880 A CN 201611073880A CN 108117523 B CN108117523 B CN 108117523B
- Authority
- CN
- China
- Prior art keywords
- acid
- anhydride
- reaction
- uracil
- ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of a compound shown as a formula 2, which comprises the following steps of mixing a compound 1 and PCl in a solvent5Performing chlorination reaction; wherein X is F, Cl, Br or I; the solvent is selected from SOCl2One or more of carbon tetrachloride, 1, 2-dichloroethane, 1,1, 1-trichloroethane, trichloroethylene and 1,1, 2-trichloroethane; the preparation method takes 5-halogenated uracil as a starting material, has simple and convenient process, high yield and environmental protection, and can be suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of halogenated uracil compounds.
Background
Palbociclib (Palbociclib), developed by Pfizer, USA as an initial solution based on endocrine therapy, is combined with letrozole for estrogen receptor positive, human epidermal growth factor receptor 2 negative (ER) that has not received systemic treatment+/HER2-) In postmenopausal women for the treatment of advanced breast cancer.
The synthetic route of palbociclib reported in patent WO2014128588a1 is shown below:
the method uses 2, 4-dichloro-5-bromopyrimidine as a starting material, ammonifies the starting material with cyclopentylamine to obtain 5-bromo-2-chloro-6-cyclopentylpyrimidine, Heck reacts with crotonic acid, amidates the cyclic product to obtain 2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one, bromizes the cyclic product to obtain 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one, and ammonifies the cyclic product with 2-amino-5- (4-N-tert-butoxycarbonyl-1-N-piperazinyl) pyridine to obtain 8-cyclopentyl-5-methyl-2- { [5- (piperazin-1-yl) pyridine -2-yl ] amino } pyrido [2,3-d ] pyrimidin-7 (8H) -one, reacted by Heck to produce 6- (1-n-butoxy-vinyl) -8-cyclopentyl-5-methyl-2- { [5- (piperazin-1-yl) pyridin-2-yl ] amino } pyrido [2,3-d ] pyrimidin-7 (8H) -one, and finally acetylated at the 6-position by acidic hydrolysis and protected by piperazine de-Boc to give palbociclib. In the route, 2, 4-dichloro-5-bromopyrimidine is an important intermediate.
In the currently reported method for preparing the raw material 2, 4-dichloro-5-bromopyrimidine, the carbonyl of uracil is mainly chlorinated, phosphorus oxychloride is mainly used as a chlorination reagent, and the reaction yield is generally about 90%. But phosphorus oxychloride is a highly toxic substance and has great harm to the body;
in addition, WO2011076419A1 describes a process for the preparation of 2, 4-difluoro-5-bromopyrimidine using PCl5As a chlorination reagent, the use of phosphorus oxychloride as a solvent which is a highly toxic reagent cannot be eliminated, the reaction temperature is high and is above 100 ℃, the yield is less than 90 percent,
disclosure of Invention
The invention aims to overcome the defects of high toxicity of a chlorination reagent or a solvent, low yield, high reaction temperature and the like of the existing preparation method of 2, 4-dichloro-5-bromopyrimidine, and provides a preparation method of a halogenated uracil compound. The preparation method takes 5-halogenated uracil as a starting material, has simple and convenient process, high yield and environmental protection, and can be suitable for industrial production.
The invention provides a preparation method of a compound shown as a formula 2, which comprises the following steps of mixing a compound 1 and PCl in a solvent5Carrying out chlorination reaction to obtain the product,
wherein X is one of F, Cl, Br or I; the solvent is selected from SOCl2One or more of carbon tetrachloride, 1, 2-dichloroethane, 1,1, 1-trichloroethane, trichloroethylene and 1,1, 2-trichloroethane.
Wherein, in the chlorination reaction, the PCl5The molar ratio of the compound 1 to the compound used may be a ratio conventionally used in the art, and the present invention is particularly preferably (2.3:1) to (3:1), and more preferably (2.5:1) to (2.8: 1).
In the chlorination reaction, the ratio of the amount of the compound 1 to the solvent can be the amount conventionally used in the reactions in the field, and the invention particularly preferably selects 0.5 mol/L-2 mol/L, and further preferably selects 0.6 mol/L-1.8 mol/L.
Wherein the temperature of the chlorination reaction can be a conventional temperature in the reaction in the field, and the temperature at which the solvent can be refluxed is particularly preferred in the present invention.
Wherein, the time of the chlorination reaction can be determined according to the change of the reaction liquid from a suspension state to a clear solution, and the end point of the reaction is monitored by a conventional detection method in the field (such as HPLC, TLC or NMR), and TLC detection is particularly preferred in the invention.
Wherein, when X in the compound shown in the formula 1 is Br, the preparation method of the compound shown in the formula 2 preferably further comprises the following step of reacting uracil with a bromination reagent under the action of acid or acid/acid anhydride; the brominating reagent is 1,3-dibromo-5,5-Dimethylhydantoin (DBH); the acid/anhydride refers to a mixture of acid and anhydride; the acid or the acid/anhydride is an organic acid; the acid anhydride is organic acid anhydride;
wherein, in the preparation method, the acid is used as a catalyst and a solvent in the invention, the organic acid can be an organic acid suitable for the reaction, and the invention particularly preferably selects acetic acid and/or propionic acid, and the acetic acid and the propionic acid are anhydrous acetic acid and anhydrous propionic acid;
in the preparation method, the acid anhydride in the acid/acid anhydride can be organic acid anhydride used for absorbing moisture in the reaction process, and the invention particularly preferably selects acetic anhydride and/or propionic anhydride;
in the preparation method, the dosage ratio of the uracil to the acid or the dosage ratio of the uracil to the acid/anhydride can be the conventional dosage ratio of the reaction in the field, and the invention particularly preferably has the dosage ratio of 0.8 mol/L-1 mol/L, and further preferably has the dosage ratio of 0.811 mol/L.
In the acid/anhydride, the molar ratio of the acid to the anhydride is 1/18-1/8, preferably 1/15-1/10. In the preparation method, the reaction temperature can be the conventional temperature of the reaction in the field, and the temperature is particularly preferably 25-70 ℃, and further preferably 50-60 ℃ in the invention.
In the preparation method, the molar amount of the brominating reagent can be the conventional amount in the reaction in the field, and the invention particularly preferably selects 0.4-1.5, preferably 0.6-1.2 of the amount of uracil.
Wherein, in the preparation method, the reaction time can be monitored by a conventional detection method in the field (such as HPLC, TLC or NMR), and the TLC method is preferred in the invention.
In the preparation method, after the reaction is finished, post-treatment can be carried out; the post-treatment is preferably carried out by dilution, suction filtration and drying. Wherein, the dilution can be carried out by adopting a conventional dilution mode in the field, and preferably, the dilution is carried out by using ethyl acetate; the suction filtration and the drying can adopt the conventional operation mode in the field.
Wherein, in the preparation method, the reaction can be carried out under the action of a catalyst, the catalyst can be a conventional catalyst for the reaction, and trimethylsilyl trifluoromethanesulfonate (TMSOTf) is particularly preferred in the invention; the ratio of the molar usage of the catalyst to the molar usage of the brominating agent can be the conventional usage in the reaction in the field, and the ratio of the molar usage of the catalyst to the molar usage of the brominating agent is particularly preferably 0.8-1.2, and more preferably 1: 1.
The preparation method of the compound shown in the formula 2 preferably further comprises the following post-treatment: and extracting, drying and concentrating the reaction mixture after the chlorination reaction. The reaction mixture is preferably mixed with ice water during the extraction; the extractant is preferably dichloromethane during the extraction;
the drying may be carried out by conventional procedures in the art;
the concentration adopts the conventional operation in the field;
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
(1) the invention employs PCl5As a chlorination reagent, the use of highly toxic phosphorus oxychloride as a solvent is avoided, and the reaction endpoint is easy to judge and control; the yield is high, and the post-treatment is simple;
(2) the reflux reaction temperature is lower, and the danger index is reduced;
(3) the solvent used in the reaction can be recycled after being dried, and is green and environment-friendly.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
5-Bromocluracil (6.0g, 31.4mmol) with PCl5(16.4g, 78.5mmol) was mixed in a reaction flask, 1, 2-dichloroethane (50mL) was added, and the reaction mixture was heated to reflux. During the reaction, the mixture changed from suspension to a pale yellow clear solution, at which time TLC showed complete reaction of the starting materials and cooled to room temperature. The reaction mixture was slowly poured into stirring ice water, stirred for 1h, extracted with DCM (3X 50mL), and the organic layer was added anhydrous MgSO4Drying, evaporating the solvent to dryness to obtain a light yellow transparent liquid. Further purification on silica gel column gave compound 2 as a colorless transparent liquid (yield 99%, purity 97.5%).
Example 2
5-Bromocluracil (6.0g, 31.4mmol) with PCl5(19.68g, 94.2mmol) was mixed in a reaction flask and SOCl was added2(50mL), the reaction mixture was heated to reflux. During the reaction, the mixture changed from suspension to a pale yellow clear solution, at which time TLC showed complete reaction of the starting materials and cooled to room temperature. The reaction mixture was slowly poured into stirring ice water, stirred for 1h, extracted with DCM (3X 50mL), and the organic layer was added anhydrous MgSO4Drying, evaporating the solvent to dryness to obtain a light yellow transparent liquid. Further purification on silica gel column gave compound 2 as a colorless transparent liquid (yield 99%, purity 97.2%).
Example 3
5-Bromocluracil (6.0g, 31.4mmol) with PCl5(16.4g, 78.5mmol) was mixed in a reaction flask, carbon tetrachloride (50mL) was added, and the reaction mixture was heated to reflux. During the reaction, the mixture changed from suspension to a pale yellow clear solution, at which time TLC showed complete reaction of the starting materials and cooled to room temperature. The reaction mixture was slowly poured into stirring ice water, stirred for 1h, extracted with DCM (3X 50mL), and the organic layer was added anhydrous MgSO4Drying, evaporating the solvent to dryness to obtain a light yellow transparent liquid. Further purification on silica gel column gave compound 2 as a colorless transparent liquid (yield 99%, purity 97%).
Example 4
5-Bromocluracil (6.0g, 31.4mmol) with PCl5(16.4g, 87.9mmol) was mixed in a reaction flask, 1, 2-trichloroethane (50mL) was added, and the reaction mixture was heated to reflux. During the reaction, the mixture changed from suspension to a pale yellow clear solution, at which time TLC showed complete reaction of the starting materials and cooled to room temperature. The reaction mixture was slowly poured into stirring ice water, stirred for 1h, extracted with DCM (3X 50mL), and the organic layer was added anhydrous MgSO4Drying, evaporating the solvent to dryness to obtain a light yellow transparent liquid. Further purification on silica gel column gave compound 2 as a colorless transparent liquid (yield 99.5%, purity 97%).
Example 5
Uracil (100g, 892.1mmol) and solvent (glacial acetic acid (1L), acetic anhydride (100mL)) were mixed in a reaction flask (white suspension), stirred at 50 ℃ for reaction, and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 153g, 535.3mmol) was added and stirred for reaction. After 1.5h, the white suspension turned to a bean curd residue, at which point TLC spots (sampled a little, diluted with THF, DCM/MeOH, 4:1 developed) showed the reaction was complete. And (3) post-treatment: the reaction mixture was diluted with EA, filtered with suction and dried in vacuo to give 5-bromouracil, compound 2, as a white solid (168.8, 99.9% yield, 99.3% purity).
Examples 6 to 12
The following examples 2 to 8 were carried out by changing the solvent, temperature and reaction time according to the procedure of example 5, and the results are shown in the following table:
example 13
Uracil (1mol), solvent (glacial acetic acid (937.5mL), acetic anhydride (62.5mL)) were mixed in a reaction flask (white suspension), stirred at 50 ℃ for reaction, and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 1.2mol) was added and stirred for reaction. After 1.5h, the white suspension turned to a bean curd residue, at which point TLC spots (sampled a little, diluted with THF, DCM/MeOH, 4:1 developed) showed the reaction was complete. And (3) post-treatment: the reaction mixture was diluted with EA, filtered, the filter cake was washed with EA, and dried under vacuum to give 5-bromouracil as a white solid (yield 99.0%, purity 99.4%).
Example 14
Uracil (0.8mol), solvent (glacial acetic acid (889ml), acetic anhydride (111ml)) were mixed in a reaction flask (white suspension), stirred at 60 ℃ for reaction, and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 1.5mol) was added and stirred for reaction. After 1.5h, the white suspension turned to a bean curd residue, at which point TLC spots (sampled a little, diluted with THF, DCM/MeOH, 4:1 developed) showed the reaction was complete. And (3) post-treatment: the reaction mixture was diluted with EA, filtered, the filter cake was washed with EA, and dried under vacuum to give 5-bromouracil as a white solid (yield 99.0%, purity 98.9%).
Example 15
Uracil (0.9mol), solvent (glacial acetic acid (889ml), acetic anhydride (111ml)) were mixed in a reaction flask (white suspension), stirred at 50 ℃ for reaction, added with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 0.45mol), and stirred for reaction. After 1.5h, the white suspension turned to a bean curd residue, at which point TLC spots (sampled a little, diluted with THF, DCM/MeOH, 4:1 developed) showed the reaction was complete. And (3) post-treatment: the reaction mixture was diluted with EA, filtered with suction, and dried in vacuo to give 5-bromouracil as a white solid (yield 99.0%, purity 98.6%).
Comparative example 1
The following operations are carried out with reference to the descriptions in Synthesis, molecular linking and ADME prediction of sodium pyridine and pyridine derivatives as anti-Chemical cancer drugs, journal of Chemical and Pharmaceutical Research, 2(5), 60-66, 2010: 5-bromouracil (250g), N-dimethylaniline (300mL) were mixed in a 2L reaction flask, and SOCl was added dropwise at 40 ℃2(600mL) and the reaction was refluxed for 5h without reaction.
Comparative example 2
5-Bromocluracil (6.0g, 31.4mmol) with PCl5(16.4g, 78.5mmol) was mixed in a reaction flask, dichloromethane (50mL) was added and the reaction mixture was heated toRefluxing and no reaction.
Comparative example 3
5-Bromocluracil (6.0g, 31.4mmol) with PCl5(16.4g, 78.5mmol) was mixed in a reaction flask, chloroform (50mL) was added, and the reaction mixture was heated to reflux without reaction.
Comparative examples 2 to 7
Reference is made to the publication at C-5 of pyrimidine and C-8 of purine nucleosides with 1,3-dibromo-5, 5-dimethylhydatono tetrahedron Letters,53(26), 3333-3336; 2012, 5 reactions were selected with high yields and the results are shown in the following table.
| Substrate | DBH(eq.) | TMSOTf(eq.) | Solvent/temperature (. degree. C.) | Yield (%) |
| 1a | 0.55 | 0.55 | DCM/40 | 98 |
| 1a | 0.55 | 0.55 | DMF/25 | 98 |
| 1a | 0.55 | 0.55 | MeCN/25 | 90 |
| 1a | 0.55 | — | DMF/25 | 95 |
| 1a | 0.55 | — | MeCN/25 | 86 |
The reaction substrate in the table above was replaced with uracil, and comparative examples 1 to 6 of the repeated experiments shown below were performed:
comparative example 2
DBH (1.4g,4.9mmol) was added to CH of uracil (1g,8.9mmol)2Cl2(15 mL). Stirring the reaction mixture at 40 deg.C for 6h, detecting by TLC that the raw material completely reacts, evaporating to remove solvent, adding ethyl acetate (20mL), pulping, vacuum filtering, and vacuum drying at 55 deg.C for 4h to obtain white solid product 0.41g, namely-5-bromouracil (24.1%)
Comparative example 3
DBH (1.4g,4.9mmol) was added to a suspension of uracil (1g,8.9mmol) in DMF (15 mL). The reaction mixture was stirred at room temperature (25 ℃) for 6h, TLC detected that the starting material was completely reacted, the solvent was evaporated, ethyl acetate (20mL) was added and slurried, filtered with suction, and dried at 55 ℃ under vacuum for 4h to give 0.77g of a white solid product, i.e., -5-bromouracil (45.3%).
Comparative example 4
DBH (1.4g,4.9mmol) was added to a suspension of uracil (1g,8.9mmol) in acetonitrile (15 mL). The reaction mixture was stirred at room temperature (25 ℃) for 6h, TLC detected that the starting material reacted completely, the solvent was evaporated to dryness, ethyl acetate (20mL) was added and slurried, filtered with suction, and dried at 55 ℃ under vacuum for 4h to give 0.51g (30.0%) of a white solid product, i.e., -5-bromouracil.
Comparative example 5
DBH (1.4g,4.9mmol), TMSOTf (1.1g,4.9mmol) added to CH of uracil (1g,8.9mmol)2Cl2(15 mL). Stirring the reaction mixture at 40 deg.C for 6h, detecting by TLC that the raw materials completely react, evaporating to remove solvent, adding ethyl acetate (20mL), pulping, vacuum filtering, and vacuum drying at 55 deg.C for 4h to obtain white solid product 0.82g, namely-5-bromouracil (48.2%)
Comparative example 6
DBH (1.4g,4.9mmol), TMSOTf (1.1g,4.9mmol) were added to a suspension of uracil (1g,8.9mmol) in DMF (15 mL). Stirring the reaction mixture at room temperature (25 deg.C) for 6h, detecting by TLC that the raw materials completely react, evaporating to remove solvent, adding ethyl acetate (20mL), pulping, filtering, vacuum drying at 55 deg.C for 4h to obtain white solid product 0.77g, namely-5-bromouracil (45.3%)
Comparative example 7
DBH (1.4g,4.9mmol), TMSOTf (1.1g,4.9mmol) were added to a suspension of uracil (1g,8.9mmol) in acetonitrile (15 mL). The reaction mixture was stirred at room temperature for 6h, TLC detected that the starting material reacted completely, the solvent was evaporated to dryness, ethyl acetate (20mL) was added and slurried, filtered under suction, and dried under vacuum at 55 ℃ for 4h to give 1.10g of a white solid product, i.e., -5-bromouracil (64.7%)
Comparative examples 8 to 19
Comparative examples 7 to 18 shown below were carried out by changing the solvent, temperature and reaction time with reference to the procedure of example 5, and the results are shown in the following table:
Claims (19)
1. a method for preparing a compound represented by the formula 2, which comprises the step of dissolving a compound 1 and PCl in a solvent5Carrying out chlorination reaction to obtain the product,
wherein X is F, Cl, Br or I; the solvent is selected from SOCl2Carbon tetrachloride, 1, 2-dichloroethane and 1,1, 2-trichloroethane.
2. The method of claim 1, wherein the PCl is5And the molar use ratio of the compound 1 is (2.3:1) to (3: 1).
3. The method of claim 2, wherein the PCl is5And the molar use ratio of the compound 1 is (2.5:1) to (2.8: 1).
4. The method according to claim 1, wherein the compound 1 and the solvent are used in a ratio of 0.5mol/L to 2 mol/L.
5. The method according to claim 4, wherein the compound 1 and the solvent are used in a ratio of 0.6mol/L to 1.8 mol/L.
6. The method of claim 1, wherein X is Br.
7. The method of claim 6, further comprising the step of reacting uracil with a brominating agent under the action of an acid or an acid/anhydride; the brominating reagent is 1,3-dibromo-5, 5-dimethylhydantoin; the acid/anhydride refers to a mixture of acid and anhydride; the acid or the acid/anhydride is an organic acid; the acid anhydride is organic acid anhydride;
8. the method according to claim 7, wherein the organic acid is acetic acid and/or propionic acid, and/or the acid anhydride of the acid/acid anhydride is acetic anhydride and/or propionic anhydride.
9. The method according to claim 7, wherein the ratio of the amount of uracil to the amount of acid is 0.8 to 1 mol/L; or the dosage ratio of the uracil to the acid/anhydride is 0.8 mol/L-1 mol/L.
10. The method according to claim 9, wherein the amount ratio of uracil to acid is 0.811 mol/L.
11. The method of claim 9, wherein the ratio of uracil to acid/anhydride is 0.811 mol/L.
12. The method according to claim 7, wherein the molar ratio of the acid to the acid anhydride in the acid/acid anhydride is 1/18-1/8; and/or the reaction temperature is 25-70 ℃.
13. The method according to claim 12, wherein the molar ratio of the acid to the acid anhydride is 1/15-1/10.
14. The method of claim 12, wherein the reaction temperature is 50 ℃ to 60 ℃.
15. The method according to claim 7, wherein the molar amount of the brominating agent is 0.5 to 1.5 times the molar amount of uracil.
16. The method of claim 15, wherein the molar amount of the brominating agent is 0.6 to 1.2 times the molar amount of uracil.
17. The method of claim 7, wherein the reaction further comprises a catalyst, and the catalyst is trimethylsilyl trifluoromethanesulfonate.
18. The method of claim 17, wherein the ratio of the molar amount of the catalyst to the molar amount of the brominating reagent is (0.8-1.2): 1.
19. the method of claim 17, wherein the molar amount of catalyst to the molar amount of brominating reagent is 1: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611073880.0A CN108117523B (en) | 2016-11-29 | 2016-11-29 | Preparation method of halogenated uracil compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611073880.0A CN108117523B (en) | 2016-11-29 | 2016-11-29 | Preparation method of halogenated uracil compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108117523A CN108117523A (en) | 2018-06-05 |
| CN108117523B true CN108117523B (en) | 2021-05-07 |
Family
ID=62225806
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611073880.0A Active CN108117523B (en) | 2016-11-29 | 2016-11-29 | Preparation method of halogenated uracil compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108117523B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109516958B (en) * | 2018-12-26 | 2020-12-08 | 杭州布朗生物医药科技有限公司 | Preparation method of 2, 4-dichloropyrimidine and derivatives thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101511359A (en) * | 2006-09-08 | 2009-08-19 | 霍夫曼-拉罗奇有限公司 | Benzotriazole kinase modulators |
| CN104788389A (en) * | 2015-04-09 | 2015-07-22 | 新乡市创新生物科技有限公司 | Preparation method of 5-bromouracil |
| WO2016022460A1 (en) * | 2014-08-03 | 2016-02-11 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Potent dual brd4-kinase inhibitors as cancer therapeutics |
-
2016
- 2016-11-29 CN CN201611073880.0A patent/CN108117523B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101511359A (en) * | 2006-09-08 | 2009-08-19 | 霍夫曼-拉罗奇有限公司 | Benzotriazole kinase modulators |
| WO2016022460A1 (en) * | 2014-08-03 | 2016-02-11 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Potent dual brd4-kinase inhibitors as cancer therapeutics |
| CN104788389A (en) * | 2015-04-09 | 2015-07-22 | 新乡市创新生物科技有限公司 | Preparation method of 5-bromouracil |
Non-Patent Citations (4)
| Title |
|---|
| 3-溴-4-氟硝基苯的合成;王林等;《精细石油化工》;20121118;第29卷(第6期);第1页右栏第1.2节，第2页表1的注释 * |
| 6-（1-溴乙基）-4-氯-5-氟嘧啶的合成工艺研究;李雪妍等;《精细化工中间体》;20130228;第43卷(第1期);第25页反应路线图，第26页左栏第2.2.1小节 * |
| Bromination at C-5 of pyrimidine and C-8 of purine nucleosides with 1,3-dibromo-5,5-dimethylhydantoin;Ramanjaneyulu Rayala et al.;《Tetrahedron Letters》;20120424;第53卷;第3334页Scheme 1，Table 1 Entry 3 * |
| 李雪妍等.6-（1-溴乙基）-4-氯-5-氟嘧啶的合成工艺研究.《精细化工中间体》.2013,第43卷(第1期),第25页反应路线图，第26页左栏第2.2.1小节. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108117523A (en) | 2018-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106749194B (en) | A kind of preparation method for pyrimidine | |
| CN105753867B (en) | A kind of preparation method of improved AVM hereinafter Batan sodium midbody compound | |
| CN107235959A (en) | A kind of novel method for synthesizing for preparing cancer therapy drug Niraparib | |
| EP3912978A1 (en) | Preparation method for morpholinquinazoline compound and midbody thereof | |
| CN104945383B (en) | Hold in the palm his preparation method of pyrrole department | |
| CN104844602B (en) | A kind of preparation method of Li Gelieting | |
| CN108117523B (en) | Preparation method of halogenated uracil compound | |
| CN107118215B (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediate | |
| CN102391288B (en) | Preparation methods of cefpirome intermediate and cefpirome | |
| CN108503597A (en) | A kind of high efficiency preparation method of Gefitinib | |
| CN103408487B (en) | Refining method of gimeracil | |
| CN110078766A (en) | Phosphonylation benzimidazole and compound of isobioquin group and preparation method thereof | |
| JPS6247193B2 (en) | ||
| CN112442032B (en) | Preparation method of medicine intermediate benzopyrimidinoquinolinone derivative | |
| CN108997349A (en) | A kind of preparation method of the epinastine in relation to substance | |
| CN106854177A (en) | A kind of preparation method of the formaldehyde of 6 chlorine, 4 pyridone 3 | |
| RU2630700C2 (en) | METHODS FOR OBTAINING 5-[2-[7-(TRIFLUOROMETHYL)-5-[4-(TRIFLUOROMETHYL)PHENYL]PYRAZOLO[1,5-a]PYRIMIDINE-3-YL]ETHINYL]-2-PYRIDINAMINE | |
| CN111057052B (en) | Method for preparing minodronic acid intermediate 2- (imidazo [1, 2-alpha ] pyridine-3-yl) acetate compound | |
| CN114560845B (en) | Crystal form alpha of quinoline compound, and preparation method and application thereof | |
| CN109400507A (en) | The synthesis of Ailamode intermediate impurities | |
| CN110551065A (en) | Deuterated Lucistanib compound and application thereof | |
| CN109956940A (en) | A kind of method that the rich former times cloth intermediate cyano reaction of pa prepares heteroaryl cyanide | |
| CN108658931A (en) | A kind of preparation method of Raltitrexed key intermediate | |
| CN110922402B (en) | C-3 iodo-indolizine compound and preparation method thereof | |
| CN115850244B (en) | Preparation method of topiroxostat |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CB03 | Change of inventor or designer information |
Inventor after: Ma Qingtong Inventor after: Chen Xudong Inventor after: Shan Xiaoyan Inventor after: Chen Yu Inventor before: Ma Qingtong Inventor before: Shan Xiaoyan Inventor before: Chen Xudong Inventor before: Chen Yu |
|
| CB03 | Change of inventor or designer information | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 200040 No. 1320 West Beijing Road, Shanghai, Jingan District Patentee after: Shanghai Pharmaceutical Industry Research Institute Co.,Ltd. Patentee after: China Pharmaceutical Industry Research Institute Co.,Ltd. Address before: 200040 No. 1320 West Beijing Road, Shanghai, Jingan District Patentee before: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY Patentee before: CHINA STATE INSTITUTE OF PHARMACEUTICAL INDUSTRY |
|
| CP01 | Change in the name or title of a patent holder |