CN108117524A - The preparation method of 5-bromouracil - Google Patents
The preparation method of 5-bromouracil Download PDFInfo
- Publication number
- CN108117524A CN108117524A CN201611073877.9A CN201611073877A CN108117524A CN 108117524 A CN108117524 A CN 108117524A CN 201611073877 A CN201611073877 A CN 201611073877A CN 108117524 A CN108117524 A CN 108117524A
- Authority
- CN
- China
- Prior art keywords
- acid
- preparation
- acid anhydrides
- reaction
- uracil
- 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.)
- Granted
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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of 5 bromouracil, under the action of acid or acid/acid anhydrides, uracil and bromide reagent are reacted using uracil as raw material for this method, you can；The bromide reagent is 1,3 dibromo, 5,5 dimethyl hydantoin；Acid/the acid anhydrides refers to the mixture of acid and acid anhydrides；Acid in the acid or acid anhydrides/acid is organic acid；The acid anhydrides is organic acid acid anhydrides；
Description
Technical field
The present invention relates to the preparation methods of 5-bromouracil.
Background technology
5-bromouracil is to prepare the important source material that pa wins former times cloth, which has a commercial offers, but higher price.
In the prior art, using uracil as raw material, there are many method for preparing 5-bromouracil, but all there is certain lack
It falls into, specifically see the table below shown：
In the preparation method for the 6 kinds of 5-bromouracil reported above there are expensive starting materials, low yield, it is complicated for operation, after
The defects of processing is difficult, of high cost, high to equipment requirement.
Bromination at C-5of pyrimidine and C-8of purine nucleosides with 1,
3-dibromo-5,5-dimethylhydantoinTetrahedron Letters,53(26),3333-3336；Remember in 2012
Reaction as follows is carried：
The reaction dissolvent be DMF, DCM or acetonitrile when, temperature is milder, high income, can reach 98%, but use price compared with
For the Me of expensive and great danger3SiSO3CF3For catalyst, without using yield during catalyst 86%~95%.
The content of the invention
The technical problems to be solved by the invention are there is original in the preparation method of existing 5-bromouracil to overcome
Expect costliness, low yield, it is complicated for operation, post-process the defects of difficult, of high cost, high to equipment requirement, and provide a kind of 5- bromines
The preparation method of uracil.The preparation method is using uracil as starting material, and simple process is with short production cycle, yield it is higher and
Cost decreases, and may be adapted to industrialized production.
The present invention provides a kind of preparation method of 5-bromouracil, it includes following steps, in acid or the work of acid/acid anhydrides
Under, uracil and bromide reagent are reacted, you can；The bromide reagent is acyl in bis- bromo- 5,5- dimethyl second of 1,3-
Urea (DBH)；Acid/the acid anhydrides refers to the mixture of acid and acid anhydrides；The acid is organic acid；The acid anhydrides is organic acid acid anhydrides；
Wherein, in the preparation method, the acid had not only made catalyst but also had made solvent use in the present invention, and described has
Machine acid can be the organic acid suitable for such reaction, acetic acid and/or propionic acid specifically preferred according to the invention, the acetic acid and the propionic acid
For acetic anhydride and anhydrous propionic acid；
In the preparation method, acid anhydrides in the acid/acid anhydrides can be to have for moisture during absorbing reaction
Machine acid acid anhydrides, acetic anhydride and/or propionic andydride specifically preferred according to the invention；
Wherein, in the preparation method, the amount ratio or the uracil of the uracil and the acid with it is described
The amount ratio of acid/acid anhydrides can be this field such reaction conventional amount used ratio, 0.8mol/L~1mol/L specifically preferred according to the invention,
Further preferred 0.811mol/L.
In the acid/acid anhydrides, the mole dosage ratio of described sour and described acid anhydrides is 1/18~1/8, preferably 1/15~1/
10.Wherein, in the preparation method, the temperature of the reaction can be the ordinary temperature of such reaction of this field, and the present invention is special
Not preferably 25 DEG C~70 DEG C, further preferred 50 DEG C~60 DEG C.
Wherein, in the preparation method, the mole dosage of the bromide reagent can be the normal of such reaction of this field
Dosage is advised, it is specifically preferred according to the invention for 0.5~1.5, preferably the 0.6~1.2 of uracil dosage.
Wherein, in the preparation method, the reaction time can be used in this field common detection methods (such as
HPLC, TLC or NMR) it is monitored, the present invention preferably TLC methods are monitored.
Wherein, it is described also to be post-processed after reaction in the preparation method；The post processing is preferably dilute
It releases, filter and dries.Wherein, it is described to dilute the conventional dilution mode that this field can be used, preferably it is diluted with ethyl acetate；
The suction filtration, the dry ordinary operation mode that this field can be used.
Wherein, in the preparation method, the reaction can also carry out under catalyst action, and the catalyst can be should
The conventional catalyst of class reaction, Trimethylsilyl trifluoromethanesulfonate (TMSOTf) specifically preferred according to the invention；The catalyst rubs
Your dosage and the mole dosage ratio of bromide reagent can be the conventional amount used of such reaction of this field, specifically preferred according to the invention 0.8
~1.2, more preferable 1:1.
On the basis of common knowledge of the art, above-mentioned each optimum condition can be combined to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is：The preparation method is using uracil as starting material, simple process, production week
Phase is short, and yield is higher and cost decreases, and may be adapted to industrialized production.
Specific embodiment
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a scope.The experimental method of actual conditions is not specified in the following example, according to conventional methods and conditions or according to business
Product specification selects.
Embodiment 1
Uracil (100g, 892.1mmol), solvent (glacial acetic acid (1L), acetic anhydride (100mL)) are mixed in reaction bulb
(white suspension), 50 DEG C are stirred to react, addition 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 153g,
535.3mmol), it is stirred to react.After 1.5h, white suspension becomes bean curd scoriform, and (sampling is a little, addition for TLC contact plates at this time
THF dilutes, DCM/MeOH, and 4:1 expansion), the reaction was complete for display.Post processing：By reaction mixture addition EA dilutions, filter, very
Sky is dry, obtains white solid, i.e. 5-bromouracil (168.8g, yield 99.9%, purity 99.3%).
Embodiment 2~8
With reference to the operation of embodiment 1, change solvent, temperature, reaction time, carry out embodiment 2~8 as follows, as a result
It is as shown in the table：
Embodiment 9
Uracil (1mol), solvent (glacial acetic acid (937.5mL), acetic anhydride (62.5mL)) are mixed in reaction bulb (white
Suspension), 50 DEG C are stirred to react, and addition 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 1.2mol) is stirred to react.
After 1.5h, white suspension becomes bean curd scoriform, and TLC contact plates (sample a little, addition THF dilutions, DCM/MeOH, 4 at this time:1 exhibition
Open), the reaction was complete for display.Post processing：By reaction mixture addition EA dilutions, filter, filter cake is washed with EA, is dried in vacuo, is obtained
To white solid, i.e. 5-bromouracil (yield 99.0%, purity 99.4%).
Embodiment 10
Uracil (0.8mol), solvent (glacial acetic acid (889ml), acetic anhydride (111ml)) are mixed in reaction bulb (white mixed
Suspension), 60 DEG C are stirred to react, and addition 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 1.5mol) is stirred to react.
After 1.5h, white suspension becomes bean curd scoriform, and TLC contact plates (sample a little, addition THF dilutions, DCM/MeOH, 4 at this time:1 exhibition
Open), the reaction was complete for display.Post processing：By reaction mixture addition EA dilutions, filter, filter cake is washed with EA, is dried in vacuo, is obtained
To white solid, i.e. 5-bromouracil (yield 99.0%, purity 98.9%).
Embodiment 11
Uracil (0.9mol), solvent (glacial acetic acid (889ml), acetic anhydride (111ml)) are mixed in reaction bulb (white mixed
Suspension), 50 DEG C are stirred to react, and addition 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 0.45mol) is stirred to react.
After 1.5h, white suspension becomes bean curd scoriform, and TLC contact plates (sample a little, addition THF dilutions, DCM/MeOH, 4 at this time:1 exhibition
Open), the reaction was complete for display.Post processing：By reaction mixture addition EA dilutions, filter, vacuum drying obtains white solid, i.e.,
5-bromouracil (yield 99.0%, purity 98.6%).
Comparative example 1~6
Reference literature Bromination at C-5of pyrimidine and C-8of purine nucleosides
with 1,3-dibromo-5,5-dimethylhydantoinTetrahedron Letters,53(26),3333-3336；
Experiment content and data recorded in 2012 select 5 higher reactions of yield, as shown in the table.
Reaction substrate in upper table is replaced with into uracil, carries out repetition Experimental comparison example 1~6 as follows：
Comparative example 1
DBH (1.4g, 4.9mmol) is added to the CH of uracil (1g, 8.9mmol)2Cl2In the suspension of (15mL).Reaction
Mixture stirs 6h at 40 DEG C, and the reaction was complete for TLC detections raw material, and solvent evaporated, addition ethyl acetate (20mL) is beaten, and is taken out
It filters, is dried in vacuo 4h at 55 DEG C, obtains white solid product, i.e. 5-bromouracil 0.41g (24.1%)
Comparative example 2
DBH (1.4g, 4.9mmol) is added in the suspension of the DMF (15mL) of uracil (1g, 8.9mmol).Reaction is mixed
It closing object and 6h is stirred under room temperature (25 DEG C), the reaction was complete for TLC detections raw material, and solvent evaporated, addition ethyl acetate (20mL) is beaten,
It filters, is dried in vacuo 4h at 55 DEG C, obtains white solid product, i.e. 5-bromouracil 0.77g (yield 45.3%).
Comparative example 3
DBH (1.4g, 4.9mmol) is added in the suspension of the acetonitrile (15mL) of uracil (1g, 8.9mmol).Reaction
Mixture stirs 6h under room temperature (25 DEG C), and the reaction was complete for TLC detections raw material, and solvent evaporated, addition ethyl acetate (20mL) is beaten
Slurry filters, and is dried in vacuo 4h at 55 DEG C, obtains white solid product, i.e. 5-bromouracil 0.51g (yield 30.0%).
Comparative example 4
DBH (1.4g, 4.9mmol), TMSOTf (1.1g, 4.9mmol) are added to the CH of uracil (1g, 8.9mmol)2Cl2
In the suspension of (15mL).Reaction mixture stirs 6h at 40 DEG C, and the reaction was complete for TLC detections raw material, and solvent evaporated adds second
Acetoacetic ester (20mL) is beaten, and is filtered, and 4h is dried in vacuo at 55 DEG C, obtains white solid product, i.e. 5-bromouracil 0.82g (is received
48.2%) rate is
Comparative example 5
DBH (1.4g, 4.9mmol), TMSOTf (1.1g, 4.9mmol) are added to the DMF of uracil (1g, 8.9mmol)
In the suspension of (15mL).Reaction mixture stirs 6h under room temperature (25 DEG C), and the reaction was complete for TLC detections raw material, solvent evaporated,
It adds ethyl acetate (20mL) to be beaten, filter, be dried in vacuo 4h at 55 DEG C, obtain white solid product, i.e. 5-bromouracil
0.77g (45.3%)
Comparative example 6
DBH (1.4g, 4.9mmol), TMSOTf (1.1g, 4.9mmol) are added to the acetonitrile of uracil (1g, 8.9mmol)
In the suspension of (15mL).6h is stirred at room temperature in reaction mixture, and the reaction was complete for TLC detections raw material, and solvent evaporated adds second
Acetoacetic ester (20mL) is beaten, and is filtered, and 4h is dried in vacuo at 55 DEG C, obtains white solid product 1.10g, i.e. 5-bromouracil (is received
64.7%) rate is
Comparative example 7~18
With reference to the operation of embodiment 1, change solvent, temperature, reaction time, carry out comparative example 7~18 as follows, as a result
It is as shown in the table：
Claims (10)
1. a kind of preparation method of 5-bromouracil, which is characterized in that it comprises the steps of, under the action of acid or acid/acid anhydrides,
Uracil and bromide reagent are reacted, you can；The bromide reagent is bis- bromo- 5,5- dimethyl hydantoins of 1,3-；Institute
State the mixture that acid/acid anhydrides refers to acid and acid anhydrides；Acid in the acid or acid/acid anhydrides is organic acid；The acid anhydrides is organic
Acid anhydrides；
2. preparation method as described in claim 1, which is characterized in that the organic acid is acetic acid and/or propionic acid；And/or
Acid anhydrides in the acid/acid anhydrides is acetic anhydride and/or propionic andydride.
3. preparation method as described in claim 1, which is characterized in that the amount ratio 0.8mol/L of the uracil and the acid
~1mol/L, preferably 0.811mol/L；Or amount ratio 0.8mol/L~1mol/L of the uracil and the acid/acid anhydrides, it is excellent
Select 0.811mol/L.
4. preparation method as described in claim 1, which is characterized in that described in the acid/acid anhydrides in the acid/acid anhydrides
The mole dosage ratio of sour and described acid anhydrides is 1/18~1/8, preferably 1/15~1/10.
5. preparation method as described in claim 1, which is characterized in that the temperature of the reaction for 25 DEG C~70 DEG C, preferably 50
DEG C~60 DEG C.
6. preparation method as described in claim 1, which is characterized in that the mole dosage of the bromide reagent is uracil mole
The 0.5~1.5 of dosage, preferably 0.6~1.2.
7. preparation method as described in claim 1, which is characterized in that the time of the reaction using HPLC, TLC or NMR into
Row monitoring.
8. preparation method as described in claim 1, which is characterized in that post-processed described after reaction；After described
Processing includes dilution, suction filtration and drying.
9. preparation method as described in claim 1, which is characterized in that the reaction carries out under catalyst action, described to urge
Agent is Trimethylsilyl trifluoromethanesulfonate.
10. preparation method as claimed in claim 9, which is characterized in that the mole dosage of the catalyst and bromide reagent
Mole dosage ratio is 0.8~1.2, preferably 1:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611073877.9A CN108117524B (en) | 2016-11-29 | 2016-11-29 | Preparation method of 5-bromouracil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611073877.9A CN108117524B (en) | 2016-11-29 | 2016-11-29 | Preparation method of 5-bromouracil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108117524A true CN108117524A (en) | 2018-06-05 |
| CN108117524B CN108117524B (en) | 2021-06-25 |
Family
ID=62226857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611073877.9A Active CN108117524B (en) | 2016-11-29 | 2016-11-29 | Preparation method of 5-bromouracil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108117524B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57130996A (en) * | 1981-02-04 | 1982-08-13 | Yamasa Shoyu Co Ltd | Preparation of 5-bromouracil nucleoside |
| CN101993447A (en) * | 2009-08-26 | 2011-03-30 | 浙江华海药业股份有限公司 | Method for synthesizing Prasugrel artificially |
| 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 |
-
2016
- 2016-11-29 CN CN201611073877.9A patent/CN108117524B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57130996A (en) * | 1981-02-04 | 1982-08-13 | Yamasa Shoyu Co Ltd | Preparation of 5-bromouracil nucleoside |
| CN101993447A (en) * | 2009-08-26 | 2011-03-30 | 浙江华海药业股份有限公司 | Method for synthesizing Prasugrel artificially |
| 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 (1)
| Title |
|---|
| 王林，等: "3-溴-4-氟硝基苯的合成", 《精细石油化工》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108117524B (en) | 2021-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103087116A (en) | Sucralose preparation method | |
| CN103755603A (en) | Preparation method for 2-amino sulfonyl-4-methylsalfonamido methyl benzoic acid methyl ester | |
| CN108117524A (en) | The preparation method of 5-bromouracil | |
| CN112939969B (en) | Preparation method of 2-acetyl-1, 10-phenanthroline | |
| CN101768165B (en) | Ellagic acid preparation method employing tara powder | |
| CN106986809B (en) | Synthesis method of 5-bromo-6-chloro-3-indoxyl | |
| CN105367508A (en) | Preparation method of parecoxib sodium synthesis technology impurities | |
| CN113336764A (en) | Bipyridine ligand with axial chirality and synthetic method thereof | |
| CN110698326B (en) | Synthesis method of 1-hydroxypyrene | |
| CN112679430B (en) | Method for preparing isoquinolinones compound | |
| US11773047B2 (en) | Method for separating trans isomeric crocetin from cis isomeric crocetin | |
| CN108117523A (en) | The preparation method of halo uracil class compound | |
| CN103043721A (en) | Method for preparing vanadyl sulfate | |
| CN106699723B (en) | A kind of preparation method of 15- crown ether -5 | |
| CN103819526B (en) | The preparation method of tea saponin stearate tensio-active agent and product | |
| CN106316937A (en) | Preparation method of fluazinam | |
| CN108117550B (en) | Preparation method of pyrido [2,3-d ] pyrimidine compound | |
| CN109369759A (en) | The synthetic method of 17 beta-cyano steroidal compounds of hydrocortisone intermediate | |
| CN105348288B (en) | A kind of synthetic method of 5,10 indoline [3,2 b] Benzazole compounds | |
| CN113292506B (en) | Preparation method of 2-amino-4, 6-dichloro-5-nitropyrimidine | |
| CN115850244B (en) | Preparation method of topiroxostat | |
| CN113527137B (en) | Preparation method of trifloxystrobin characteristic impurities | |
| CN108341770A (en) | A kind of preparation method of Sorafenib compound | |
| CN109320433B (en) | Preparation method of 4-trifluoromethyl benzonitrile | |
| CN108484497B (en) | Synthetic method of 3-amino-7-chloroquinoline |
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 |