CN108117524B - The preparation method of 5-bromouracil - Google Patents
The preparation method of 5-bromouracil Download PDFInfo
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- CN108117524B CN108117524B CN201611073877.9A CN201611073877A CN108117524B CN 108117524 B CN108117524 B CN 108117524B CN 201611073877 A CN201611073877 A CN 201611073877A CN 108117524 B CN108117524 B CN 108117524B
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- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims description 17
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000002253 acid Substances 0.000 claims abstract description 26
- 229940035893 uracil Drugs 0.000 claims abstract description 26
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 16
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical group CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 150000007524 organic acids Chemical class 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- 125000004018 acid anhydride group Chemical group 0.000 claims description 8
- 238000010790 dilution Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 5
- 235000013527 bean curd Nutrition 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000007547 defect Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000002212 purine nucleoside Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
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
本发明公开了一种5‑溴尿嘧啶的制备方法，该方法以尿嘧啶为原料，在酸或酸/酸酐的作用下，将尿嘧啶与溴化试剂进行反应，即可；所述溴化试剂为1,3‑二溴‑5,5‑二甲基乙内酰脲；所述酸/酸酐是指酸和酸酐的混合物；所述酸或酸酐/酸中的酸均为有机酸；所述酸酐为有机酸酸酐； The invention discloses a method for preparing 5-bromouracil. The method uses uracil as a raw material, and under the action of an acid or an acid/acid anhydride, reacts uracil with a brominating reagent, and that is enough; The reagent is 1,3-dibromo-5,5-dimethylhydantoin; the acid/acid anhydride refers to the mixture of acid and acid anhydride; the acid in the acid or acid anhydride/acid is an organic acid; The acid anhydride is an organic acid anhydride; 
Description
Technical Field
The invention relates to a preparation method of 5-bromouracil.
Background
5-bromouracil is an important raw material for preparing palbociclib, and the raw material is commercially available but has higher price.
In the prior art, uracil is used as a raw material, and a plurality of methods for preparing 5-bromouracil exist, but certain defects exist, and are specifically shown in the following table:
the preparation methods of the 6 reported 5-bromouracil have the defects of expensive raw materials, low yield, complex operation, difficult post-treatment, high cost, high requirement on equipment and the like.
Bromine at C-5of pyridine and C-8of purine nucleosides with 1,3-dibromo-5,5-dimethylhydantoin tetrahedron Letters,53(26), 3333-3336; 2012 describes the reaction as shown below:
when the reaction solvent is DMF, DCM or acetonitrile, the temperature is mild, the yield is high and can reach 98 percent, but the use of the expensive and dangerous Me3SiSO3CF3The yield is 86-95% when the catalyst is not used.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects of expensive raw materials, low yield, complex operation, difficult post-treatment, high cost, high equipment requirement and the like in the existing preparation method of 5-bromouracil. The preparation method takes uracil as a starting material, has simple and convenient process, short production period, higher yield and lower cost, and can be suitable for industrial production.
The invention provides a preparation method of 5-bromouracil, which comprises the following steps of reacting uracil with a brominating 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 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 0.5-1.5, 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 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.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method takes uracil as a starting material, has simple and convenient process, short production period, higher yield and lower cost, and can be suitable for industrial production.
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
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 afford 5-bromouracil as a white solid (168.8g, 99.9% yield, 99.3% purity).
Examples 2 to 8
The following examples 2 to 8 were carried out by changing the solvent, temperature and reaction time according to the procedure of example 1, and the results are shown in the following table:
example 9
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 10
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 11
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 examples 1 to 6
Reference is made to the publication at C-5of pyrimidine and C-8of 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.
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 1
DBH (1.4g,4.9mmol) was added to CH of uracil (1g,8.9mmol)2Cl2(15mL) ofAnd (4) suspending in a liquid. Stirring the reaction mixture at 40 deg.C for 6h, detecting by TLC that the raw material is completely reacted, evaporating to remove solvent, adding ethyl acetate (20mL), pulping, filtering, vacuum drying at 55 deg.C for 4h to obtain white solid product, i.e. 5-bromouracil 0.41g (24.1%)
Comparative example 2
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 a white solid product, i.e., 0.77g of 5-bromouracil (yield 45.3%).
Comparative example 3
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 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 a white solid product, i.e., 0.51g of 5-bromouracil (30.0% yield).
Comparative example 4
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 ℃ for 6h, detecting by TLC that the raw materials completely react, evaporating the solvent to dryness, adding ethyl acetate (20mL), pulping, filtering, and vacuum drying at 55 ℃ for 4h to obtain a white solid product, namely 0.82g of 5-bromouracil (yield is 48.2%)
Comparative example 5
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, namely 5-bromouracil 0.77g (45.3%)
Comparative example 6
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, slurried, filtered under suction, and vacuum dried at 55 ℃ for 4h to give 1.10g of a white solid product, i.e., 5-bromouracil (yield 64.7%)
Comparative examples 7 to 18
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 1, and the results are shown in the following table:
Claims (6)
1. a preparation method of 5-bromouracil is characterized by comprising the following steps of reacting uracil with a brominating agent under the action of acid or acid/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/acid anhydride is organic acid; the acid anhydride is organic acid anhydride; the molar amount of the bromination reagent is 0.6-1.2 of that of uracil; the organic acid is acetic acid; the acid anhydride in the acid/acid anhydride is acetic anhydride;
the dosage ratio of the uracil to the acid is 0.8 mol/L-1 mol/L; or the dosage ratio of the uracil to the acid/anhydride is 0.8 mol/L-1 mol/L;
in the acid/anhydride, the molar ratio of the acid to the anhydride in the acid/anhydride is 1/18-1/8;
the reaction temperature is 25-70 ℃;
2. the method according to claim 1, wherein the amount ratio of uracil to acid is 0.811 mol/L; and/or the dosage ratio of the uracil to the acid/anhydride is 0.811 mol/L.
3. The method according to claim 1, wherein the molar ratio of the acid to the acid anhydride in the acid/acid anhydride is 1/15 to 1/10.
4. The method of claim 1, wherein the reaction temperature is 50 ℃ to 60 ℃.
5. The method of claim 1, wherein the time of the reaction is monitored by HPLC, TLC or NMR.
6. The production method according to claim 1, wherein a post-treatment is performed after the reaction is completed; the post-treatment comprises dilution, suction filtration and drying.
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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 |
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- 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 |
|---|
| 3-溴-4-氟硝基苯的合成;王林，等;《精细石油化工》;20121130;第29卷(第6期);1-4 * |
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