CN102702114A - Method for preparing nitro orotic acid - Google Patents
Method for preparing nitro orotic acid Download PDFInfo
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- CN102702114A CN102702114A CN2012101736672A CN201210173667A CN102702114A CN 102702114 A CN102702114 A CN 102702114A CN 2012101736672 A CN2012101736672 A CN 2012101736672A CN 201210173667 A CN201210173667 A CN 201210173667A CN 102702114 A CN102702114 A CN 102702114A
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- methyl uracil
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- temperature
- acid
- organic solvent
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- 238000000034 method Methods 0.000 title claims abstract description 23
- PXQPEWDEAKTCGB-UHFFFAOYSA-N vitamin B13 Natural products OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 title abstract description 6
- -1 nitro orotic acid Chemical compound 0.000 title abstract description 5
- 229960005010 orotic acid Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 7
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims abstract description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 3
- SHVCSCWHWMSGTE-UHFFFAOYSA-N 6-methyluracil Chemical compound CC1=CC(=O)NC(=O)N1 SHVCSCWHWMSGTE-UHFFFAOYSA-N 0.000 claims description 34
- OPGJGRWULGFTOS-UHFFFAOYSA-N 5-nitro-2,4-dioxo-1h-pyrimidine-6-carboxylic acid Chemical compound OC(=O)C=1NC(=O)NC(=O)C=1[N+]([O-])=O OPGJGRWULGFTOS-UHFFFAOYSA-N 0.000 claims description 24
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 20
- 229910017604 nitric acid Inorganic materials 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 14
- LIVYMRJSNFHYEN-UHFFFAOYSA-N 6-methyl-5-nitro-1h-pyrimidine-2,4-dione Chemical compound CC=1NC(=O)NC(=O)C=1[N+]([O-])=O LIVYMRJSNFHYEN-UHFFFAOYSA-N 0.000 claims description 13
- 238000006396 nitration reaction Methods 0.000 claims description 13
- 230000001590 oxidative effect Effects 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 abstract 1
- 238000007796 conventional method Methods 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000010792 warming Methods 0.000 description 8
- 238000004064 recycling Methods 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 2
- 238000002715 modification method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- NOHUXXDTQJPXSB-UHFFFAOYSA-N 2-acetyloxybenzoic acid;2-[[2-[bis(2-hydroxyethyl)amino]-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-6-yl]-(2-hydroxyethyl)amino]ethanol Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 NOHUXXDTQJPXSB-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 229940003558 aggrenox Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing nitro orotic acid, and belongs to the field of chemical synthesis. According to the method, the conventional method for preparing the nitro orotic acid is improved. The method is characterized in that the nitro orotic acid (III) is obtained by performing nitratlon reaction of 6-methyl urea pyrimidine (I) and subsequent oxidation reaction of 5-nitryl-6-methyl urea pyrimidine (II) at the temperature of between 50 and 80 DEG C in the presence of a specific organic solvent and a catalyst, wherein the organic solvent is selected from at least one of chloroform, dichloroethane, dichloromethane, n-pentane, normal hexane or normal heptane; and the catalyst is acid, and preferably is concentrated sulfuric acid. By the method, the reaction can be performed stably at the temperature of between 50 and 80 DEG C, so that risk of a production process is reduced greatly, and the method has the great advantage in the aspect of safety. In addition, the product is high in purity, so that the purification coat is reduced, and the yield of the process is improved.
Description
Technical field
The present invention relates to a kind of preparation method of compound, particularly a kind of method for preparing nitroorotic acid.Belong to the field of chemical synthesis.
Background technology
Nitroorotic acid is the key intermediate of synthetic DP, and DP is the precursor of synthetic Persantin and Aggrenox.
Several kinds of methods that prepare nitroorotic acid known in the state of the art:
Nitroorotic acid can be by the nitration reaction preparation of vitamin B13, the report at initial stage (M.Bachstez, Ber.dtsch.chem.Ges.63; 1930,1000 and H.Biltz, Ann 456; 1924,165) show that this reaction yield is lower, though (CN 101812023) such as the Luo Erfu of Boehringer Ingelheim company are optimized this reaction; Reaction yield has been brought up to 90%, but because raw materials cost is higher, this method is not used on a large scale in industry at present.
F.G.Fshcher etc. (Ann.572,1951,217) have reported by 4-methyl-2-deracil and have prepared nitroorotic acid sylvite as starting raw material that yield is about 50-55%.
Nitroorotic acid also can be by oxidizing reaction preparation (R.Behrend, Ann.251,1889 of the nitration reaction of 6-methyl uracil and follow-up 5-nitro-6-methyl uracil; 238 and H.Biltz, Ann.413,1916; 110 and Takehiko; US5389641,24), this is the commercial run of present scale operation nitroorotic acid.
This commercial run becomes 5-nitro-6-methyl uracil owing to nitric acid and 6-methyl uracil are earlier nitrated; Slowly be warming up to 110 ℃ of 5-nitro-6-methyl uracils again and carry out oxidizing reaction; Emit great amount of heat in the reaction process; If controlled temperature well, reaction system has the danger of heavy explosion.
Summary of the invention
The objective of the invention is to overcome the problem that current mass preparation nitroorotic acid is produced, proposed a kind of modification method for preparing nitroorotic acid, adopt this method to carry out the security of scale operation thereby improved.
The preparation method of a kind of nitroorotic acid of the present invention is characterized in that obtaining nitroorotic acid (III) through the oxidizing reaction of the nitration reaction of 6-methyl uracil (I) and follow-up 5-nitro-6-methyl uracil (II),
Described nitration reaction is under 50-80 ℃ temperature, in the presence of specific organic solvent and catalyzer, with concentrated nitric acid (nitrosonitric acid) with 6-methyl uracil (I) nitrated be 5-nitro-6-methyl uracil (II);
Described oxidizing reaction is under 50-80 ℃ temperature, in the presence of specific organic solvent and catalyzer, 5-nitro-6-methyl uracil (II) is oxidized to nitroorotic acid (III);
Wherein, to be selected from chloroform, ethylene dichloride, methylene dichloride, Skellysolve A, normal hexane or normal heptane wherein at least a for described organic solvent;
Wherein, described catalyzer is a kind of acid.
Wherein, the purpose of the existence of this specific solvent be through the condensing reflux of this solvent and the time remove the heat that reaction is put, thereby the danger of avoiding reaction system to blast.
In the present invention, preferred, the nitration reaction of described 6-methyl uracil and follow-up oxidizing reaction are carried out in same system simultaneously.
In the present invention, preferred, the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction are under 55 ℃ temperature, to carry out.
In the present invention, preferred, in the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction, concentrated nitric acid is dropwise to join to contain in 6-methyl uracil and specific organic solvent and the mixture of catalysts; After dropwising, stirred 30-60 hour, stop heating after reaction is accomplished, in system, add entry 50-80 ℃ temperature refluxed; Keep system temperature to be no more than 35 ℃, layering, water layer is cooled to 1-5 ℃; Suction filtration after this temperature keeps 3 hours, drying obtains product.
In the present invention, preferred, the mol ratio of 6-methyl uracil and concentrated nitric acid is 1: 5-14, the mol ratio of preferred 6-methyl uracil and concentrated nitric acid is 1: 12.
In the present invention, preferred, described catalyzer is the vitriol oil.
Preferably, the mol ratio of the vitriol oil and nitrosonitric acid is 1: 3 to 1: 40, and more preferably, the ratio of the vitriol oil and concentrated nitric acid is 1: 7.7.
In the present invention, preferred, the mol ratio of the 6-methyl uracil and the vitriol oil is 1: 0.3-3.
In the present invention, preferred, 6-methyl uracil and specific organic solvent and mol ratio be 1: 1-30, preferred, the mol ratio of 6-methyl uracil and organic solvent is 1: 17.7.
Adopt modification method of the present invention to solve the associated problem in the current large-scale production process.
The most important thing is; The invention solves the risk of reaction system bumping even blast; This is because the present invention has changed the existence of the vitriol oil and specific organic solvent in feed way and the reaction system of 6-methyl uracil and nitric acid in 6-methyl uracil nitration reaction and the follow-up oxidizing reaction; Make this reaction under 50-80 ℃ temperature, steadily to carry out, greatly reduce the danger in the production technique, aspect security, have very big advantage.
The productive rate of product (75-85%) is close with prior art, but purity is very high, has reduced the purifying cost, has improved the earning rate of this technology.
Present method is after reaction is accomplished in addition, and nitroorotic acid can be separated with free acid form, thereby has avoided additional processing steps.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage of the present invention and characteristics will be more clear along with description.But these embodiment only are exemplary, scope of the present invention are not constituted any restriction.It will be understood by those skilled in the art that and down can make amendment with form or replace without departing from the spirit and scope of the present invention, but these modifications and replacing all fall in protection scope of the present invention the details of technical scheme of the present invention.
The preparation of embodiment 1 nitroorotic acid
1.8kg (18.18mol) vitriol oil (98%) is mixed stirring with 17kg (142.9mol) chloroform, and disposable then adding 1.5kg (11.6mol) 6-methyl uracil is warming up to 50 ℃.Controlled temperature is at 50-55 ℃, splashes into the concentrated nitric acid (98%) of 9kg (140mol) to this mixture, after dropwising, stirs 30 hours (HPLC detects to reacting completely) in this temperature refluxed.
Stop heating after reaction is accomplished, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, chloroform layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, suction filtration after this temperature keeps 3 hours, and drying obtains product.
Output: 1.96kg (84.1%);
Purity: 97.6% (HPLC).
The preparation of embodiment 2 nitroorotic acids
1.8kg (18.18mol) vitriol oil (98%) is mixed stirring with 17kg (142.9mol) chloroform, and disposable then adding 1.5kg (11.6mol) 6-methyl uracil is warming up to 50 ℃.Controlled temperature is at 50-55 ℃, splashes into the concentrated nitric acid (98%) of 4.5kg (70mol) to this mixture, after dropwising, stirs 30 hours (HPLC detects to reacting completely) in this temperature refluxed.
Stop heating after reaction is accomplished, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, chloroform layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, suction filtration after this temperature keeps 3 hours, and drying obtains product.
Output: 1.31kg (56%);
Purity: 97.0% (HPLC).
The preparation of embodiment 3 nitroorotic acids
1.8kg (18.18mol) vitriol oil (98%) is mixed stirring with 17kg (142.9mol) chloroform, and disposable then adding 1.5kg (11.6mol) 6-methyl uracil is warming up to 50 ℃.Controlled temperature is at 50-55 ℃, splashes into the concentrated nitric acid (98%) of 10.5kg (163mol) to this mixture, after dropwising, stirs 30 hours (HPLC detects to reacting completely) in this temperature refluxed.
Stop heating after reaction is accomplished, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, chloroform layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, suction filtration after this temperature keeps 3 hours, and drying obtains product.
Output: 1.86kg (80.1%);
Purity: 97.7% (HPLC).
The preparation of embodiment 4 nitroorotic acids
0.36kg (3.636mol) vitriol oil (98%) is mixed stirring with 17kg (142.9mol) chloroform, and disposable then adding 1.5kg (11.6mol) 6-methyl uracil is warming up to 50 ℃.Controlled temperature is at 50-55 ℃, splashes into the concentrated nitric acid (98%) of 9kg (140mol) to this mixture, after dropwising, stirs 56 hours (HPLC detects to reacting completely) in this temperature refluxed.
Stop heating after reaction is accomplished, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, chloroform layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, suction filtration after this temperature keeps 3 hours, and drying obtains product.
Output: 1.77kg (76.2%);
Purity: 96.3% (HPLC).
The preparation of embodiment 5 nitroorotic acids
0.347kg (3.50mol) vitriol oil (98%) is mixed stirring with 12.6kg (174mol) Skellysolve A, and disposable then adding 1.5kg (11.6mol) 6-methyl uracil is warming up to 50 ℃.Controlled temperature is at 50-55 ℃, splashes into the concentrated nitric acid (98%) of 9kg (140mol) to this mixture, after dropwising, stirs 30 hours (HPLC detects to reacting completely) in this temperature refluxed.
Stop heating after reaction is accomplished, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, the Skellysolve A layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, suction filtration after this temperature keeps 3 hours, and drying obtains product.
Output: 1.93kg (83.2%);
Purity: 97.3% (HPLC).
The preparation of embodiment 6 nitroorotic acids
1.8kg (18.18mol) vitriol oil (98%) is mixed stirring with 14.2kg (143.5mol) ethylene dichloride, and disposable then adding 1.5kg (11.6mol) 6-methyl uracil is warming up to 70 ℃.Controlled temperature splashes into 9kg (140mol) concentrated nitric acid (98%) at 65-75 ℃ to this mixture, after dropwising, stirs 30 hours (HPLC detects to reacting completely) in this temperature refluxed.
Stop heating after reaction is accomplished, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, the ethylene dichloride layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, suction filtration after this temperature keeps 3 hours, and drying obtains product.
Output: 1.97kg (85%);
Purity: 98% (HPLC).
The preparation of embodiment 7 nitroorotic acids
1.8kg (18.18mol) vitriol oil (98%) is mixed stirring with 14.3kg (166mol) normal hexane, and disposable then adding 1.5kg (11.6mol) 6-methyl uracil is warming up to 65 ℃.Controlled temperature splashes into 9kg (140mol) concentrated nitric acid (98%) at 65-70 ℃ to this mixture, after dropwising, stirs 30 hours (HPLC detects to reacting completely) in this temperature refluxed.
Stop heating after reaction is accomplished, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, normal hexane mixes layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, suction filtration after this temperature keeps 3 hours, and drying obtains product.
Output: 2.01kg (86%);
Purity: 96.5% (HPLC).
Claims (10)
1. the preparation method of a nitroorotic acid is characterized in that obtaining nitroorotic acid (III) through the oxidizing reaction of the nitration reaction of 6-methyl uracil (I) and follow-up 5-nitro-6-methyl uracil (II),
Described nitration reaction is under 50-80 ℃ temperature, in the presence of specific organic solvent and catalyzer, with concentrated nitric acid with 6-methyl uracil (I) nitrated be 5-nitro-6-methyl uracil (II);
Described oxidizing reaction is under 50-80 ℃ temperature, in the presence of specific organic solvent and catalyzer, 5-nitro-6-methyl uracil (II) is oxidized to nitroorotic acid (III);
Wherein, to be selected from chloroform, ethylene dichloride, methylene dichloride, Skellysolve A, normal hexane or normal heptane wherein at least a for described organic solvent;
Wherein, described catalyzer is a kind of acid.
2. according to the described method of claim 1, it is characterized in that the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction carry out simultaneously in same system.
3. according to the described method of claim 2, it is characterized in that concentrated nitric acid is dropwise to join to contain in 6-methyl uracil and specific organic solvent and the mixture of catalysts in the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction; After dropwising, stirred 30-60 hour, stop heating after reaction is accomplished 50-80 ℃ temperature refluxed; In system, add entry, keep system temperature to be no more than 35 ℃, layering; Water layer is cooled to 1-5 ℃; Suction filtration after this temperature keeps 3 hours, drying obtains product.
4. according to each described method of claim 1-3, it is characterized in that the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction are under 55 ℃ temperature, to carry out.
5. according to the described method of claim 1, the mol ratio that it is characterized in that 6-methyl uracil and concentrated nitric acid is 1: 5-14, preferred, the mol ratio of 6-methyl uracil and concentrated nitric acid is 1: 12.
6. according to the described method of claim 1, it is characterized in that described catalyzer is the vitriol oil.
7. according to the described method of claim 6, the mol ratio that it is characterized in that the 6-methyl uracil and the vitriol oil is 1: 0.3-3.
8. according to the described method of claim 6, the mol ratio that it is characterized in that the vitriol oil and concentrated nitric acid is 1: 3 to 1: 40.
9. according to the described method of claim 8, the mol ratio that it is characterized in that the vitriol oil and concentrated nitric acid is 1: 7.7.
10. according to the described method of claim 1, the mol ratio that it is characterized in that 6-methyl uracil and organic solvent is 1: 1-30, preferred, the mol ratio of 6-methyl uracil and organic solvent is 1: 17.7.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946887A (en) * | 2017-03-24 | 2017-07-14 | 大连万福制药有限公司 | It is a kind of to introduce the new technology that catalyst optimization synthesizes Dipyridamole |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946887A (en) * | 2017-03-24 | 2017-07-14 | 大连万福制药有限公司 | It is a kind of to introduce the new technology that catalyst optimization synthesizes Dipyridamole |
| CN106946887B (en) * | 2017-03-24 | 2019-05-28 | 大连万福制药有限公司 | A kind of preparation method introducing catalyst optimization synthesis Dipyridamole |
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| CN102702114B (en) | 2014-12-17 |
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