Method for preparing 5-bromopyrimidine
By using deaminating reaction of 2-amino-5-bromopyrimidine with nitrite in the presence of diazotization reagent, combining organic acids and amines or quaternary ammonium salts and quaternary phosphine catalysts, the methods for preparing 5-bromopyrimidine in the prior art have poor reproducibility and large energy consumption, and the preparation effect of high yield and low energy consumption is achieved.
Patent Information
- Application Number
- CN202411798735.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-09
- Publication Date
- 2025-03-14
AI Technical Summary
The method for preparing 5-bromopyrimidine in the prior art has problems such as poor reproducibility, high energy consumption, high industrialization difficulty, low yield and high raw material cost.
2-amino-5-bromopyrimidine was used as the starting material, and the reaction was carried out under mild conditions by deaminating the amino reaction with nitrite in the presence of diazotization reagent, and an ion-pair salt catalyst formed by organic acids or amines or quaternary ammonium salts and quaternary phosphine salts were controlled to carry out the reaction under mild conditions.
The production of 5-bromopyrimidine in high yields has been achieved, which reduces energy consumption and reduces the generation of three wastes, has excellent product quality and is simple and easy to obtain.
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Figure CN119613346A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of 5-bromopyrimidine preparation, in particular to a method for preparing 5-bromopyrimidine. Background Art
[0002] 5-Bromopyrimidine, CAS No. 4595-59-9, is a white crystal that is easily sublimated. It is an important pharmaceutical and chemical intermediate with broad application prospects in the fields of medicine, chemical industry, and scientific research.
[0003] US3956301,1976,A discloses a method of using pyrimidine hydrochloride as a raw material to react with liquid bromine at 130°C to obtain 5-bromopyrimidine with a yield of 88%. However, repeated literature found that the method had poor reproducibility, high reaction temperature, high energy consumption, and a large amount of waste acid, making it difficult to industrialize. US4252955,1981,A discloses a method of using 3,4-dibromo-5-hydroxyfuran-2(5H)-one as a raw material and formamide and boric anhydride at 183°C to obtain 5-bromopyrimidine with a yield of 48%. This method has low yield and high energy consumption. CN117865898,2024,A uses tri(pentafluorophenyl)borane instead of boric anhydride at 90°C to obtain 5-bromopyrimidine with a yield of 82%, but the raw material cost of this method is high. US2003 / 149064, 2003, A1 discloses a method of preparing 5-bromo-2,4-dichloropyrimidine with sulfonamide at 100°C with a yield of 34%. The method has a low yield and high raw material cost. Jose C. Gonzalez-Gomez et al. disclosed a method of one-pot deamination of nitrite catalyzed by salicylic acid (Advanced Synthesis & Catalysis, 2017, 359), but did not study 5-bromopyrimidine. The preparation method has mild reaction conditions and a small amount of catalyst, but the yield of electron-deficient aromatic amine is low and more by-products are produced. Summary of the invention
[0004] The object of the present invention is to provide a method for preparing 5-bromopyrimidine to solve the problems raised in the above background technology.
[0005] To achieve the above object, the present invention provides the following technical solution: a method for preparing 5-bromopyrimidine, comprising the following steps:
[0006] S1. Raw material preparation: prepare 2-amino-5-bromopyrimidine, solvent, nitrite as starting materials, as well as diazotization reagent and catalyst for deamination reaction. The catalyst is an ion pair salt catalyst formed by organic acid and amine or quaternary ammonium salt or quaternary phosphonium salt, and its general formula is RCOO - N + R1R2R3R4;
[0007] S2, product preparation: 2-amino-5-bromopyrimidine is dispersed in a solvent, a catalyst and a nitrite are added to cause a deamination reaction via a diazonium salt intermediate, and a crude product 5-bromopyrimidine is prepared by reaction;
[0008] S3, post-treatment: the crude product obtained in the above step S2 is subjected to post-treatment to obtain 5-bromopyrimidine. The post-treatment is to perform desolventizing by room temperature vacuum distillation, washing with dilute hydrochloric acid, and heating vacuum distillation to obtain the 5-bromopyrimidine product after the reaction is completed.
[0009] Preferably, the solvent in step S1 is an aromatic hydrocarbon, a halogenated hydrocarbon, or an ether solvent. Preferably, the solvent is at least one of toluene, dichloromethane, and tetrahydrofuran.
[0010] Preferably, the organic acid in step S1 has the general formula of RCOOH, R=C1~C 15 The aromatic or alkyl group of the organic acid includes salicylic acid, sodium salicylate, 2-hydroxy-4,5-dimethoxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,5-dihydroxyterephthalic acid, 2,6-dihydroxybenzoic acid, 3-methylsalicylic acid, 4-nitrosalicylic acid, 4-methoxysalicylic acid, 4-trifluoromethylsalicylic acid, 5-nitrosalicylic acid, and citric acid.
[0011] Preferably, the amine in step S1 includes secondary amine and tertiary amine, and the general formula is R1N(R2)R3, wherein R1=C1~C 15 aromatic or alkyl, R2 is hydrogen or C1~C 15 aromatic or alkyl, R3 is hydrogen or C1~C 15 aromatic or alkyl, R3 is hydrogen or C1~C 15 The aromatic group or alkyl group, the secondary amine and tertiary amine include diethylamine, triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine compounds, and preferably, the yield is higher when triethylamine is used.
[0012] Preferably, the ammonium salt and the quaternary phosphonium salt in step S1 have the general formula R1R2R3R4N + X - or R1R2R3R4P + X - , R1=C1~C 15 aromatic or alkyl, R2=C1~C 15 aromatic or alkyl, R3=C1~C 15 aromatic or alkyl, R4=C1~C 15The ammonium salt and the quaternary phosphonium salt include ammonium acetate, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylphosphonium bromide, tetra-n-butylphosphonium bromide and triphenylmethylphosphonium bromide compounds.
[0013] Preferably, the catalyst in step S1 may also be a bifunctional catalyst containing both a carboxyl group and an amino group in one molecule, such as L-proline, hydroxyproline, trimethylglycine, or acetylglycine.
[0014] Preferably, the catalyst in step S1 may also be a combination of two or more of an organic acid, an amine, a quaternary ammonium salt and a quaternary phosphonium salt.
[0015] Preferably, the nitrite in step S1 is tert-butyl nitrite, isobutyl nitrite, n-butyl nitrite, or isopropyl nitrite; preferably isopropyl nitrite.
[0016] Preferably, the deamination temperature in step S2 is 20°C to 60°C; preferably 35°C to 45°C, which enables the deamination reaction to occur smoothly with fewer side reactions.
[0017] Preferably, the reaction time in step S2 is 6 to 24 hours, preferably 10 to 16 hours, and the amount of the catalyst used is 0.1 mol% to 50 mol%.
[0018] Compared with the prior art, the present invention has the following beneficial effects:
[0019] The method uses 2-amino-5-bromopyrimidine as a starting raw material, which is simple and easy to obtain. 5-bromopyrimidine is prepared by catalytic deamination. The catalytic system is simple and effective. 5-bromopyrimidine can be obtained in high yield under mild conditions. There are less three wastes in production, the product quality is good, the yield is greatly improved, the reaction conditions are mild, and the energy consumption is reduced. BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1 It is a flow chart of the present invention. DETAILED DESCRIPTION
[0021] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0022] See also Figure 1 The present invention provides a method for preparing 5-bromopyrimidine, comprising the following steps:
[0023] S1. Raw material preparation: prepare 2-amino-5-bromopyrimidine, solvent, nitrite as starting materials, as well as diazotization reagent and catalyst for deamination reaction. The catalyst is an ion pair salt catalyst formed by organic acid and amine or quaternary ammonium salt or quaternary phosphonium salt, and its general formula is RCOO - N + R1R2R3R4;
[0024] S2, product preparation: 2-amino-5-bromopyrimidine is dispersed in a solvent, a catalyst and a nitrite are added to cause a deamination reaction via a diazonium salt intermediate, and a crude product 5-bromopyrimidine is prepared by reaction;
[0025] S3, post-treatment: the crude product obtained in the above step S2 is subjected to post-treatment to obtain 5-bromopyrimidine. After the reaction is completed, the crude product is subjected to vacuum distillation at room temperature for desolventizing, washed with dilute hydrochloric acid, and heated for vacuum distillation to obtain the 5-bromopyrimidine product;
[0026] The solvent in step S1 is an aromatic hydrocarbon, a halogenated hydrocarbon, or an ether solvent, and a preferred solvent is at least one of toluene, dichloromethane, and tetrahydrofuran.
[0027] The general formula of the organic acid in step S1 is RCOOH, where R=C1~C 15 The aromatic or alkyl group of step S1 is selected from the group consisting of salicylic acid, sodium salicylate, 2-hydroxy-4,5-dimethoxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,5-dihydroxyterephthalic acid, 2,6-dihydroxybenzoic acid, 3-methylsalicylic acid, 4-nitrosalicylic acid, 4-methoxysalicylic acid, 4-trifluoromethylsalicylic acid, 5-nitrosalicylic acid and citric acid. The amine in step S1 includes secondary amine and tertiary amine, and the general formula is R1N(R2)R3, wherein R1=C1~C 15 aromatic or alkyl, R2 is hydrogen or C1~C 15 aromatic or alkyl, R3 is hydrogen or C1~C 15 aromatic or alkyl, R3 is hydrogen or C1~C 15 The aromatic or alkyl group of the secondary amine and the tertiary amine include diethylamine, triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine compounds. Triethylamine is preferably used with higher yield. The general formula of the ammonium salt and the quaternary phosphonium salt in step S1 is R1R2R3R4N + X - or R1R2R3R4P + X - , R1=C1~C 15 aromatic or alkyl, R2=C1~C 15 aromatic or alkyl, R3=C1~C 15 aromatic or alkyl, R4=C1~C 15aromatic or alkyl, X = fluorine, chlorine, bromine or other organic anions, ammonium salts, quaternary phosphonium salts include ammonium acetate, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylphosphonium bromide, tetra-n-butylphosphonium bromide, triphenylmethylphosphonium bromide compounds.
[0028] The catalyst in step S1 can also be a bifunctional catalyst containing both carboxyl and amino groups in one molecule, such as L-proline, hydroxyproline, trimethylglycine, acetylglycine. The catalyst in step S1 can also be a combination of two or more of an organic acid, an amine, a quaternary ammonium salt and a quaternary phosphonium salt as a catalyst. The nitrite in step S1 is tert-butyl nitrite, isobutyl nitrite, n-butyl nitrite, isopropyl nitrite, preferably isopropyl nitrite.
[0029] The deamination temperature in step S2 is 20°C to 60°C; preferably 35 to 45°C, which allows the deamination reaction to occur smoothly and with fewer side reactions. The reaction time in step S2 is 6 to 24 hours, preferably 10 to 16 hours, and the amount of catalyst used is 0.1 mol% to 50 mol%.
[0030] Preparation of 2-amino-5-bromopyrimidine: In a 500mL three-necked flask, 105.08g (1.1mol) of guanidine hydrochloride and 50mL of concentrated hydrochloric acid were added, and 164.20g (1.0mol) of 1,1,3,3-tetramethoxypropane was added. The temperature was raised to 45°C and the reaction was carried out for 5h. After the reaction was completed, the pH was adjusted to 9-10 with 10wt% NaOH, and the mixture was extracted with ethyl acetate and concentrated to obtain 87.50g (yield: 92%) of milky white solid 2-aminopyrimidine. In a 2500mL three-necked flask, 87.50g (0.92mol) of 2-aminopyrimidine obtained in the previous step was added, 1000mL of acetonitrile was injected as solvent, and 136.78g (0.478mol) of dibromohydantoin was added. The mixture was reacted for 1h at room temperature. After the reaction was completed, the milky white target product 2-amino-5-bromopyrimidine was directly filtered to obtain 153.68g (yield: 96%).
[0031] Embodiment 1:
[0032] In a 500mL three-necked flask, add 15.0g (0.0862mol) of 2-amino-5-bromopyrimidine, 1.19g of salicylic acid, and 150mL of tetrahydrofuran. Control the temperature at 35℃~40℃, and dropwise add 19.20g (0.216mol) of isopropyl nitrite. After the addition is complete, keep the temperature to react for 16h. After the reaction is completed, perform vacuum distillation at room temperature to desolventize, wash with dilute hydrochloric acid, and heat to distill under reduced pressure to obtain 5.51g (yield: 40.2%) of white crystalline product.
[0033] Embodiment 2:
[0034] In a 500mL three-necked flask, add 15.0g (0.0862mol) of 2-amino-5-bromopyrimidine, 1.19g of salicylic acid, and 150mL of tetrahydrofuran. Control the temperature at 35℃~40℃, and dropwise add 19.20g (0.216mol) of isopropyl nitrite and 0.44g of triethylamine. After the addition is complete, keep the temperature for 16h. After the reaction is completed, perform desolventization by vacuum distillation at room temperature, wash with dilute hydrochloric acid, and heat and vacuum distillation to obtain 11.68g (yield: 85.2%) of white crystalline product.
[0035] Embodiment 3:
[0036] In a 500mL three-necked flask, add 15.0g (0.0862mol) of 2-amino-5-bromopyrimidine, 1.19g of salicylic acid, and 150mL of tetrahydrofuran. Control the temperature at 35℃~40℃, and dropwise add 22.22g (0.216mol) of tert-butyl nitrite and 0.44g of triethylamine. After the addition is complete, keep the temperature for 16h. After the reaction is completed, distill under reduced pressure at room temperature for solvent removal, wash with dilute hydrochloric acid, and heat and distill under reduced pressure to obtain 10.53g (yield: 76.8%) of white crystalline product.
[0037] Embodiment 4:
[0038] In a 500mL three-necked flask, add 15.0g (0.0862mol) of 2-amino-5-bromopyrimidine, 1.19g of salicylic acid, and 150mL of tetrahydrofuran. Control the temperature at 35℃~40℃, and dropwise add 22.22g (0.216mol) of isobutyl nitrite and 0.44g of triethylamine. After the addition is complete, keep the temperature for 16h. After the reaction is completed, distill under reduced pressure at room temperature for solvent removal, wash with dilute hydrochloric acid, and heat and distill under reduced pressure to obtain 10.83g (yield: 79.0%) of white crystalline product.
[0039] Embodiment 5:
[0040] In a 500mL three-necked flask, add 15.0g (0.0862mol) of 2-amino-5-bromopyrimidine, 1.19g of salicylic acid, and 150mL of 2-methyltetrahydrofuran. Control the temperature at 35℃~40℃, and dropwise add 19.20g (0.216mol) of isopropyl nitrite and 0.44g of triethylamine. After the addition is complete, keep the temperature for 16h. After the reaction is completed, perform desolventization by vacuum distillation at room temperature, wash with dilute hydrochloric acid, and heat and vacuum distillation to obtain 10.91g (yield: 79.6%) of white crystalline product.
[0041] Embodiment 6:
[0042] In a 500mL three-necked flask, add 15.0g (0.0862mol) of 2-amino-5-bromopyrimidine, 1.19g of salicylic acid, 1.39g of tetrabutylammonium bromide, and 150mL of tetrahydrofuran. Control the temperature at 35℃~40℃, and dropwise add 19.20g (0.216mol) of isopropyl nitrite. After the addition is complete, keep the temperature for 16h. After the reaction is completed, perform desolventization by vacuum distillation at room temperature, wash with dilute hydrochloric acid, and heat and vacuum distillation to obtain 11.03g (yield: 80.5%) of white crystalline product.
[0043] Embodiment 7:
[0044] In a 500mL three-necked flask, add 2-amino-5-bromopyrimidine 15.0g (0.0862mol), salicylic acid 1.19g, tetrahydrofuran 150mL, control the temperature at 35℃~40℃, add isopropyl nitrite 19.20g (0.216mol), triethylamine 0.44g, tetrabutylammonium bromide 1.39g dropwise, after the addition is complete, keep warm and react for 16h. After the reaction is completed, desolventize by vacuum distillation at room temperature, wash with dilute hydrochloric acid, and heat and vacuum distill to obtain 11.93g (yield: 87.1%) of white crystalline product;
[0045] In summary, when only an organic acid catalyst is added, the yield is 40.2%, when the catalyst is an organic acid and an amine forming an ion pair salt, the yield is greatly increased to 85.2%, when the catalyst is an organic acid and a quaternary ammonium salt, the yield is 80.5%, and when the catalyst organic acid and an amine are used at the same time to form an ion pair salt and a quaternary ammonium salt, the yield is increased to 87.1%;
[0046] When used specifically, the present invention provides a method for preparing 5-bromopyrimidine, which uses 2-amino-5-bromopyrimidine as a starting raw material. The raw material is simple and easily available, and 5-bromopyrimidine is prepared by catalytic deamination. The catalytic system is simple and effective, the yield is greatly improved, the reaction conditions are mild, and the energy consumption is reduced.
[0047] Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for preparing 5-bromopyrimidine, characterized in that: The following steps are involved: S1. Raw material preparation: prepare 2-amino-5-bromopyrimidine, solvent, nitrite as starting materials, as well as diazotization reagent and catalyst for deamination reaction. The catalyst is an ion pair salt catalyst formed by organic acid and amine or quaternary ammonium salt or quaternary phosphonium salt, and its general formula is RCOO - N + R1R2R3R4; S2, product preparation: 2-amino-5-bromopyrimidine is dispersed in a solvent, a catalyst and a nitrite are added to cause a deamination reaction via a diazonium salt intermediate, and a crude product 5-bromopyrimidine is prepared by reaction; S3, post-treatment: the crude product obtained in the above step S2 is subjected to post-treatment to obtain 5-bromopyrimidine. The post-treatment is to perform desolventizing by room temperature vacuum distillation, washing with dilute hydrochloric acid, and heating vacuum distillation to obtain the 5-bromopyrimidine product after the reaction is completed.
2. A method for preparing 5-bromopyrimidine according to claim 1, characterized in that: The solvent in step S1 is an aromatic hydrocarbon, a halogenated hydrocarbon, or an ether solvent. Preferably, the solvent is at least one of toluene, dichloromethane, and tetrahydrofuran.
3. A method for preparing 5-bromopyrimidine according to claim 1, characterized in that: The organic acid in step S1 has the general formula of RCOOH, R=C1~C 15 The aromatic or alkyl group of the organic acid includes salicylic acid, sodium salicylate, 2-hydroxy-4,5-dimethoxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,5-dihydroxyterephthalic acid, 2,6-dihydroxybenzoic acid, 3-methylsalicylic acid, 4-nitrosalicylic acid, 4-methoxysalicylic acid, 4-trifluoromethylsalicylic acid, 5-nitrosalicylic acid, and citric acid.
4. A method for preparing 5-bromopyrimidine according to claim 1, characterized in that: The amine in step S1 includes secondary amine and tertiary amine, and the general formula is R1N(R2)R3, wherein R1=C1-C 15 aromatic or alkyl, R2 is hydrogen or C1~C 15 aromatic or alkyl, R3 is hydrogen or C1~C 15 aromatic or alkyl, R3 is hydrogen or C1~C 15 The aromatic group or alkyl group, the secondary amine and tertiary amine include diethylamine, triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine compounds.
5. A method for preparing 5-bromopyrimidine according to claim 1, characterized in that: In step S1, the ammonium salt and the quaternary phosphonium salt have the general formula of R1R2R3R4N + X - or R1R2R3R4P + X - , R1=C1~C 15 aromatic or alkyl, R2=C1~C 15 aromatic or alkyl, R3=C1~C 15 aromatic or alkyl, R4=C1~C 15 The ammonium salt and the quaternary phosphonium salt include ammonium acetate, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylphosphonium bromide, tetra-n-butylphosphonium bromide and triphenylmethylphosphonium bromide compounds.
6. A method for preparing 5-bromopyrimidine according to claim 1, characterized in that: The catalyst in step S1 may also be a bifunctional catalyst containing both a carboxyl group and an amino group in one molecule, such as L-proline, hydroxyproline, trimethylglycine, or acetylglycine.
7. A method for preparing 5-bromopyrimidine according to claim 1, characterized in that: The catalyst in step S1 may also be a combination of two or more of an organic acid, an amine, a quaternary ammonium salt and a quaternary phosphonium salt.
8. A method for preparing 5-bromopyrimidine according to claim 1, characterized in that: The nitrite in step S1 is tert-butyl nitrite, isobutyl nitrite, n-butyl nitrite, or isopropyl nitrite.
9. A method for preparing 5-bromopyrimidine according to claim 1, characterized in that: The deamination temperature in step S2 is 20°C to 60°C; preferably 35°C to 45°C, which can make the deamination reaction occur smoothly and have fewer side reactions.
10. A method for preparing 5-bromopyrimidine according to claim 1, characterized in that: The reaction time in step S2 is 6 to 24 hours, and the amount of the catalyst used is 0.1 mol% to 50 mol%.