Synthesis method of 2-cyano-5-fluorobenzyl bromide
By adopting bromine and substitution reaction methods in the synthesis of 2-cyano-5-fluorotoluene, the problems of raw material residues and dibromide are solved, the conversion and yield are improved, the purification process is simplified and the purification process is reduced. The cost.
Patent Information
- Application Number
- CN202411550849.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-01
- Publication Date
- 2025-02-11
AI Technical Summary
In the prior art, the synthesis method of 2-cyano-5-fluorobromobenzylbenzyl is produced by the production of impurities such as raw material residues and dibromide impurities, resulting in a cumbersome purification process and high cost.
By mixing 2-cyano-5-fluorotoluene with a solvent and heating it, adding an initiator and a bromine reagent to perform a bromine reaction, then adding bromine reagent and organic base to the mixture dropwise to perform a substitution reaction, and finally performing a substitution reaction Post-treatment to obtain 2-cyano-5-fluorobromobenzyl.
It significantly improves the conversion and yield of the reaction, effectively controls the production of raw material residues and dibromide impurities, simplifies the purification method, and reduces costs.
Smart Images
Figure CN119409595A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of drug preparation, and in particular to a method for synthesizing 2-cyano-5-fluorobenzyl bromide. Background Art
[0002] Trelagliptin is a DPP-4 inhibitor, an oral hypoglycemic drug that can inhibit DPP-4 and control blood sugar levels. Incretin is a hormone secreted by the intestine that can stimulate the secretion of insulin and thus lower blood sugar levels. However, the hormone has a short duration of action in the body and will be decomposed by the DPP-4 enzyme after a period of time. Trelagliptin can inhibit the activity of the DPP-4 enzyme, slow down the decomposition rate of incretin, thereby increasing the activity of incretin, and achieve the purpose of controlling blood sugar. When blood sugar is high, it can inhibit the inactivation of incretin, and generally does not inhibit when blood sugar reaches normal levels or is low. In clinical applications, trelagliptin can not only be used alone, but also can be used in combination with other hypoglycemic drugs to achieve a better hypoglycemic effect. The drug has relatively small side effects and relatively little impact on liver and kidney function. Trelagliptin has a long half-life and can be released slowly, so that its drug concentration in the body remains stable. It can be taken once a week, reducing the inconvenience caused by frequent injections or oral medications. For patients who need long-term blood sugar control, medication compliance and convenience can be improved to a certain extent.
[0003] 2-Cyano-5-fluorobenzyl bromide is a key intermediate for preparing trelagliptin. In the prior art, the direct bromination of benzyl bromide with bromination reagents such as NBS and dibromohydantoin is a common and relatively direct method for synthesizing benzyl bromide. However, the above method will have residual raw materials, dibrominated impurities, and even polybrominated impurities. These impurities are not much different from the product in polarity, have similar boiling points, and are very similar in properties in all aspects. In addition, the benzyl bromide compound itself is relatively irritating, so it is more complicated to purify, and it is easy to cause discomfort when entering the human body. At present, initiators such as AIBN and BPO are usually introduced to control the reaction temperature, substrate concentration, etc. in an appropriate optimal state, but dibromination and residual raw materials are still inevitable, and purification methods such as distillation, column, and recrystallization are cumbersome. Summary of the invention
[0004] The object of the present invention is to provide a method for synthesizing 2-cyano-5-fluorobenzyl bromide. The method provided by the present invention significantly improves the conversion rate and yield of the reaction, effectively controls the residual raw materials, reduces the generation of impurities such as dibrominated impurities, reduces the total amount and types of impurities, and thus simplifies the purification method.
[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:
[0006] The present invention provides a method for synthesizing 2-cyano-5-fluorobenzyl bromide, comprising the following steps:
[0007] (1) mixing 2-cyano-5-fluorotoluene and a solvent, heating the mixture, adding an initiator and a bromination reagent, performing a bromination reaction, and obtaining a mixed solution;
[0008] (2) Adding a bromine reagent and an organic base dropwise to the mixed solution obtained in step (1) in sequence to carry out a substitution reaction, and obtaining 2-cyano-5-fluorobenzyl bromide after post-treatment.
[0009] Preferably, the heating temperature in step (1) is 80-85°C.
[0010] Preferably, in step (1), the initiator and the bromination reagent are added in 1 to 3 batches.
[0011] Preferably, the initiator in step (1) is at least one of AIBN and BPO.
[0012] Preferably, the bromination reagent is at least one of N-bromosuccinimide and dibromohydantoin.
[0013] Preferably, when the brominating agent is N-bromosuccinimide, the molar ratio of N-bromosuccinimide to 2-cyano-5-fluorotoluene is (1.05-1.5):1; when the brominating agent is dibromohydantoin, the molar ratio of dibromohydantoin to 2-cyano-5-fluorotoluene is (0.55-0.9):1.
[0014] Preferably, the debromination agent in step (2) is at least one of diethyl phosphite and dimethyl phosphite.
[0015] Preferably, the organic base in step (2) is at least one of triethylamine and N,N-diisopropylethylamine.
[0016] Preferably, the temperature of the substitution reaction in step (2) is -5 to 5°C, and the time of the substitution reaction is 20 to 40 minutes.
[0017] Preferably, the post-treatment in step (2) comprises: adding water, adjusting pH with acid, extraction, washing with brine, drying, filtering with petroleum ether and recrystallization.
[0018] The invention provides a method for synthesizing 2-cyano-5-fluorobenzyl bromide, wherein a suitable solvent, a brominating agent, and an initiator are selected according to the properties of a substrate 2-cyano-5-fluorotoluene, a certain reaction temperature is controlled, the reaction is promoted to be fully carried out, and the residual raw materials in the mixed solution are reduced, and then a brominating agent and an organic base are sequentially dripped into the mixed solution at a relatively low temperature, and the mixture is kept warm for a substitution reaction to achieve the purpose of brominating, convert the dibrominated impurities into target products, and finally improve the conversion rate of the substrate, and after simple post-treatment, 2-cyano-5-fluorobenzyl bromide with high yield is prepared. The synthetic method provided by the invention has few crude impurities, high yield, easy purification, reduced cost, strong selectivity for bromination reaction of the substrate, avoids bromination reaction under sealed conditions, and has increased safety. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 The invention provides a synthetic route of 2-cyano-5-fluorobenzyl bromide. DETAILED DESCRIPTION
[0020] The present invention provides a method for synthesizing 2-cyano-5-fluorobenzyl bromide, comprising the following steps:
[0021] (1) mixing 2-cyano-5-fluorotoluene and a solvent, heating the mixture, adding an initiator and a bromination reagent, performing a bromination reaction, and obtaining a mixed solution;
[0022] (2) Adding a bromine reagent and an organic base dropwise to the mixed solution obtained in step (1) in sequence to carry out a substitution reaction, and obtaining 2-cyano-5-fluorobenzyl bromide after post-treatment.
[0023] In the present invention, unless otherwise specified, the raw materials used are conventional commercial products in the art.
[0024] The invention prepares a mixed solution by heating 2-cyano-5-fluorotoluene and a solvent, adding an initiator and a bromination reagent, and performing a bromination reaction.
[0025] In the present invention, the heating temperature is preferably 80-85° C., more preferably 82-84° C. In the present invention, the initiator and the bromination agent are preferably added in 1-3 batches, more preferably in 2 batches. The present invention promotes the forward reaction and reduces the residual raw materials by adding the initiator and the bromination agent in batches.
[0026] In the present invention, the initiator is preferably at least one of AIBN and BPO. In the present invention, the molar ratio of the initiator to 2-cyano-5-fluorotoluene is preferably (0.05-0.2):1.
[0027] In the present invention, the bromination reagent is preferably at least one of N-bromosuccinimide and dibromohydantoin; when the bromination reagent is N-bromosuccinimide, the molar ratio of N-bromosuccinimide to 2-cyano-5-fluorotoluene is preferably (1.05-1.5):1; when the bromination reagent is dibromohydantoin, the molar ratio of dibromohydantoin to 2-cyano-5-fluorotoluene is preferably (0.55-0.9):1. The present invention promotes the full reaction of the substrate and reduces the residual raw materials in the mixed solution by appropriately increasing the amount of the bromination reagent.
[0028] In the present invention, the temperature of the bromination reaction is preferably 80-85°C, more preferably 82-84°C; the time of the bromination reaction is preferably 1-4h, more preferably 1.5-3h. In the present invention, the bromination reaction is terminated when the content of the substrate is preferably ≤5% as determined by HPLC during the bromination reaction.
[0029] After the bromination reaction is completed, the product of the bromination reaction is preferably cooled to below 20° C., filtered, and the filter cake is rinsed with dichloroethane, and the filter residue is discarded to obtain a mixed solution.
[0030] After obtaining the mixed solution, the present invention sequentially adds a bromine reagent and an organic base to the mixed solution to carry out a substitution reaction, and obtains 2-cyano-5-fluorobenzyl bromide through post-treatment.
[0031] In the present invention, the debromination agent is preferably at least one of diethyl phosphite and dimethyl phosphite. In the present invention, the temperature of the debromination agent added dropwise is preferably <0°C; the time of the debromination agent added dropwise is preferably 20 to 50 minutes, more preferably 25 to 40 minutes.
[0032] In the present invention, the organic base is preferably at least one of triethylamine and N,N-diisopropylethylamine. In the present invention, the temperature of the organic base added dropwise is preferably -5 to 5°C; the time of the bromine removal reagent added dropwise is preferably 2 to 5 hours, more preferably 2.5 to 4 hours.
[0033] In the present invention, the temperature of the substitution reaction is -5 to 5°C, and the time of the substitution reaction is 20 to 40 minutes.
[0034] The invention adjusts the amount of bromine reagent added, the temperature and time of substitution reaction according to the content of dibrominated impurities in the mixed solution, so that the dibrominated impurities are converted into target products, thereby improving the conversion rate of the substrate and the yield of the target product.
[0035] In the present invention, the post-treatment preferably includes: adding water, adjusting pH with acid, extraction, washing with brine, drying, filtering with petroleum ether and recrystallization, and more preferably: adding water to the product of the substitution reaction, adding hydrochloric acid to adjust pH to 4-5, extracting the aqueous phase obtained after separation with dichloroethane, discarding the aqueous phase, combining the organic phases, washing with brine, discarding the aqueous phase, and drying the organic phase with anhydrous sodium sulfate to obtain a dried organic phase; concentrating the dried organic phase under reduced pressure until there is no solvent, adding petroleum ether and heating to dissolve, standing to cool and filtering in sequence to obtain a crude product; mixing the crude product with n-heptane, heating to reflux, and then cooling, crystallizing, centrifuging and eluting with petroleum ether in sequence to obtain 2-cyano-5-fluorobenzyl bromide.
[0036] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. 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.
[0037] Example 1
[0038] A method for synthesizing 2-cyano-5-fluorobenzyl bromide, comprising the following steps:
[0039] (1) Add 165 kg of ethylene dichloride to a reaction kettle, start stirring, then add 26.5 kg of 2-cyano-5-fluorotoluene, 19.05 kg of dibromohydantoin, and 1.6 kg of AIBN, raise the temperature to 83° C., reflux for bromination reaction for 1 hour, cool to 60-70° C., add 19.05 kg of dibromohydantoin and 1.6 kg of AIBN for the second time, continue the bromination reaction for 1 hour, and terminate the bromination reaction when the content of the substrate raw material is less than 5% by HPLC detection, cool to below 20° C., filter, rinse 100 kg of the filter cake with ethylene dichloride, discard the filter residue, and combine the filtrate to obtain a mixed solution;
[0040] (2) adding the mixed solution to a reaction kettle, cooling the temperature to below 0°C, dripping 8.5 kg of diethyl phosphite, dripping for 30 min, controlling the temperature at -5 to 5°C, dripping 7.2 kg of triethylamine, dripping for 3 h, maintaining the temperature at -5 to 5°C for 30 min of substitution reaction, taking samples for HPLC / GC detection, terminating the reaction when the substitution reaction is complete, and obtaining a substitution reaction product;
[0041] Add 100 kg of water to the substitution reaction product, add hydrochloric acid to adjust the pH to 4-5, separate the liquids, extract the aqueous phase once with 50 kg of dichloroethane, separate the liquids, discard the aqueous phase, wash the combined organic phases with 50 kg of brine, discard the aqueous phase, and dry the organic phase with 11 kg of anhydrous sodium sulfate to obtain a dry organic phase;
[0042] The substitution reaction product was concentrated under reduced pressure until there was no solvent, 35 kg of petroleum ether was added, and the mixture was heated to 50-60°C to dissolve, and the mixture was allowed to stand until the temperature dropped to 10°C, and filtered to obtain 79 kg of a crude product;
[0043] The 79 kg crude product was mixed with 120 kg n-heptane, heated to 80° C., refluxed for 2 h, and after the material was observed to be completely dissolved, cooled to 10-20° C. for crystallization, and centrifuged and washed with petroleum ether in sequence to obtain 58 kg of 2-cyano-5-fluorobenzyl bromide, GC≧99.5%, and dibrominated impurities of 0.25%.
[0044] Comparative Example 1
[0045] A method for preparing 2-cyano-5-fluorobenzyl bromide, comprising the following steps:
[0046] 26.5 kg of 2-cyano-5-fluorotoluene and 265 L of acetonitrile were mixed, 38.1 kg of dibromohydantoin bromination reagent and 3.5 kg of BPO initiator were added, and the temperature was raised to 90°C under closed conditions for bromination reaction for 3 hours to obtain 67 kg of crude product. HPLC detection showed that the remaining substrate raw material in the crude product was 15%, the product was 75%, and the dibrominated impurity was 10%. The crude product was purified by a 2.5 m high distillation column and then recrystallized with n-heptane to obtain 41 kg of qualified product that met the requirements. HPLC detection showed that the remaining substrate raw material in the product was 7%, the product was 87%, and the dibrominated impurity was 6%.
[0047] In summary, compared with Comparative Example 1 using a conventional preparation method, Example 1 of the present invention significantly improves the conversion rate and yield of the reaction, effectively controls the residual raw materials, reduces the generation of impurities such as dibrominated impurities, reduces the total amount and types of impurities, and thus simplifies the purification method.
[0048] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.
Claims
1. A method for synthesizing 2-cyano-5-fluorobenzyl bromide, characterized in that: The following steps are involved: (1) mixing 2-cyano-5-fluorotoluene and a solvent, heating the mixture, adding an initiator and a bromination reagent, performing a bromination reaction, and obtaining a mixed solution; (2) Adding a bromine reagent and an organic base dropwise to the mixed solution obtained in step (1) in sequence to carry out a substitution reaction, and obtaining 2-cyano-5-fluorobenzyl bromide after post-treatment.
2. The synthesis method according to claim 1, characterized in that The heating temperature in step (1) is 80-85°C.
3. The synthesis method according to claim 1, characterized in that In the step (1), the initiator and the bromination reagent are added in 1 to 3 batches.
4. The synthesis method according to claim 1 or 3, characterized in that The initiator in step (1) is at least one of AIBN and BPO.
5. The synthesis method according to claim 3, characterized in that The bromination reagent is at least one of N-bromosuccinimide and dibromohydantoin.
6. The synthesis method according to claim 5, characterized in that When the bromination reagent is N-bromosuccinimide, the molar ratio of N-bromosuccinimide to 2-cyano-5-fluorotoluene is (1.05-1.5):1; when the bromination reagent is dibromohydantoin, the molar ratio of dibromohydantoin to 2-cyano-5-fluorotoluene is (0.55-0.9):
1.
7. The synthesis method according to claim 1, characterized in that The debromination agent in step (2) is at least one of diethyl phosphite and dimethyl phosphite.
8. The synthesis method according to claim 1, characterized in that The organic base in step (2) is at least one of triethylamine and N,N-diisopropylethylamine.
9. The synthesis method according to claim 1, characterized in that The temperature of the substitution reaction in step (2) is -5 to 5°C, and the time of the substitution reaction is 20 to 40 minutes.
10. The synthesis method according to claim 1, characterized in that The post-treatment in step (2) includes: adding water, adjusting pH with acid, extraction, washing with brine, drying, filtering with petroleum ether and recrystallization.