Synthesis method of 6-bromine-5-amino-3, 4-dihydro-2h-1-benzopyran-8-formic acid and derivative of 6-bromine-5-amino-3, 4-dihydro-2h-1-benzopyran-8-formic acid
By using a new synthetic route with inexpensive catalysts and specific solvents, the problems of long, dangerous, and costly synthesis of 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid in existing technologies have been solved, achieving safe and efficient compound synthesis suitable for scale-up production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- 付绪威
- Filing Date
- 2026-03-23
- Publication Date
- 2026-05-26
AI Technical Summary
Existing methods for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives are lengthy, dangerous, and costly, making them unsuitable for large-scale production.
A novel synthetic route is adopted, using inexpensive and readily available catalysts such as iron powder and copper powder instead of expensive palladium on carbon. The intermediate compound is generated by reacting 1,3-dihalopropane with the compound, and the reaction is carried out in a specific solvent, which simplifies the steps and reduces the hazards.
It enables safe and efficient compound synthesis, is suitable for scale-up production, reduces costs, and simplifies the operation process.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives, belonging to the field of pharmaceutical intermediate preparation technology. Background Technology
[0002] 6-Bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives are important intermediates for GlaxoSmithKline's 5-HT4 receptor activator drug (5-amino-6-bromo-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}-3,3-dihydro-2H-benzopyran-8-carboxamide). Currently, there are no related synthetic technology patents in China.
[0003] The existing synthetic route is reported in patent US20070232657A1:
[0004] The main problems are that the second step uses sodium hydride, which is very dangerous; the fourth step uses palladium on carbon, which is expensive; and the whole process has 7 steps, which is quite long.
[0005] Therefore, the synthesis and scale-up of 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives remains a challenge, and it is essential to find a cheap, safe, efficient synthetic route suitable for scale-up production. Summary of the Invention
[0006] The purpose of this invention is to provide a method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives. This method aims to solve the technical problems of long steps, high risks, and high costs in existing synthetic methods for 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives, achieving a safe and efficient synthesis method suitable for large-scale production. To achieve the above objective, this invention employs the following technical solution.
[0007] A synthetic method for 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives, the synthetic route is as follows:
[0008] The synthesis steps include: Step (1): Compound 1 in the route is dissolved in solvent 4 and reacts with 1,3-dihalopropane to generate compound 2; Step (2): Compound 2 is dissolved in solvent 5 and compound 3 is generated under the action of catalyst 6.
[0009] Wherein, X1 and X2 are halogens, and X1 and X2 may be the same; R1 is hydrogen, methyl, ethyl, formyl, acetyl, benzyl, benzoyl, tert-butoxycarbonyl, and R2 is hydrogen, methyl, or ethyl, and R1 and R2 may be the same.
[0010] Preferably, X1 and X2 are bromine; R1 is acetyl and R2 is methyl.
[0011] Solvent 4 in step (1) is one or more of toluene, N,N-dimethylformamide, bromobenzene, chlorobenzene, dichloromethane, dibromomethane, 1,2-dichloroethane, and 1,2-dibromoethane.
[0012] Preferably, solvent 4 is toluene.
[0013] Solvent 5 in step (2) is one or more of bromobenzene, chlorobenzene, xylene, dichlorobenzene, dibromobenzene, N,N-dimethylformamide, and N,N-dimethylacetamide.
[0014] Preferably, the solvent 5 is bromobenzene.
[0015] The catalyst 6 in step (2) is one or more of the following: iron powder, copper powder, cuprous chloride, copper chloride, ferrous chloride, ferric chloride, ferrous bromide, ferric bromide, cuprous bromide, and copper bromide.
[0016] Preferably, the catalyst is a mixture of ferric bromide and cuprous bromide; the molar ratio of ferric bromide to cuprous bromide is 0.2-3.0:1.
[0017] The preparation method in step 1 is as follows: Compound 1 was dissolved in solvent 4, potassium carbonate was added, and the molar ratio of potassium carbonate to compound 1 was 0.5-5.0:1; 1,3-dibromopropane was added, and the molar ratio of 1,3-dihalopropane to compound 1 was 0.5-5.0:1; the reaction was carried out at 40-80℃ for 1-5 hours.
[0018] The preparation method in step 2 is as follows: Compound 2 is dissolved in solvent 5, and catalyst 6 is added. The molar ratio of catalyst 6 to compound 2 is 0.1-3.0:1. The reaction is carried out at 70-130℃ for 2-6 hours.
[0019] The post-processing in step 1 is as follows: at 10-50℃, deionized water is added for washing, the organic phase is separated, dried with anhydrous sodium sulfate, filtered, and the organic phase is concentrated to obtain compound 2. The mass ratio of deionized water to compound 1 is 1.0-4.0:1.
[0020] The post-processing in step 2 is as follows: at 10-50℃, filter, add deionized water to wash the filtrate, separate the organic phase, dry with anhydrous sodium sulfate, filter, concentrate the organic phase to obtain compound 3, and the mass ratio of deionized water to compound 1 is 1.0-4.0:1.
[0021] Compared with the prior art, the beneficial effects achieved by the present invention are: 1. The raw materials are cheap and readily available, the reaction steps are few, and no expensive catalysts or hazardous excipients are used.
[0022] It is suitable for large-scale production. After process optimization and improvement, the operation is relatively simple and suitable for industrial production. Implementation
[0023] The present invention will be further described below with reference to embodiments. These embodiments are only used to more clearly illustrate the technical solutions of the present invention and should not be construed as limiting the scope of protection of the present invention. Example 1
[0024] (1) Synthesis of compound 2
[0025] Raw material 1 (100 g, 0.478 mol, 1 eq) was dissolved in 600 g of toluene, and potassium carbonate (329.82 g, 2.39 mol, 5 eq) and 1,3-dibromopropane (482.52 g, 2.39 mol, 5 eq) were added. The mixture was reacted at 80 °C for 5 hours. The temperature was lowered to 50 °C, and the mixture was washed with 400 g of deionized water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2 (122 g, 0.3695 mol), with a yield of 77.3%.
[0026] (2) Synthesis of compound 3
[0027] Compound 2 (100 g, 0.303 mol, 1 eq) was dissolved in 600 g of bromobenzene, and ferric bromide (201.41 g, 0.681 mol, 2.25 eq) and cuprous bromide (32.58 g, 0.227 mol, 0.75 eq) were added. The mixture was reacted at 130 °C for 6 hours. The mixture was cooled to 50 °C, filtered, and the filtrate was washed with 400 g of deionized water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 3 (68 g, 0.207 mol), with a yield of 68.42%. Example 2
[0028] (1) Synthesis of compound 2
[0029] Raw material 1 (100 g, 0.653 mol, 1 eq) was dissolved in 200 g of dichloromethane, and potassium carbonate (45.06 g, 0.327 mol, 0.5 eq) and 1,3-bromochloropropane (51.4 g, 0.327 mol, 0.5 eq) were added. The mixture was reacted at 40 °C for 1 hour. The mixture was cooled to 10 °C, washed with 100 g of deionized water, separated from the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2 (61 g, 0.266 mol), with a yield of 40.67%.
[0030] (2) Synthesis of compound 3
[0031] Compound 2 (100 g, 0.435 mol, 1 eq) was dissolved in 200 g of chlorobenzene, and ferric chloride (14.12 g, 0.87 mol, 0.2 eq) was added; the reaction was carried out at 70 °C for 2 hours. The mixture was cooled to 10 °C, filtered, and the filtrate was washed with 100 g of deionized water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 3 (53 g, 0.233 mol), with a yield of 53.47%. Example 3
[0032] (1) Synthesis of compound 2
[0033] Raw material 1 (100 g, 0.369 mol, 1 eq) was dissolved in 300 g of 1,2-dichloroethane, and potassium carbonate (61.04 g, 0.442 mol, 1.2 eq) and 1,3-dibromopropane (81.85 g, 0.405 mol, 1.1 eq) were added. The reaction was carried out at 65 °C for 4 hours. The mixture was cooled to 20 °C, washed with 300 g of deionized water, separated from the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2 (106 g, 0.270 mol), with a yield of 73.31%.
[0034] (2) Synthesis of compound 3
[0035] Compound 2 (100 g, 0.255 mol, 1 eq) was dissolved in xylene, and cuprous bromide (29.25 g, 0.204 mol, 0.8 eq) was added; the reaction was carried out at 120 °C for 4 hours. The mixture was cooled to 30 °C, filtered, and the filtrate was washed with 200 g of deionized water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 3 (61 g, 0.156 mol), with a yield of 61.32%.
Claims
1. A method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives, characterized in that: The synthetic route is The synthesis steps include: Step (1): Compound 1 in the route is dissolved in solvent 4 and reacts with 1,3-dibromopropane to generate compound 2; Step (2): Compound 2 is dissolved in solvent 5 and compound 3 is generated under the action of catalyst 6. Wherein, X1 and X2 are halogens, and X1 and X2 may be the same; R1 is hydrogen, methyl, ethyl, formyl, acetyl, benzyl, benzoyl, tert-butoxycarbonyl, and R2 is hydrogen, methyl, or ethyl, and R1 and R2 may be the same.
2. The method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives as described in claim 1, characterized in that, Solvent 4 in step (1) is one or more of toluene, N,N-dimethylformamide, bromobenzene, chlorobenzene, dichloromethane, dibromomethane, 1,2-dichloroethane, and 1,2-dibromoethane.
3. The method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives as described in claim 1, characterized in that, Solvent 5 in step (2) is one or more of bromobenzene, chlorobenzene, xylene, dichlorobenzene, dibromobenzene, N,N-dimethylformamide, and N,N-dimethylacetamide.
4. The method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives as described in claim 1, characterized in that, The catalyst 6 in step (2) is one or more of the following: iron powder, copper powder, cuprous chloride, copper chloride, ferrous chloride, ferric chloride, ferrous bromide, ferric bromide, cuprous bromide, and copper bromide.
5. The method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives as described in claim 1, characterized in that, The method in step 1 is as follows: Compound 1 was dissolved in solvent 4, potassium carbonate was added, and the molar ratio of potassium carbonate to compound 1 was 0.5-5.0:1; 1,3-dihalopropane was added, and the molar ratio of 1,3-dihalopropane to compound 1 was 0.5-5.0:1; the reaction was carried out at 40-80℃ for 1-5 hours.
6. The method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives as described in claim 1, characterized in that, The method in step 2 is as follows: Compound 2 is dissolved in solvent 5, and catalyst 6 is added. The molar ratio of catalyst 6 to compound 2 is 0.1-3.0:
1. The reaction is carried out at 70-130℃ for 2-6 hours.
7. The method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives as described in claim 1, characterized in that, The post-processing in step 1 is as follows: at 10-50℃, deionized water is added for washing, the organic phase is separated, dried with anhydrous sodium sulfate, filtered, and the organic phase is concentrated to obtain compound 2. The mass ratio of deionized water to compound 1 is 1.0-4.0:
1.
8. The method for synthesizing 6-bromo-5-amino-3,4-dihydro-2h-1-benzopyran-8-carboxylic acid and its derivatives as described in claim 1, characterized in that, The post-processing in step 2 is as follows: at 10-50℃, filter, add deionized water to wash the filtrate, separate the organic phase, dry with anhydrous sodium sulfate, filter, concentrate the organic phase to obtain compound 3, and the mass ratio of deionized water to compound 1 is 1.0-4.0:1.