Preparation method of phentolamine EP impurity acid salt
The method for synthesizing phentolamine EP impurity acid salts solves the problem of the lack of existing methods for synthesizing phentolamine EP impurities, and realizes the preparation of high-purity phentolamine EP impurities, providing important test samples for drug quality control and research.
Patent Information
- Application Number
- CN202511759634.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-27
- Publication Date
- 2026-01-16
AI Technical Summary
The lack of synthetic methods for phentolamine EP impurities in existing literature affects drug quality control and research.
Using resorcinol (compound I) and p-toluidine (compound II) as raw materials, phentolamine EP impurity salts were synthesized through dehydration, nucleophilic substitution, and amidation of esters. The acid was then removed by conventional freeing operations to obtain high-purity phentolamine EP impurities.
The preparation method has a reasonable process design, the product purity can reach over 99%, the operation is simple, the raw materials are readily available, and the environmental protection effect is good. It provides high-purity test samples for the study of phentolamine EP.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing a compound, and more particularly to a method for preparing phentolamine EP impurity salt. Background Technology
[0002] With the advancement of technology and the progress of the times, people have gained a more comprehensive understanding of the importance of scientifically evaluating the quality, safety, and efficacy of drugs before they are marketed. Among these evaluations, the control of impurities in drugs is closely related to drug quality. Impurities are often related to drug safety and, in a few cases, also to efficacy. Therefore, controlling impurity levels is receiving increasing attention from pharmaceutical professionals during the drug development and research process.
[0003] Phentolamine is an alpha-adrenergic receptor blocker. Clinically, it is used for vasospastic disorders such as acroarticular arterial spasm (Raynaud's disease), cyanosis of the hands and feet, septic shock, and diagnostic tests for pheochromocytoma. It is also effective for ventricular premature beats. The impurity of phentolamine, phentolamine EP impurity, has the following structural formula:
[0004] .
[0005] Phentolamine EP impurity is listed as phentolamine EP impurity A in the European Pharmacopoeia and is also a USP related compound A. To date, no reports on the synthesis method of this impurity compound have been found in existing literature databases. Therefore, there is an urgent need to develop a method for preparing this phentolamine EP impurity for the purpose of studying phentolamine impurities and providing a reference for improving drug quality. Summary of the Invention
[0006] Purpose of the invention: The purpose of this invention is to provide a method for preparing phentolamine EP impurity acid salt with a reasonable process design and high purity. In use, the acid is removed through conventional free operation to obtain phentolamine EP impurity, providing test samples for phentolamine EP research and having important application value.
[0007] Technical solution: The preparation method of the phentolamine EP impurity acid salt of the present invention includes the following steps:
[0008] (1) Using compound I resorcinol and compound II p-toluidine as raw materials, a solvent was added to carry out a dehydration reaction to obtain intermediate product III;
[0009] (2) Take intermediate product III, add solvent, add base, add benzyl bromide, and carry out nucleophilic substitution reaction to generate intermediate product IV;
[0010] (3) Take intermediate product IV, add solvent, add base, add ethyl bromoacetate, and carry out nucleophilic substitution reaction to obtain intermediate product V;
[0011] (4) Dissolve intermediate product V in a solvent, add N-tert-butoxycarbonyl-1,2-ethylenediamine, and then add a base to carry out the amidation reaction of the ester to obtain intermediate product VI;
[0012] (5) Dissolve intermediate product VI in acid and carry out a deprotection reaction to obtain the final product VII, where X represents hydrochloric acid, sulfuric acid, acetic acid, formic acid, or trifluoroacetic acid; the synthetic route is as follows:
[0013] .
[0014] Preferably, in step (1), the temperature of the dehydration reaction is 30~70℃ and the reaction time is 6~24 hours. More preferably, the reaction time is 12~18 hours.
[0015] Preferably, in step (1), the solvent is acetonitrile, acetone, dichloromethane or methanol.
[0016] Preferably, in step (2), the temperature of the nucleophilic reaction is 20~70℃ and the reaction time is 1~16 hours; more preferably, the reaction time is 1~10 hours.
[0017] Preferably, in step (2), the alkali is sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or triethylamine; the molar ratio of intermediate product III to alkali is 1:1 to 1:8; more preferably, the molar ratio of intermediate product III to alkali is 1:1 to 1:4.
[0018] Preferably, in step (2), the solvent is tetrahydrofuran.
[0019] Preferably, in step (3), the temperature of the nucleophilic substitution reaction is 20~60℃, and the reaction time is 2~24 hours. More preferably, the reaction time is 8~16 hours.
[0020] Preferably, in step (3), the molar ratio of intermediate product IV to ethyl bromoacetate is 1:1 to 1:6. More preferably, the molar ratio of intermediate product IV to ethyl bromoacetate is 1:1 to 1:3.
[0021] Preferably, in step (3), the solvent is acetonitrile, acetone, dichloromethane or tetrahydrofuran.
[0022] Preferably, in step (3), the alkali is potassium carbonate, triethylamine, sodium carbonate, or sodium hydride. More preferably, the molar ratio of intermediate product IV to alkali is 1:2 to 1:5.
[0023] Preferably, in step (4), the amidation reaction temperature of the ester is 20~70℃, and the reaction time is 2~18 hours. More preferably, the reaction time is 10~16 hours.
[0024] Preferably, in step (4), the alkali is triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or sodium hydride; the molar ratio of intermediate product V to alkali is 1:1 to 1:8. More preferably, the molar ratio of intermediate product V to alkali is 1:2 to 1:6.
[0025] Preferably, in step (4), the solvent is tetrahydrofuran, acetonitrile, acetone or methanol.
[0026] Preferably, in step (5), the temperature of the deprotection reaction is 10~60℃ and the reaction time is 1~10 hours.
[0027] Preferably, in step (5), the acid is trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, or sulfuric acid.
[0028] Preferably, the method for removing acid from phentolamine EP impurity salt by freeing is as follows: dissolve phentolamine EP impurity salt in water, add saturated sodium bicarbonate aqueous solution to adjust pH=8, extract with ethyl acetate, dry the organic layer with anhydrous sodium sulfate, and then evaporate to dryness to obtain free phentolamine EP impurity.
[0029] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The preparation method of phentolamine EP impurity salt of the present invention has a reasonable process design and the purity of the product can reach more than 99%; (2) The method of the present invention is simple to operate, the raw materials are readily available, the reaction process is controllable and the environmental protection effect is good; (3) The phentolamine EP impurity salt prepared by the present invention can be used to remove the acid to obtain phentolamine EP impurity, which provides test samples for the study of phentolamine EP and has important research value in clinical pharmacokinetic studies. Attached Figure Description
[0030] Figure 1 This is a synthetic route diagram for the phentolamine EP impurity acid salt of the present invention.
[0031] Figure 2 The NMR spectrum of the final product of phentolamine EP impurity acid salt prepared in Example 1 of this invention;
[0032] Figure 3 This is a liquid phase diagram of the final product of phentolamine EP impurity acid salt prepared in Example 1 of the present invention. Detailed Implementation
[0033] The technical solution of the present invention will be further described below with reference to the embodiments.
[0034] Example 1
[0035] The preparation method of phentolamine EP impurity acid salt of the present invention, the synthetic route is as follows: Figure 1 As shown, it includes the following steps:
[0036] (1) Preparation of compound III: 10 g of compound I resorcinol was dissolved in 50 mL of acetonitrile, and 9.7 g of compound II p-toluidine was added. The reaction was carried out at 50 °C for 16 hours. After the reaction was completed, the mixture was filtered, the reaction solution was evaporated to dryness, and the crude product was purified by column chromatography using a dichloromethane and methanol system with a volume ratio of 10:1 to obtain 15.5 g of white solid intermediate product III, with a yield of 86%.
[0037] (2) Preparation of compound IV: 15 g of intermediate product III was dissolved in 150 mL of tetrahydrofuran, 6 g of sodium hydride reagent (containing 60 wt% sodium hydride) and 12.8 g of benzyl bromide were added, and the reaction was carried out at 70 °C for 6 hours. The reaction was monitored by TLC (the developing solvent was dichloromethane:methanol = 15:1). 300 mL of water was added in an ice bath, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The organic layers were combined and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography with a dichloromethane and methanol volume ratio of 20:1 to obtain 20 g of white solid intermediate product IV, with a yield of 92%.
[0038] (3) Preparation of compound V: 10 g of intermediate product IV was dissolved in 100 mL of acetone solvent, 15.9 g of potassium carbonate was added, and then 11.5 g of ethyl bromoacetate was added. The reaction solution was reacted at 40 °C for 12 hours. The reaction was monitored by TLC (the developing solvent was dichloromethane:methanol = 20:1). The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain crude product. It was purified by column chromatography using a dichloromethane and methanol volume ratio of 30:1 to obtain 10.2 g of brown oily V, with a yield of 78%.
[0039] (4) Preparation of compound VI: 5 g of intermediate product V was dissolved in 50 mL of tetrahydrofuran, 2.1 g of N-tert-butoxycarbonyl-1,2-ethylenediamine was added, and 5.4 g of triethylamine was added. The reaction was carried out at 70 °C for 12 hours. After the reaction was completed, the reaction solution was dried by rotary evaporation. The crude product was purified by column chromatography using a dichloromethane and methanol system with a volume ratio of 30:1 to obtain 5.2 g of white solid intermediate product VI, with a yield of 80%.
[0040] (5) Preparation of compound VII: 2 g of intermediate VI was dissolved in 20 mL of trifluoroacetic acid and reacted at 30 °C for 4 hours. After the reaction was complete, the reaction solution was evaporated to dryness. The crude product was purified by column chromatography using a 10:1 volume ratio of dichloromethane and methanol to obtain 1.4 g of light purple solid VII (phentolamine EP impurity trifluoroacetate), with a yield of 82.9% and HPLC: 99.63%. NMR results are shown in [reference needed]. Figure 2(DMSO-d6), from the graph, the δ values are: 9.16 (br, 1H), 8.14 (t, 1H), 7.73 (br, 3H), 7.14–6.95 (m, 5H), 6.23 (m, 3H), 4.20 (s, 2H), 3.32 (m, 2H), 2.84 (m, 2H), 2.27 (s, 3H). See the liquid phase diagram. Figure 3 The purity is 99.6344%.
[0041] Example 2
[0042] The method for preparing phentolamine EP impurity salt of the present invention includes the following steps:
[0043] (1) Preparation of compound III: 10 g of compound I resorcinol was dissolved in 50 mL of acetone, and 9.7 g of compound II p-toluidine was added. The reaction was carried out at 30 °C for 12 hours. After the reaction was completed, the mixture was filtered, the reaction solution was evaporated to dryness, and the crude product was purified by column chromatography using a dichloromethane and methanol system with a volume ratio of 10:1 to obtain 14 g of white solid intermediate product III, with a yield of 77%.
[0044] (2) Preparation of compound IV: 10 g of intermediate product III was dissolved in 100 mL of tetrahydrofuran, 2 g of sodium hydride reagent (containing 60 wt% sodium hydride) and 8.6 g of benzyl bromide were added, and the reaction was carried out at 20 °C for 6 hours. The reaction was monitored by TLC (the developing solvent was dichloromethane:methanol = 15:1). 200 mL of water was added to the ice bath, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The organic layers were combined and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography with a dichloromethane and methanol volume ratio of 20:1 to obtain 12 g of white solid intermediate product IV, with a yield of 82%.
[0045] (3) Preparation of compound V: 10 g of intermediate IV was dissolved in 100 mL of acetone solvent, 15.9 g of potassium carbonate was added, and then 5.8 g of ethyl bromoacetate was added. The reaction solution was reacted at 20 °C for 12 hours. The reaction was monitored by TLC (the developing solvent was dichloromethane:methanol = 20:1). The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography using a dichloromethane and methanol volume ratio of 30:1 to obtain 9.8 g of brown oily intermediate V, with a yield of 75%.
[0046] (4) Preparation of compound VI: 5 g of intermediate product V was dissolved in 50 mL of tetrahydrofuran, 2.1 g of N-tert-butoxycarbonyl-1,2-ethylenediamine was added, and 8.1 g of triethylamine was added. The reaction was carried out at 20 °C for 12 hours. After the raw materials were completely reacted, the reaction solution was dried by rotary evaporation. The crude product was purified by column chromatography using a dichloromethane and methanol system with a volume ratio of 30:1 to obtain 4.3 g of white solid intermediate product VI, with a yield of 66%.
[0047] (5) Preparation of compound VII: 2 g of intermediate product VI was dissolved in 20 mL of formic acid and reacted at 10 °C for 4 hours. After the raw material was completely reacted, the reaction solution was dried by rotary evaporation. The crude product was purified by column chromatography using a 10:1 volume ratio of dichloromethane and methanol to obtain 1 g of pale yellow solid VII (phentolamine EP impurity formate), with a yield of 71%.
[0048] Example 3
[0049] The method for preparing phentolamine EP impurity salt of the present invention includes the following steps:
[0050] (1) Preparation of compound III: 10 g of compound I resorcinol was dissolved in 50 mL of methanol, and 9.7 g of compound II p-toluidine was added. The reaction was carried out at 70 °C for 16 hours. After the reaction was completed, the mixture was filtered, the reaction solution was evaporated to dryness, and the crude product was purified by column chromatography using a dichloromethane and methanol system with a volume ratio of 10:1 to obtain 13 g of white solid intermediate product III, with a yield of 72%.
[0051] (2) Preparation of compound IV: 10 g of intermediate product III was dissolved in 150 mL of tetrahydrofuran, 8 g of sodium hydride reagent (containing 60 wt% sodium hydride) and 8.6 g of benzyl bromide were added, and the reaction was carried out at 50 °C for 6 hours. The reaction was monitored by TLC (the developing solvent was dichloromethane:methanol = 15:1). 200 mL of water was added to the ice bath, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The organic layers were combined and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography with a dichloromethane and methanol volume ratio of 20:1 to obtain 11 g of white solid intermediate product IV, with a yield of 76%.
[0052] (3) Preparation of compound V: 10 g of intermediate product IV was dissolved in 100 mL of acetone solvent, 15.9 g of potassium carbonate was added, and then 17.3 g of ethyl bromoacetate was added. The reaction solution was reacted at 60 °C for 12 hours. The reaction was monitored by TLC (the developing solvent was dichloromethane:methanol = 20:1). The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography using a dichloromethane and methanol volume ratio of 30:1 to obtain 9.5 g of brown oily intermediate product V, with a yield of 73%.
[0053] (4) Preparation of compound VI: 5 g of intermediate product V was dissolved in 50 mL of tetrahydrofuran, 2.1 g of N-tert-butoxycarbonyl-1,2-ethylenediamine was added, and 5.4 g of triethylamine was added. The reaction was carried out at 50 °C for 12 hours. After the raw materials were completely reacted, the reaction solution was dried by rotary evaporation. The crude product was purified by column chromatography using a dichloromethane and methanol system with a volume ratio of 30:1 to obtain 4.6 g of white solid VI, with a yield of 71%.
[0054] (5) Preparation of compound VII: 2 g of compound VI was dissolved in 20 mL of acetic acid and reacted at 60 °C for 4 hours. After the raw materials were completely reacted, the reaction solution was dried by rotary evaporation. The crude product was purified by column chromatography using a dichloromethane and methanol system with a volume ratio of 10:1 to obtain 1.1 g of pale yellow solid VII (phentolamine EP impurity acetate), with a yield of 75%.
Claims
1. A process for the preparation of a phenolamine EP impurity acid salt, characterized in that, The method comprises the following steps: (1) taking compound I resorcinol and compound II p-toluidine as raw materials, adding a solvent, and performing a dehydration reaction to obtain intermediate product III; (2) taking intermediate product III, adding a solvent, adding a base, and adding benzyl bromide, and performing a nucleophilic substitution reaction to obtain intermediate product IV; (3) taking intermediate product IV, adding a solvent, adding a base, and adding ethyl bromoacetate, and performing a nucleophilic substitution reaction to obtain intermediate product V; (4) taking intermediate product V, dissolving it in a solvent, adding N-tert-butyloxycarbonyl-1,2-ethanediamine, and adding a base, and performing an ester amidation reaction to obtain intermediate product VI; (5) taking intermediate product VI, dissolving it in an acid, and performing a deprotection reaction to obtain final product VII, wherein X represents hydrochloric acid, sulfuric acid, acetic acid, formic acid or trifluoroacetic acid; the synthesis route is as follows: 。 2. The process for the preparation of a phenolamine EP impurity acid salt according to claim 1, characterized in that, In step (1), the dehydration reaction is performed at a temperature of 30-70 DEG C.
3. The process for preparing a phenolotamine EP impurity acid salt according to claim 1, characterized in that, In step (1), the solvent is acetonitrile, acetone, dichloromethane or methanol.
4. The process for preparing a phenolamine EP impurity acid salt according to claim 1, characterized in that, In step (2), the nucleophilic reaction is performed at a temperature of 20-70 DEG C.
5. The process for preparing a phenolotamine EP impurity acid salt according to claim 1, characterized in that, In step (2), the base is sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine; the molar ratio of intermediate product III to the base is 1:1-1:
8.
6. The process for preparing a phenolamine EP impurity acid salt according to claim 1, characterized in that, In step (3), the nucleophilic substitution reaction is performed at a temperature of 20-60 DEG C.
7. The process for preparing a phenolotamine EP impurity acid salt according to claim 1, characterized in that, In step (3), the molar ratio of intermediate product IV to ethyl bromoacetate is 1:1-1:
6.
8. The process for preparing a phenolotamine EP impurity acid salt according to claim 1, characterized in that, In step (4), the ester amidation reaction is performed at a temperature of 20-70 DEG C.
9. The process for preparing a phenolotamine EP impurity acid salt according to claim 1, characterized in that, In step (4), the base is triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or sodium hydride; the molar ratio of intermediate product V to the base is 1:1-1:
8.
10. The process for preparing a phenolotamine EP impurity acid salt according to claim 1, characterized in that, In step (5), the deprotection reaction is performed at a temperature of 10-60 DEG C.