Preparation method of lacidipine intermediate
Patent Information
- Application Number
- CN202380083405.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-12-27
- Filing Date
- 2023-12-22
- Publication Date
- 2025-07-29
AI Technical Summary
In the existing synthesis method of lacidipine intermediate, the reaction yield is low and there is Z isomer impurity, and the use of sodium hydroxide as an alkali reagent can easily lead to emulsification problems, affecting the safety and efficiency of industrial production.
Using an organic base as a catalyst in an organic solvent, Compound II and Compound III are reacted to generate a lacidipine intermediate, avoiding the use of sodium hydroxide, and using appropriate temperatures and types of organic bases to improve reaction efficiency and product purity.
The yield and purity of compound I are significantly improved, the production of Z isomer impurities is avoided, the reaction conditions are simplified, the production of by-products is reduced, and the industrial application value is improved.
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Abstract
Description
A preparation method of lacidipine intermediate Technical Field
[0001] The present invention relates to the field of chemical synthesis, and in particular to a method for preparing a lacidipine intermediate. Background Art
[0002] Heart disease, including hypertension, angina, and arrhythmias, has become a major health hazard for middle-aged and elderly people in recent years. Lacidipine, a dihydropyridine calcium antagonist, is commonly used to treat hypertension and atherosclerosis. It also exhibits excellent antioxidant properties and vascular selectivity, and is currently widely used clinically.
[0003] Compound I is an important intermediate in the synthesis of lacidipine. Currently, CN102464608A discloses the synthesis of Compound I, using o-phthalaldehyde (Compound II) and tert-butyloxycarbonylmethyltriphenylphosphonium bromide (Compound III) as raw materials and sodium hydroxide as the base reagent. The synthesis route is as follows, and the reaction yield is 52%.
[0004] Summary of the Invention
[0005] The present invention provides a method for preparing a lacidipine intermediate I: Compound II and Compound III react in an organic solvent in the presence of an organic base to generate a lacidipine intermediate shown in Formula I.
[0006] In some embodiments, the organic solvent is selected from one or more of toluene, dichloromethane, tetrahydrofuran, acetonitrile, ethanol, and tert-butanol.
[0007] In some embodiments, the organic base is a basic organic amine.
[0008] In some embodiments, the basic organic amine is one or more of triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene (DBU).
[0009] In some embodiments, the reaction temperature is -20°C to 50°C, preferably -10°C to 20°C.
[0010] In some embodiments, the amount of Compound II used is 1.0 to 1.5 molar equivalents of Compound III.
[0011] In some embodiments, the amount of the organic base used is 1.0 to 3.0 molar equivalents of compound III.
[0012] In some embodiments, a lithium salt is added to the reaction.
[0013] In some embodiments, the lithium salt is lithium chloride or lithium bromide.
[0014] Compared with the prior art, the preparation method of the present invention can effectively avoid the production of o-carboxybenzyl alcohol, reduce the Z isomer impurity, and significantly improve the yield and purity of compound I. The reaction raw materials are inexpensive and readily available, the reaction conditions are simple and mild, and the operation is simple, which has great application value in industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG1 is a liquid chromatogram of a liquid chromatography-mass spectrometry (LC-MS) diagram of the compound obtained in Example 1.
[0016] FIG2 is an ion flow diagram of the liquid chromatography-mass spectrometry (LC-MS) diagram of the compound obtained in Example 1.
[0017] FIG3 is a mass spectrum at a retention time of 2.672 min in FIG2 .
[0018] FIG4 is a hydrogen NMR spectrum (400 Hz, DMSO-d6) of the compound obtained in Example 1.
[0019] FIG5 is a high performance liquid chromatography (HPLC) chart of the compound obtained in Example 1. DETAILED DESCRIPTION
[0020] All ranges recited herein include those endpoints of the range between the two values recited. Regardless of whether or not indicated, all values recited herein include the expected experimental error, technical error, and instrument error of the given technology used to measure the value. When the degree of error is not recited, all values recited herein include a range of ±10% of the recited value.
[0021] In the present invention, unless otherwise specified, % refers to weight / weight (w / w) percentage.
[0022] In the present invention, the term "equivalent" refers to the molar ratio of the reactants to compound III.
[0023] In the present invention, the HPLC detection method is as follows:
[0024] The technical solution of the present invention will be further described in detail below through specific examples and in conjunction with the accompanying drawings. The examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Unless otherwise specified, the materials and reagents used are all commercially available reagents and materials.
[0025] Example 1
[0026] Under N2 protection, 100 g of compound III was added to a three-necked flask, dissolved in 300 mL of toluene, and stirred at room temperature. 34 g of compound II was then added, and then cooled to -10°C. 27 g of triethylamine was dissolved in 200 mL of toluene and added dropwise to the reaction system. The temperature was controlled at -10°C. After the addition was complete, the reaction was allowed to proceed for 1 to 2 hours.
[0027] The reaction solution was filtered, and 31 g of anhydrous calcium bromide and 200 mL of toluene were added to the filtrate. The mixture was stirred at room temperature for 10-15 hours, filtered, and the filtrate was concentrated to dryness. 60 mL of ethyl acetate and 120 mL of petroleum ether were added to the concentrate, and the temperature was programmed to -45°C over 4 hours. The mixture was filtered to obtain 41.3 g of the target compound I, with a yield of 80.9%. The obtained compound was analyzed by liquid chromatography-mass spectrometry (LC-MS), nuclear magnetic resonance spectroscopy (NMR), and high-performance liquid chromatography (HPLC). As shown in Figures 1 to 4, Compound I was successfully obtained. As shown in Figure 5, the purity of Compound I was 97.78%.
[0028] Example 2
[0029] Under N2 protection, 10 g of compound III was added to a three-necked flask, dissolved in 30 mL of acetonitrile, and stirred at room temperature. 4.5 g of compound II was then added, and then cooled to -10°C. 4.4 g of N-methylmorpholine was dissolved in 20 mL of acetonitrile and added dropwise to the reaction system. The temperature was controlled at -10°C, and the reaction was allowed to react for 1 to 2 hours after the addition was complete.
[0030] The reaction solution was filtered, 5 g of anhydrous calcium bromide was added to the filtrate, and the mixture was stirred at room temperature for 10-15 h. The mixture was filtered and the filtrate was concentrated. 3.6 g of the target compound I was obtained by column chromatography with a yield of 72%, a purity of 90%, and a Z isomer content of 1.8%.
[0031] Example 3
[0032] Under nitrogen protection, add 10g of compound III to a three-necked flask, dissolve it in 30mL of ethanol, and stir at room temperature. Then add 3.0g of compound II. Then, cool to -20°C, dissolve 3.3g of N,N-diisopropylethylamine in 20mL of ethanol, and add it dropwise to the reaction system. Maintain the temperature at -20°C, and react for 1-2 hours after the addition is complete.
[0033] The reaction solution was filtered, 5 g of anhydrous calcium bromide was added to the filtrate, and the mixture was stirred at room temperature for 10-15 h. The mixture was filtered and the filtrate was concentrated. 39.9 g of the target compound I was obtained by column chromatography with a yield of 78%, a purity of 96.3%, and a Z isomer content of 2.0%.
[0034] Example 4
[0035] Under nitrogen protection, add 10g of compound III to a three-necked flask, dissolve it in 30mL of tetrahydrofuran, and stir at room temperature. Then add 3.4g of compound II and 1.8g of lithium chloride. Then, cool to -0°C, dissolve 3.3g of N,N-diisopropylethylamine in 20mL of tetrahydrofuran, and add it dropwise to the reaction system. Maintain the temperature at 0°C. After the addition is complete, react for 1-2 hours.
[0036] The reaction solution was filtered, 5 g of anhydrous calcium bromide was added to the filtrate, and the mixture was stirred at room temperature for 10 to 15 h. The mixture was filtered and the filtrate was concentrated. 41.5 g of the target compound I was obtained by column chromatography with a yield of 91%, a purity of 97.1%, a Z isomer content of 1.2%, and no o-carboxybenzyl alcohol was detected.
[0037] Comparative Example 1
[0038] Under nitrogen protection, add 10g of compound III to a three-necked flask, dissolve it in 50mL of tetrahydrofuran, and stir at room temperature. Then add 3.4g of compound II. Then, cool to -10°C and add 1g of sodium hydride in four batches to the reaction system. Maintain the temperature at -10°C and allow to react for 1-2 hours after addition.
[0039] The reaction solution was poured into 100 mL of ice-cold brine to quench, and 50 mL of tert-methyl ether was added. The aqueous phase was separated and removed, and the organic phase was dried over 5 g of anhydrous sodium sulfate. 5.5 g of anhydrous calcium bromide was added to the organic phase, and the mixture was stirred at room temperature for 10 to 15 h. The mixture was filtered and the filtrate was concentrated to obtain 3.6 g of the target compound I with a yield of 70% and a purity of 79%. The main by-product was the disubstituted impurity 1.
[0040] Using sodium hydride as an alkaline reagent to participate in the reaction will produce hydrogen, which is dangerous and not conducive to the safe conduct of the reaction.
[0041] Comparative Example 2
[0042] Under nitrogen protection, add 10g of compound III to a three-necked flask, dissolve it in 100mL of dichloromethane, and stir at room temperature. Then add 3.4g of compound II. Then, cool to -10°C, dissolve 1.5g of sodium hydroxide in 50mL of water, cool to room temperature, and add dropwise to the reaction system. Maintain the temperature at -10°C. After the addition is complete, react for 1-2 hours.
[0043] The aqueous phase was separated and removed, and the organic phase was dried over 5 g of anhydrous sodium sulfate. 4.5 g of anhydrous calcium bromide was added to the organic phase, and the mixture was stirred at room temperature for 10 to 15 h. The mixture was filtered and the filtrate was concentrated to obtain 4.6 g of the target compound I with a yield of 60% and a purity of 85%, containing approximately 4% Z isomer impurity and 2.5% o-carboxybenzyl alcohol.
[0044] After scaling up this preparation method, the reaction results deteriorate with each order of magnitude due to mass transfer issues. Furthermore, the organic solvent, dichloromethane, easily emulsifies with the sodium hydroxide solution, making subsequent separation difficult.
[0045] Comparative Example 3
[0046] Under nitrogen protection, 10g of Compound III was added to a three-necked flask and dissolved in 30mL of tetrahydrofuran. The mixture was stirred at room temperature, followed by the addition of 3.4g of Compound II. The mixture was then cooled to -10°C, and 3g of potassium tert-butoxide was dissolved in 40mL of tetrahydrofuran and added dropwise to the reaction system. The temperature was maintained at -10°C, and the reaction was allowed to proceed for 1-2 hours after the addition was complete. The yield of the target compound I was less than 30%.
[0047] Comparative Example 4
[0048] Under nitrogen protection, 10 g of compound III was added to a three-necked flask and dissolved in 100 mL of tetrahydrofuran. The mixture was stirred at room temperature, followed by the addition of 3.4 g of compound II. The mixture was then cooled to -10°C. 12 mL of lithium diisopropylamide (2 mol / L) was dissolved in 20 mL of tetrahydrofuran and added dropwise to the reaction system, maintaining the internal temperature at no more than -70°C. After the addition was complete, the reaction was allowed to proceed for 1-2 hours, followed by natural warming. The yield of compound I was less than 40%.
[0049] The preparation method of the present invention does not use sodium hydroxide as an alkaline reagent, thereby avoiding emulsification of sodium hydroxide with the organic solvent used in the reaction. In addition, the use of an organic base also effectively avoids the mass transfer problem of the two-phase method during industrial scale-up.
[0050] It should be understood that the above-described embodiments are only preferred solutions of the present invention and do not limit the present invention in any form. Other variations and modifications are possible without exceeding the technical solutions described in the claims.
Claims
1. A method for preparing a lacidipine intermediate I, characterized in that: Compound II reacts with compound III in an organic solvent in the presence of an organic base to generate a lacidipine intermediate shown in formula I.
2. The method for preparing the intermediate I according to claim 1, characterized in that: The organic solvent is selected from one or more of toluene, dichloromethane, tetrahydrofuran, acetonitrile, ethanol and tert-butanol.
3. The preparation method according to claim 1, characterized in that: The organic base is a basic organic amine.
4. The preparation method according to claim 3, characterized in that: The alkaline organic amine is one or more of triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene (DBU). The preparation method according to claim 1 , wherein the reaction temperature is -20° C. to 50° C. The preparation method according to claim 1 , wherein the reaction temperature is -10° C. to 20° C.
7. The preparation method according to claim 1, wherein the amount of compound II used is 1.0 to 1.5 molar equivalents of compound III.
8. The preparation method according to claim 1, wherein the amount of the organic base used is 1.0 to 3.0 molar equivalents of compound III.
9. The preparation method according to claim 1, wherein a lithium salt is added during the reaction.
10. The preparation method according to claim 9, wherein the lithium salt is lithium chloride or lithium bromide.
11. Lacidipine intermediate I obtained by the preparation method according to any one of claims 1 to 10, 12. A method for preparing lacidipine from the lacidipine intermediate I according to claim 11.
13. Lacidipine obtained by the preparation method according to claim 12.