Synthesis method of 1, 2, 3, 9-tetrahydro-4H-2-carbazole-4-ketone

Abstract

The invention discloses a preparation method of a compound shown as a formula II, under the action of zinc chloride, a compound shown as a formula I reacts at the reaction temperature of more than or equal to 120 DEG C to obtain the compound shown as the formula II, and the reaction formula is shown in the specification. The synthesis method of the 3, 4, 5, 6, 7, 9-tetrahydro-4H-2-carbazole-4-ketone has the advantages of simple operation, short reaction time, cheap and easily available raw materials, high product purity and high yield, and is very suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical intermediate synthesis, and in particular to a method for preparing carvedilol intermediate. Background Technology

[0002] Carvedilol is a third-generation beta-blocker with α and β receptor blocking, calcium antagonism, antioxidant, anti-cell proliferation, and cell-protective effects. It can be used to treat hypertension, angina pectoris, and congestive heart failure, and can significantly reduce the mortality rate of patients with congestive heart failure. Its structural formula is shown below:

[0003]

[0004] 4-Hydroxycarbazole is a key intermediate of carvedilol, and its structural formula is shown below:

[0005]

[0006] CN102190613B discloses the main route for preparing 4-hydroxycarbazole as follows:

[0007]

[0008] This synthetic route is short and uses inexpensive and readily available raw materials. The second step, the synthesis of 1,2,3,9-tetrahydro-4H-2-carbazole-4-one, mainly involves two catalytic systems: a strong acid catalytic system or a zinc chloride and acetic acid catalytic system. FR1566173 discloses a method for synthesizing 1,2,3,9-tetrahydro-4H-2-carbazole-4-one in a strong acid catalytic system. The reaction solution of this method typically contains large amounts of trifluoroacetic acid, sulfuric acid, or phosphoric acid, and the post-processing generates a large amount of acidic wastewater, creating significant wastewater treatment challenges. JP2005200344 and DE2928483 disclose methods for synthesizing 1,2,3,9-tetrahydro-4H-2-carbazole-4-one in a zinc chloride and acetic acid system. However, these methods result in numerous impurities in the reaction solution and low yields.

[0009] Given the aforementioned problems, it is essential to develop a low-cost, high-yield, and more environmentally friendly synthetic route for the synthesis of 1,2,3,9-tetrahydro-4H-2-carbazole-4-one. Summary of the Invention

[0010] This invention provides a method for preparing a compound of formula II, comprising the following steps:

[0011] Step (1): Under the action of zinc chloride, compound I reacts at a reaction temperature of ≥120℃ to give compound II, as shown in the following reaction formula:

[0012]

[0013] In some embodiments, the reaction temperature is 120–170°C, preferably 120–150°C, and more preferably 125–135°C.

[0014] In some embodiments, the reaction does not involve acetic acid.

[0015] In some embodiments, the reaction is carried out under solvent-free conditions.

[0016] In some embodiments, the reaction is carried out in the presence of organic solvent A; said organic solvent A includes a nonpolar solvent; said nonpolar solvent is preferably selected from any one or more of aromatic hydrocarbon solvents and halogenated aromatic hydrocarbon solvents, and more preferably from any one or more of cumene, xylene, chlorobenzene, and mesitylene.

[0017] In some embodiments, the volume of organic solvent A required per gram of compound I in the reaction is ≤20 mL, preferably 5 to 15 mL, and more preferably 10 mL.

[0018] In some embodiments, the organic solvent A further comprises a polar solvent selected from any one or more of ethyl acetate, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone, and tetrahydrofuran, preferably selected from any one or more of DMSO, methanol, ethanol, n-butanol, methyl ketone, methyl isobutyl ketone, and tetrahydrofuran, and more preferably n-butanol; the weight of the polar solvent is 1 / 15 to 1 / 99 of the weight of the nonpolar solvent, preferably 1 / 19 to 1 / 99.

[0019] In some embodiments, the molar ratio of the compound of formula I to zinc chloride is 1:2 to 1:10, preferably 1:2.5 to 1:7, and more preferably 1:3 to 1:5.

[0020] In some embodiments, the reaction time is 3 to 10 hours, more preferably 3 to 5 hours.

[0021] In some embodiments, the preparation method further includes the following steps:

[0022] (2-1) After the reaction is complete, add organic solvent B directly or remove organic solvent A and then add organic solvent B. Control the temperature to temperature A and stir to dissolve the residue in the system to obtain the residual liquid.

[0023] (2-2) Add an aqueous solution of inorganic salt or an aqueous solution of inorganic acid to the residue obtained in step (2-1), stir at temperature B, and then filter while hot. Wash the filter residue with organic solvent B and combine the filtrates. Evaporate part of the organic solvent B and crystallize to obtain compound II.

[0024] In some embodiments, in steps (2-1) and (2-2), the organic solvent A is as described above; the organic solvent B is selected from any one or more of ethyl acetate, dichloromethane, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone, and tetrahydrofuran, preferably selected from any one or more of DMSO, methanol, ethanol, n-butanol, methyl ketone, methyl isobutyl ketone, and tetrahydrofuran, and more preferably n-butanol; the temperature A is 60–120°C, preferably 80–110°C, and more preferably 100–110°C; the temperature B is 60–100°C, preferably 80–100°C; the stirring time is ≥0.5h, preferably ≥1h, and more preferably ≥2h.

[0025] In some embodiments, the ratio of the volume of organic solvent B in step (2-1) to the mass of the compound of formula I added at the beginning of the reaction is ≥5:1 mL / g, preferably ≥7.5:1 mL / g.

[0026] In some embodiments, the inorganic salt mentioned in step (2-2) is a carbonate, bicarbonate, phosphate, or dihydrogen phosphate, preferably potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, ammonium carbonate, sodium phosphate, disodium hydrogen phosphate, ammonium phosphate, diammonium hydrogen phosphate, potassium phosphate, or dipotassium hydrogen phosphate, and more preferably sodium carbonate.

[0027] In some embodiments, the inorganic acid mentioned in step (2-2) is phosphoric acid.

[0028] In some embodiments, the molar ratio of the inorganic acid or inorganic salt in step (2-2) to the zinc chloride added at the beginning of the reaction is ≥1.0, preferably 1.0 to 1.5, and more preferably 1.0 to 1.2.

[0029] In some embodiments, the ratio of the volume of the solution during crystallization in step (2-2) to the mass of the compound of formula I added at the beginning of the reaction is 1:1 to 5:1 mL / g, preferably 2:1 to 4:1 mL / g, and more preferably 3:1 mL / g.

[0030] In some embodiments, the solvent for crystallization in step (2-2) is n-butanol; the crystallization temperature is -10 to 20°C, preferably -5 to 10°C, and more preferably -5 to 0°C.

[0031] The present invention also provides a method for preparing carvedilol or its salt, the method comprising the preparation method of the compound of formula II above.

[0032] The method for synthesizing compound II (1,2,3,9-tetrahydro-4H-2-carbazole-4-one) provided by this invention is simple to operate, has a short reaction time, uses inexpensive and readily available raw materials, produces high-purity products, and has a high yield, making it very suitable for industrial production. Detailed Implementation

[0033] Terminology and Explanation:

[0034] In this invention, "removing the reaction solvent of the reaction" only means that the operation of removing the solvent occurs, and does not necessarily mean that the reaction solvent is completely removed.

[0035] When xylene, chlorobenzene, or mesitylene is used as a solvent, in some embodiments, the raw materials and products are not completely dissolved in the solvent during the reaction, and a viscous paste is obtained after the reaction is completed.

[0036] Polar solvents are solvents containing polar groups such as hydroxyl and carbonyl groups. Common polar solvents include: ethyl acetate, dichloromethane, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone, tetrahydrofuran, water, glycerol, propylene glycol, chloroform, etc.

[0037] Nonpolar solvents are solvents with low dielectric constants and uniform charge distribution in their molecules. Common polar solvents include benzene, petroleum ether, n-hexane, toluene, cumene, xylene, chlorobenzene, mesitylene, etc.

[0038] Xylene is any one of p-xylene, o-xylene, and m-xylene, or a mixture thereof.

[0039] In this invention, the A or B in organic solvent A and organic solvent B have no specific meaning and are only used to distinguish organic solvents in different steps.

[0040] In this invention, the A or B in temperature A and temperature B have no specific meaning and are only used to distinguish the temperature in different steps.

[0041] In this invention, the purity of the product was determined by HPLC. HPLC determination conditions: Instrument: Liquid chromatograph equipped with a UV detector; Column: Shimpack CLC-ODS; Mobile phase: buffer solution: acetonitrile = 65:35 (V / V); The buffer solution was prepared by weighing 1.77 g of potassium dihydrogen phosphate into 650 mL of purified water, dissolving it completely, and adjusting the pH to 2.0 with concentrated phosphoric acid; The diluent was used as the mobile phase; Detection wavelength: 220 nm; Column temperature: 25 °C; Flow rate: 1.0 mL / min; Retention time: 7.38 min.

[0042] In this invention, the content of residual Zn in the yield was determined by inductively coupled plasma mass spectrometry.

[0043] The following examples illustrate some embodiments and aspects of the invention. It will be apparent to those skilled in the art that various modifications, additions, substitutions, etc., can be made without altering the spirit or scope of the invention, and such modifications and variations are covered by the invention as defined in the appended claims. The invention disclosed herein is further illustrated by the following examples, which should in no way be construed as limiting.

[0044] All raw materials used in the examples are commercially available.

[0045] Example 1

[0046] 94.34 g of zinc chloride and 40 g of 1,3-cyclohexanedione monophenylhydrazone were added to 400 mL of xylene, stirred and heated to 125–130 °C, and reacted for 5 h. After the reaction was completed, xylene was removed by distillation. Then, 300 mL of n-butanol was added, and the temperature was controlled at 110 °C. The distillation residue was dissolved under stirring to obtain a residual liquid. Sodium carbonate aqueous solution (73.4 g of sodium carbonate dissolved in 300 mL of water) was slowly added to the residual liquid, and the mixture was stirred at 80–100 °C for 2 h. Then, the mixture was filtered while hot and washed with 100 mL of n-butanol to separate the organic layer. The organic layer was washed with water. Part of the n-butanol was removed from the organic layer under reduced pressure until the remaining volume was 120 mL. Then, the mixture was cooled to -5–0 °C to crystallize for 1.5 h. After filtration and drying, 30.4 g of 1,2,3,9-tetrahydro-4H-2-carbazole-4-one was obtained, with a yield of 83.0%, HPLC purity of 99.72%, and zinc content of 398 ppm.

[0047] Example 2

[0048] 23.59 g of zinc chloride and 10 g of 1,3-cyclohexanedione monophenylhydrazone were placed in a reactor, stirred and heated to 135 °C, and reacted for 4 h. After the reaction was completed, 75 mL of n-butanol was added and the temperature was controlled at 110 °C. The mixture obtained from the reaction was dissolved under stirring to obtain a residual liquid. Sodium carbonate aqueous solution (18.35 g of sodium carbonate dissolved in 75 mL of water) was slowly added to the residual liquid and stirred at 80–100 °C for 2 h. Then, the mixture was filtered while hot and washed with 25 mL of n-butanol to separate the organic layer. The organic layer was washed with water. Part of the n-butanol was removed from the organic layer under reduced pressure until the remaining volume was 30 mL. Then, the mixture was cooled to -5–0 °C to crystallize for 1.5 h. After filtration and drying, 6.95 g of 1,2,3,9-tetrahydro-4H-2-carbazole-4-one was obtained, with a yield of 75.9%, HPLC purity of 99.85%, and zinc content of 86 ppm.

[0049] Example 3

[0050] 94.34 g of zinc chloride and 40 g of 1,3-cyclohexanedione monophenylhydrazone were added to 400 mL of mesitylene, stirred and heated to 135 °C, and reacted for 3 h. After the reaction was completed, the mesitylene was poured off. Then, 300 mL of n-butanol was added, and the temperature was controlled at 110 °C. The distillation residue was dissolved under stirring to obtain a residual liquid. Sodium carbonate aqueous solution (73.4 g of sodium carbonate dissolved in 300 mL of water) was slowly added to the residual liquid, and the mixture was stirred at 80–100 °C for 2 h. Then, the mixture was filtered while hot and washed with 100 mL of n-butanol to separate the organic layer. The organic layer was washed with water. The organic layer was evaporated under reduced pressure to remove some of the n-butanol until the remaining volume was 120 mL. Then, the mixture was cooled to -5–0 °C to crystallize for 1.5 h. After filtration and drying, 27.6 g of 1,2,3,9-tetrahydro-4H-2-carbazole-4-one was obtained, with a yield of 75.3%, HPLC purity of 99.92%, and zinc content of 767 ppm.

[0051] Example 4

[0052] 47.2 g of zinc chloride and 20 g of 1,3-cyclohexanedione monophenylhydrazone were added to 200 mL of chlorobenzene, stirred and heated to 130 °C, and reacted for 4 h. After the reaction was completed, the chlorobenzene was poured off. Then, 150 mL of n-butanol was added, and the temperature was controlled at 110 °C. The distillation residue was dissolved under stirring to obtain a residual liquid. Sodium carbonate aqueous solution (36.7 g of sodium carbonate dissolved in 150 mL of water) was slowly added to the residual liquid, and the mixture was stirred at 80–100 °C for 2 h. Then, the mixture was filtered while hot and washed with 50 mL of n-butanol to separate the organic layer. The organic layer was washed with water. Part of the n-butanol was removed from the organic layer under reduced pressure until the remaining volume was 60 mL. Then, the mixture was cooled to -5–0 °C to crystallize for 1.5 h. After filtration and drying, 14.50 g of 1,2,3,9-tetrahydro-4H-2-carbazole-4-one was obtained, with a yield of 79.1%, HPLC purity of 98.91%, and zinc content of 129 ppm.

[0053] Example 5

[0054] Weigh 47.2 g of zinc chloride and 20 g of 1,3-cyclohexanedione monophenylhydrazone, add 200 mL of xylene, heat to 135 °C and react for 3 h. After the reaction is complete, pour off the xylene. Then add 150 mL of n-butanol and control the temperature at 110 °C. Stir to dissolve the distillation residue to obtain the residual liquid. Slowly add 100 mL of water and 40 g of 85% phosphoric acid solution to the residual liquid, and stir at 80–100 °C for 2 h. Then filter while hot and wash with 50 mL of n-butanol to separate the layers. After separation, wash the organic layer with water. Distill off some of the n-butanol from the organic layer under reduced pressure until the remaining volume is 60 mL. Then cool to -5–0 °C to crystallize for 1.5 h, filter, and dry to obtain 13.85 g of 1,2,3,9-tetrahydro-4H-2-carbazole-4-one, with a yield of 75.5%, HPLC purity of 99.75%, and zinc content of 449 ppm.

[0055] Example 6

[0056] 47.2 g of zinc chloride and 20 g of 1,3-cyclohexanedione monophenylhydrazone were added to a mixed solution of 163.4 g xylene (190 mL) and 8.6 g n-butanol (10.6 mL). The mixture was stirred and heated to 125 °C for 4 h. After the reaction was completed, the xylene was poured off, and then 150 mL of n-butanol was added. The temperature was controlled at 110 °C, and the distillation residue was dissolved under stirring to obtain a residual liquid. A sodium carbonate aqueous solution (36.7 g of sodium carbonate dissolved in 150 mL of water) was slowly added to the residual liquid. The mixture was stirred at 80–100 °C for 2 hours, then filtered while hot and washed with 50 mL of n-butanol to separate the organic layer. The organic layer was then washed with water. Part of the n-butanol was evaporated from the organic layer under reduced pressure until the remaining volume was 60 mL. The mixture was then cooled to -5–0 °C to crystallize for 1.5 hours. After filtration and drying, 13.80 g of 1,2,3,9-tetrahydro-4H-2-carbazole-4-one was obtained, with a yield of 75.3%, an HPLC purity of 98.8%, and a zinc content of 161 ppm.

Claims

1. A method for preparing a compound of formula II, characterized in that, Includes the following steps: Step (1): Under the action of zinc chloride, compound I reacts at a reaction temperature of ≥120℃ to give compound II, as shown in the following reaction formula:

2. The method according to claim 1, characterized in that, The reaction temperature is 120–170°C, preferably 120–150°C, and more preferably 125–135°C.

3. The method according to any one of claims 1-2, characterized in that, The reaction did not involve acetic acid.

4. The method according to any one of claims 1-3, characterized in that, The reaction was carried out in the absence of solvent.

5. The method according to any one of claims 1-3, characterized in that, The reaction is carried out in the presence of organic solvent A; the organic solvent A contains a nonpolar solvent; the nonpolar solvent is preferably selected from any one or more of aromatic hydrocarbon solvents and halogenated aromatic hydrocarbon solvents, and more preferably from any one or more of cumene, xylene, chlorobenzene, and mesitylene.

6. The method according to claim 5, characterized in that, The organic solvent A also contains a polar solvent, which is selected from any one or more of ethyl acetate, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone, and tetrahydrofuran. Preferably, it is selected from any one or more of DMSO, methanol, ethanol, n-butanol, methyl ketone, methyl isobutyl ketone, and tetrahydrofuran. More preferably, it is n-butanol. The weight of the polar solvent is 1 / 15 to 1 / 99 of the weight of the non-polar solvent, preferably 1 / 19 to 1 / 99.

7. The method according to any one of claims 1-6, characterized in that, The molar ratio of the compound of Formula I to zinc chloride is 1:2 to 1:10, preferably 1:2.5 to 1:7, and more preferably 1:3 to 1:

5.

8. The method according to any one of claims 1-7, characterized in that, The preparation method further includes the following steps: (2-1) After the reaction is complete, add organic solvent B directly or remove organic solvent A and then add organic solvent B. Control the temperature to temperature A and stir to dissolve the residue in the system to obtain the residual liquid. (2-2) Add an aqueous solution of inorganic salt or an aqueous solution of inorganic acid to the residue obtained in step (2-1), stir at temperature B, and then filter while hot. Wash the filter residue with organic solvent B and combine the filtrates. Separate the filtrates into layers. Evaporate part of the organic solvent B from the organic phase and crystallize to obtain compound of formula II.

9. The method according to claim 8, characterized in that, In steps (2-1) and (2-2), the organic solvent A is as described above; the organic solvent B is selected from any one or more of ethyl acetate, dichloromethane, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone, and tetrahydrofuran, preferably selected from any one or more of DMSO, methanol, ethanol, n-butanol, methyl ketone, methyl isobutyl ketone, and tetrahydrofuran, and more preferably n-butanol; the temperature A is 60–120°C, preferably 80–110°C, and even more preferably 100–110°C; the temperature B is 60–100°C, preferably 80–100°C; the stirring time is ≥0.5 h, preferably ≥1 h, and more preferably ≥2 h; the ratio of the volume of the organic solvent B in step (2-1) to the mass of the compound of formula I added at the beginning of the reaction is ≥5:1 mL / g, preferably ≥7.5:1 mL / g.

10. The method according to any one of claims 8-9, characterized in that, The inorganic salt mentioned in step (2-2) is a carbonate, bicarbonate, phosphate, or dihydrogen phosphate, preferably potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, ammonium carbonate, sodium phosphate, disodium hydrogen phosphate, ammonium phosphate, diammonium hydrogen phosphate, potassium phosphate, or dipotassium hydrogen phosphate, and more preferably sodium carbonate.

11. The method according to any one of claims 8-9, characterized in that, The inorganic acid mentioned in step (2-2) is phosphoric acid.

12. The method according to any one of claims 8-11, characterized in that, The ratio of the volume of the solution during crystallization in step (2-2) to the mass of the compound of formula I added at the beginning of the reaction is 1:1 to 5:1 mL / g, preferably 2:1 to 4:1 mL / g, and more preferably 3:1 mL / g; the solvent during crystallization in step (2-2) is n-butanol, and the crystallization temperature is -10 to 20°C, preferably -5 to 10°C, and more preferably -5 to 0°C.

13. A method for preparing carvedilol or a salt thereof, the method comprising the method according to any one of claims 1-12.

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