A method for synthesizing ondansetron intermediate tetrahydrocarbazolone

Abstract

The invention belongs to the field of drug synthesis, and specifically relates to a synthesis method of tetrahydrocarbazolone, an intermediate of ondansetron, wherein 2-bromo-2-cyclohexene-1-one and 2-nitrobenzeneboric acid are used as raw materials, tetrakis(triphenylphosphine)palladium is used as a catalyst, a coupling reaction is performed to generate a compound shown in formula III, and then iron powder is used to reduce the compound shown in formula II, and then anhydrous phosphoric acid cyclization reaction is performed to obtain the compound. The method has high conversion rate, saves reaction time, avoids the use of ionic liquid catalysts while ensuring yield, and does not need to increase subsequent three waste treatment steps.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing tetrahydrocarbazolone, an ondansetron intermediate. Background Art

[0002] Ondansetron, chemical name is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-one, chemical formula is C 18 H 19 N3O is a potent and highly selective 5-HT3 receptor antagonist launched by Glaxo in the 1990s. It is clinically used to prevent or treat nausea and vomiting caused by chemotherapy drugs (such as cisplatin, doxorubicin, etc.) and radiotherapy.

[0003] The synthesis of ondansetron mainly relies on chemical methods, and is usually obtained by four steps of substitution, coupling, etc. of the intermediate tetrahydrocarbazolone (Formula I). ​​However, as a key raw material for preparing ondansetron, tetrahydrocarbazolone (Formula I) has a low synthesis yield, usually only about 20% in total yield, and the quality of the synthesized product is poor, which seriously affects the product quality of ondansetron. Therefore, the improvement of the synthesis process of the intermediate tetrahydrocarbazolone (Formula I) will have extensive social and economic benefits.

[0004] Chinese patent (CN201110229623.2) discloses a method for synthesizing indole compounds, which involves a method for synthesizing tetrahydrocarbazolone, and the yield can reach more than 90%. The synthetic route involved is as follows:

[0005]

[0006] This synthetic route uses 1,3-cyclohexanedione and phenylhydrazine hydrochloride as starting materials, and uses sulfonic acid ionic liquid as a catalyst to synthesize tetrahydrocarbazolone (Formula I). ​​Although ionic liquids have the advantages of being non-volatile, non-flammable, having a wide liquid temperature range and being reusable, the toxicity of ionic liquids, the three wastes treatment of ionic liquids, and the high price of ionic liquids still need time to be solved. Therefore, it is urgent to design a new method for synthesizing tetrahydrocarbazolone, an intermediate of ondansetron. Summary of the invention

[0007] In order to overcome the above technical problems, the present invention provides a new synthesis method of ondansetron intermediate tetrahydrocarbazolone, which avoids using the above ionic liquid catalyst.

[0008] The technical solutions to the above technical problems are as follows:

[0009] 2-bromo-2-cyclohexene-1-one and 2-nitrophenylboric acid are used as raw materials, and a coupling reaction is performed under the action of a catalyst to generate a compound shown in formula III, wherein the catalyst is tetrakis(triphenylphosphine)palladium, and then iron powder is used to reduce the compound shown in formula II, and then anhydrous phosphoric acid cyclization reaction is performed to obtain an ondansetron intermediate tetrahydrocarbazolone shown in formula I;

[0010] The synthetic route is as follows:

[0011]

[0012] The following steps are involved:

[0013] Coupling reaction (step S1): 2-bromo-2-cyclohexene-1-one and 2-nitrobenzeneboric acid are added to a reaction vessel with a stirrer in a weight ratio of 1:0.95-1.4, and tetrakis(triphenylphosphine)palladium, alkaline aqueous solution and 1,2-dimethoxyethane are added and stirred to mix evenly, and the weight ratio of tetrakis(triphenylphosphine)palladium to 2-bromo-2-cyclohexene-1-one is 0.07-0.13:1; the mixed solution is transferred into a sealed tube, reacted at 80-95°C for 7-8h, and then the mixed solution is added dropwise to an ice-water mixture, extracted with ethyl acetate, and then washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure, and recrystallized with methanol and acetic acid to obtain a compound shown in formula III; the alkaline aqueous solution is preferably a 2mol / L K3PO4 aqueous solution.

[0014] Reduction reaction (step S2): water and ethanol are mixed in a volume ratio of 1:3-4 and added into a reaction container, and then the compound represented by formula III obtained in step S1 is added into the reaction bottle in a weight-to-volume ratio of 1 g:28-38 mL of the water-to-ethanol mixture, and concentrated hydrochloric acid is added under stirring, and the weight-to-volume ratio of the compound represented by formula III to concentrated hydrochloric acid is 1 g:3-7 mL; iron powder is then added, and the weight of the iron powder added is 0.75-3 times that of the compound represented by formula III; heating reaction is carried out for 0.5-1 h, and after the reaction, the mixture is poured into an ice-water mixture, and the pH is adjusted to 7-8 with a 50% sodium hydroxide solution, extracted with dichloromethane, and rotary evaporated to obtain the compound represented by formula II.

[0015] Cyclization reaction (step S3): Under nitrogen protection, the compound of formula II obtained in step S2 is heated until completely melted, and anhydrous phosphoric acid 0.8 to 1.2 times the weight of the compound of formula II is slowly added dropwise, the temperature is raised to 180 to 190°C, and the reaction is stirred for 2 to 3 hours. After the reaction, it is poured into an ice-water mixture, and the pH is adjusted to 7±0.05 with a 5% sodium hydroxide solution, filtered, and the filtrate is extracted with CH2Cl, and the organic layers are combined and washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and CH2Cl is recovered by vacuum rotary evaporation to obtain the compound of formula I. Anhydrous phosphoric acid is prepared by phosphoric acid with a mass concentration of 85% and P2O5 in a mass ratio of 10:3.

[0016] The beneficial effects of the present invention are:

[0017] The invention synthesizes the target product, ondansetron intermediate tetrahydrocarbazolone, of the structure shown in Formula I by three steps of coupling, reduction and cyclization. The synthesis route is novel and simple, the raw materials are easily available, and it has the following advantages:

[0018] (1) The catalyst used is tetrakis(triphenylphosphine)palladium, which is non-toxic. In addition, since the temperature in step S1 is controlled at 85-95° C., the raw material 2-bromo-2-cyclohexene-1-one can be melted and completely dissolved in the reaction system, and the reaction can be kept in a reflux state. The reaction is carried out in a sealed tube to ensure the forward direction of the reaction, which will inevitably increase the conversion rate and save the reaction time. While ensuring the equivalent yield of the Chinese patent (CN201110229623.2), the use of ionic liquid catalysts is avoided, and there is no need to add subsequent three waste treatment steps;

[0019] (2) In step S2, a large number of reduction processes are used, which is simple and convenient, easy to post-process, has good reaction selectivity, and high product quality;

[0020] (3) In step S3, anhydrous phosphoric acid is creatively used as a cyclization reagent. After the reaction is completed, the subsequent processing steps are simple;

[0021] (4) The process of the present invention has a short reaction time and an HPLC purity of more than 99%, which is suitable for large-scale production and promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0023] Figure 1 is the H NMR spectrum of the compound represented by Formula I prepared in Example 1 of the present invention;

[0024] Figure 2 This is the NMR carbon spectrum of the compound represented by Formula I prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0025] Embodiment 1:

[0026] Step S1: Add 1 kg of 2-bromo-2-cyclohexene-1-one and 0.95 kg of 2-nitrobenzeneboric acid into a reaction container with a stirrer, add 70 g of tetrakis(triphenylphosphine)palladium, 1 L of 2 mol / L K3PO4 aqueous solution and 2 L of 1,2-dimethoxyethane and stir to mix evenly; transfer the mixed solution into a sealed tube, react at 85° C. for 8 h, then add the mixed solution dropwise into an ice-water mixture, extract three times with 500 mL of ethyl acetate, then wash with saturated NaCl solution, dry over anhydrous sodium sulfate, filter, recover ethyl acetate by rotary evaporation under reduced pressure, and recrystallize with a mixed solution of methanol and acetic acid in a volume ratio of 50:1 to obtain a compound shown in formula III, with a yield of 83.7%.

[0027] The compound shown in formula III has the following NMR spectrum data:

[0028] 1 H NMR (300MHz, DMSO-d6) δ: 8.82 (d, J=9.0Hz, 1H, -Ar-H), 7.89~7.76 (m, 3H, -Ar-H), 6.39 ( t, J=9.0Hz, 1H), 3.40 (t, J=6.0Hz, 2H, -CH2-), 2.10 (m, 2H, -CH2-), 1.61 (m, 2H, -CH2-); 13 C NMR (75MHz; DMSO-d6) δ: 199.27, 146.09, 142.32, 139.83, 135.49, 131.83, 129.28, 127.35, 123.74, 37.19, 27.40, 23.26; HR (ESI) MS (m / z): [M+H] + :218.0706.

[0029] The purity was determined by HPLC to be 97.6%.

[0030] Step S2: Mix 7L of water and 21L of ethanol and add them into a reaction bottle, then add 1kg of the compound represented by formula III obtained in step S1, add 3L of concentrated hydrochloric acid under stirring, and then add 750g of iron powder; heat to react for 1h, pour into an ice-water mixture after the reaction, adjust the pH to 7-8 with 50% sodium hydroxide solution, extract with dichloromethane, and rotary evaporate to obtain the compound represented by formula II, with a yield of 98.5%.

[0031] The compound shown in formula II has the following NMR spectrum data:

[0032] 1H NMR (300MHz, DMSO-d6) δ: 8.53 (d, J=9.0Hz, 1H), 6.89~6.56 (m, 4H), 5.0 (s, 2H, -NH2), 3.28 (t, J=6.0Hz, 2H, -CH2-), 2.04 (m, 2H, -CH2-), 1.59 (m, 2H, -CH2-); 13 C NMR (75MHz, DMSO-d6) δ: 199.27, 147.39, 141.23, 136.22, 129.72, 131.83, 12 3.81, 121.52, 119.60, 116.34, 37.51, 26.60, 23.25; HR(ESI)MS(m / z): [M+H] + :188.0103.

[0033] The purity was determined by HPLC to be 98.3%.

[0034] Step S3: Under nitrogen protection, 1 kg of the compound shown in formula II obtained in step S2 was heated until completely melted, 800 g of anhydrous phosphoric acid was slowly added dropwise, the temperature was raised to 190°C, and the reaction was stirred for 2 hours. After the reaction, it was poured into an ice-water mixture, and the pH was adjusted to 7±0.05 with a 5% sodium hydroxide solution. The mixture was filtered, and the filtrate was extracted with CH2Cl. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and CH2Cl was recovered by vacuum rotary evaporation to obtain a compound shown in formula I in a yield of 95.3%.

[0035] Wherein, anhydrous phosphoric acid is prepared by phosphoric acid with a mass concentration of 85% and P2O5 in a mass ratio of 10:3.

[0036] The compound shown in formula I has the following NMR spectrum data:

[0037] 1 H NMR (300MHz, DMSO-d6) δ: 11.83 (s, 1H, -NH), 7.88~7.83 (m, 1H, -Ar-H), 7.41 (d, J=9.0Hz, 1H, -Ar-H), 7.18~ 7.05 (m, 2H, -Ar-H), 2.95 (t, J = 9.0Hz, 2H, -CH2-), 2.40 (t, J = 6.0Hz, 2H, -CH2-), 2.14 ~ 2.10 (m, 2H, -CH2-); 13C NMR (75MHz, DMSO-d6) δ: 192.93, 152.36, 135.82, 124.52, 122.47, 121.50, 120.27, 111.71, 111.58, 37.89, 23.41, 22.77; HR (ESI) MS (m / z): [M+H] + :186.0823.

[0038] The purity was determined by HPLC to be 99.2%.

[0039] Embodiment 2:

[0040] Step S1: 1 kg of 2-bromo-2-cyclohexene-1-one and 1.4 kg of 2-nitrobenzeneboric acid are added to a reaction bottle with a stirrer, 130 g of tetrakis(triphenylphosphine)palladium, 1 L of 2 mol / L alkaline sodium phosphate aqueous solution and 2 L of 1,2-dimethoxyethane are added and stirred to mix evenly, the mixed solution is transferred into a sealed tube, reacted at 80° C. for 7 h, then the mixed solution is added dropwise to an ice-water mixture, extracted four times with 550 mL of ethyl acetate, then washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and ethyl acetate is recovered by vacuum rotary evaporation, and recrystallized with a mixed solution of methanol and acetic acid in a volume ratio of 50:1 to obtain a compound shown in formula III, with a yield of 88.2%.

[0041] Step S2: 7.6L of water and 30.4L of ethanol were mixed and added to a reaction bottle, and then 1kg of the compound represented by formula III obtained in step S1 was added, 7L of concentrated hydrochloric acid was added under stirring, and then 3kg of iron powder was added; heating reaction was carried out for 0.5h, and after the reaction, the mixture was poured into an ice-water mixture, the pH was adjusted to 7-8 with 50% sodium hydroxide solution, extracted with dichloromethane, and rotary evaporated to obtain the compound represented by formula II, with a yield of 99.4%.

[0042] Step S3: Under nitrogen protection, 1 kg of the compound shown in formula II obtained in step S2 was heated until completely melted, 1.2 kg of anhydrous phosphoric acid was slowly added dropwise, the temperature was raised to 180°C, and the reaction was stirred for 3 hours. After the reaction, it was poured into an ice-water mixture, and the pH was adjusted to 7±0.05 with a 5% sodium hydroxide solution. The mixture was filtered, and the filtrate was extracted with CH2Cl. The organic layers were combined and washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and CH2Cl was recovered by vacuum rotary evaporation to obtain a compound shown in formula I in a yield of 96.7%.

[0043] Wherein, anhydrous phosphoric acid is prepared by phosphoric acid with a mass concentration of 85% and P2O5 in a mass ratio of 10:3.

[0044] Embodiment 3:

[0045] Step S1: 1 kg of 2-bromo-2-cyclohexene-1-one and 1.2 kg of 2-nitrobenzeneboric acid are added to a reaction bottle with a stirrer, 100 g of tetrakis(triphenylphosphine)palladium, 1 L of 2 mol / L alkaline phosphoric acid aqueous solution and 2 L of 1,2-dimethoxyethane are added and stirred to mix evenly, the mixed solution is transferred into a sealed tube, reacted at 90° C. for 7.5 h, then the mixed solution is added dropwise to an ice-water mixture, extracted five times with 520 mL of ethyl acetate, then washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and ethyl acetate is recovered by vacuum rotary evaporation, and recrystallized with a mixed solution of methanol and acetic acid in a volume ratio of 50:1 to obtain a compound shown in formula III, with a yield of 86.4%.

[0046] Step S2: 7.3L of water and 33.58L of ethanol were mixed and added to a reaction bottle, and then 1kg of the compound represented by formula III obtained in step S1 was added, 5L of concentrated hydrochloric acid was added under stirring, and then 1.8kg of iron powder was added; heating reaction was carried out for 45min, and after the reaction, the mixture was poured into an ice-water mixture, the pH was adjusted to 7-8 with 50% sodium hydroxide solution, and the mixture was extracted with dichloromethane, and the compound represented by formula II was obtained by rotary evaporation, and the yield was 99.0%.

[0047] Step S3: Under nitrogen protection, 1 kg of the compound shown in formula II obtained in step S2 was heated until completely melted, 1 kg of anhydrous phosphoric acid was slowly added dropwise, the temperature was raised to 185°C, and the reaction was stirred for 2.5 hours. After the reaction, it was poured into an ice-water mixture, and the pH was adjusted to 7±0.05 with a 5% sodium hydroxide solution. The mixture was filtered, and the filtrate was extracted with CH2Cl. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and CH2Cl was recovered by rotary evaporation under reduced pressure to obtain the compound shown in formula I in a yield of 96.3%.

[0048] Wherein, anhydrous phosphoric acid is prepared by phosphoric acid with a mass concentration of 85% and P2O5 in a mass ratio of 10:3.

[0049] Comparative Example 1:

[0050] The compound described in Formula I was synthesized by the method of Example 21 in a method for synthesizing indole compounds invented by Li Bailin in Chinese patent (CN201110229623.2). Sulfonic acid ionic liquid [(HSO3-p)2im][CF3SO3] (0.125 mmol), phenylhydrazine hydrochloride (25 mmol), 1,3-cyclohexanedione (25 mmol) and 15 mL of water were added to the reaction vessel in sequence, placed in a microwave reactor, and subjected to microwave reaction at 100°C for 15 minutes under mechanical stirring. The mixture was cooled to room temperature, and the mixed solution was directly filtered and dried to obtain 4.37 g with a yield of 95%.

[0051] The comparison results of the product synthesized by the method of the present invention and the product synthesized in Comparative Example 1 are shown in Table 1 below:

[0052] Table 1

[0053] Yield of compound of formula I purity toxicity Three Waste Treatment Example 1 95.3％ 99.2％ Non-toxic No treatment required Example 2 96.7％ / Non-toxic No treatment required Example 3 96.3％ / Non-toxic No treatment required Comparative Example 1 95％ / Catalyst is toxic Need to be processed

[0054] Therefore, the invention avoids the use of ionic liquid catalysts while ensuring a yield comparable to that of the Chinese patent (CN201110229623.2), and does not require the addition of subsequent three waste treatment steps.

[0055] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any simple modification or equivalent changes made to the above embodiments based on the technical essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for synthesizing ondansetron intermediate tetrahydrocarbazolone shown in formula I, characterized in that: 2-bromo-2-cyclohexene-1-one and 2-nitrobenzeneboric acid are used as raw materials, and a coupling reaction is performed in the presence of a catalyst to generate a compound shown in formula III, wherein the catalyst is tetrakis(triphenylphosphine)palladium, and then iron powder is used to reduce the compound shown in formula II, and then anhydrous phosphoric acid cyclization reaction is performed to obtain the compound; in: Step S1, coupling reaction: 2-bromo-2-cyclohexene-1-one and 2-nitrobenzeneboric acid are added to a reaction vessel with a stirrer, tetrakis(triphenylphosphine)palladium, alkaline aqueous solution and 1,2-dimethoxyethane are added and stirred to mix evenly, the mixed solution is transferred into a sealed tube, reacted at 80-95° C. for 7-8 hours, then the mixed solution is added dropwise to an ice-water mixture, extracted with ethyl acetate, then washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, the solvent is evaporated under reduced pressure, and recrystallized with methanol and acetic acid to obtain a compound shown in formula III; Step S2, reduction reaction: water, ethanol and the compound represented by formula III obtained in step S1 are added to a reaction container, concentrated hydrochloric acid is added under stirring, and then iron powder is added, and the mixture is heated for reaction. After the reaction, the mixture is poured into an ice-water mixture, and the pH is adjusted to 7-8 with 50% sodium hydroxide solution, and the mixture is extracted with dichloromethane, and the compound represented by formula II is obtained by rotary evaporation; Step S3, cyclization reaction: under nitrogen protection, the compound of formula II obtained in step S2 is heated until completely melted, anhydrous phosphoric acid is slowly added dropwise, the temperature is raised to 180-190° C., and the mixture is stirred for reaction for 2-3 hours. After the reaction, the mixture is poured into an ice-water mixture, and the pH is adjusted to 7±0.05 with a 5% sodium hydroxide solution, filtered, and the filtrate is extracted with CH2Cl, the organic layers are combined and washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and CH2Cl is recovered by vacuum rotary evaporation to obtain a compound of formula I; The synthetic route is as follows:

2. The synthesis method according to claim 1, characterized in that In step S1, the 2-bromo-2-cyclohexene-1-one and 2-nitrobenzeneboric acid are added to the reaction bottle in a weight ratio of 1:0.95-1.4, and the weight ratio of the 2-bromo-2-cyclohexene-1-one to tetrakis(triphenylphosphine)palladium is 1:0.07-0.

13.

3. The synthesis method according to claim 1, characterized in that In step S1, the alkaline aqueous solution is a K3PO4 aqueous solution with a concentration of 2 mol / L.

4. The synthesis method according to claim 1, characterized in that In step S2, water and ethanol are mixed in a volume ratio of 1:3-4, the weight-to-volume ratio of the mixture of the compound represented by formula III, water and ethanol is 1 g:28-38 mL; the weight-to-volume ratio of the compound represented by formula III and concentrated hydrochloric acid is 1 g:3-7 mL; the weight of the iron powder added is 0.75-3 times that of the compound represented by formula III.

5. The synthesis method according to claim 1, characterized in that In step S2, the heating reaction time is 0.5 to 1 h.

6. The synthesis method according to claim 1, characterized in that In step S3, the amount of anhydrous phosphoric acid added is 0.8 to 1.2 times the weight of the compound represented by formula II.

7. The synthesis method according to claim 1, characterized in that In step S3, the anhydrous phosphoric acid is prepared by mixing phosphoric acid with a mass concentration of 85% and P2O5 in a mass ratio of 10:3.

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