Preparation method of tropisetron hydrochloride

Abstract

The invention provides a preparation method of tropisetron hydrochloride, which comprises the following steps: (1) mixing benzyl phenyl hydroxylamine, methyl propiolate and a first condensing agent for reaction to obtain a compound 4; (2) mixing and reacting the compound 4 obtained in the step (1) with palladium on carbon and hydrogen to obtain a compound 5, and then hydrolyzing to obtain a compound 6; and (3) mixing the compound 6 obtained in the step (2) with alpha-tropine and a second condensing agent for reaction, and then performing hydrochloric acidification to obtain tropisetron hydrochloride. The preparation method provided by the invention has the advantages of cheap and easily available initial raw materials, short synthesis route, high yield and low cost, uses the green and environment-friendly condensing agent, avoids the pollution caused by using oxalyl chloride or thionyl chloride as an acylation reagent in the traditional process, and is simple to operate and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and particularly relates to a preparation method of tropisetron hydrochloride. Background Art

[0002] Tropisetron hydrochloride is a potent and selective 5HT3 receptor antagonist developed by Novartis and launched in the UK in 1992 under the trade name Navoban. It is used to prevent and treat nausea and vomiting caused by radiotherapy and chemotherapy. The chemical name of Tropisetron hydrochloride is indole-3-carboxylic acid 1αH, 5αH-tropane-3α-ol ester hydrochloride, and its structural formula is as follows:

[0003]

[0004] Currently, the preparation methods of tropisetron hydrochloride disclosed in the literature are mainly limited to the following literature reports:

[0005] US Patent No. 4797406A1 uses 3-indolecarboxylic acid as the starting material, reacts it with oxalyl chloride, and treats it with dichloromethane and n-hexane to obtain 3-indolecarboxylic acid chloride, which is then reacted with tropane alcohol under n-butyl lithium activation to produce lithium tropane, and then post-treated to obtain tropisetron, which is finally salified with hydrochloric acid to prepare tropisetron hydrochloride:

[0006]

[0007] This method was the earliest adopted method and the earliest patented technology reported in the literature. However, the process uses highly toxic oxalyl chloride as an acylating agent, which puts tremendous pressure on industrial production and environmental protection.

[0008] At the same time, US Pat. No. 4,797,406A1 discloses another synthesis method, which uses indolecarboxylic acid as a starting material, synthesizes indoleyl chloride with thionyl chloride, and then synthesizes tropisetron free base under the catalysis of butyl lithium, and forms a salt with hydrochloric acid to produce the tropisetron hydrochloride product.

[0009]

[0010] This method is an improvement on the previous method. Oxalyl chloride is replaced by thionyl chloride, which improves the acylating agent. The advantage is that the application of the acylating agent is increased. However, the operation safety is not high and the cost is not reduced because thionyl chloride cannot significantly reduce the production cost compared with oxalyl chloride.

[0011] Therefore, there is the shortcoming that raw material toxicity is high and pollution is big in the existing synthesis process of tropisetron hydrochloride, brings huge pressure for industrialized production, and total yield is low, reagent price is expensive, and cost is high. Therefore, how to provide a preparation method of tropisetron hydrochloride with low toxicity, high safety, low cost and high yield has become a problem to be solved urgently. Summary of the Invention

[0012] In view of the deficiencies in the prior art, the present invention aims to provide a method for preparing tropisetron hydrochloride. The preparation method provided by the present invention has cheap and readily available starting materials, a short synthetic route, a high yield, low cost, uses a green and environmentally friendly condensing agent, avoids the pollution caused by using oxalyl chloride or thionyl chloride as an acylating agent in the traditional process, is simple to operate, and is suitable for industrial production.

[0013] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0014] The present invention provides a method for preparing tropisetron hydrochloride, which comprises the following steps:

[0015] (1) mixing benzylphenylhydroxylamine, methyl propiolate and a first condensing agent to react to obtain compound 4;

[0016]

[0017] (2) Compound 4 obtained in step (1) is mixed with palladium carbon and hydrogen to react to obtain compound 5, which is then hydrolyzed to obtain compound 6;

[0018]

[0019] (3) mixing the compound 6 obtained in step (2) with α-tropine and a second condensing agent for reaction, and then hydrochloridizing to obtain tropisetron hydrochloride;

[0020]

[0021] The specific preparation method has cheap and readily available starting materials, a short synthetic route, a high yield, and low cost. It uses a green and environmentally friendly condensation agent, avoids the pollution caused by using oxalyl chloride or thionyl chloride as an acylating agent in the traditional process, is simple to operate, and is suitable for industrial production.

[0022] Preferably, the first condensing agent in step (1) includes DMAP (4-dimethylaminopyridine).

[0023] Preferably, the reaction in step (1) is carried out in a solvent, and the solvent includes any one or a combination of at least two of acetonitrile, ethyl acetate, toluene or tetrahydrofuran, preferably toluene.

[0024] The above-mentioned specific solvent selection can effectively improve the reaction yield.

[0025] Preferably, the reaction temperature in step (1) is 10-70°C, and the reaction time is 48-72h, wherein the temperature can be 10°C, 20°C, 30°C, 40°C, 50°C, 60°C or 70°C, etc., and the reaction time can be 48h, 50h, 55h, 60h, 65h, 70h or 72h, etc., but are not limited to the values ​​listed above. Other values ​​not listed within the above numerical range are also applicable.

[0026] Preferably, the reaction of compound 4 with palladium carbon and hydrogen in step (2) is carried out in a solvent, and the solvent includes any one of methanol, ethanol or isopropanol or a combination of at least two of them, preferably methanol.

[0027] The above-mentioned specific solvent selection can effectively improve the reaction yield.

[0028] Preferably, the pressure of the mixed reaction of compound 4 with palladium carbon and hydrogen in step (2) is 8-12 kPa, such as 8 kPa, 9 kPa, 10 kPa, 11 kPa or 12 kPa, but is not limited to the values ​​listed above. Other values ​​not listed within the above numerical range are also applicable.

[0029] Preferably, the hydrolysis temperature in step (2) is 50-70°C, such as 50°C, 55°C, 60°C, 65°C or 70°C, but is not limited to the values ​​listed above. Other values ​​not listed within the above numerical range are also applicable.

[0030] Preferably, the second condensing agent in step (3) includes T3P (1-propyl phosphoric acid cyclic anhydride) and / or T4P (1-butyl phosphoric acid anhydride).

[0031] Preferably, the molar ratio of compound 6 to α-tropine and the second condensing agent in step (3) is 1:(1-1.4):(1.3-1.7), wherein the number of parts of α-tropine can be 1, 1.1, 1.2, 1.3 or 1.4, etc., and the number of parts of the second condensing agent can be 1.3, 1.4, 1.5, 1.6 or 1.7, etc., but are not limited to the values ​​listed above. Other values ​​not listed within the above numerical range are also applicable.

[0032] Preferably, the reaction temperature in step (3) is 10-30°C, and the reaction time is 3-5h, wherein the temperature can be 10°C, 15°C, 20°C, 25°C or 30°C, and the reaction time can be 3h, 3.5h, 4h, 4.5h or 5h, but is not limited to the values ​​listed above. Other values ​​not listed within the above numerical range are also applicable.

[0033] The present invention also provides application of the above preparation method in the preparation of tropisetron hydrochloride.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The invention provides a preparation method of tropisetron hydrochloride. The method has cheap and readily available starting raw materials, a short synthetic route, high yield, low cost, uses a green and environmentally friendly condensing agent, avoids pollution caused by using oxalyl chloride or thionyl chloride as an acylating agent in a traditional process, is simple to operate, and is suitable for industrial production. The method also effectively improves the reaction yield by selecting a specific solvent. DETAILED DESCRIPTION

[0036] In order to further illustrate the technical means and effects adopted by the present invention, the technical solutions of the present invention are further described below in conjunction with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0037] Example 1

[0038] This embodiment provides a method for preparing tropisetron hydrochloride, and the specific steps are as follows:

[0039] (1) 4A molecular sieves were added to a toluene (640 mL) solution of N-benzyl-N-phenylhydroxylamine 2 (86.2 g, 0.426 mol). DMAP (6.0 g, 0.049 mol) and methyl propiolate 3 (54 g, 0.562 mol) were added thereto at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then at 20°C for 48 hours. Ethyl acetate (500 mL) was added, filtered, and the organic phase was washed three times with water (3×200 mL). The organic phase was collected and concentrated under reduced pressure to obtain an oily substance. The oily substance was dissolved in 160 mL of ethanol, 320 mL of n-heptane was added, stirred for 2 hours, filtered, and dried under vacuum at 50°C for 12 hours to obtain 1-benzyl-1H-indole-3-carboxylic acid methyl ester 4 (95.6 g; 82% yield) as a white solid.

[0040]

[0041] (2) Add 50 g of 1-benzyl-1H-indole-3-carboxylic acid methyl ester 4, 550 mL of methanol, and 12 g of 5% Pd / C to a high-pressure reactor, replace the atmosphere with nitrogen three times, introduce hydrogen, maintain the pressure in the reactor at 10 kPa, and react at 35°C for 3 hours. After the reaction, filter out the solid, add purified water, add 20% sodium hydroxide solution dropwise to pH = 9.5, heat to 60°C and stir for 3 hours. After the reaction, cool, add dichloromethane and stir for 10 minutes, let stand and separate, add 12% hydrochloric acid dropwise to the aqueous phase to pH = 3, cool to 0°C and stir for 2 hours, filter, and vacuum dry at 50°C to obtain a white solid with a yield of 87%.

[0042]

[0043] (3) 3-Indolecarboxylic acid 6 (16.1 g, 100 mmol), α-tropine (14.1 g, 100 mmol), and 32 mL of pyridine were added to a four-necked flask. 2 equiv of T4P ethyl acetate solution was added under stirring. The reaction was continued at 20°C for 3 h. After the reaction was completed, 20 mL of purified water and 120 mL of ethyl acetate were added and stirred for 10 min. The organic phase was collected and washed three times with purified water (3×20 mL). The organic phase was collected and the solvent was evaporated under reduced pressure to obtain an oil. 120 mL of acetone was added and stirred. Concentrated hydrochloric acid was added dropwise until the pH was below 3 and stirred for 30 min. The temperature was lowered to 5°C and stirred for 2 h. The white solid was filtered and dried under vacuum to obtain 27.24 g of white solid tropisetron hydrochloride with a yield of 85%. Characterization data are as follows:

[0044] 1 HNMR(DMSO-D6)δ:2.11(d,2H,CH2),2.30(d,4H,CH2),2.50(m,2H,CH2),2.67(s,3H,CH3),3.8 7(s,2H,CH),5.15(s,H,CH),8.04(m,H,CH),8.06(d,H,CH),10.80(s,H,HCl),12.10(s,H,NH).

[0045]

[0046] Example 2

[0047] This embodiment provides a method for preparing tropisetron hydrochloride. The specific steps are the same as those in Example 1, except that toluene is replaced with an equal amount of tetrahydrofuran in step (1).

[0048] Example 3

[0049] This embodiment provides a method for preparing tropisetron hydrochloride. The specific steps are the same as those in Example 1 except that toluene is replaced with an equal amount of acetonitrile in step (1).

[0050] Example 4

[0051] This embodiment provides a method for preparing tropisetron hydrochloride. The specific steps are the same as those in Example 1 except that methanol is replaced with an equal amount of ethanol in step (1).

[0052] Example 5

[0053] This embodiment provides a method for preparing tropisetron hydrochloride. The specific steps are the same as those in Example 1 except that methanol is replaced with an equal amount of isopropanol in step (1).

[0054] Example 6

[0055] This example provides a method for preparing tropisetron hydrochloride. The specific steps are the same as those in Example 1, except that T4P is replaced with an equimolar amount of T3P in step (3).

[0056] Comparative Example 1

[0057] This comparative example provides a preparation method of tropisetron hydrochloride, and the specific steps are as follows:

[0058] 1. Preparation of indole-3-carbonyl chloride:

[0059]

[0060] 2.0 kg of indole-3-carboxylic acid and 2.2 kg of thionyl chloride were added to the reactor. After the addition was completed, the reactor was quickly sealed, stirring was started, and the temperature was raised to reflux (77-79 ° C). The reaction was kept at reflux for 24 hours, and then the temperature was lowered to below 30 ° C. After that, about 2 / 3 of the amount of thionyl chloride was distilled off under reduced pressure. The mixture was naturally cooled to room temperature and crystallized for 4 hours. The precipitated product was filtered and the filter cake was washed three times with a small amount of ether to obtain indole-3-carbonyl chloride. The solid was dried in vacuo at 40 ° C for 8 hours to obtain 1.62 kg of solid with a yield of 73%.

[0061] 2. Preparation of Tropisetron:

[0062]

[0063] 1.42 kg of tropine and 11.2 kg of tetrahydrofuran were added to the reactor in sequence. The reaction liquid temperature was controlled between 0-10°C and nitrogen was introduced into the reactor. After 5 minutes, 0.77 kg of n-butyl lithium / 1.5 kg of n-hexane solution was slowly and uniformly added using a dried constant pressure funnel. The addition was completed over about 2.5-3 hours. After the addition was completed, the reaction was continued for 1 hour. The n-hexane was evaporated under reduced pressure at a temperature below 68°C. 10.5 kg of tetrahydrofuran was added and stirred evenly. The lithium salt was stored in tetrahydrofuran. The reactor was sealed and set aside for use before proceeding directly to the next step. 1.2 kg of indole-3-carbonyl chloride was added in batches to a reaction vessel of tropane lithium salt / tetrahydrofuran. After the reaction was completed, the prescribed amount of purified water was drawn in, and the reaction was stirred at 20-25° C. for 26 hours. After the reaction time was up, TLC (developing solvent: chloroform: methanol: concentrated ammonia solution = 8:2:1) was performed to confirm that the reaction was complete. After the reaction was complete, 5.5 kg of dichloromethane was added for extraction, and the layers were separated by standing. The aqueous layer was discarded, and the organic layer was drawn into a treatment vessel, and then washed with 5.5 kg of the prescribed amount of 5% NaOH solution, retaining the dichloromethane layer. The dichloromethane layer was drawn into a treatment vessel and washed with 2.5 kg of 2 mol / L The HCl solution was extracted twice, the aqueous layer was retained, and the pH value was adjusted to about 7 with 2N sodium hydroxide solution; then extracted with 2.5 kg of dichloromethane, the organic phase was collected, and the aqueous layer was discarded; 0.5 kg of anhydrous sodium sulfate was added to the collected organic phase and dried for more than 1 hour, filtered, and the filtrate was pumped into a distillation kettle and the dichloromethane was evaporated under reduced pressure below 40°C; after the distillation was completed, 10.5 kg of ethyl acetate was added to the distillation kettle, the temperature was raised to reflux (77-79°C), refluxed for 1 hour, cooled to room temperature, crystallized for 2 hours, filtered, and dried in vacuo at 40°C for 5 hours to obtain 1.53 kg of tropisetron (light yellow) with a yield of 81%.

[0064] 4. Tropisetron salt formation:

[0065]

[0066] 8 kg of anhydrous ethanol was pumped into a reactor, stirring was started, and 1.5 kg of tropisetron was added; at the same time, 0.62 kg of hydrochloric acid and 2.3 kg of anhydrous ethanol were added to another reactor to prepare a hydrochloric acid-ethanol solution, and the prepared solution was added dropwise to the tropisetron solution at 20-25°C. After the addition was completed, the reaction was continued at 20-25°C for 1 hour, the temperature was lowered to 0-5°C, and the mixture was stirred for crystallization for 2 hours. The material was discharged, filtered, and dried in vacuo at 50°C for 5 hours to obtain 1.26 kg of a white solid with a yield of 84%.

[0067] Effect comparison:

[0068] The total yields of Examples 1-6 and Comparative Example 1 were calculated and the statistics are as follows:

[0069] Group Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 1 Yield (%) 60.6 58.4 58.6 57.5 55.8 59.2 49.6

[0070] From the above data, it can be found that compared with the prior art, the method provided by the present invention does not require the use of acylating agents such as oxalyl chloride or dichloride, is safer and less polluting; at the same time, the use of specific reagents and solvents further improves the reaction yield.

[0071] The applicant declares that the present invention illustrates the preparation method of tropisetron hydrochloride of the present invention by means of the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials of the product of the present invention, addition of auxiliary ingredients, selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

[0072] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0073] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for preparing tropisetron hydrochloride, characterized in that, The preparation method comprises the following steps: (1) mixing benzylphenylhydroxylamine, methyl propiolate and a first condensing agent to react to obtain compound 4; (2) Compound 4 obtained in step (1) is mixed with palladium carbon and hydrogen to react to obtain compound 5, which is then hydrolyzed to obtain compound 6; (3) mixing the compound 6 obtained in step (2) with α-tropine and a second condensing agent for reaction, and then hydrochloridizing to obtain tropisetron hydrochloride; 2. The preparation method according to claim 1, characterized in that In step (1), the first condensing agent includes DMAP.

3. The preparation method according to claim 1 or 2, characterized in that The reaction in step (1) is carried out in a solvent, which includes any one or a combination of at least two of acetonitrile, ethyl acetate, toluene or tetrahydrofuran, preferably toluene.

4. The preparation method according to any one of claims 1 to 3, characterized in that The reaction temperature of step (1) is 10-70° C. and the reaction time is 48-72 h.

5. The preparation method according to any one of claims 1 to 4, characterized in that In step (2), the compound 4 is mixed with palladium carbon and hydrogen in a solvent, wherein the solvent comprises any one of methanol, ethanol or isopropanol or a combination of at least two thereof, preferably methanol.

6. The preparation method according to any one of claims 1 to 5, characterized in that The pressure of the reaction mixture of compound 4, palladium carbon and hydrogen in step (2) is 8-12 kPa.

7. The preparation method according to any one of claims 1 to 6, characterized in that The hydrolysis temperature in step (2) is 50-70°C.

8. The preparation method according to any one of claims 1 to 7, characterized in that In step (3), the second condensing agent includes T3P and / or T4P.

9. The preparation method according to any one of claims 1 to 8, characterized in that The molar ratio of compound 6, α-tropine and the second condensing agent in step (3) is 1:(1-1.4):(1.3-1.7).

10. The preparation method according to any one of claims 1 to 9, characterized in that The reaction temperature in step (3) is 10-30° C. and the reaction time is 3-5 h.

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