A process for the preparation of a varenicline intermediate

Abstract

The application belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of a varenicline intermediate. The method comprises the following steps: 1) in the presence of an organic solvent A, a compound of formula 4 is used as raw material, ammonium acetate and a reducing agent are added, and a compound of formula 3 or a salt thereof is obtained through reaction; 2) in an organic solvent B, the compound of formula 3 or the salt thereof is reacted with trifluoroacetic anhydride or trifluoroacetic ethyl ester under the action of a base to obtain a compound of formula 2; and 3) in the presence of a solvent C and a catalyst, the compound of formula 2 is subjected to nitration reaction with a nitrating agent to obtain a compound of formula 1. The application solves the problems of the prior art, such as complicated steps, low atom utilization rate, high cost and the like, provides a novel route, directly introduces an amino group, does not need to be deprotected, has good atom economy, has mild reaction conditions, is simple in post-treatment, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of synthetic chemistry of drugs, and particularly relates to a preparation method of a varenicline intermediate. BACKGROUND

[0002] Varenicline tartrate (first approved for marketing in the United States on May 10, 2006, and in China on July 31, 2008) is mainly used for adult smoking cessation drugs. Varenicline selectively binds to alpha4beta2 nicotine acetylcholine receptors, has high affinity with the receptors, and the subtype binding produces agonistic effect, while blocking the binding of nicotine to the receptors, thereby playing a smoking cessation role.

[0003] The key intermediate of varenicline is 2,3,4,5-tetrahydro-7,8-dinitro-3-(trifluoroacetyl)-1,5-methano-1H-3-benzazepine (CAS: 230615-59-5), the structure of which is shown in the following formula 1:

[0004]

[0005] The prior art discloses a preparation method of the key intermediate of varenicline 2,3,4,5-tetrahydro-7,8-dinitro-3-(trifluoroacetyl)-1,5-methano-1H-3-benzazepine, which is mainly shown in route 1:

[0006]

[0007] The preparation of the compound of formula 1 in route 1 is through benzylamine amination reduction, salt hydrochloride purification, hydrogenation debenzyl, N protection by introducing trifluoroacetyl, and nitration. There are problems such as complicated steps, low atom utilization rate, high cost, high risk, low efficiency, and difficulty in industrial production. SUMMARY

[0008] The technical problem to be solved by the present application is to provide a new improved method for preparing the varenicline intermediate represented by the compound of formula (1), which uses ammonium acetate, in-situ reduction amination, novel route, simple steps, directly introduces amino group, does not need deprotection, has good atom economy, and high yield. Therefore, the present application provides a preparation method of the key intermediate of varenicline, which has market value and is suitable for industrial production.

[0009] The first aspect of the present application provides a preparation method of a compound of formula (3) and a salt thereof,

[0010]

[0011] comprising the following steps:

[0012] The compound of formula (4)

[0013]

[0014] In the presence of organic solvent A, ammonium acetate and a reducing agent are added to react and give the compound of formula (3) or its salt.

[0015] As a further improvement of the present invention, the molar ratio of the compound of formula (4) to ammonium acetate is 1:(0.5-5), preferably 1:(1-2), and more preferably 1:2.

[0016] As a further improvement of the present invention, the reducing agent is selected from sodium cyanoborohydride or sodium borohydride acetate; preferably sodium borohydride acetate.

[0017] As a further improvement of the present invention, the molar ratio of the compound of formula (4) to the reducing agent is 1:(0.5 to 5), preferably 1:(1 to 2.5), and more preferably 1:(2 to 2.5).

[0018] As a further improvement of the present invention, the compound of formula (3) or a salt thereof is a compound of formula (3-a).

[0019]

[0020] As a further improvement of the present invention, the method for preparing the compound of formula (3-a) includes the following steps:

[0021] The hydrogen chloride solution was reacted with the compound of formula (3) to obtain the compound of formula (3-a).

[0022] As a further improvement of the present invention, the hydrogen chloride solution is selected from ethyl acetate solution of hydrogen chloride, dichloromethane solution of hydrogen chloride, tetrahydrofuran solution of hydrogen chloride, and acetone solution of hydrogen chloride, preferably ethyl acetate solution of hydrogen chloride.

[0023] As a further improvement of the present invention, the concentration of the hydrogen chloride solution is 0.5 to 5 mol / L, preferably 1 to 2 mol / L.

[0024] As a further improvement of the present invention, the organic solvent A is selected from one or a combination of alcohol solvents, ether solvents or haloalkane solvents; the alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol or n-butanol; the ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran or diethyl ether; the haloalkane solvent is selected from chloroform, dichloromethane or dichloroethane; preferably dichloromethane.

[0025] As a further improvement of the present invention, the mass-volume ratio (g:mL) of the compound of formula (4) to organic solvent A is 1:(5-10), preferably 1:(6-8).

[0026] As a further improvement of the present invention, the reaction temperature is 5 to 30°C, preferably 15 to 25°C.

[0027] As a further improvement of the present invention, the stirring reaction time is 0.5 to 5 h, preferably 1 to 2 h, and more preferably 2 h.

[0028] As a further improvement of the present invention, the reaction may optionally include a separation step, which includes: adjusting pH with alkali, allowing the mixture to stand and separate, concentrating, filtration and rinsing.

[0029] As a further improvement of the present invention, in the separation step, the pH is ≥10, and preferably a strong alkaline solution of 5-40% is used, more preferably a 30% sodium hydroxide solution.

[0030] The compound of formula (4) of the present invention is obtained by conventional preparation methods in the prior art, for example, according to the journal article (Chemical Communications (Cambridge) (1999), (9), 819-820).

[0031] A second aspect of the present invention provides a method for preparing a compound of formula (2),

[0032]

[0033] Includes the following steps:

[0034] In organic solvent B, the compound of formula (3) or its salt synthesized by the preparation method provided in the first part above is reacted with trifluoroacetic anhydride or ethyl trifluoroacetate under the action of an alkali to obtain the compound of formula (2).

[0035] As a further improvement of the present invention, the alkali is selected from inorganic alkali or organic alkali, preferably triethylamine or diisopropylethylamine, and more preferably triethylamine.

[0036] As a further improvement of the present invention, the molar ratio of the compound of formula (3) or its salt to the base is 1:(0.5 to 5), preferably 1:(1 to 2), and in some specific embodiments, the molar ratio of the compound of formula (3) or its salt to the base is 1:2.

[0037] As a further improvement of the present invention, the molar ratio of the compound of formula (3) or its salt to trifluoroacetic anhydride or ethyl trifluoroacetate is 1:(0.5-3), preferably 1:(1-2), and in some specific embodiments, the molar ratio of the compound of formula (3) or its salt to trifluoroacetic anhydride or ethyl trifluoroacetate is 1:1.5.

[0038] As a further improvement of the present invention, the organic solvent B is selected from one or more combinations of alcohol solvents or haloalkane solvents; the alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol or n-butanol; the haloalkane solvent is selected from chloroform, dichloromethane or dichloroethane; preferably dichloromethane.

[0039] As a further improvement of the present invention, the mass-volume ratio (g:mL) of the compound of formula (3) or its salt to organic solvent B is 1:(5-12), preferably 1:(6-10), more preferably 1:(8-10); in some specific embodiments, the mass-volume ratio of the compound of formula (3) or its salt to organic solvent B is 1:8.

[0040] As a further improvement of the present invention, the reaction temperature of the compound of formula (3) or its salt with trifluoroacetic anhydride or ethyl trifluoroacetate is 10 to 30°C, preferably room temperature.

[0041] As a further improvement of the present invention, the compound of formula (3) is the compound of formula (3-a).

[0042] As a further improvement of the present invention, a separation step is also included, which may optionally include: quenching, layering, extraction, concentration, pulping and filtration.

[0043] As a further improvement of the present invention, the solvent used for quenching is an acid, preferably 1-3 mol / L dilute hydrochloric acid, and in some specific embodiments, the quenching solvent is 2 mol / L dilute hydrochloric acid.

[0044] As a further improvement of the present invention, the solvent used for extraction is a halohydrocarbon, preferably dichloromethane.

[0045] As a further improvement of the present invention, the solvent used for pulping is a poor solvent, preferably n-heptane.

[0046] As a further improvement of the present invention, the separation step includes: quenching the reaction with 2 mol / L dilute hydrochloric acid, separating the layers, extracting with aqueous dichloromethane, concentrating, slurrying with n-heptane, and filtering.

[0047] A third aspect of the present invention provides a method for preparing a compound of formula (1),

[0048]

[0049] Includes the following steps:

[0050] In the presence of solvent C and catalyst, the compound of formula (2) synthesized by the preparation method provided in the second part above is subjected to nitration reaction with a nitrating agent to obtain the compound of formula (1).

[0051] As a further improvement of the present invention, in the nitration reaction, the catalyst is selected from one of phosphoric acid, polyphosphoric acid, methanesulfonic acid, chlorosulfonic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, acetic acid, acetic anhydride, boron trifluoride ether, perchloric acid, or phosphomolybdic acid, preferably trifluoromethanesulfonic acid.

[0052] As a further improvement of the present invention, in the nitration reaction, the molar ratio of the compound of formula (2) to the catalyst is 1:(3-7), preferably 1:(3-5), and in some specific embodiments, the molar ratio of the compound of formula (2) to the catalyst is 1:5.

[0053] As a further improvement of the present invention, in the nitration reaction, the solvent C is selected from one of alcohols, nitriles, chloroalkanes or aromatic hydrocarbons, ketones, ethers, aliphatic or aromatic hydrocarbons, and esters, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, butyronitrile, acrylonitrile, dichloromethane, dichloroethane, chloroform, chlorobenzene, acetone, propane, butanone, methyl isobutyl ketone, diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene, xylene, benzene, ethyl acetate, propyl acetate, or butyl acetate, more preferably dichloromethane.

[0054] As a further improvement of the present invention, in the nitration reaction, the volume of solvent C is 5 to 15 times the mass of the compound of formula (2), preferably 8 to 10 times.

[0055] As a further improvement of the present invention, in the nitration reaction, the nitrating agent is selected from nitric acid and fuming nitric acid, preferably fuming nitric acid.

[0056] As a further improvement of the present invention, in the nitration reaction, the mass ratio of the compound of formula (2) to the nitrating agent is 1:(0.1 to 1), preferably 1:0.6.

[0057] As a further improvement of the present invention, the nitration reaction also includes separation steps: quenching, separation, extraction, washing, concentration, pulping, filtration, and drying.

[0058] As a further improvement of the present invention, the nitration reaction separation step includes: quenching with water, separation, extraction with dichloromethane, washing with saturated sodium bicarbonate solution, concentration, pulping with n-heptane at 50°C, filtration, and drying.

[0059] A fourth aspect of the present invention provides for applying the aforementioned preparation route to the preparation of vareniclan.

[0060] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0061] 1. This invention uses ammonium acetate for in-situ reducing amination, which is novel and simple in procedure;

[0062] 2. This invention directly introduces amino groups without deprotection, resulting in good atom economy, a short route, and high yield;

[0063] 3. The reaction conditions of this invention are mild, the post-processing is simple, the cost is low, and it is suitable for industrial production. Attached Figure Description

[0064] Figure 1 The compound of formula 3 obtained in Example 1 1 H-NMR spectrum;

[0065] Figure 2 The compound of formula 2 obtained in Example 2 1 H-NMR spectrum;

[0066] Figure 3 The compound of formula 1 obtained in Example 3 1 H-NMR spectrum. Detailed Implementation

[0067] To facilitate understanding of the present invention by those skilled in the art, the technical solution of the present invention is further described below with reference to specific embodiments. It should be understood that the following embodiments are not intended to limit the scope and spirit of the claims. Unless otherwise specified, the raw materials, reagents, or solvents used in the present invention are commercially available or prepared according to conventional methods in the art. Experimental methods with specific conditions not specifically described are performed according to conventional practices in the art.

[0068] Example 1:

[0069] Compound 4 (25 g, 0.14 mol) was dissolved in 200 mL of dichloromethane at room temperature. Ammonium acetate (22.1 g, 0.28 mol) was added at room temperature, and the mixture was stirred for 1 h. The temperature was controlled at 15–25 °C, and sodium borohydride acetate (67 g, 0.31 mol) was added in batches, stirring for 2 h. After the reaction was complete, 2 L of 30% sodium hydroxide solution was added dropwise to adjust the pH to ≥10. The aqueous phase was discarded after standing and the organic phase was concentrated at 30–50 °C. At 10–20 °C, 120 mL of 1 mol / L hydrogen chloride / ethyl acetate solution was added, and the mixture was cooled to 0–5 °C and stirred for 2–4 h. The mixture was filtered, and the filter cake was washed with ethyl acetate to obtain approximately 21.3 g of a white solid, with a yield of 76.2%. 1 H-NMR such as Figure 1 As shown.

[0070] Example 2:

[0071] 50 g (0.26 mol) of compound 3-a was dissolved in 400 mL of dichloromethane, and 51.6 g (0.51 mol) of triethylamine and 81.9 g (0.39 mol) of trifluoroacetic anhydride were added. The mixture was stirred at room temperature for 5 h until the reaction was complete. The reaction was quenched by adding 100 mL of 2 mol / L dilute hydrochloric acid. After separation, the aqueous phase was extracted with 400 mL of dichloromethane. The combined organic phases were concentrated, and the mixture was stirred with 200 mL of n-heptane. Filtration yielded 63.2 g of a white solid, with a yield of 96.9%. 1 H-NMR such as Figure 2 As shown.

[0072] Example 3:

[0073] 179.9 g of trifluoromethanesulfonic acid was cooled to 0–5 °C, and 37 g of fuming nitric acid was added dropwise at 5 ± 5 °C. A DCM solution of compound 2 (60 g dissolved in 600 mL of dichloromethane) was then added dropwise, and the reaction was continued at 23 ± 2 °C for 6 h. After the reaction was complete, 1200 mL of water was added to quench the reaction. The mixture was separated, and the aqueous phase was extracted again with 600 mL of dichloromethane. The combined organic phases were washed with 600 mL of saturated sodium bicarbonate solution. The organic phase was concentrated, and 500 mL of n-heptane was added and the mixture was stirred at 50 °C. The mixture was filtered, dried, and 55.2 g of a white solid was obtained, with a yield of 68%. 1 H-NMR such as Figure 3 As shown.

[0074] Example 4:

[0075] Compound 4 (25 g, 0.14 mol) was dissolved in 200 mL of dichloromethane at room temperature. Ammonium acetate (55.3 g, 0.7 mol) was added at room temperature, and the mixture was stirred for 1 h. Sodium borohydride acetate (67 g, 0.31 mol) was added in batches at 15–25 °C, and the mixture was stirred for 2 h. After the reaction was complete, 2 L of 30% sodium hydroxide solution was added dropwise to adjust the pH to ≥10. The aqueous phase was discarded after standing and the organic phase was concentrated at 30–50 °C. At 10–20 °C, 120 mL of 1 mol / L hydrogen chloride / ethyl acetate solution was added, and the mixture was cooled to 0–5 °C and stirred for 2–4 h. The mixture was filtered, and the filter cake was washed with ethyl acetate to obtain approximately 21.1 g of an off-white solid, with a yield of 75.4%.

[0076] Example 5:

[0077] Compound 4 (25 g, 0.14 mol) was dissolved in 200 mL of dichloromethane at room temperature. Ammonium acetate (22.1 g, 0.28 mol) was added at room temperature, and the mixture was stirred for 1 h. Sodium borohydride acetate (151.3 g, 0.7 mol) was added in batches at 15–25 °C, and the mixture was stirred for 2 h. After the reaction was complete, 2 L of 30% sodium hydroxide solution was added dropwise to adjust the pH to ≥10. The aqueous phase was discarded after standing and the organic phase was concentrated at 30–50 °C. At 10–20 °C, 120 mL of 1 mol / L hydrogen chloride / ethyl acetate solution was added, and the mixture was cooled to 0–5 °C and stirred for 2–4 h. The mixture was filtered, and the filter cake was washed with ethyl acetate to obtain approximately 22.1 g of an off-white solid, with a yield of 79.2%.

[0078] Comparative Example 1:

[0079] Compound 4 (25 g, 0.14 mol) was dissolved in 200 mL of tetrahydrofuran at room temperature. Ammonium acetate (22.1 g, 0.28 mol) was then added at room temperature, and the mixture was stirred for 1 h. Sodium borohydride (13.3 g, 0.35 mol) was added in portions, and the mixture was stirred for 2 h after each addition, while maintaining the temperature between 0 and 5 °C. After the reaction was complete, TLC (petroleum ether: ethyl acetate = 4:1) did not detect any product.

[0080] Comparative Example 2:

[0081] Compound 4 (25 g, 0.14 mol) was dissolved in 200 mL of dichloromethane at room temperature. Ammonium acetate (22.1 g, 0.28 mol) was then added at room temperature, and the mixture was stirred for 1 h. Sodium borohydride (13.3 g, 0.35 mol) was added in portions, and the mixture was stirred for 2 h, while maintaining the temperature between 0 and 5 °C. After the reaction was complete, TLC (petroleum ether: ethyl acetate = 4:1) did not detect the product.

[0082] Comparative Example 3:

[0083] Compound 4 (25 g, 0.14 mol) was dissolved in 200 mL of tetrahydrofuran at room temperature. Ammonium acetate (22.1 g, 0.28 mol) was then added at room temperature, and the mixture was stirred for 1 h. Lithium aluminum hydride (13.3 g, 0.35 mol) was added in portions at 0–5 °C, and the mixture was stirred for 2 h. After the reaction was complete, TLC (petroleum ether: ethyl acetate = 4:1) did not detect any product.

Claims

1. A method for preparing a compound of formula (3) and its salt, It includes the following steps: Make compound (4) In the presence of organic solvent A, ammonium acetate and a reducing agent are added to react and obtain compound (3) or its salt; the reducing agent is sodium borohydride acetate; the organic solvent A is dichloromethane; the reaction temperature is 15~25℃.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the compound of formula (4) to ammonium acetate is 1: (0.5~5).

3. The preparation method according to claim 2, characterized in that, The molar ratio of the compound of formula (4) to ammonium acetate is 1: (1~2).

4. The preparation method according to claim 1, characterized in that, The molar ratio of the compound of formula (4) to the reducing agent is 1: (0.5~5).

5. The preparation method according to claim 4, characterized in that, The molar ratio of the compound of formula (4) to the reducing agent is 1: (1~2.5).

6. The preparation method according to claim 5, characterized in that, The molar ratio of the compound of formula (4) to the reducing agent is 1: (2~2.5).

7. The preparation method according to claim 1, characterized in that, The salt of the compound of formula (3) is the compound of formula (3-a). The compound of formula (3-a) is prepared by reacting a hydrogen chloride solution with the compound of formula (3), wherein the hydrogen chloride solution is selected from an ethyl acetate solution of hydrogen chloride, a dichloromethane solution of hydrogen chloride, a tetrahydrofuran solution of hydrogen chloride, or an acetone solution of hydrogen chloride.

8. The preparation method according to claim 7, characterized in that, The hydrogen chloride solution is an ethyl acetate solution of 0.5~5 mol / L hydrogen chloride.

9. The preparation method according to any one of claims 1 to 8, characterized in that, The ratio of the mass of the compound in formula (4) to the volume of organic solvent A is 1 g : (5~10) mL.

10. The preparation method according to claim 1, characterized in that, The mass ratio of the compound of formula (4) to the volume ratio of dichloromethane is 1g: (6~8)mL; And / or, the reaction further includes a separation step, which includes: adjusting pH with alkali, allowing the mixture to stand and separate, concentrating, cooling, stirring, filtration and rinsing.

11. The preparation method according to claim 10, characterized in that, The separation step involves adjusting the pH to ≥10 with alkali.

12. The preparation method according to any one of claims 1 to 8, characterized in that, The compound of formula (3) or its salt, in organic solvent B, reacts with trifluoroacetic anhydride or ethyl trifluoroacetate under the action of an alkali to obtain the compound of formula (2). 。 13. The preparation method according to claim 12, characterized in that, The alkali is selected from inorganic or organic alkalis; And / or, the molar ratio of the compound of formula (3) or its salt to the base is 1:(0.5~5); And / or, the molar ratio of the compound of formula (3) or its salt to trifluoroacetic anhydride or ethyl trifluoroacetate is 1: (0.5~3); And / or, the organic solvent B is selected from one or more combinations of alcohol solvents or haloalkane solvents; And / or, the mass ratio of the compound of formula (3) or its salt to the volume ratio of organic solvent B is 1 g: (5~12) mL; And / or, the reaction temperature of the compound of formula (3) or its salt with trifluoroacetic anhydride or ethyl trifluoroacetate is 10~30℃.

14. The preparation method according to claim 13, characterized in that, The base is selected from triethylamine or diisopropylethylamine; And / or, the molar ratio of the compound of formula (3) or its salt to the base is 1: (1~2); And / or, the molar ratio of the compound of formula (3) or its salt to trifluoroacetic anhydride or ethyl trifluoroacetate is 1: (1~2); And / or, when the organic solvent B is an alcohol solvent, the alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol or n-butanol; when the organic solvent B is a haloalkane solvent, the haloalkane solvent is selected from chloroform, dichloromethane or dichloroethane. And / or, the mass ratio of the compound of formula (3) or its salt to the volume ratio of organic solvent B is 1 g : (6~10) mL; And / or, the reaction temperature of the compound of formula (3) or its salt with trifluoroacetic anhydride or ethyl trifluoroacetate is room temperature.

15. The preparation method according to claim 14, characterized in that, The base is triethylamine; And / or, the haloalkane solvent is dichloromethane; And / or, the mass ratio of the compound of formula (3) or its salt to the volume ratio of organic solvent B is 1 g : (8~10) mL.

16. The preparation method according to claim 12, characterized in that, The compound of formula (2) is nitrated with a nitrating agent in the presence of solvent C and a catalyst to obtain the compound of formula (1); 。 17. The preparation method according to claim 16, characterized in that, The catalyst is selected from one of phosphoric acid, polyphosphoric acid, methanesulfonic acid, chlorosulfonic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, acetic acid, acetic anhydride, boron trifluoride ether, perchloric acid, or phosphomolybdic acid. And / or, the molar ratio of the compound of formula (2) to the catalyst is 1: (3~7); And / or, the solvent C is selected from one of alcohols, nitriles, chloroalkanes, aliphatic hydrocarbons, aromatic hydrocarbons, ketones, ethers or esters; And / or, the volume of solvent C is 5 to 15 times the mass of the compound of formula (2); And / or, the nitrating agent is nitric acid; And / or, the mass ratio of the compound of formula (2) to the nitrating agent is 1: (0.1~1).

18. The preparation method according to claim 17, characterized in that, The catalyst is trifluoromethanesulfonic acid; And / or, the molar ratio of the compound of formula (2) to the catalyst is 1: (3~5); And / or, the solvent C is selected from one of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, butyronitrile, acrylonitrile, dichloromethane, dichloroethane, chloroform, chlorobenzene, acetone, butanone, methyl isobutyl ketone, diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene, xylene, benzene, ethyl acetate, propyl acetate, or butyl acetate; And / or, the volume of solvent C is 8 to 10 times the mass of the compound of formula (2); And / or, the nitric acid is fuming nitric acid; And / or, the mass ratio of the compound of formula (2) to the nitrifying agent is 1:0.6.

Images