Preparation method of zalpyrazolam

Abstract

The invention relates to zalpyrazolam, in particular to a preparation method of zalpyrazolam. The method comprises the following steps: carrying out nucleophilic substitution reaction on a compound A and a compound B to obtain a compound C; performing oxidation reaction on the compound C to obtain a compound D; performing reduction reaction on the compound D to obtain a compound E; carrying out nucleophilic substitution reaction on the compound E and a compound F to obtain a compound G, and carrying out ring closing reaction on the compound G and a compound H to obtain a compound I; the compound I is subjected to a thio reaction to obtain a compound J; performing ring closing reaction on the compound J and a compound K to obtain a compound L; performing demethylation reaction on the compound L to obtain a compound M; performing chlorination reaction on the compound M to obtain a compound N (zalpyrazolam); the invention provides a brand new preparation method of zalpyrazolam, which has the advantages of simple route, cheap and easily available raw materials, mild conditions and high reaction yield, and greatly reduces the production cost of zalpyrazolam.

Description

Technical Field

[0001] This invention relates to zapyzolam, and more specifically to a method for preparing zapyzolam. Background Technology

[0002] Zapizolam is a benzodiazepine that exerts its central inhibitory effect by enhancing the activity of GABA type A receptors. GABA is a major inhibitory neurotransmitter in the central nervous system; after binding to its receptors, it promotes the opening of chloride ion channels, reduces neuronal excitability, and thus produces sedative, anti-anxiety, and hypnotic effects. This mechanism is similar to that of early barbiturates, but benzodiazepines have gradually replaced barbiturates in clinical use due to their wider safety profile. The development of benzodiazepines began in the 1960s, with chlordiazepoxide (Librium) and diazepam (Valium) as representatives, solving the problems of high addictiveness and narrow therapeutic window of barbiturates. Zapizolam, as a subsequently developed benzodiazepine derivative, further optimized its efficacy and safety, and is used to treat anxiety disorders and insomnia, especially for symptoms such as difficulty falling asleep and sleep maintenance disorders. It has been approved for marketing in several countries, including Japan, the United States, and China, for the induction and maintenance of general anesthesia. Research on zalpizolam reflects the evolution of sedative-hypnotic drugs from broad-spectrum inhibitors (such as barbiturates) to targeted modulators (such as GABA receptor subtype-selective drugs). 8-chloro-6-(2-chloro-phenyl)-4H-benzo[ f [1,2,4]triazolo[4,3-a][1,4]diazepine, CAS Registry No.: 64098-32-4, structural formula as follows:

[0003] Using literature search tools such as Reaxys and SciFinder, the main synthetic route was found to be: US4110455 discloses a nine-step reaction using 2,6-dichloro-3-nitropyridine and 2-chlorophenylacetonitrile as starting materials, involving nucleophilic substitution, oxidation, reduction, nucleophilic addition, nucleophilic substitution, nucleophilic addition, closing of the seven-membered and five-membered rings, and reduction, with an overall yield of 5.3%.

[0004] Summary of the Invention

[0005] This invention provides a novel method for preparing zapyzolam. The specific technical solution is as follows:

[0006] Includes the following steps: S1: Synthesis of Compound C Compound A and compound B were dissolved in a solvent, the gas was displaced, an alkali was added, the reaction was carried out in an ice bath, and the reaction was monitored until the raw materials disappeared. The reaction was quenched, extracted and dried, the solvent was removed by filtration and concentration, and the mixture was pulped to obtain compound C. S2: Synthesis of Compound D Compound C was dissolved in a solvent, salt and oxidant were added, and the reaction was carried out in an ice bath. The reaction was monitored until the starting material disappeared, the reaction was quenched, extracted, dried, and the solvent was concentrated to obtain compound D. S3: Synthesis of Compound E Compound D was dissolved in a solvent, salt and reducing agent were added, and the reaction was monitored until the starting material disappeared. The reaction was filtered, the filtrate was extracted and dried, and the solvent was removed by filtration and concentration to obtain compound E. S4: Synthesis of Compound I Compound E was dissolved in an organic solvent, the gas was displaced, and compound F was added under ice bath conditions. The reaction was carried out under ice bath conditions until the starting material disappeared, thus obtaining solution G. Compound H and salt were added, the gas was displaced, the reaction was heated, and the reaction was carried out under conditions until the starting material disappeared. The solvent was concentrated, and the solution was purified by column chromatography to obtain compound I.

[0007] S5: Synthesis of Compound J Compound I was dissolved in a solvent, a thioreagent was added, the reaction was heated, and the reaction was monitored until the starting material disappeared. The reaction was then quenched, extracted, dried, concentrated to remove the solvent, passed through a column, and slurried to obtain compound J. S6: Synthesis of Compound L Compound J was dissolved in an organic solvent, compound K was added, and the mixture was monitored until the starting material disappeared. The solvent was then concentrated and the mixture was passed through a column to obtain compound L. S7: Synthesis of Compound M Compound L was dissolved in an organic solvent, the gas was replaced, acid was added under an ice bath, the reaction was heated, and the reaction was monitored until the raw material disappeared. The reaction was then quenched, and the filtered cake was used to obtain compound M. S8: Synthesis of Compound N Compound M was dissolved in an organic solvent, salt and phosphorus oxychloride were added, the gas was replaced, the reaction was heated, and the reaction was monitored until the starting material disappeared. The solvent was concentrated, purified by column chromatography, and the mixture was slurryed to obtain compound N.

[0008] The method is characterized in that the solvent used in step S1 is any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, ethylene glycol dimethyl ether, N,N-dimethylformamide, and N,N-dimethylacetamide; the base is any one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium diisopropylamino, and lithium bis(trimethylsilylamino)amine; the molar ratio of compound A: compound B: base is 1:1:1 to 1:1.5:1.5; and the reaction temperature is -78 to 25°C.

[0009] The method is characterized in that the organic solvent used in step S2 is any one or more of acetonitrile, tetrahydrofuran, acetone, dioxane, and ethanol; the oxidant is any one or more of hydrogen peroxide, m-chloroperoxybenzoic acid, and potassium persulfate; the molar ratio of compound C: salt: oxidant is 1:1:1 to 1:3:5; and the reaction temperature is 0-50℃.

[0010] The method is characterized in that the organic solvent used in step S3 is any one or more of methanol, ethanol, tetrahydrofuran, dioxane, water, and acetic acid; the salt is any one or more of ammonium chloride, stannous chloride, and sodium sulfide; the catalyst is iron powder or zinc powder; the molar ratio of compound D: salt: catalyst is 1:5:5~1:10:10; and the reaction temperature is 25-80℃.

[0011] The method is characterized in that the organic solvent used in step S4 is any one or more of ethanol, isopropanol, N,N-dimethylformamide, and N,N-dimethylacetamide; the base is any one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, and sodium bicarbonate; the molar ratio of compound D:compound E:base is 1:1:0 to 1:4:8; and the reaction temperature is 0-110℃. The salt is any one or more of ammonium acetate, ammonium chloride, ammonium bicarbonate, and ammonia water; the molar ratio of compound G:compound H:salt is 1:1:1 to 1:4:4; and the reaction temperature is 50-90℃.

[0012] The method is characterized in that the organic solvent used in step S5 is any one or more of toluene, pyridine, 1,2-dichloroethane, ethylene glycol dimethyl ether, and tetrahydrofuran; the thioreagent is Lawson's reagent or tetraphosphorus decasulfide; the molar ratio of compound I to thioreagent is 1:1 to 1:2; and the reaction temperature is 65-110℃.

[0013] The method is characterized in that the organic solvent used in step S6 is any one or more of methanol, ethanol, and n-butanol; the molar ratio of compound J to compound K is 1:3 to 1:10; and the reaction temperature is 65-120℃.

[0014] The method is characterized in that the organic solvent used in step S7 is any one or more of water, acetic acid, N,N-dimethylformamide, acetonitrile, toluene, chloroform, dioxane, and dimethyl sulfoxide; the acid is any one or more of hydrochloric acid and hydrobromic acid; the molar ratio of compound L to acid is 1:5 to 1:10; and the reaction temperature is 50-120℃.

[0015] The method is characterized in that the organic solvent used in step S8 is any one or more of chloroform, acetonitrile, phosphorus oxychloride, sulfonium chloride, toluene, 1,2-dichloroethane, and dichloromethane; the chlorination reagent is any one or more of phosphorus oxychloride, sulfonium chloride, and phosphorus pentachloride; the molar ratio of compound M to chlorination reagent is 1:1 to 1:10; and the reaction temperature is 20-110℃.

[0016] Beneficial effects 1) This invention relates to a novel method for preparing zapyzolam standard and its active ingredient. Specifically, this invention uses 2-chloro-6-methoxy-3-nitropyridine (CAS: 38533-61-8, 100g / 111RMB), which is less expensive, to replace 2,6-dichloro-3-nitropyridine in the original technology. Its advantages are firstly, higher atom utilization and the absence of positional isomers resulting from nucleophilic substitution; secondly, the methoxy group is more stable than the chlorine group. 2) The reduction of compound D nitro in this invention uses iron powder and ammonium chloride, thus avoiding the use of the dangerous reagent Raney nickel.

[0017] 3) Another advantage of this invention is that the conditions for closing the seven-membered ring are simple to operate, no hydrogen chloride gas is required, which facilitates the scale-up of the reaction, and there are only 8 steps, making the operation simple and eliminating the bottleneck of scale-up process. 4) The raw materials are inexpensive and widely available, the operation is simple, the reaction conditions are mild, and the reagents used are common reagents. The overall yield of the 8-step reaction is doubled compared to the original technology. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the following specific embodiments provide a more detailed description of the invention. Unless otherwise specified, the experimental methods used in this invention are conventional methods. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0019] The reaction process of the present invention can be monitored using conventional monitoring methods in the art (e.g., TLC, LCMS or NMR), and the reaction endpoint is generally the disappearance of the starting material.

[0020] Example 1 Example 1 of the present invention provides a method for preparing compound C, the route of which is as follows:

[0021] Compound A (10 g, 53.19 mmol) and compound B (8.43 g, 55.85 mmol) were dissolved in tetrahydrofuran (100 mL). Under a nitrogen atmosphere and an ice bath, bis(trimethylsilylaminolithium) (63.8 mL, 63.8 mmol) was added dropwise to the reaction solution, and the mixture was stirred for 3 hours under an ice bath. The starting material was monitored by TLC until it disappeared. The reaction solution was quenched with saturated ammonium chloride (50 mL), concentrated, and then extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and column filtered (petroleum ether / ethyl acetate = 5 / 1) to give 13.1 g of compound C as a pale yellow solid, yield: 81%, purity: 95%.

[0022] The compound C obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z): 303.04. Example 2 Example 2 of the present invention provides a method for preparing compound D, the route of which is as follows:

[0023] Under ice bath conditions, a solution of potassium cyanate (6.13 g, 75.64 mmol) in water and a solution of hydrogen peroxide (12.9 g, 113.46 mmol) in water were added to a solution of compound C (11.46 g, 37.82 mmol) in THF (115 mL). The mixture was stirred at room temperature for 16 hours. TLC showed that the starting material had reacted completely. The reaction solution was quenched with saturated sodium sulfite (50 mL) solution, concentrated, extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 11.6 g of compound D as a pale yellow solid, yield: 100%, purity: 92%.

[0024] The compound D obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z): 292.02. Example 3 Example 3 of the present invention provides a method for preparing compound E, the route of which is as follows:

[0025] Compound D (11.6 g, 39.73 mmol) was dissolved in a mixed solvent of THF (50 mL), MeOH (50 mL), and H₂O (50 mL). Iron powder (11.12 g, 198.63 mmol) and NH₄Cl (21.06 g, 397.3 mmol) were added, and the mixture was stirred at 75 °C for 2 hours. TLC showed that the reaction proceeds were complete. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with methanol. The filtrate was concentrated and extracted with DCM (50 mL * 3). The organic phase was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated to obtain a light green oil. Yield of 10.0 g of compound E: 96%, purity: 92%.

[0026] The compound E obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z): 262.05. Example 4 Example 4 of the present invention provides a method for preparing compound I, the route of which is as follows:

[0027] Compound E (10.0 g, 38.17 mmol) was dissolved in isopropanol (100 mL). Compound F (17.25 g, 152.67 mmol) was added dropwise under a nitrogen atmosphere in an ice bath, and the mixture was stirred for 1 h. TLC showed that the starting material had reacted completely. NH4OAc (5.91 g, 76.80 mmol) and hexamethylenetetramine H (10.75 g, 76.80 mmol) were added, and the mixture was stirred at 80 °C for 3 h. LCMS showed that the starting material had reacted completely. Water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were separated and combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (dichloromethane / methanol = 30 / 1) to give 9.5 g of compound I, yield: 90%, purity: 98%.

[0028] The compound I obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z): 301.06 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.64 (s, 1H), 7.58 – 7.55 (m, 2H), 7.47 –7.41 (m, 3H), 4.28 (s, 2H), 3.49 (s, 3H). Example 5 Example 5 of the present invention provides a method for preparing compound I, the route of which is as follows:

[0029] Compound E (10.0 g, 38.17 mmol) was dissolved in N,N-dimethylformamide (100 mL). Compound F (17.25 g, 152.67 mmol) was added dropwise under a nitrogen atmosphere in an ice bath, and the mixture was stirred for 1 h. TLC showed that the starting material had reacted completely. 30% ammonia (8.96 g, 76.80 mmol) and hexamethylenetetramine H (10.75 g, 76.80 mmol) were added, and the mixture was stirred at 80 °C for 2.5 h. LCMS showed that the starting material had reacted completely. Water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were separated and combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (dichloromethane / methanol = 30 / 1) to give 8.5 g of compound I, yield: 80%, purity: 97%.

[0030] ESI-MS (m / z): 301.06 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.64 (s, 1H), 7.58 – 7.55 (m, 2H), 7.47 –7.41 (m, 3H), 4.28 (s, 2H), 3.49 (s, 3H). Example 6 Example 6 of the present invention provides a method for preparing compound J, the route of which is as follows:

[0031] Compound I (4 g, 13.28 mmol) was dissolved in ethylene glycol dimethyl ether (40 mL) and added to Lawson's reagent (8.06 g, 19.94 mmol). The mixture was stirred at 75 °C for 2 hours. LC-MS showed that the reaction proceeds were complete. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and column-secured (petroleum ether / ethyl acetate = 5 / 1) to obtain the crude product. The crude product was slurried with tertiary methyl ether to give a yellow solid, 2.0 g of compound J, yield: 48%, purity: 95%.

[0032] The compound J obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z): 317.04. Example 7 Example 7 of the present invention provides a method for preparing compound L, the route of which is as follows:

[0033] Compound K (1 g, 3.15 mmol) and compound J (0.946 g, 15.77 mmol) were dissolved in n-butanol (20 mL). The mixture was stirred at 80 °C for 6 hours. LC-MS showed that the starting materials had reacted completely. The reaction solution was concentrated to dryness, diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and column-sected (DCM / MeOH = 20 / 1) to give a yellow solid, 700 mg of compound L, yield: 69%, purity: 95%.

[0034] The compound L obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z): 325.07. Example 8 Example 8 of the present invention provides a method for preparing compound L, the route of which is as follows:

[0035] Compound L (400 mg, 1.23 mmol) was dissolved in HOAc (4 mL), and HBr / HOAc (4 mL) solution was added. After purging with nitrogen, the reaction was stirred at 100 °C for 1.25 h. LCMS showed that the starting material had completely reacted. The reaction solution was cooled to room temperature, and ethyl acetate (20 mL) was added. The mixture was filtered to obtain a filter cake, which was then concentrated to give a yellow solid. 500 mg of compound M was yielded, yield: 100%, purity: 90%.

[0036] The compound M obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z): 311.06. Example 9 Example 9 of the present invention provides a method for preparing compound N (zapyrazolium), the route of which is as follows:

[0037] Compound M (600 mg, 1.54 mmol) was dissolved in acetonitrile (20.0 mL), and POCl3 (2.36 g, 15.4 mmol) and NH4Cl (916.2 mg, 15.4 mmol) were added. After purging with nitrogen, the reaction was stirred at 85 °C for 6 hours. LC-MS showed that the starting material had reacted completely. The reaction solution was concentrated, and the crude product was diluted with water (50.0 mL), extracted with ethyl acetate (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (DCM / MeOH = 30 / 1) to obtain the crude product. The crude product was slurried with acetonitrile to give a white solid, 248 mg of compound N, yield: 49%, purity: 97%.

[0038] The compound N obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z) 329.02 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.33 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.00(d, J = 8.4 Hz, 1H), 7.64 – 7.62 (m, 1H), 7.48 – 7.40 (m, 3H), 5.04 (s, 2H).

Claims

1. A method for preparing zapyrazolam, characterized in that, To achieve this, follow these steps: Includes the following steps: S1: Synthesis of Compound C Compound A and compound B were dissolved in a solvent, the gas was displaced, an alkali was added, the reaction was carried out in an ice bath, and the reaction was monitored until the raw materials disappeared. The reaction was quenched, extracted and dried, the solvent was removed by filtration and concentration, and the mixture was pulped to obtain compound C. S2: Synthesis of Compound D Compound C was dissolved in a solvent, salt and oxidant were added, and the reaction was carried out in an ice bath. The reaction was monitored until the starting material disappeared, the reaction was quenched, extracted, dried, and the solvent was concentrated to obtain compound D. S3: Synthesis of Compound E Compound D was dissolved in a solvent, salt and reducing agent were added, and the reaction was monitored until the starting material disappeared. The reaction was filtered, the filtrate was extracted and dried, and the solvent was removed by filtration and concentration to obtain compound E. S4: Synthesis of Compound I Compound E was dissolved in an organic solvent, the gas was displaced, and compound F was added under ice bath conditions. The reaction was carried out under ice bath conditions until the starting material disappeared, thus obtaining solution G. Compound H and a salt were added, the gas was displaced, and the reaction was heated. The reaction was carried out under heating conditions until the starting material disappeared. The solvent was concentrated, and the solution was purified by column chromatography to obtain compound I. S5: Synthesis of Compound J Compound I was dissolved in a solvent, a thioreagent was added, the reaction was heated, and the reaction was monitored until the starting material disappeared. The reaction was then quenched, extracted, dried, concentrated to remove the solvent, passed through a column, and slurried to obtain compound J. S6: Synthesis of Compound L Compound J was dissolved in an organic solvent, compound K was added, and the mixture was monitored until the starting material disappeared. The solvent was then concentrated and the mixture was passed through a column to obtain compound L. S7: Synthesis of Compound M Compound L was dissolved in an organic solvent, the gas was replaced, acid was added under an ice bath, the reaction was heated, and the reaction was monitored until the raw material disappeared. The reaction was then quenched, and the filtered cake was used to obtain compound M. S8: Synthesis of compound N Compound M was dissolved in an organic solvent, salt and phosphorus oxychloride were added, the gas was replaced, the reaction was heated, and the reaction was monitored until the starting material disappeared. The solvent was concentrated, purified by column chromatography, and the mixture was slurryed to obtain compound N.

2. The method according to claim 1, characterized in that, The solvent used in step S1 is any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, ethylene glycol dimethyl ether, N,N-dimethylformamide, and N,N-dimethylacetamide; the base is any one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium diisopropylamino, and lithium bis(trimethylsilylamino)amine; the molar ratio of compound A:compound B:base is 1:1:1 to 1:1.5:1.5; and the reaction temperature is -78 to 25°C.

3. The method according to claim 1, characterized in that, The organic solvent used in step S2 is any one or more of acetonitrile, tetrahydrofuran, acetone, dioxane, and ethanol; the oxidant is any one or more of hydrogen peroxide, m-chloroperoxybenzoic acid, and potassium persulfate; the molar ratio of compound C: salt: oxidant is 1:1:1 to 1:3:5; and the reaction temperature is 0-50℃.

4. The method according to claim 1, characterized in that, The organic solvent used in step S3 is any one or more of methanol, ethanol, tetrahydrofuran, dioxane, water, and acetic acid; the salt is any one or more of ammonium chloride, stannous chloride, and sodium sulfide; the catalyst is iron powder or zinc powder; the molar ratio of compound D: salt: catalyst is 1:5:5~1:10:10; the reaction temperature is 25-80℃.

5. The method according to claim 1, characterized in that, The organic solvent used in step S4 is any one or more of ethanol, isopropanol, N,N-dimethylformamide, and N,N-dimethylacetamide; the base is any one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, and sodium bicarbonate; the molar ratio of compound D:compound E:base is 1:1:0 to 1:4:8; the reaction temperature is 0-110℃. The salt is any one or more of ammonium acetate, ammonium chloride, ammonium bicarbonate, and ammonia water; the molar ratio of compound G:compound H:salt is 1:1:1 to 1:4:4; the reaction temperature is 50-90℃.

6. The method according to claim 1, characterized in that, The organic solvent used in step S5 is any one or more of toluene, pyridine, 1,2-dichloroethane, ethylene glycol dimethyl ether, and tetrahydrofuran; the thioreagent is Lawson's reagent or tetraphosphorus decasulfide; the molar ratio of compound I to thioreagent is 1:1 to 1:2; and the reaction temperature is 65-110℃.

7. The method according to claim 1, characterized in that, The organic solvent used in step S6 is any one or more of methanol, ethanol, and n-butanol; the molar ratio of compound J to compound K is 1:3 to 1:10; and the reaction temperature is 65-120℃.

8. The method according to claim 1, characterized in that, The organic solvent used in step S7 is any one or more of water, acetic acid, N,N-dimethylformamide, acetonitrile, toluene, chloroform, dioxane, and dimethyl sulfoxide; the acid is any one or more of hydrochloric acid and hydrobromic acid; the molar ratio of compound L to acid is 1:5 to 1:10; and the reaction temperature is 50-120℃.

9. The method according to claim 1, characterized in that, The organic solvent used in step S8 is any one or more of chloroform, acetonitrile, phosphorus oxychloride, sulfonium chloride, toluene, 1,2-dichloroethane, and dichloromethane; the chlorination reagent is any one or more of phosphorus oxychloride, sulfonium chloride, and phosphorus pentachloride; the molar ratio of compound M to chlorination reagent is 1:1 to 1:10; and the reaction temperature is 20-110℃.

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