A process for the preparation of a non-oxazinatan novel

Abstract

The application provides a novel method for preparing high-purity fezolinetant through only 2-step reactions, the route has high yield, is environment-friendly, helps to reduce the production cost of fezolinetant, alleviates the accessibility problem, and makes the patients with vasomotor symptoms (hot flashes) of perimenopausal women in China benefit.

Description

Invention Field

[0001] This invention belongs to the field of chemical pharmaceuticals, specifically relating to a novel preparation method of fezolinetant, a drug for treating vasomotor symptoms (hot flashes) in perimenopausal women. Background Technology

[0002] Menopausal vasomotor syndrome (VMS) is primarily caused by decreased or fluctuating estrogen levels after menopause, leading to unstable vasomotor function and resulting in characteristic symptoms, mainly hot flashes and / or excessive sweating. VMS has a high incidence during menopause and is the most common menopausal symptom for which women seek treatment. Menopause is a natural change in a woman's life, typically occurring between the ages of 45 and 55, and is an inevitable stage for women. The demand for VMS treatment in my country is large and continuously growing. Furthermore, with social progress, increased education levels among women, and improved accessibility to health education, this potential market continues to expand. VMS severely impacts patients' physical comfort and sleep quality, and in severe cases, it can last for five years or longer, causing significant distress to women's personal health, workplace, and even family life. Therefore, effective treatments to alleviate symptoms are urgently needed.

[0003] Currently, the primary treatment for VMS (Vaginal Menstrual Syndrome) worldwide is hormone replacement therapy (HRT), including estrogen-only therapy and sequential estrogen-progestin therapy. Multiple studies have shown that HRT can significantly improve patient symptoms and is currently the most effective treatment. However, long-term hormone use may increase the risk of venous thromboembolism. Therefore, patients with coronary heart disease, stroke, high risk of venous thromboembolism, or a history of hormone-dependent cancer should avoid HRT, which limits its use.

[0004] Fizzonite is the first FDA-approved NK3 receptor antagonist for menopausal venous dysmenorrhea (VMS), and it is also the world's first non-hormonal treatment for VMS with a novel mechanism of action. This is a milestone in women's health treatment, as fizzonite has revolutionized the traditional treatment model for VMS and changed the VMS drug market landscape, with far-reaching significance. Fizzonite selectively targets the neurokinin 3 (NK3) receptor, blocking the binding of NK3 to Kisspeptin / neurokine / dynorphin (KNDy) neurons, thereby regulating neuronal activity in the brain's thermoregulatory center (hypothalamus), reducing the frequency and severity of menopausal-related moderate to severe VMS, with efficacy comparable to HRT, and rapid onset within one week. Long-term safety studies have shown that fizzonite has no risk of endometrial hyperplasia or cancer. Its side effects include common adverse drug reactions such as abdominal pain and diarrhea, and while elevated liver transaminases or liver damage should be noted, the incidence is low, and its safety is significantly superior to HRT drugs.

[0005] The global VMS market has enormous potential and continues to grow. While hormone replacement therapy (HRT) remains the primary and effective treatment for moderate to severe menopausal VMS, the approval of fezlonetine tablets offers a new and novel treatment option for VMS, especially for patients who are intolerant to HRT, representing a significant breakthrough in the care of postmenopausal women.

[0006] Fezonnettan, chemically known as (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2],4]triazolo[4,3-a]pyrazin-7(8H)-yl]methyl ketone, has the molecular formula: C 16 H 15 FN6OS, molecular weight: 358.39, CAS number: 1629229-37-3, chemical structure formula as follows:

[0007]

[0008] Existing technical document patent CN201480018469 reports the synthetic route of fezonine, as follows:

[0009]

[0010] This route uses (R)-3-methylpiperazin-2-one, ethyl 3-methyl-1,2,4-thiadiazole-5-carboxylate, and p-fluorobenzoyl chloride as starting materials to prepare fezonetan via a 5-step reaction. However, this route is long, has a low overall yield, and uses the highly toxic reagent hydrazine hydrate, which puts significant environmental pressure on the environment. Summary of the Invention

[0011] The purpose of this invention is to overcome the shortcomings of the prior art and provide a novel preparation method for fezonelanth, a drug for treating vasomotor symptoms (hot flashes) in perimenopausal women. The method is as follows:

[0012]

[0013] Step 1: Compounds of formula a and formula b are prepared by acylation docking reaction to obtain intermediate compound c;

[0014] Step 2: Intermediate compound c and compound d are coupled via a Suzuki coupling reaction to yield fezonatetan;

[0015] In compound a, the R group is a hydroxyl or chlorine group;

[0016] In compounds of formula b and formula c, the X1 group is chlorine, bromine or iodine, preferably bromine or iodine;

[0017] In compound d, the X2 group is chlorine, bromine, or iodine, preferably bromine or iodine.

[0018] The synthetic route of this invention differs from that reported in prior art document CN201480018469. The purpose of this invention is to provide a novel two-step method for preparing high-purity fezonelant, characterized by a short route, high product purity, high yield, inexpensive and readily available starting materials, the absence of highly toxic reagents, and environmental friendliness.

[0019] In the amidation reaction of step 1 of this invention, when the R group in formula a is chlorine (formula aI, 4-fluorobenzoyl chloride), the reaction catalyst is an inorganic base, selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium hydroxide, or sodium hydroxide, preferably sodium bicarbonate or potassium bicarbonate with weaker basicity, which can significantly reduce the generation of hydrolysis byproducts and ensure complete reaction. When the R group in formula a is hydroxyl (formula a-II, 4-fluorobenzoic acid), the reaction requires the addition of an acylating agent and an organic base, wherein the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), O-benzotriazole-N,N,N,N-tetramethylurea hexafluorophosphate (HBTU), or diisopropylcarbodiimide (DIC); the organic base is selected from triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine (DMAP), or N-methylmorpholine. When the acylating agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) and the organic base is 4-dimethylaminopyridine (DMAP), the reaction effect is optimal and there are fewer byproducts, making it the preferred choice.

[0020] In step 2 of this invention, the Suzuki coupling reaction can be carried out by first reacting compound d with dipentanoyl diboron to generate intermediate pinacol ester of borate, and then reacting it with compound c to prepare fezonatetan, as detailed below:

[0021]

[0022] In step 2 of this invention, the Suzuki coupling reaction can also be carried out by first reacting compound c with dipentanoyl diboron to generate intermediate pinacol ester of borate, and then reacting it with compound d to prepare fezonatetan, as detailed below:

[0023]

[0024] In step 2 of this invention, the Suzuki coupling reaction, regardless of the reaction sequence described above, requires the addition of acetate, a palladium catalyst, and an inorganic base to catalyze the reaction. The acetate is selected from potassium acetate or sodium acetate, preferably potassium acetate. The palladium catalyst is selected from bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (PdCl2(dppf)), tetra(triphenylphosphine)palladium (0), bis(tricyclohexylphosphine)palladium (0), or bis(tri-O-toluenephosphine)palladium (0), preferably PdCl2(PPh3)2 or PdCl2(dppf). The inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or potassium phosphate, preferably sodium bicarbonate or potassium bicarbonate with lower alkalinity, and particularly preferably potassium bicarbonate with higher water solubility.

[0025] In step 2 of this invention, the amide structure in compound C and the product fezlonetane may hydrolyze under alkaline reaction conditions during the Suzuki coupling reaction. However, fortunately, our company effectively controlled the reaction conditions, such as selecting a weaker inorganic base, strictly controlling the feed ratio of each material, minimizing the reaction time, and performing post-treatment recrystallization purification. This effectively avoided and eliminated potential amide bond hydrolysis byproducts, resulting in high-purity fezlonetane. The effective control of these byproducts is crucial to the implementation of this invention and is its greatest highlight.

[0026] This invention provides a novel two-step method for preparing high-purity fezlonetine. This route offers significant advantages over existing technologies, including a shorter route, higher product purity, higher yield, no use of highly toxic reagents, and greater environmental friendliness. This new route helps reduce the production cost of fezlonetine, alleviates its accessibility issues, and benefits a large number of perimenopausal women in China suffering from hot flashes. Attached Figure Description

[0027] Figure 1 Process route diagram of the present invention Specific implementation methods:

[0028] The technical solutions in the embodiments of the present invention will be described in detail below with reference to the embodiments of the present invention. However, the following embodiments are only used to understand the present invention and cannot limit the present invention. The present invention can be implemented in many different ways as defined and covered by the claims.

[0029] The following will further illustrate the new synthetic method of fezonectane and its advantages in conjunction with Examples 1 and 9 of the present invention.

[0030] Example 1: Synthesis of (R)-(4-fluorophenyl)(3-iodo-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (formula cI)

[0031]

[0032] (R)-3-bromo-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (formula bI, 108.5 g, 0.5 mol) and 500 mL of dichloromethane were added to a three-necked flask and stirred to dissolve. 500 mL of saturated sodium bicarbonate solution was added, and 4-fluorobenzoyl chloride (formula aI, 79.3 g, 0.5 mol) was added dropwise at room temperature. After the addition was complete, the reaction was continued at room temperature for 10 h. The mixture was separated, and the organic phase was washed with 600 mL of water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was added to n-hexane and stirred to disperse. The mixture was filtered to give the title compound, formula cI (157.7 g, 93% yield), Ms m / z 339.0 (M+1). 1 H NMR (400MHz, CDCl3): δ1.46 (d, 3H), 3.61-3.71 (m, 2H), 4.01-4.03 (t, 2H), 4.96 (q, 1H), 7.36 (t, 2H), 8.10 (t, 2H).

[0033] Example 2: Synthesis of (R)-(4-fluorophenyl)(3-iodo-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (formula cI)

[0034]

[0035] 4-Fluorobenzoic acid (formula a-II, 70.0 g, 0.5 mol), (R)-3-bromo-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (formula bI, 108.5 g, 0.5 mol), 4-dimethylaminopyridine (73.3 g, 0.6 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-carbodiimide (ECDI, 77.6 g, 0.5 mol), and 600 mL of dichloromethane were added to a three-necked flask. The mixture was stirred at room temperature for 5 h until the reaction was complete. 600 mL of water was added, and the mixture was stirred and separated. The organic phase was washed first with 500 mL of saturated sodium bicarbonate solution, then with 600 mL of water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dispersed in n-hexane and filtered to obtain the title compound, formula cI (152.6 g, 90% yield). Ms m / z 339.0(M+1).

[0036] Example 3: Synthesis of (R)-(4-fluorophenyl)(3-iodo-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (formula c-II)

[0037]

[0038] (R)-3-iodo-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (formula b-II, 132.0 g, 0.5 mol) and 550 mL of dichloromethane were added to a three-necked flask and stirred to dissolve. 500 mL of saturated sodium bicarbonate solution was added, and 4-fluorobenzoyl chloride (formula aI, 79.3 g, 0.5 mol) was added dropwise at room temperature. After the addition was complete, the reaction was continued at room temperature for 10 h. The mixture was separated, and the organic phase was washed with 600 mL of water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dispersed in n-hexane and filtered to obtain the title compound, formula c-II (181.5 g, 94% yield), Ms m / z 387.0 (M+1).

[0039] Example 4: Synthesis of Fezonine 1

[0040]

[0041] 5-Bromo-3-methyl-1,2,4-thiadiazole (formula dI, 35.8 g, 0.2 mol), dipentanoyl diborone (66.0 g, 0.26 mol), potassium acetate (58.9 g, 0.6 mol), PdCl2(PPh3)2 (7.0 g, 10 mmol), and 400 mL of 1,2-dimethoxyethane (DME) were placed in a three-necked flask and heated to 80-85 °C for 4 h until the reaction was complete. After cooling to room temperature, 230 mL of saturated KHCO3 solution and (R)-(4-fluorophenyl)(3-bromodiphenyl)2 were added. -8-Methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl ketone (formula cI, 67.8 g, 0.2 mol), heated to 80-85 °C, and the reaction was terminated when the liquid phase monitoring showed complete reaction. The mixture was filtered while hot, separated, and the organic phase was washed twice with water (300 ml / time). The solvent was evaporated under reduced pressure, and the residue was dispersed in n-hexane, filtered, and the filter cake was dried. The residue was recrystallized with anhydrous ethanol-water mixed solvent and dried to obtain fezoniltan (54.5 g, purity 99.2%, yield 76%), Ms m / z 359.1 (M+1). 1 H NMR (400MHz, CDCl3): δ1.47 (d, 3H), 2.38 (s, 3H), 3.60-3.70 (m, 2H), 4.00-4.02 (t, 2H), 4.95 (q, 1H), 7.38 (t, 2H), 8.11 (t, 2H).

[0042] Example 5: Synthesis of Fezonnett 2

[0043]

[0044] 5-Bromo-3-methyl-1,2,4-thiadiazole (formula dI, 35.8 g, 0.2 mol), dipentanoyl diborone (66.0 g, 0.26 mol), potassium acetate (58.9 g, 0.6 mol), PdCl2(PPh3)2 (7.0 g, 10 mmol), and 400 mL of 1,2-dimethoxyethane (DME) were placed in a three-necked flask and heated to 80-85 °C for 4 h until the reaction was complete. After cooling to room temperature, 230 mL of saturated KHCO3 solution and (R)-(4-fluorophenyl)(3-iodo- 8-Methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (formula c-II, 77.2 g, 0.2 mol) was heated to 80-85 °C. The reaction was terminated when the liquid phase was monitored to be complete. The mixture was filtered while hot, separated, and the organic phase was washed twice with water (300 ml each time). The solvent was evaporated under reduced pressure, and the residue was dispersed in n-hexane. The mixture was filtered, the filter cake was dried, and recrystallized with anhydrous ethanol-water mixed solvent. The product was dried to obtain fezoniltan (55.9 g, purity 99.5%, yield 78%), Ms m / z 359.1 (M+1).

[0045] Example 6: Synthesis of Fezonendane 3

[0046]

[0047] 5-Iodo-3-methyl-1,2,4-thiadiazole (formula d-II, 45.2 g, 0.2 mol), dipentanoyl diborone (66.0 g, 0.26 mol), potassium acetate (58.9 g, 0.6 mol), PdCl2(PPh3)2 (7.0 g, 10 mmol), and 400 mL of 1,2-dimethoxyethane (DME) were placed in a three-necked flask and heated to 80-85 °C for 4 h until the reaction was complete. After cooling to room temperature, 230 mL of saturated KHCO3 solution and (R)-(4-fluorophenyl)(3- Bromo-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (formula cI, 67.8 g, 0.2 mol) was heated to 80-85 °C. The reaction was terminated when the liquid phase was monitored to be complete. The mixture was filtered while hot, separated, and the organic phase was washed twice with water (300 ml each time). The solvent was evaporated under reduced pressure, and the residue was dispersed in n-hexane. The mixture was filtered, the filter cake was dried, and recrystallized with anhydrous ethanol-water mixed solvent. The product was dried to obtain fezoniltan (53.8 g, purity 99.0%, yield 75%), Ms m / z 359.1 (M+1).

[0048] Example 7: Synthesis of Fezonnett 4

[0049]

[0050] 5-Iodo-3-methyl-1,2,4-thiadiazole (formula d-II, 45.2 g, 0.2 mol), dipentanoyl diborone (66.0 g, 0.26 mol), potassium acetate (58.9 g, 0.6 mol), PdCl2(PPh3)2 (7.0 g, 10 mmol), and 400 mL of 1,2-dimethoxyethane (DME) were placed in a three-necked flask and heated to 80-85 °C for 4 h until the reaction was complete. After cooling to room temperature, 230 mL of saturated KHCO3 solution and (R)-(4-fluorophenyl)(3- Iodo-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (formula cI, 77.2 g, 0.2 mol) was heated to 80-85 °C. The reaction was terminated when the liquid phase was monitored to be complete. The mixture was filtered while hot, separated, and the organic phase was washed twice with water (300 ml each time). The solvent was evaporated under reduced pressure, and the residue was dispersed in n-hexane. The mixture was filtered, the filter cake was dried, and recrystallized with anhydrous ethanol-water mixed solvent. The product was dried to obtain fezoniltan (56.6 g, purity 99.4%, yield 79%), Ms m / z 359.1 (M+1).

[0051] Example 8: Synthesis of Fezonnett 5

[0052]

[0053] 5-Bromo-3-methyl-1,2,4-thiadiazole (formula dI, 35.8 g, 0.2 mol), dipentanoyl diborone (66.0 g, 0.26 mol), potassium acetate (58.9 g, 0.6 mol), PdCl2 (dppf) (7.3 g, 10 mmol), and 400 mL of 1,2-dimethoxyethane (DME) were placed in a three-necked flask and heated to 80-85 °C for 4 h until the reaction was complete. After cooling to room temperature, 230 mL of saturated KHCO3 solution and (R)-(4-fluorophenyl)(3-bromo- 8-Methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (formula cI, 67.8 g, 0.2 mol) was heated to 80-85 °C. The reaction was terminated when the liquid phase was monitored to be complete. The mixture was filtered while hot, separated, and the organic phase was washed twice with water (300 ml each time). The solvent was evaporated under reduced pressure, and the residue was dispersed in n-hexane. The mixture was filtered, the filter cake was dried, and recrystallized with anhydrous ethanol-water mixed solvent. The product was dried to obtain fezoniltan (52.3 g, purity 98.9%, yield 73%), Ms m / z 359.1 (M+1).

[0054] Example 9: Synthesis of Fezonantane 6

[0055]

[0056] (R)-(4-fluorophenyl)(3-bromo-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (formula cI, 67.8 g, 0.2 mol), dipentanoyl diborone (66.0 g, 0.26 mol), potassium acetate (58.9 g, 0.6 mol), PdCl2(PPh3)2 (7.0 g, 10 mmol), and 400 ml of 1,2-dimethoxyethane (DME) were placed in a three-necked flask and heated to 80-85 °C for 3 h until the reaction proceeded. Completely cool to room temperature, add 230 ml of saturated KHCO3 solution and 5-bromo-3-methyl-1,2,4-thiadiazole (formula dI, 35.8 g, 0.2 mol), heat to 80-85 °C, terminate the reaction when the liquid phase monitoring shows complete reaction, filter, separate the liquid and organic phase, wash twice with water (300 ml / time), evaporate the solvent under reduced pressure, disperse the residue in n-hexane, filter, dry the filter cake, recrystallize with anhydrous ethanol-water mixed solvent, and dry to obtain fezoniltan (50.1 g, purity 98.7%, yield 70%), Ms m / z 359.1 (M+1).

[0057] Compared with the fezolinate synthetic routes reported in existing technical documents, the routes described in Examples 1-9 of this invention are shorter, have higher yields, do not require harsh reaction conditions, and do not use highly toxic reagents, which is of great significance for the industrialization of fezolinate active pharmaceutical ingredient.

[0058] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing fezonelam, characterized in that, The method is as follows: The compound of formula d first reacts with dipentanoyl diboron to generate intermediate borate pinacol ester, and then reacts with the compound of formula c in the presence of acetate, palladium catalyst and inorganic base to prepare fezonatetan; In compound c, the X1 group is bromine or iodine; In compound d, the X2 group is bromine or iodine; The acetate is selected from potassium acetate or sodium acetate; The palladium catalyst is selected from bis(triphenylphosphine)palladium dichloride or dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium; The inorganic base is selected from sodium bicarbonate or potassium bicarbonate; The reaction solvent is selected from 1,2-dimethoxyethane, and the reaction temperature is 80-85℃.

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