A route to construct non-azaniane chiral fragments and intermediates and methods of preparation

Abstract

The application provides a route for constructing a non-Fezolintant chiral fragment and an intermediate and a preparation method, relates to the technical field of organic synthesis and preparation of drug intermediates, and provides the route for constructing the non-Fezolintant chiral fragment and the intermediate (a compound of formula G, formula H, formula I and formula J) and the preparation method, as shown in the following synthetic route. The application provides a new route for synthesizing a key intermediate (intermediate A0) of Fezolintant (non-Fezolintant), raw materials are easy to obtain, chemical reaction conditions of each step are mild, and each intermediate has high chiral purity, so that the chiral purity of the product can be improved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis and preparation of bulk drug intermediates, and in particular to a route for constructing a nonazonaitand chiral fragment, an intermediate thereof, and a preparation method thereof. Background Art

[0002] Menopausal vasomotor syndrome (VMS) is primarily caused by decreased or fluctuating estrogen levels after menopause, leading to unstable vasoconstriction and resulting in characteristic symptoms, primarily hot flashes and / or excessive sweating. VMS can severely impact a patient's physical comfort and sleep quality, and in severe cases, can persist for five years or longer, significantly impacting their personal health, work, and even their families. Therefore, effective treatments to alleviate symptoms are urgently needed. VMS is highly prevalent during menopause and is the most common menopausal symptom for which women seek treatment.

[0003] Currently, the primary treatment for menopausal VMS worldwide is hormone replacement therapy (HRT), including estrogen-only and sequential estrogen-progestin therapy. Multiple studies have demonstrated that HRT can significantly improve symptoms and is currently the most effective treatment. However, long-term use may increase the risk of venous thromboembolism. Therefore, patients with a high risk of coronary heart disease, stroke, venous thromboembolism, or a history of hormone-dependent cancers should avoid HRT. Furthermore, the long-standing fear of hormones further limits HRT use.

[0004] Fezolinetant (molecular structure below), a small molecule oral drug, selectively targets the neurokinin 3 (NK3) receptor. By binding to the NK3 receptor, it blocks the binding of NK3 to kisspeptin / neurokinin / dynorphin (KNDy) neurons, thereby regulating neuronal activity in the brain's temperature regulation center (hypothalamus) and reducing the frequency and severity of moderate to severe VMS associated with menopause.

[0005] Fezolinetant structure

[0006] Fizonaitant is the first NK3 receptor antagonist used for menopausal VMS, providing a new mechanism of treatment option for female VMS patients, especially for those who are intolerant to HRT.

[0007] Currently, the synthesis methods of fezonetant mainly include the following routes.

[0008] Ogeda patent WO2011 / 121137 discloses the following route 1:

[0009]

[0010] Route 1

[0011] Route 1: Chiral piperazinone A1 is used as the starting material. After protection of the amino group with tert-butyloxycarbonyl (Boc), compound A2 is obtained. A2 then reacts with an ethoxylium salt in the presence of a base to produce the iminoether compound A3. A3 is then substituted with thiadiazole hydrazide and subjected to dehydration and cyclization to further produce compound A4. Deprotection under acidic conditions yields the chiral key intermediate A0, which is then reacted with 4-fluorobenzoic acid or its derivatives to produce fezonetant.

[0012] The chiral piperazinone A1 used in this solution is expensive, and the overall cost is high.

[0013] In addition, this route has a significant disadvantage. It is easy to racemize in steps 2 and 3, making it difficult to obtain chiral compounds A4 and A0 with high chiral purity (>80% ee), and cannot be used to prepare the active pharmaceutical ingredient fezonetant.

[0014] Ageda further improved on this route, and patent CN103906750 B9 disclosed the following route 2:

[0015]

[0016] Route 2

[0017] Similarly, the route is to use ketone A1 as the starting material, which is protected by amino group, reacted with ethoxylium salt, substituted with thiadiazole hydrazide, dehydrated and cyclized, deprotected, and condensed with 4-fluorobenzoic acid or its derivatives to obtain fezonetant.

[0018] The biggest difference between Route 2 and Route 1 is that the Boc protecting group is replaced with N-sp 3 Protective group. Perhaps it is the weakening of the electron-withdrawing effect that reduces the risk of racemization of the chiral center and improves the chiral purity.

[0019] Since this route also uses expensive chiral piperazinone, and the ethoxylium salt reagent in the second step is relatively expensive and has a low yield, the overall production cost is relatively high. In addition, because the second-step product is a high-boiling-point liquid, it is relatively difficult to purify.

[0020] In subsequent further research, Ogeda invented the following route three:

[0021]

[0022] Route 3

[0023] This route still starts with the same chiral piperazinone, undergoes a condensation reaction with 4-fluorobenzoic acid, then reacts with an ethoxylium salt to obtain the iminoether compound C3, and finally reacts with thiadiazole hydrazide to obtain the active ingredient of fenazolin.

[0024] Obviously, compared with the first two routes, this route has the advantage of being shorter. 2 The chiral purity of the final product is reduced due to the presence of protective groups. In addition, the reported yields of the last two steps of this route are both below 50%, and the overall material consumption is relatively high, leaving much room for improvement.

[0025] In 2023, Beijing Kanglisheng Pharmaceutical Technology Development Co., Ltd.'s patent CN117510506A disclosed the following route four. Its key technology lies in the last step, which uses a metal-catalyzed scheme to perform Suzuki coupling on the triazole ring and the thiadiazole ring.

[0026]

[0027] Route 4

[0028] This route is shorter than previously published routes and appears to offer significant cost advantages. However, in practice, obtaining the chiral raw material D1 presents a significant challenge, creating a potential supply risk for industrialization. Furthermore, the use of precious metals in the final coupling step can result in excessive levels of precious metals in the final active pharmaceutical ingredient, posing a significant quality risk for oral preparations intended for high-dose, long-term use.

[0029] In summary, the existing technology for synthesizing fezonetant still has a large room for improvement. Based on this, the present invention provides a new route for synthesizing fezonetant. Summary of the Invention

[0030] In response to the above problems, the present invention provides a method for preparing a key intermediate of zonetant. The starting materials of this route are easily available, the chemical reaction conditions of each step are mild, and the chiral purity of each intermediate is high, which is beneficial to improving the chiral purity of the product, facilitating large-scale production and reducing costs.

[0031] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0032] In one aspect, the present invention provides a compound of formula G, the structure of which is shown below:

[0033]

[0034] Wherein, PG1 is a protecting group.

[0035] Preferably, PG1 is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; further preferably, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0036] In another aspect, the present invention provides a method for preparing a compound of formula G, comprising the following steps:

[0037]

[0038] Chiral alanine formula E undergoes a condensation reaction with thiadiazole hydrazide formula F to obtain a dihydrazide compound formula G;

[0039] Wherein, PG1 is a protecting group.

[0040] Preferably, PG1 is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; further preferably, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0041] Preferably, the condensation reaction is selected from the reaction of Formula E with Formula F in the presence of a condensing agent or the condensation of Formula E with isobutyl chloroformate in the presence of a base to form a mixed anhydride, which is then reacted with Formula F; further preferably, the condensation reaction is the condensation of Formula E with isobutyl chloroformate in the presence of a base to form a mixed anhydride, which is then reacted with Formula F.

[0042] Preferably, the base is selected from at least one of N-methylmorpholine and N,N-diisopropylethylamine; more preferably, the base is selected from N-methylmorpholine.

[0043] The condensing agent is selected from at least one of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, methylethylphosphonic anhydride, diphenylphosphonyl chloride, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; further preferably, the condensing agent is selected from at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0044] Preferably, the condensation reaction further comprises a solvent.

[0045] Preferably, the solvent is selected from at least one of tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, and dichloromethane; more preferably, the solvent is selected from ethyl acetate.

[0046] In one aspect, the present invention provides a compound of formula H, the structure of which is shown below:

[0047]

[0048] Wherein, PG1 is a protecting group.

[0049] Preferably, PG1 is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; further preferably, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0050] In another aspect, the present invention provides a method for preparing a compound of formula H, comprising the following steps:

[0051]

[0052] The dihydrazide compound G reacts in the presence of a condensing agent, undergoes dehydration and ring closure, and obtains compound H;

[0053] Wherein, PG1 is a protecting group.

[0054] Preferably, PG1 is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; further preferably, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0055] Preferably, the condensing agent is selected from at least one of Burgess reagent and a combination reagent of iodine and triphenylphosphine; further preferably, the condensing agent is selected from Burgess reagent.

[0056] Preferably, the structure of the Burgess reagent is as follows:

[0057]

[0058] Wherein, R1, R2, R3, and R4 are each independently selected from an alkyl group.

[0059] Preferably, the reaction further comprises a solvent.

[0060] Preferably, the solvent is selected from at least one of tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, and dichloromethane; more preferably, the solvent is dichloromethane.

[0061] In one aspect, the present invention provides a compound of formula I, the structure of which is shown below:

[0062] .

[0063] In another aspect, the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0064]

[0065] Deprotecting the compound of formula H to obtain the compound of formula I or a salt thereof;

[0066] Wherein, PG1 is a protecting group.

[0067] Preferably, PG1 is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; further preferably, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0068] Preferably, the salt is selected from hydrochloride, hydrogen bromide, p-toluenesulfonate or methanesulfonate.

[0069] In one aspect, the present invention provides a compound of formula J, the structure of which is shown below:

[0070]

[0071] Wherein, PG2 is a protecting group.

[0072] Preferably, PG2 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0073] In another aspect, the present invention provides a method for preparing a compound of formula J, comprising the following steps:

[0074]

[0075] Compound I undergoes a substitution reaction with the side chain to obtain a compound of formula J;

[0076] Wherein, PG2 is a protecting group.

[0077] Preferably, PG2 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0078] Preferably, the side chain is selected from 2-PG2 aminoacetaldehyde, 2-PG2 aminoethyl bromide, 2-PG2 amino-1-toluenesulfonyloxyethane, 2-PG2 amino-1-methylsulfonyloxyethane, 1,2,3-oxathiazolidine-3-PG 2- at least one of 2,2-dioxides;

[0079] The structure of the above side chain is as follows:

[0080] 、 、 、 .

[0081] In another aspect, the present invention provides the use of the compound of formula G described above in the synthesis of the key intermediate A0 of fezonetant.

[0082] The present invention provides the use of the compound of formula H described above in the synthesis of the key intermediate A0 of zonetant.

[0083] The present invention provides the use of the compound of formula I described above in the synthesis of a key intermediate A0 of fezonetant.

[0084] The present invention provides the use of the compound of formula J described above in the synthesis of the key intermediate A0 of fezonetant.

[0085] In another aspect, the present invention provides a method for preparing a key intermediate A0 of zonetant, comprising the above-mentioned compound of formula G, compound of formula H, compound of formula I, and compound of formula J. The synthetic route is as follows:

[0086]

[0087] Among them, PG1 and PG2 are protecting groups.

[0088] Preferably, PG1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; PG2 is selected from tert-butoxycarbonyl or benzyloxycarbonyl; further preferably, PG1 is selected from tert-butoxycarbonyl or benzyloxycarbonyl; PG2 is selected from tert-butoxycarbonyl or benzyloxycarbonyl;.

[0089] Preferably, the specific reaction process of step 5 is: the compound of formula J is deprotected to obtain a diamine structure Ja; the diamine structure Ja is extremely unstable in an alkaline state, and further undergoes a molecular reaction to obtain compound Jb, and finally further obtains compound A0 under heating conditions.

[0090] The reaction mechanism of step 5 is as follows:

[0091] .

[0092] Compared with the prior art, the present invention has the following beneficial effects:

[0093] 1. The present invention provides a new route for synthesizing the key intermediate of Fezolintant (key intermediate A0 of Fezolintant), which provides new ideas and possibilities for the synthesis of key intermediate A0 of Fezolintant.

[0094] 2. The raw materials of the new route provided by the present invention are easily available, the chemical reaction conditions of each step are mild, and the chiral purity of each intermediate is high, which is conducive to improving the chiral purity of the product.

[0095] 3. The present invention also provides four new compounds: compound G, compound H, compound I, and compound J. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 Compound G1 1 HNMR spectrum;

[0097] Figure 2 Compound G2 1 HNMR spectrum;

[0098] Figure 3 Compound H1 1 HNMR spectrum;

[0099] Figure 4 Compound H2 1 HNMR spectrum;

[0100] Figure 5Compound I1 1 HNMR spectrum;

[0101] Figure 6 Compound J1 1 HNMR spectrum;

[0102] Figure 7 Compound J2 1 HNMR spectrum;

[0103] Figure 8 Compound A0 1 HNMR spectrum;

[0104] Figure 9 is the chiral purity spectrum of compound A0;

[0105] Figure 10 Fezolintant 1 HNMR spectrum;

[0106] Figure 11 This is the chiral purity spectrum of Fezolintant. DETAILED DESCRIPTION

[0107] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further illustrated below in conjunction with specific embodiment, but the following embodiment is only a preferred embodiment of the present invention, not all. Based on the embodiment in the embodiment, other embodiments obtained by those skilled in the art without making creative work all fall within the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their source is not specifically limited. The technology and scientific terms used in the embodiment have the meaning commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0108] Glossary:

[0109] Boc: tert-butyloxycarbonyl

[0110] Cbz: benzyloxycarbonyl

[0111] PMB: p-methoxybenzyl

[0112] DCC: Dicyclohexylcarbodiimide DCC

[0113] DIC: Diisopropylcarbodiimide

[0114] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

[0115] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0116] CDI: Carbonyldiimidazole

[0117] Example 1:

[0118]

[0119] Compound E1 (54.0 g, 1.0 eq.), N-methylmorpholine (34.6 g, 1.2 eq.), and tetrahydrofuran (540 mL) were added to a 100 mL three-necked flask and cooled to 0°C under nitrogen. While maintaining the temperature between -10 and 10°C, isobutyl chloroformate (40.9 g, 1.05 eq.) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 20 minutes. Compound F (45.1 g, 1.0 eq.) was then added portionwise. After the addition was complete, the mixture was stirred at this temperature for 10 minutes. A 10% aqueous solution of citric acid was added. The tetrahydrofuran was removed by concentration under reduced pressure, and the mixture was extracted twice with dichloromethane. The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to yield 76.1 g of compound G1 (81% yield) as a pale yellow solid with a chiral purity of 99.9%.

[0120] LCMS, [M+Na]=352;

[0121] 1 HNMR (CDCl3) δ9.63 (br, 2H), 5.32 (br, 1H), 4.43 (br, 1H), 2.70 (s,3H), 1.46 (br, 12H).

[0122] The compound showed enone configuration interchange in NMR.

[0123] Example 2:

[0124]

[0125] To a 500 mL three-necked flask, add 380 mL of tetrahydrofuran and chlorosulfonic acid isocyanate (48.9 g, 3.0 eq.). Cool to 0-10°C under nitrogen. Add methanol (11.1 g, 3.0 eq.) dropwise while maintaining the temperature. Stir for 10 minutes to obtain solution A.

[0126] In another 1000 mL three-necked reaction flask, compound G1 (38.0 g, 1.0 eq.), triethylamine (75.8 g, 6.5 eq.), and tetrahydrofuran (380 mL) were added and cooled to 0-10°C under nitrogen to obtain solution B. Solution A was added dropwise to solution B, and the temperature was raised to 20-40°C for 30 hours. The reaction solvent was concentrated, and the concentrate was diluted with 500 mL of dichloromethane, washed with 5% sodium bicarbonate solution, and dried over saturated sodium chloride. The organic phase was concentrated to dryness and purified by silica gel column chromatography to obtain 30.5 g of compound H1 (85% yield) as a white solid with a chiral purity of 99.9%.

[0127] LCMS, [M+H]=312;

[0128] 1 HNMR (CDCl3) δ5.25 (br, 1H), 2.82 (s, 3H), 2.72 (s, 1H), 1.70 (d,3H), 1.46 (s, 9H).

[0129] Example 3:

[0130]

[0131] Compound H1 (12.0 g, 1.0 eq.) and 60 mL of dioxane were added to a 250 mL three-necked flask and stirred until dissolved. A 4 M solution of hydrogen chloride in dioxane (60 mL) was then added dropwise at 20-30°C. After the addition was complete, the mixture was stirred at room temperature for 2 hours, filtered, and oven-dried to obtain 9.1 g of compound I1 (95% yield) as a white solid with a chiral purity of 99.9%.

[0132] LCMS: [M+1]=212;

[0133] 1 HNMR (D2O) δ5.01 (q, 1H), 2.88 (s, 3H), 1.75 (d, 3H).

[0134] Example 4:

[0135]

[0136] Compound E2 (5 g, 1.0 eq.), N-methylmorpholine (2.7 g, 1.2 eq.), and 50 mL of tetrahydrofuran were added to a 100 mL three-necked flask and cooled to 0°C under nitrogen. While maintaining the temperature between -10 and 10°C, isobutyl chloroformate (3.2 g, 1.05 eq.) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 20 minutes. Compound F (3.5 g, 1.0 eq.) was then added portionwise. After the addition was complete, the mixture was stirred at this temperature for 10 minutes. A 10% aqueous solution of citric acid was added. The tetrahydrofuran was removed by concentration under reduced pressure, and the mixture was extracted twice with dichloromethane. The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to yield 6.7 g of compound G2 (82% yield) as a light yellow oil with a chiral purity of 99.9%.

[0137] LCMS, [M+1]=364;

[0138] 1 HNMR (CDCl3) δ9.29 (br, 2H), 7.36 (m, 5H), 5.45 (br, 1H), 5.16 (m,2H), 4.48 (m, 1H), 2.72 (s, 3H), 1.49 (d, 3H).

[0139] Example 5:

[0140]

[0141] Add 50 mL of tetrahydrofuran and chlorosulfonic acid isocyanate (5.8 g, 3.0 eq.) to a 100 mL three-necked flask, cool to 0-10°C under nitrogen, add methanol (1.32 g, 3.0 eq.) dropwise while keeping warm, and stir for 10 minutes to obtain solution A.

[0142] In another 250 mL three-necked reaction flask, compound G2 (5.0 g, 1.0 eq.), triethylamine (9.0 g, 6.5 eq.), and 50 mL of tetrahydrofuran were added and cooled to 0-10°C under nitrogen to obtain solution B. Solution A was added dropwise to solution B, and the temperature was raised to 20-40°C for 24 hours. The reaction solvent was concentrated, and the concentrate was diluted with 100 mL of dichloromethane, washed with 5% sodium bicarbonate solution, and dried over saturated sodium chloride. The organic phase was concentrated to dryness and purified by silica gel column chromatography to obtain 3.94 g of compound H2 (83% yield) as a light yellow liquid with a chiral purity of 99.9%.

[0143] LCMS: [M+1]=346;

[0144] 1HNMR (CDC13) δ 7.37 (m, 5H ), 5.48 (br, 1H ), 5.32 (m, 1H ), 5.17 (m,2H), 2.83 (s, 3H), 1.72 (d, 3H).

[0145] Example 6:

[0146]

[0147] In a 100 mL single neck flask, add H2(1 g, 1.0 eq.), 30 mL methanol, 2 mL hydrogen chloride methanol solution (4M), 0.3 g 10% palladium on carbon. Vacuum, nitrogen replacement 3 times, then stir overnight at room temperature under hydrogen atmosphere. Filter the palladium on carbon, wash with methanol. Concentrate the filtrate to dryness, add 20 mL ethyl acetate, shake at room temperature for 30 minutes, filter, dry to get 0.7 g compound II, yield 98%, white solid. Chiral purity 99.9%.

[0148] Example 7:

[0149]

[0150] In a 250 mL three neck flask, add compound II (10 g, 1.0 eq.), Boc amino acetaldehyde (7.7 g, 1.2 eq.), 100 mL dichloromethane, nitrogen protection, temperature between 0-10°C, add sodium triacetyloxyborohydride (17.2 g, 2.0 eq.) in batches. After dropwise addition, stir at room temperature for 2 hours. Wash the reaction solution with 5% sodium bicarbonate, saturated brine respectively. Concentrate the organic phase to dryness to get the crude product, which is purified by silica gel column chromatography to get 12.2 g compound J2, yield 85%, white solid. Chiral purity 99.9%.

[0151] LCMS: [M+1]=355;

[0152] 1 HNMR (CDC13) δ 7.37 (m, 5H ), 5.48 (br, 1H ), 5.32 (m, 1H ), 5.17 (m,2H), 2.83 (s, 3H), 1.72 (d, 3H).

[0153] Example 8:

[0154]

[0155] Compound I1 (13.5 g, 1.0 eq.), Cbz-aminoacetaldehyde (9.4 g, 1.2 eq.), and 135 mL of dichloromethane were added to a 250 mL three-necked flask. The mixture was cooled to between 0-10°C under nitrogen. Sodium triacetoxyborohydride (17.2 g, 2.0 eq.) was then added portionwise while maintaining the temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 5% sodium bicarbonate and then saturated brine. The organic phase was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to yield 13.5 g of compound J2 (83% yield) as a light yellow oil with a chiral purity of 99.9%.

[0156] LCMS: [M+1]=402;

[0157] 1 HNMR (CDCl3) δ7.28 (m, 5H), 5.26 (brs, 1H ), 5.1 (s, 2H ), 4.24 (m, 1H), 3.35 (m, 2H), 2.82 (s, 3H), 2.77 (m, 2H), 1.60 (d, 3H).

[0158] Example 9:

[0159]

[0160] Compound I1 (10 g, 1.0 eq.) and 120 mL of ethyl acetate were added to a 250 mL three-necked flask. The pH was adjusted to 8-9 with 2% sodium hydroxide solution while stirring. The layers were separated, and the aqueous phase was extracted once with 50 mL of ethyl acetate. The combined organic phases were concentrated to dryness to obtain the free base of compound I1. Acetonitrile (80 mL), N-Boc-bromoethylamine (10.8 g, 1.2 eq.), and triethylamine (4.9 g, 1.2 eq.) were added, and the mixture was heated to 70-80°C under nitrogen for 16 hours. The reaction solution was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 12.45 g of compound J1 (87% yield) as a white solid with a chiral purity of 99.9%.

[0161] Example 10:

[0162]

[0163] In a 250 mL flask, add compound I1 (1 g, 1.0 eq.), 25 mL ethyl acetate, adjust pH = 8-9 with 2% sodium hydroxide solution under stirring, separate the phases, extract the aqueous phase with 20 mL ethyl acetate once. Concentrate the combined organic phase to dryness to obtain the free base of compound I1. Add 20 mL acetonitrile, N-Boc-2-phenylsulfonyloxyethylamine (1.5 g, 1.2 eq.), triethylamine (0.48 g, 1.2 eq.), heat to 70-80 °C under nitrogen protection for 16 hours. Concentrate the reaction liquid to dryness to obtain the crude product, which is purified by silica gel column chromatography to obtain 1.1 g of compound J1, a white solid, with a yield of 78% and a chiral purity of 99.9%.

[0164] Example 11:

[0165]

[0166] In a 250 mL flask, add compound I1 (1 g, 1.0 eq.), 25 mL ethyl acetate, adjust pH = 8-9 with 2% sodium hydroxide solution under stirring, separate the phases, extract the aqueous phase with 20 mL ethyl acetate once. Concentrate the combined organic phase to dryness to obtain the free base of compound I1. Add 20 mL acetonitrile, 1,2,3-oxathiazolidine-3-Boc-2,2-dioxide (1.1 g, 1.2 eq.), triethylamine (0.48 g, 1.2 eq.), heat to 50-60 °C under nitrogen protection for 16 hours. Concentrate the reaction liquid to dryness to obtain the crude product, which is purified by silica gel column chromatography to obtain 1.2 g of compound J1, a white solid, with a yield of 84% and a chiral purity of 99.9%.

[0167] Example 12:

[0168]

[0169] In a 250 mL flask, add J1 (10 g, 1.0 eq.), 40 mL ethyl acetate, then keep the temperature between 20-30 °C, dropwise add hydrogen chloride in dioxane solution (4 M, 40 mL), after the dropwise addition is complete, keep stirring for 2 hours, concentrate the reaction liquid to dryness, then add 50 mL methanol, triethylamine (8.6 g, 3 eq.), heat to 50-60 °C for 1 hour. Concentrate the reaction liquid to dryness to obtain the crude product, which is purified by silica gel column chromatography to obtain 6.2 g of compound A0, a white solid, with a yield of 93% and a chiral purity of 99.2%.

[0170] LCMS: [M+1]=237;

[0171] 1 HNMR (CDCl3) δ4.68 (m, 1H ), 4.28 (m, 2H ), 3.50 (m, 1H ), 3.25 (m,1H ), 2.76 (s, 3H), 2.76 (s, 3H), 1.72 (d, 3H).

[0172] Example 13:

[0173]

[0174] To a 100 mL three-necked flask, add J1 (2.1 g, 1.0 eq.) and 20 mL of acetonitrile. Iodotrimethylsilane (4.0 g, 4 eq.) was then added dropwise, maintaining the temperature between 20-30°C. After complete addition, the mixture was stirred for 30 minutes. Then, 20 mL of methanol and triethylamine (2.5 g, 5 eq.) were added dropwise. The temperature was raised to 50-60°C and the reaction was allowed to proceed for 4 hours. The reaction solution was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to yield 0.94 g of compound A0 (80% yield) as an off-white solid. The chiral purity was 99.0%.

[0175] Example 14: Synthesis of Fezolinetant

[0176]

[0177] To a 250 mL three-necked flask, add A0 (8 g, 1.0 eq.), 80 mL of dichloromethane, and triethylamine (5.1 g, 1.5 eq.). The mixture was then cooled to between 0-10°C and 4-fluorobenzoyl chloride (5.9 g, 1.1 eq.) was added dropwise. After the addition was complete, the mixture was stirred for 30 minutes. The reaction mixture was washed with water and then saturated brine. The organic phase was concentrated to dryness, and the crude product was recrystallized from ethanol and water to obtain 9.8 g of the fenazolin compound (81% yield) as an off-white solid. The HPLC purity was 99.6%, and the chiral purity was 99.9%.

[0178] LCMS: [M+1]=359;

[0179] 1 HNMR (CDCl3)δ7.51 (m, 2H ), 7.16 (m, 2H ), 5.77 (m, 1H ),4.90 (m, 1H), 4.62 (m, 1H ), 4.28 (m, 1H ), 3.55 (m, 1H ), 2.75 (s, 3H), 1.75 (d, 3H).

[0180] Comparative Example 1:

[0181] Compared with Example 1, only N-methylmorpholine was changed to triethylamine.

[0182]

[0183] Compound E1 (5.0 g, 1.0 eq.), triethylamine (3.2 g, 1.2 eq.), and tetrahydrofuran (50 mL) were added to a 100 mL three-necked flask and cooled to 0°C under nitrogen. While maintaining the temperature within the flask between -10 and 10°C, isobutyl chloroformate (3.8 g, 1.05 eq.) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 20 minutes. Compound F (4.2 g, 1.0 eq.) was then added portionwise. After the addition was complete, the mixture was stirred at this temperature for 10 minutes. A 10% aqueous solution of citric acid was added. The tetrahydrofuran was removed by concentration under reduced pressure, and the mixture was extracted twice with dichloromethane. The resulting organic phase was concentrated to yield the crude product. The crude product was purified by silica gel column chromatography to yield 6.5 g of compound G1 (75% yield) as a pale yellow solid with a chiral purity of 99.9%.

[0184] Comparative Example 2:

[0185] Compared with Example 1, the condensing agent is changed to carbonyldiimidazole, specifically:

[0186]

[0187] To a 100 mL three-necked flask, add compound E1 (5.0 g, 1.0 eq.) and 50 mL of acetonitrile and cool to 0°C under nitrogen. Maintain the temperature of the reaction flask between 0 and 10°C and add carbonyldiimidazole (4.7 g, 1.1 eq.) portionwise. After addition, stir at this temperature for 30 minutes. Then add compound F (4.2 g, 1.0 eq.) portionwise. After addition, stir at this temperature for 10 minutes. Concentrate under reduced pressure to remove the acetonitrile, add dichloromethane, and wash with 10% aqueous citric acid. The resulting organic phase is concentrated to yield the crude product. The crude product is purified by silica gel column chromatography to yield 6.2 g of compound G1 (72% yield) as a pale yellow solid with a chiral purity of 98.2%.

[0188] Comparative Example 3:

[0189] Compared with Example 1, the reaction temperature and reaction time were changed, specifically:

[0190]

[0191] Compound E1 (5.0 g, 1.0 eq.), N-methylmorpholine (3.2 g, 1.2 eq.), and 50 mL of tetrahydrofuran were added to a 100 mL three-necked flask and cooled to 0°C under nitrogen. While maintaining the temperature within the flask between 20 and 30°C, isobutyl chloroformate (3.8 g, 1.05 eq.) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 20 minutes. Compound F (4.2 g, 1.0 eq.) was then added portionwise. After the addition was complete, the mixture was stirred at this temperature for 10 minutes. A 10% aqueous solution of citric acid was added. The tetrahydrofuran was removed by concentration under reduced pressure, and the mixture was extracted twice with dichloromethane. The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to yield 7.2 g of compound G1 (83% yield) as a pale yellow solid with a chiral purity of 97.5%.

[0192] Comparative Example 4:

[0193] Compared with Example 2, the condensing agent is replaced, specifically phosphorus oxychloride:

[0194]

[0195] In a separate 1000 mL three-necked reaction flask, compound G1 (5.0 g, 1.0 eq.), triethylamine (7.7 g, 5 eq.), and dichloromethane (mL) were added. The mixture was cooled to 0-10°C under nitrogen, and phosphorus oxychloride (3.5 g, 1.5 eq.) was added dropwise while maintaining the temperature. After the addition was complete, the mixture was heated to reflux and reacted for 3 hours. The reaction solution was added to 200 mL of ice water, and the organic phase was separated, washed with 5% sodium bicarbonate solution, and dried over saturated sodium chloride. The organic phase was concentrated to dryness and purified by silica gel column chromatography to obtain 1.5 g of compound H1 (32% yield) as a white solid with a chiral purity of 99.9%.

[0196] Comparative Example 5:

[0197] Compared with Example 7, the addition amount of the raw materials was changed, specifically:

[0198]

[0199] Compound I1 (5 g, 1.0 eq.), Boc-aminoacetaldehyde (4.8 g, 1.5 eq.), and 70 mL of dichloromethane were added to a 250 mL three-necked flask. The mixture was cooled to between 0-10°C under nitrogen. Sodium triacetoxyborohydride (8.6 g, 2.0 eq.) was then added portionwise while maintaining the temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 5% sodium bicarbonate and then saturated brine. The organic phase was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to yield 5.1 g of compound J2 (71% yield) as a white solid with a chiral purity of 99.9%.

[0200] Comparative Example 6:

[0201] Compared with Example 12, the condensation reaction solvent was changed, specifically:

[0202]

[0203] To a 250 mL three-necked flask, J1 (10 g, 1.0 eq.) and 40 mL of dioxane were added dropwise. The mixture was then kept warm between 20-30°C. A 4 M solution of hydrogen chloride in dioxane (40 mL) was then added dropwise. After complete addition, the mixture was stirred for 2 hours. The reaction solution was concentrated to dryness. 50 mL of ethyl acetate and triethylamine (8.6 g, 3 eq.) were then added. The reaction mixture was heated to 50-60°C for 1 hour. The reaction solution was cooled to room temperature and washed with 40 mL of saturated sodium bicarbonate. The aqueous layer was separated and washed once with 30 mL of ethyl acetate. The combined layers were concentrated to dryness and slurried in 40 mL of n-heptane to obtain 6.0 g of compound A0, a 90% yield, as an off-white solid with a chiral purity of 99.3%.

[0204] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A compound of formula J, characterized in that Its structure is as follows: Wherein, PG2 is a protecting group; the PG2 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

2. The method for preparing the compound of formula J according to claim 1, characterized in that The following steps are involved: Compound I undergoes a substitution reaction with the side chain to obtain a compound of formula J; wherein PG2 is as described in claim 1; The side chain is selected from 2-PG2 aminoacetaldehyde, 2-PG2 aminoethyl bromide, 2-PG2 amino-1-toluenesulfonyloxyethane, 2-PG2 amino-1-methylsulfonyloxyethane, 1,2,3-oxathiazolidine-3-PG 2- At least one of the 2,2-dioxides.

3. A compound of formula I, characterized in that Its structure is as follows: 。 4. Use of the compound of formula I according to claim 3 in the synthesis of the key intermediate A0 of fezonetant.

5. Use of the compound of formula J according to claim 1 in the synthesis of the key intermediate A0 of fezonetant.

6. A method for preparing a key intermediate A0 of zonetant, characterized in that: The compound of formula I according to claim 3 is used to prepare the compound of formula J according to claim 1, and then the key intermediate A0 of fezonetant is prepared from the compound of formula J according to claim 1. The synthetic route is as follows: 。

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