Route for constructing fezolinetant chiral fragment, and intermediates thereof and preparation method therefor

Abstract

The present invention relates to the technical fields of organic synthesis and preparation of bulk drug intermediates. Provided are a route for constructing a fezolinetant chiral fragment, and intermediates thereof and a preparation method therefor. The provided route for constructing a fezolinetant chiral fragment, and intermediates thereof (compounds of formula G, formula H, formula I and formula J) and the preparation method therefor are as shown in the following synthesis route. Further provided is a new route for synthesizing a key intermediate (intermediate A0) of fezolinetant. In the route, the raw materials are readily available, the steps involve mild chemical reaction conditions, and the intermediates have high chiral purity, which is conducive to improving the chiral purity of the product. Formula E, Formula F

Description

A route for constructing chiral fragments of nonzonantan, its intermediates, and preparation methods.

[0001] This invention claims priority to Chinese Patent Application No. 2024109294803, filed on July 11, 2024, entitled "A route for constructing a chiral fragment of nonzonantan, its intermediates and preparation method", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of organic synthesis and preparation of drug substance intermediates, specifically to a route for constructing a chiral fragment of nonzonantane, its intermediates, and preparation methods. Background Technology

[0003] 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 can severely impact a woman's physical comfort and sleep quality, and in severe cases, it can last for five years or longer, causing significant distress to a woman's personal health, workplace, and even family life. Therefore, effective treatments to alleviate these symptoms are urgently needed. VMS has a high incidence during menopause and is the most common menopausal symptom that women seek treatment for.

[0004] 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 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. Furthermore, the long-standing fear of hormones further limits the use of HRT.

[0005] The small molecule oral drug fezolinetant (molecular structure shown below) selectively targets the neurokinin 3 (NK3) receptor. By binding to the NK3 receptor, it blocks the binding of NK3 to Kisspeptin / neurokine / dynorphin (KNDy) neurons, thereby regulating neuronal activity in the brain's thermoregulatory center (hypothalamus) and reducing the frequency and severity of menopausal-related moderate to severe VMS.

[0006] Fezonnetan is the first NK3 receptor antagonist for menopausal VMS, providing a novel treatment option for female VMS patients, especially those who are intolerant to HRT.

[0007] Currently, the main synthetic methods for fezonine include the following routes.

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

[0009] Route 1

[0010] Route 1 uses chiral piperazine A1 as the starting material, which is protected with a tert-butyloxycarbonyl (Boc) amino group to give compound A2. A2 reacts with an ethoxyonium salt in the presence of a base to give an imine ether compound A3. A3 undergoes substitution with thiadiazolyl hydrazide, followed by dehydration and ring closure to give compound A4. Under acidic conditions, deprotection yields the chiral key intermediate A0, which is finally reacted with 4-fluorobenzoic acid or its derivative to give fezonetan.

[0011] The chiral piperazine A1 used in this scheme is expensive, resulting in a high overall cost.

[0012] In addition, this route has a significant drawback: it is prone to racemization in steps 2 and 3, making it difficult to obtain chiral compounds A4 and A0 with high chiral purity (>80% ee), and therefore cannot be used to prepare the active pharmaceutical ingredient fezoniltan.

[0013] Ageda further improved upon this approach, and patent CN103906750 B9 disclosed the following second approach:

[0014] Route 2

[0015] Similarly, using secondary phenacetin A1 as the starting material, after amino protection, it reacts with ethoxyonium salt, undergoes thiadiazole hydrazide substitution, dehydration and ring closure, deprotection, and condensation with 4-fluorobenzoic acid or its derivative to obtain fezonatetan.

[0016] The biggest change between Route 2 and Route 1 is that the Boc protection base has been replaced with N-sp. 3 Protecting group. Perhaps due to the reduced electron-withdrawing effect, the risk of racemization of the chiral center is lowered, thus improving chiral purity.

[0017] Because this route also uses expensive chiral piperazine ketones, and the ethoxyonium salt reagent in the second step is expensive and has a low yield, the overall production cost is high. In addition, because the product in the second step is a high-boiling-point liquid, purification is also relatively difficult.

[0018] In subsequent research, Ogeda invented the following route three:

[0019] Route 3

[0020] The route still starts with the same chiral piperazine, which undergoes a condensation reaction with 4-fluorobenzoic acid, then reacts with ethoxyonium salt to give imine ether compound C3, and finally reacts with thiadiazole hydrazide to give the active ingredient fezoniltan.

[0021] Clearly, this route has the advantage of being shorter than the previous two. However, because it uses N-sp... 2 The protection group reduces the chiral purity of the final product. Furthermore, the reported yields of the last two steps in this route are both below 50%, and the overall material consumption is relatively high, indicating significant room for improvement.

[0022] In 2023, Beijing Kanglisheng Pharmaceutical Technology Development Co., Ltd. disclosed the following route four in patent CN117510506A. 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.

[0023] Route 4

[0024] This route is shorter than all previously published routes, seemingly offering a significant cost advantage. However, obtaining the chiral raw material D1 will be a major challenge in practical application, posing a potential supply risk for industrialization. Furthermore, the final step using precious metals for coupling could lead to excessive levels of precious metals in the final active pharmaceutical ingredient, posing a significant quality risk for an oral formulation requiring large doses and long-term use.

[0025] In summary, existing techniques for synthesizing fezonelanthus have significant room for improvement. Therefore, this invention provides a novel route for the synthesis of fezonelanthus.

[0026] Summary of the Invention

[0027] To address the aforementioned problems, this invention provides a method for preparing key intermediates of fenzonalant. This route uses readily available starting materials, employs mild chemical reaction conditions in each step, and produces intermediates with high chiral purity, which is beneficial for improving the chiral purity of the product, facilitating large-scale production, and reducing costs.

[0028] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0029] On one hand, the present invention provides a compound of formula G, the structure of which is shown below:

[0030] PG1 is a protecting group.

[0031] Preferably, PG1 is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; more preferably, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0032] On the other hand, the present invention provides a method for preparing compound G, comprising the following steps:

[0033] Chiral alanine E undergoes a condensation reaction with thiadiazolyl hydrazide F to give diacyl hydrazide compound G.

[0034] PG1 is a protecting group.

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

[0036] 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 acid anhydride, which is then reacted with formula F; more preferably, the condensation reaction is the condensation of formula E with isobutyl chloroformate in the presence of a base to form a mixed acid anhydride, which is then reacted with formula F.

[0037] 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.

[0038] The condensing agent is selected from at least one of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, methylethylphosphonic anhydride, diphenylphosphonic chloride, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; more preferably, the condensing agent is selected from at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0039] Preferably, the condensation reaction further includes a solvent.

[0040] 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.

[0041] On one hand, the present invention provides a compound of formula H, the structure of which is shown below:

[0042] PG1 is a protecting group.

[0043] Preferably, PG1 is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; more preferably, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0044] On the other hand, the present invention provides a method for preparing a compound of formula H, comprising the following steps:

[0045] The dihydrazide compound G reacts in the presence of a condensing agent, undergoes dehydration and ring closure, to give compound H;

[0046] PG1 is a protecting group.

[0047] Preferably, PG1 is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; more preferably, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0048] Preferably, the condensing agent is selected from at least one of Burgess reagent and iodine and triphenylphosphine combination reagent; more preferably, the condensing agent is selected from Burgess reagent.

[0049] Preferably, the structure of the Burgess reagent is as follows:

[0050] R1, R2, R3, and R4 are each independently selected from alkyl groups.

[0051] Preferably, the reaction further includes a solvent.

[0052] Preferably, the solvent is selected from at least one of tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, and dichloromethane; more preferably, the solvent is dichloromethane.

[0053] On one hand, the present invention provides a compound of formula I, the structure of which is shown below:

[0054] On the other hand, the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0055] Deprotecting compound H yields compound I or its salt;

[0056] PG1 is a protecting group.

[0057] Preferably, PG1 is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl; more preferably, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

[0058] Preferably, the salt is selected from hydrochloride, hydrogen bromide, p-toluenesulfonate, or methanesulfonate.

[0059] On one hand, the present invention provides a compound of formula J, the structure of which is shown below:

[0060] PG2 is a protecting group.

[0061] Preferably, PG2 is selected from tert-butoxycarbonyl or benzyloxycarbonyl.

[0062] On the other hand, the present invention provides a method for preparing compound J, comprising the following steps:

[0063] Compound I undergoes a substitution reaction with its side chain to yield compound J.

[0064] PG2 is a protecting group.

[0065] Preferably, PG2 is selected from tert-butoxycarbonyl or benzyloxycarbonyl.

[0066] Preferably, the side chain is selected from 2-PG2-aminoacetaldehyde, 2-PG2-aminoethyl bromide, 2-PG2-amino-1-p-toluenesulfonyloxyethane, 2-PG2-amino-1-methylsulfonyloxyethane, and 1,2,3-oxathiazolidin-3-PG 2- At least one of 2,2-dioxides;

[0067] The structure of the above side chain is shown below:

[0068] In another aspect, the present invention provides the application of the above-described compound of formula G in the synthesis of the key intermediate A0 of fenzonectan.

[0069] This invention provides the application of the above-described compound of formula H in the synthesis of the key intermediate A0 of nonazolin.

[0070] This invention provides the application of the compound of formula I described above in the synthesis of the key intermediate A0 of fenzonetanil.

[0071] This invention provides the application of the compound of formula J described above in the synthesis of the key intermediate A0 of fezoniltan.

[0072] Furthermore, this invention provides a method for preparing the key intermediate A0 of fezoniltan, comprising the above-mentioned compounds G, H, I, and J, with the synthetic route shown below:

[0073] Among them, PG1 and PG2 are protecting groups.

[0074] Preferably, PG1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl, or trifluoroacetyl; PG2 is selected from tert-butoxycarbonyl or benzyloxycarbonyl; more preferably, PG1 is selected from tert-butoxycarbonyl or benzyloxycarbonyl; PG2 is selected from tert-butoxycarbonyl or benzyloxycarbonyl.

[0075] Preferably, the specific reaction process of step 5 is as follows: compound J is deprotected to obtain diamine structure Ja; the diamine structure Ja is unstable in the alkaline state and undergoes further molecular reactions to obtain compound Jb, and finally compound A0 is obtained under heating conditions.

[0076] The reaction mechanism pathway in step 5 is shown below:

[0077] Compared with the prior art, the present invention has the following beneficial effects:

[0078] 1. This invention provides a new route for synthesizing the key intermediate of Fezolintant (A0), offering new ideas and possibilities for the synthesis of the key intermediate A0 of Fezolintant.

[0079] 2. The new route provided by this invention uses readily available raw materials, has mild chemical reaction conditions in each step, and the intermediates have high chiral purity, which is beneficial to improving the chiral purity of the product.

[0080] 3. This invention also provides four new compounds: compound G, compound H, compound I, and compound J. Attached Figure Description

[0081] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0082] Figure 1 shows compound G1. 1 HNMR spectrum;

[0083] Figure 2 shows compound G2. 1 HNMR spectrum;

[0084] Figure 3 shows compound H1. 1 HNMR spectrum;

[0085] Figure 4 shows compound H2. 1 HNMR spectrum;

[0086] Figure 5 shows compound I1. 1 HNMR spectrum;

[0087] Figure 6 shows compound J1. 1 HNMR spectrum;

[0088] Figure 7 shows compound J2. 1 HNMR spectrum;

[0089] Figure 8 shows compound A0. 1 HNMR spectrum;

[0090] Figure 9 shows the chiral purity spectrum of compound A0;

[0091] Figure 10 shows Fezolintant 1 HNMR spectrum;

[0092] Figure 11 shows the chiral purity spectrum of Fezolintant. Detailed Implementation

[0093] To make the technical means, creative features, achieved objectives, and effects of this invention readily understandable, the invention is further illustrated below with specific embodiments. However, these embodiments are merely preferred embodiments and not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the scope of protection of this invention. It is worth noting that the raw materials used in this invention are all common commercially available products, and their sources are not specifically limited. The technical and scientific terms used in the embodiments have the meanings commonly understood by those skilled in the art to which this invention pertains.

[0094] Definitions:

[0095] Boc: tert-Butoxycarbonyl

[0096] Cbz: Benzyloxycarbonyl

[0097] PMB: p-Methoxybenzyl

[0098] DCC: Dicyclohexylcarbodiimide DCC

[0099] DIC: Diisopropylcarbodiimide

[0100] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

[0101] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0102] CDI: Carbonyldiimidazole

[0103] Example 1:

[0104] 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 protection. The temperature inside the reaction flask was maintained between -10 and 10 °C, and 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, and then compound F (45.1 g, 1.0 eq.) was added in portions. 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 mixture was concentrated under reduced pressure to remove tetrahydrofuran, and extracted twice with dichloromethane. The resulting organic phase was concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography to give 76.1 g of compound G1 (81% yield), a pale yellow solid with a chiral purity of 99.9%.

[0105] LCMS, [M+Na] = 352;

[0106] 1 HNMR(CDCl3)δ9.63(br,2H),5.32(br,1H),4.43(br,1H),2.70(s,3H),1.46(br,12H).

[0107] In NMR, compounds exhibit enone configuration interchange.

[0108] Example 2:

[0109] Add 380 mL of tetrahydrofuran and 48.9 g of chlorosulfonic acid isocyanate (3.0 eq.) to a 500 mL three-necked flask. Cool to 0-10 °C under nitrogen protection. Add methanol (11.1 g, 3.0 eq.) dropwise while maintaining the temperature. Stir for 10 minutes to obtain solution A.

[0110] In another 1000 mL three-necked flask, compound G1 (38.0 g, 1.0 eq.), triethylamine (75.8 g, 6.5 eq.), and 380 mL of tetrahydrofuran were added. The mixture was cooled to 0–10 °C under nitrogen protection to obtain solution B. Solution A was added dropwise to solution B, and the mixture was heated to 20–40 °C and reacted 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 give 30.5 g of compound H1, 85% yield, as a white solid. The chiral purity was 99.9%.

[0111] LCMS,[M+H]=312;

[0112] 1HNMR(CDCl3)δ5.25(br,1H),2.82(s,3H),2.72(s,1H),1.70(d,3H),1.46(s,9H).

[0113] Example 3:

[0114] 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. Then, a 4 M, 60 mL solution of dioxane and hydrogen chloride was added dropwise at 20-30 °C. After the addition was complete, the mixture was stirred at room temperature for 2 hours, filtered, and dried to obtain 9.1 g of compound I1, 95% yield, as a white solid. The chiral purity was 99.9%.

[0115] LCMS:[M+1]=212;

[0116] 1 HNMR(D2O)δ5.01(q,1H),2.88(s,3H),1.75(d,3H).

[0117] Example 4:

[0118] 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 protection. The temperature inside the reaction flask was maintained between -10 and 10 °C, and 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 added in portions. 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 mixture was concentrated under reduced pressure to remove tetrahydrofuran, and extracted twice with dichloromethane. The resulting organic phase was concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography to obtain 6.7 g of compound G2 (82% yield), a pale yellow oil with a chiral purity of 99.9%.

[0119] LCMS,[M+1]=364;

[0120] 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).

[0121] Example 5:

[0122] 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 protection, add methanol (1.32 g, 3.0 eq.) dropwise while maintaining the temperature, and stir for 10 minutes to obtain solution A.

[0123] In another 250 mL three-necked flask, compound G2 (5.0 g, 1.0 eq.), triethylamine (9.0 g, 6.5 eq.), and 50 mL of tetrahydrofuran were added. The mixture was cooled to 0–10 °C under nitrogen protection to obtain solution B. Solution A was added dropwise to solution B, and the mixture was heated to 20–40 °C and reacted 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 give 3.94 g of compound H2 (83% yield), a pale yellow liquid with a chiral purity of 99.9%.

[0124] LCMS:[M+1]=346;

[0125] 1 HNMR(CDCl3)δ7.37(m,5H),5.48(br,1H),5.32(m,1H),5.17(m,2H),2.83(s,3H),1.72(d,3H).

[0126] Example 6:

[0127] In a 100 mL single-necked flask, add H2 (1 g, 1.0 eq.), 30 mL methanol, 2 mL hydrogen chloride methanol solution (4 M), and 0.3 g of 10% palladium on carbon. Evacuate the flask, purge with nitrogen three times, and then stir overnight at room temperature under a hydrogen atmosphere. Filter the palladium on carbon and wash with methanol. Concentrate the filtrate to dryness to obtain a crude product. Add 20 mL of ethyl acetate, stir at room temperature for 30 minutes, filter, and dry to give 0.7 g of compound I1, 98% yield, as a white solid. Chiral purity 99.9%.

[0128] Example 7:

[0129] Compound I1 (10 g, 1.0 eq.), Boc aminoacetaldehyde (7.7 g, 1.2 eq.), and 100 mL dichloromethane were added to a 250 mL three-necked flask. Under nitrogen protection, the mixture was cooled to between 0 and 10 °C, and sodium triacetoxyborohydride (17.2 g, 2.0 eq.) was added dropwise while maintaining the temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 5% sodium bicarbonate and saturated brine. The organic phase was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 12.2 g of compound J2, in 85% yield, as a white solid. The chiral purity was 99.9%.

[0130] LCMS: [M+1] = 355;

[0131] 1 HNMR(CDCl3)δ6.96(br,1H),5.1(s,2H),4.27(q,1H),3.21(m,2H),2.82(s,3H),2.77(m,2H),1.62(d,3H).

[0132] Example 8:

[0133] Compound I1 (13.5 g, 1.0 eq.), Cb2 aminoacetaldehyde (9.4 g, 1.2 eq.), and 135 mL of dichloromethane were added to a 250 mL three-necked flask. Under nitrogen protection, the mixture was cooled to between 0 and 10 °C, and sodium triacetoxyborohydride (17.2 g, 2.0 eq.) was added dropwise while maintaining the temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 5% sodium bicarbonate and saturated brine. The organic phase was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 13.5 g of compound J2, in 83% yield, as a pale yellow oil. The chiral purity was 99.9%.

[0134] LCMS:[M+1]=402;

[0135] 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).

[0136] Example 9:

[0137] Compound I1 (10 g, 1.0 eq.) and 120 mL of ethyl acetate were added to a 250 mL three-necked flask. While stirring, the pH was adjusted to 8-9 with 2% sodium hydroxide solution. The mixture was separated, and the aqueous phase was extracted once with 50 mL of ethyl acetate. The combined organic phases were concentrated to dryness to give the free base of compound I1. 80 mL of acetonitrile, 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 for 16 hours under nitrogen protection. The reaction solution was concentrated to dryness to give the crude product. The crude product was purified by silica gel column chromatography to give 12.45 g of compound J1, 87% yield, as a white solid. The chiral purity was 99.9%.

[0138] Example 10:

[0139] Compound I1 (1 g, 1.0 eq.) and 25 mL of ethyl acetate were added to a 250 mL three-necked flask. While stirring, the pH was adjusted to 8-9 with 2% sodium hydroxide solution. The mixture was separated, and the aqueous phase was extracted once with 20 mL of ethyl acetate. The combined organic phases were concentrated to dryness to give the free base of compound I1. 20 mL of acetonitrile, N-Boc-2-benzenesulfonyloxyethylamine (1.5 g, 1.2 eq.), and triethylamine (0.48 g, 1.2 eq.) were added, and the mixture was heated to 70-80 °C for 16 hours under nitrogen protection. The reaction solution was concentrated to dryness to give the crude product. The crude product was purified by silica gel column chromatography to give 1.1 g of compound J1, 78% yield, as a white solid. The chiral purity was 99.9%.

[0140] Example 11:

[0141] Compound I1 (1 g, 1.0 eq.) and 25 mL of ethyl acetate were added to a 250 mL three-necked flask. While stirring, the pH was adjusted to 8-9 with 2% sodium hydroxide solution. The mixture was separated, and the aqueous phase was extracted once with 20 mL of ethyl acetate. The combined organic phases were concentrated to dryness to give the free base of compound I1. 20 mL of acetonitrile, 1,2,3-oxathiazolidin-3-Boc-2,2-dioxide (1.1 g, 1.2 eq.), and triethylamine (0.48 g, 1.2 eq.) were added, and the mixture was heated to 50-60 °C for 16 hours under nitrogen protection. The reaction solution was concentrated to dryness to give a crude product. The crude product was purified by silica gel column chromatography to give 1.2 g of compound J1, 84% yield, as a white solid. The chiral purity was 99.9%.

[0142] Example 12:

[0143] In a 250 mL three-necked flask, J1 (10 g, 1.0 eq.) and 40 mL of ethyl acetate were added. The mixture was then kept at 20-30 °C, and a 4 M dioxane solution (40 mL) of hydrogen chloride was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 2 hours. The reaction solution was concentrated to dryness, and then 50 mL of methanol and triethylamine (8.6 g, 3 eq.) were added. The mixture was heated to 50-60 °C and reacted for 1 hour. The reaction solution was concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to give 6.2 g of compound A0, with a yield of 93%, as an off-white solid. The chiral purity was 99.2%.

[0144] LCMS:[M+1]=237;

[0145] 1HNMR(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).

[0146] Example 13:

[0147] In a 100 mL three-necked flask, J1 (2.1 g, 1.0 eq.) and 20 mL of acetonitrile were added. The mixture was then kept at 20-30 °C, and trimethyliodosilane (4.0 g, 4 eq.) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 30 minutes. Then, 20 mL of methanol was added, followed by triethylamine (2.5 g, 5 eq.). The mixture was heated to 50-60 °C and reacted for 4 hours. The reaction solution was concentrated to dryness to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain 0.94 g of compound A0, with a yield of 80%, as an off-white solid. The chiral purity was 99.0%.

[0148] Example 14: Synthesis of Fezolinetant

[0149] In 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.). Then cool to between 0 and 10 °C and add 4-fluorobenzoyl chloride (5.9 g, 1.1 eq.) dropwise. After the addition is complete, maintain the temperature and stir for 30 minutes. Wash the reaction solution with water and saturated brine, respectively. Concentrate the organic phase to dryness. Recrystallize the crude product from ethanol and water to give 9.8 g of fezolinate, 81% yield, as an off-white solid. HPLC purity: 99.6%, chiral purity: 99.9%.

[0150] LCMS: [M+1] = 359;

[0151] 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).

[0152] Comparative Example 1:

[0153] Compared to Example 1, only N-methylmorpholine was changed to triethylamine.

[0154] Compound E1 (5.0 g, 1.0 eq.), triethylamine (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 protection. The temperature inside the reaction flask was maintained between -10 and 10 °C, and isobutyl chloroformate (3.8 g, 1.05 eq.) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 20 minutes. Compound F (4.2 g, 1.0 eq.) was added in portions. After the addition was complete, the mixture was kept at this temperature and stirred for 10 minutes. A 10% aqueous solution of citric acid was added. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and extracted twice with dichloromethane. The resulting organic phase was concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography to give 6.5 g of compound G1, 75% yield, as a pale yellow solid with a chiral purity of 99.9%.

[0155] Comparative Example 2:

[0156] Compared with Example 1, the condensing agent was changed to carbonyl diimidazole, specifically:

[0157] Compound E1 (5.0 g, 1.0 eq.) and 50 mL of acetonitrile were added to a 100 mL three-necked flask, and the mixture was cooled to 0 °C under nitrogen protection. The temperature inside the reaction flask was maintained between 0 and 10 °C, and carbonyl diimidazole (4.7 g, 1.1 eq.) was added in portions. After the addition was complete, the mixture was stirred at this temperature for 30 minutes, and then compound F (4.2 g, 1.0 eq.) was added in portions. After the addition was complete, the mixture was stirred at this temperature for 10 minutes. The mixture was concentrated under reduced pressure to remove acetonitrile, and then washed with dichloromethane and a 10% citric acid aqueous solution. The resulting organic phase was concentrated to obtain a crude product. The crude product was subjected to silica gel column chromatography to give 6.2 g of compound G1, with a yield of 72%, as a pale yellow solid. The chiral purity was 98.2%.

[0158] Comparative Example 3:

[0159] Compared with Example 1, the reaction temperature and reaction time were changed, specifically:

[0160] 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 protection. The temperature inside the reaction flask was maintained between 20 and 30 °C, and 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, and then compound F (4.2 g, 1.0 eq.) was added in portions. 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 mixture was concentrated under reduced pressure to remove tetrahydrofuran, and extracted twice with dichloromethane. The resulting organic phase was concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography to give 7.2 g of compound G1, with a yield of 83%, as a pale yellow solid. The chiral purity was 97.5%.

[0161] Comparative Example 4:

[0162] Compared to Example 2, the condensing agent was changed to phosphorus oxychloride:

[0163] In another 1000 mL three-necked 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 protection, and phosphorus oxychloride (3.5 g, 1.5 eq.) was added dropwise while maintaining the temperature. After the addition was complete, the mixture was refluxed for 3 hours. The reaction solution was added to 200 mL of ice water, and the organic phase was separated. The solution was then 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 give 1.5 g of compound H1 (32% yield), a white solid with a chiral purity of 99.9%.

[0164] Comparative Example 5:

[0165] Compared to Example 7, the amount of raw materials added was changed, specifically:

[0166] 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. Under nitrogen protection, the mixture was cooled to between 0 and 10 °C, and sodium triacetoxyborohydride (8.6 g, 2.0 eq.) was added dropwise while maintaining the temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 5% sodium bicarbonate and saturated brine, respectively. The organic phase was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 5.1 g of compound J2, with a yield of 71%, as a white solid. The chiral purity was 99.9%.

[0167] Comparative Example 6:

[0168] Compared to Example 12, the solvent for the condensation reaction was changed, specifically:

[0169] In a 250 mL three-necked flask, add J1 (10 g, 1.0 eq.) and 40 mL of dioxane. Maintain the temperature between 20-30 °C and add a 4 M, 40 mL solution of dioxane chloride dropwise. After the addition is complete, maintain the temperature and stir for 2 hours. Concentrate the reaction solution to dryness, then add 50 mL of ethyl acetate and triethylamine (8.6 g, 3 eq.). Heat to 50-60 °C and react for 1 hour. Cool the reaction solution to room temperature, add 40 mL of saturated sodium bicarbonate and wash. Separate the aqueous layer and wash once with 30 mL of ethyl acetate. Combine the several layers and concentrate to dryness. Add 40 mL of n-heptane and slurry to obtain 6.0 g of compound A0, 90% yield, as an off-white solid. Chiral purity 99.3%.

[0170] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A compound of formula G, characterized in that, Its structure is as follows: PG1 is a protecting group.

2. The compound according to claim 1, characterized in that, The PG1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl, or trifluoroacetyl.

3. The compound according to claim 2, characterized in that, The PG1 is selected from tert-butoxycarbonyl or benzyloxycarbonyl.

4. A method for preparing the compound of formula G according to any one of claims 1-3, characterized in that, Includes the following steps: Chiral alanine E undergoes a condensation reaction with thiadiazolyl hydrazide F to give diacyl hydrazide compound G. Wherein, PG1 is as described in any one of claims 1-3.

5. The preparation method according to claim 4, characterized in that, 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 acid anhydride, which is then reacted with formula F.

6. The preparation method according to claim 5, characterized in that, The condensation reaction is described as follows: Formula E condenses with isobutyl chloroformate in the presence of a base to form a mixed acid anhydride, which then reacts with Formula F.

7. The preparation method according to claim 6, characterized in that, The base is selected from at least one of N-methylmorpholine and N,N-diisopropylethylamine.

8. The preparation method according to claim 4, characterized in that, The condensation reaction further includes a solvent; the solvent is selected from at least one of tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, and dichloromethane.

9. A compound of formula H, characterized in that, Its structure is as follows: PG1 is a protecting group.

10. The compound according to claim 9, characterized in that, The PG1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl, or trifluoroacetyl.

11. The compound according to claim 10, characterized in that, PG1 is selected from tert-butyloxycarbonyl or benzyloxycarbonyl.

12. A method for preparing the compound of formula H according to any one of claims 9-11, characterized in that, Includes the following steps: The dihydrazide compound G reacts in the presence of a condensing agent, undergoes dehydration and ring closure, to give compound H; Wherein, PG1 is as described in any one of claims 9-11.

13. The preparation method according to claim 12, characterized in that, The condensing agent is selected from at least one of Burgess reagents and a combination of iodine and triphenylphosphine.

14. The preparation method according to claim 13, characterized in that, The condensing agent is selected from Burgess reagents, and the structure of the Burgess reagent is as follows: R1, R2, R3, and R4 are each independently selected from alkyl groups.

15. The preparation method according to claim 12, characterized in that, The reaction further includes a solvent selected from at least one of tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, and dichloromethane.

16. A compound of formula I, characterized in that, Its structure is as follows:

17. The method for preparing the compound of formula I according to claim 16, characterized in that, Includes the following steps: Deprotecting compound H yields compound I or its salt; Wherein, PG1 is as described in any one of claims 9-11.

18. The preparation method according to claim 17, characterized in that, The salt is selected from hydrochloride, hydrogen bromide, p-toluenesulfonate, or methanesulfonate.

19. A compound of formula J, characterized in that, Its structure is as follows: PG2 is a protecting group.

20. The compound according to claim 19, characterized in that, The PG2 is selected from tert-butoxycarbonyl or benzyloxycarbonyl.

21. A method for preparing the compound of formula J according to any one of claims 19-20, characterized in that, Includes the following steps: Compound I undergoes a substitution reaction with its side chain to yield compound J. Wherein, PG2 is as described in any one of claims 19-20.

22. The preparation method according to claim 21, characterized in that, The side chain is selected from 2-PG2-aminoacetaldehyde, 2-PG2-aminoethyl bromide, 2-PG2-amino-1-p-toluenesulfonyloxyethane, 2-PG2-amino-1-methylsulfonyloxyethane, and 1,2,3-oxathiazolidin-3-PG 2- At least one of 2,2-dioxides.

23. Use of the compound of formula G according to any one of claims 1-3 in the synthesis of the key intermediate A0 of fenzonetan.

24. Use of the compound of formula H according to any one of claims 9-11 in the synthesis of the key intermediate A0 of fenzonectan.

25. Use of the compound of formula I according to claim 16 in the synthesis of the key intermediate A0 of fenzonetan.

26. Use of the compound of formula J according to any one of claims 19-20 in the synthesis of the key intermediate A0 of fezoniltan.

27. A method for preparing a key intermediate A0 of fezoniltan, characterized in that, The synthetic route for compounds comprising formula G according to any one of claims 1-3, formula H according to any one of claims 9-11, formula I according to claim 16, and formula J according to any one of claims 19-20 is shown below:

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