Preparation method of AT-406 intermediate

Abstract

The invention provides a preparation method of an AT-406 intermediate, and belongs to the technical field of medical intermediates. According to the method, methyl L-pyroglutamate is subjected to ethynylation, and a selected ester solvent and a hydroboration reagent are subjected to hydroboration reductive amination reaction, so that the reaction selectivity can be improved, isomer impurities are reduced, separation and purification are easy, a single cis-configuration product can be obtained, and the ee value can reach 99.5% or above. The specific hydroboration reagent and the oxidation reagent are selected, so that the use of ozone and reagents with strong mercaptan odor is avoided, the selectivity of intramolecular reaction is improved, the generation of byproducts is reduced, separation and purification are easy, the catalyst and the byproducts are non-toxic and pollution-free to the environment, and the method is suitable for industrial production. The invention provides a method suitable for industrial production to obtain the AT-406 intermediate.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediates technology, specifically relating to a method for preparing AT-406 intermediate. Background Technology

[0002] Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, with over 60% of HNSCC patients diagnosed at an advanced stage. Patients with locally advanced HNSCC have a poor prognosis; approximately 50%–60% experience local recurrence within two years, 20%–30% experience distant metastasis, and the 5-year overall survival rate is <50%.

[0003] Apoptosis is an important programmed cell death mechanism that eliminates unwanted or abnormal cells, and resistance to apoptosis is one of the classic hallmarks of cancer. The inhibitory apoptosis factor (IAP) family is a newly discovered class of structurally homologous apoptosis-inhibiting proteins. They are highly conserved endogenous anti-apoptotic gene family expression products independent of the Bcl-2 family, inhibiting apoptosis by binding to terminal effectors caspase-3 and 7 and interfering with caspase-9 activity.

[0004] Xevinapant (AT-406) is a potential "first-in-class" drug, an oral potent IAP antagonist that is a potent inhibitor of apoptosis proteins. It is currently undergoing a Phase III clinical trial, and multiple clinical trials for the treatment of solid tumors are underway, including non-small cell lung cancer, ovarian cancer, and head and neck tumors. It is expected to become the first IAP antagonist to be marketed.

[0005] Xevinapant (AT-406) contains a core skeleton of 1,5-diazabicyclo[6,3,0]undecane, therefore, the 1,5-diazabicyclo[6,3,0]undecane amino acid is a key intermediate in the synthesis of Xevinapant (AT-406). Among the reported synthetic methods, patent WO2008128171A3 discloses a method using L-pyroglutamic acid as a starting material, but it employs propylene alkylation, resulting in poor reaction selectivity, a 3:1 isomer impurity ratio, and difficulty in separation. Similarly, the olefin oxidation uses ozone, making large-scale industrial production impossible. The article published in J. Org. Chem in 2022 by Yanzhi Zhang, Yibo Wang, Guangjun Xie, Junyang Chen, Ankang Hu, Runmei Wang, Tianchen He, Dilawo Duolikun, and Haiying Sun reported that the preparation method disclosed in the report used grubbsll catalyst, which is expensive, involves many mitsunobo reaction byproducts that are difficult to separate and purify, and uses thiols with strong odors. This route is also not suitable for industrial production. Summary of the Invention

[0006] To address the technical challenges of expensive catalysts, poor reaction selectivity, and strong odor in the preparation of AT-406 intermediates, this invention provides a method for preparing AT-406 intermediates. This method avoids the use of ozone and thiols, which have strong odors, while improving the selectivity of intramolecular reactions and reducing the formation of byproducts.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0008] A method for preparing an AT-406 intermediate, wherein the AT-406 intermediate is such as compound I. a As shown:

[0009]

[0010] The preparation method includes the following steps:

[0011] (1) Compound 1 was reacted with ditert-butyl dicarbonate under the action of a catalyst to carry out the Boc protecting group reaction, and compound 2 was obtained.

[0012]

[0013] (2) Compound 2 and ethynyl Grignard reagent were subjected to a Grignard reaction under a nitrogen atmosphere to prepare compound 3;

[0014]

[0015] Wherein, R is one of TMS, TES, or TIS;

[0016] (3) Under a nitrogen atmosphere, compound 3 undergoes a borohydride reduction amination reaction with a borohydride reagent in an ester solvent and an acidic system to prepare compound 4;

[0017]

[0018] Wherein, R is one of TMS, TES, or TIS;

[0019] (4) Compound 4 is first de-ethynyl protecting group (such as one of trimethylsilyl-TMS, triethylsilyl-TES, or triisopropylsilyl-TIS) in polar solvent A, and then de-Boc protecting group in polar solvent B to obtain compound 5.

[0020]

[0021] (5) Compound 5 and N-tert-butoxycarbonyl-3-[(benzyloxycarbonyl)amino]-L-alanine (compound 6) were condensed under condensing agent conditions to prepare compound 7;

[0022]

[0023] (6) Compound 7 was reacted with a borohydride reagent under a nitrogen atmosphere, and then reacted with an oxidant to prepare compound 8;

[0024]

[0025] (7) Compound 8 was placed in a hydrogen atmosphere and under hydrogenation catalyst conditions underwent a hydrogenation-reduction ring-closure reaction to obtain compound I. a .

[0026] Furthermore, in step (1), the catalyst is selected from DMAP, triethylamine, pyridine, etc., preferably DMAP.

[0027] Further, in step (2), the ethynyl Grignard reagent is selected from one of trimethylsilylethynyl magnesium bromide, trimethylsilylethynyl magnesium chloride, triethylsilylethynyl magnesium bromide, triisopropylsilylethynyl magnesium bromide, etc.; preferably trimethylsilylethynyl magnesium bromide.

[0028] Furthermore, in step (3), the ester solvent is selected from one of ethyl acetate, isopropyl acetate, methyl acetate, butyl acetate, etc.; preferably ethyl acetate.

[0029] Furthermore, in step (3), the borohydride reagent is selected from one of sodium triacetylborohydride, sodium cyanoborohydride, sodium borohydride, borane complex, etc.; preferably sodium triacetylborohydride.

[0030] Using an acetylene-based Grignard reagent as a protecting group in the reaction with the ketone provides greater steric hindrance, resulting in better steric selectivity and smaller trans isomers during the cyclization reaction in the hydroboration reduction amination step. Furthermore, the ester solvent and hydroboration reagent selected in step (3) further enhance the reaction selectivity and reduce isomer impurities. In particular, when using sodium triacetylborohydride, which has significant steric hindrance, as the hydroboration reagent, the reduction selectivity is good, unaffected by the carbonyl group in compound 4, and extremely high cis configurations of compound 5 can be obtained, with ee values ​​even exceeding 99.5%.

[0031] Further, in step (4), the polar reagent A can be one of tetrabutylammonium fluoride, trifluoroacetic acid, boron tribromide, etc., more preferably tetrabutylammonium fluoride; the polar reagent B can be one of trifluoroacetic acid, hydrogen chloride-ethanol solution, p-toluenesulfonic acid, more preferably trifluoroacetic acid.

[0032] Furthermore, the condensation reagent in step (5) is selected from one or more combinations of EDCI / HOBt, T3P, and HATU, more preferably EDCI / HOBt.

[0033] Furthermore, in step (6), the borohydride reagent is selected from 9-BBN, 9-BBN dimer, and boranetetrahydrofuran complex; more preferably, it is 9-BBN. 9-BBN has large steric hindrance, and it is easier to obtain a highly regioselective product by borohydride reaction, that is, to obtain a single cis configuration compound 8 with an ee value of more than 99.5%.

[0034] Furthermore, the oxidant in step (6) can be sodium perborate, hydrogen peroxide, etc.; more preferably sodium perborate. Sodium perborate is used as an oxidant, and compounds 7 and 8 will undergo hydrolysis in an alkaline system. Sodium perborate, as a neutral reagent, can avoid side reactions.

[0035] Preferably, the catalyst in step (7) is selected from palladium on carbon, palladium hydroxide, and Raney nickel, more preferably palladium on carbon. Although palladium on carbon and palladium hydroxide are expensive catalysts, they can be recycled and reused after the reaction.

[0036] In some embodiments, the molar ratio of compound 1 to ditert-butyl dicarbonate and catalyst in step (1) is 1:1.0 to 1.5:0.05 to 0.2, preferably 1:1.1:0.1.

[0037] In some embodiments, the molar ratio of compound 2 to acetylene Grignard reagent in step (2) is 1:1.2 to 2.0, preferably 1:1.5;

[0038] In some embodiments, the reaction temperature of step (2) is -10 to 10°C, preferably 0 to 5°C.

[0039] In some embodiments, the molar ratio of compound 3 to borohydride reagent in step (3) is 1:1.2 to 1.8; preferably 1:1.5; and the mass ratio of compound 3 to ester solvent is 1:1 to 4, preferably 1:2.

[0040] In some embodiments, the reagent used to adjust the acidic system in step (3) is trifluoroacetic acid or acetic acid. In some embodiments, trifluoroacetic acid is used to adjust the acidic system in step (3), and the molar ratio of compound 3 to trifluoroacetic acid can be 1:3.0–5.0. In some embodiments, acetic acid is used to adjust the acidic system in step (3), and the molar ratio of compound 3 to acetic acid can be 1:4.0–6.0.

[0041] In some embodiments, the reaction temperature of step (3) is 0 to 20°C, preferably 10 to 20°C.

[0042] In some embodiments, the molar ratio of compound 4 to polar solvent A and polar solvent B in step (4) is 1:0.9-1.2:2.0-4.0, preferably 1:1.0:3.0.

[0043] In some embodiments, the reaction in step (5) needs to be carried out in an alkaline system, and the adjusting reagent can be, for example, DIEA; in some embodiments, EDCI / HOBt is selected as the condensation reagent in step (5), and the molar ratio of compound 5 to EDCI and HOBt is 1:1.2-2.0:1.2-2.0, preferably 1:1.5:1.5.

[0044] In some embodiments, the molar ratio of compound 6 to borohydride reagent and oxidant in step (6) is 1:2.0-3.0:3.0-5.0, preferably 1:2.5:3.0.

[0045] In some embodiments, the reaction temperature of step (6) is -5 to 30°C, preferably 0 to 10°C.

[0046] In some embodiments, the mass ratio of compound 7 to catalyst in step (7) is 1:0.05 to 0.2, preferably 1:0.1.

[0047] In some embodiments, the pressure of the hydrogen atmosphere in step (7) is 1 to 5 psi, preferably 4 psi.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] (1) In this invention, L-pyroglutamic acid methyl ester is ethynylated, and the selected ester solvent and borohydride reagent undergo a borohydride reduction amination reaction, which can improve the reaction selectivity, reduce isomer impurities, facilitate separation and purification, and obtain a single cis configuration product with an ee value of over 99.5%.

[0050] (2) In the prior art, propylene alkylation is used, and subsequent steps require ozone oxidation, which involves the Mitsunobo reaction and the use of odorous thiol reagents and Grubbsll catalysts. On the one hand, there are many reaction byproducts that are difficult to separate and purify; on the other hand, the catalysts are difficult to obtain and costly, and the toxic reagents are difficult to handle and have harmful effects on the human body. The present invention selects specific borohydride reagents and oxidizing reagents, avoiding the use of ozone and thiol reagents with strong odors. At the same time, it improves the selectivity of intramolecular reactions, reduces the generation of byproducts, and is easy to separate and purify. The catalyst itself and the byproducts are non-toxic and do not pollute the environment. It provides a method suitable for industrial production to obtain AT-406 intermediate. Attached Figure Description

[0051] Figure 1 This is the proton NMR spectrum of compound 4 prepared in Example 3-1;

[0052] Figure 2 This is the proton NMR spectrum of compound 7 prepared in Example 5;

[0053] Figure 3 Compound I was prepared in Example 7-1. a The hydrogen spectrum. Detailed Implementation

[0054] The present invention will be further described below with reference to specific embodiments, but the scope and content of protection claimed by the present invention are not limited to the following embodiments.

[0055] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0056] The meanings of the chemical abbreviations used in the instruction manual are as follows:

[0057] Boc: tert-Butoxycarbonyl

[0058] TMS: Trimethylsilyl

[0059] TES: Triethylsilyl

[0060] TIS: Triisopropylsilyl

[0061] DMAP: 4-Dimethylaminopyridine

[0062] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0063] HOBt: 1-Hydroxybenzotriazole

[0064] T3P: 1-n-Propylphosphine

[0065] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0066] 9-BBN: 9-Boronbicyclo[3,3,1]-nonane

[0067] DIEA: N,N-Diisopropylethylamine

[0068] Example 1: Preparation of Compound 2

[0069]

[0070] 400 g of compound 1 and 1.2 L of dichloromethane were added to a 5 L four-necked flask. 34 g of DMAP was added at room temperature, followed by 670 g of di-tert-butyl dicarbonate. The reaction was allowed to proceed for 6 h. 2 L of water was added to quench the reaction. The mixture was separated, the organic phase was concentrated, and crystallization occurred upon cooling. A yellow solid precipitated. The mixture was filtered to obtain 543 g of a white solid of compound 2, with a yield of 80% and a purity of 99.2%.

[0071] Example 2: Preparation of Compound 3

[0072] Example 2-1

[0073]

[0074] Under a nitrogen atmosphere, 3.4 kg of trimethylsilylethynyl magnesium bromide solution was added to a 10 L four-necked flask, and the temperature was lowered to 0-5 °C. 1 L of tetrahydrofuran solution containing 43 g of compound 2 prepared according to the method of Example 1 was added dropwise to the system, and the temperature was controlled at 0-5 °C. The reaction was stopped after 2 h of addition. The reaction was quenched by adding ammonium chloride solution. The mixture was separated, and the organic phase was concentrated until no fraction was distilled to obtain 534 g of compound 3 in an oily form, with a yield of 70% and a purity of 97%.

[0075] Example 2-2

[0076] In this example, the Grignard reagent was replaced with trimethylsilylenyne magnesium chloride, and all other conditions were the same as in Example 2-1. Compound 3 was obtained in 68% yield and with a purity of 97%.

[0077] Example 2-3

[0078] In this example, the Grignard reagent was replaced with triethylsilylethynylmagnesium bromide, and all other conditions were the same as in Example 2-1. Compound 3 was obtained in 61% yield with a purity of 96.5%.

[0079] Examples 2-4

[0080] In this example, the Grignard reagent was replaced with triisopropylsilylethynylmagnesium bromide, and all other conditions were the same as in Example 2-1. Compound 3 was obtained in 53% yield and with a purity of 96.1%.

[0081] Examples 2-5

[0082] In this example, the feed equivalence ratio of compound 2 to Grignard reagent was changed from 1:1.5 to 1:1.2, while all other conditions remained the same as in Example 2-1. Compound 3 was obtained in 61% yield with a purity of 96.4%.

[0083] Examples 2-6

[0084] In this example, the reaction temperature was changed from 0–5°C to 5–10°C, while all other conditions remained the same as in Example 2-1. Compound 3 was obtained in 67% yield with a purity of 95.9%.

[0085] Example 3: Preparation of Compound 4

[0086] Example 3-1

[0087]

[0088] Compound 3, prepared according to the method of Example 2-1, was added to a 2L four-necked flask at a depth of 534g and 1L of ethyl acetate. The mixture was stirred until dissolved. The temperature was then lowered to 10-15°C. 497g of sodium triacetylborohydride was added in portions, and the temperature was maintained at 10-15°C. 713g of trifluoroacetic acid was added dropwise, and the reaction was maintained at this temperature for 12 hours. The reaction mixture was then quenched dropwise with 25% dipotassium hydrogen phosphate solution. The mixture was separated, concentrated, and yielded 305g of an oily substance containing compound 4, with a yield of 60% and a purity of 99.2%. The ee value of the product was 99.6%.

[0089] A suitable amount of the obtained compound 4 was analyzed for 1H NMR. The results were as follows: 1H NMR (DMSO, 400 MHz) δ 4.49–4.44 (m, 1H), 4.17 (s, 1H), 3.64 (s, 3H), 2.17 (s, 2H), 1.895 (s, 2H), 1.41–1.35 (m, 9H). Figure 1 This is the corresponding proton spectrum.

[0090] Example 3-2

[0091] In this example, the organic solvent was changed from ethyl acetate to isopropyl acetate, while all other conditions remained the same as in Example 3-1. Compound 4 was obtained in 57% yield with a purity of 98.9%. The ee value of the product was 99.2%.

[0092] Example 3-3

[0093] In this example, the reaction temperature was changed from 10–20°C to 0–10°C, while all other conditions remained the same as in Example 3-1. Compound 4 was obtained in 54% yield with a purity of 99.1%. The ee value of the product was 99.5%.

[0094] Examples 3-4

[0095] In this embodiment, the amounts of sodium triacetylborohydride and trifluoroacetic acid were adjusted. The equivalent ratio of compound 3, sodium triacetylborohydride, and trifluoroacetic acid was changed from 1:1.5:4.0 to 1:2.0:5.0. All other conditions remained the same as in Example 3-1. Compound 4 was obtained in 52% yield with a purity of 99.0%. The ee value of the product was 99.4%.

[0096] Comparative Examples 3-5

[0097] In this comparative example, the organic solvent was changed from ethyl acetate to dichloromethane, while all other conditions remained the same as in Example 3-1. The ee value of the product was 55.1%. Compound 4 required multiple recrystallizations to obtain an ee value >99.0%.

[0098] Comparative Examples 3-6

[0099] In this comparative example, the organic solvent was changed from ethyl acetate to acetonitrile, while all other conditions remained the same as in Example 3-1. The ee value of the product was 71.9%. Compound 4 required three recrystallizations to obtain an ee value >99.0%, but the yield was less than 10% after three purifications.

[0100] Comparative Examples 3-7

[0101] In this comparative example, the organic solvent ethyl acetate was changed to 3 L, while all other conditions remained the same as in Example 3-1. Compound 4 was obtained in a yield of only 32% with a purity of 98.5%. The ee value of the product was 98.9%.

[0102] Comparative Examples 3-8

[0103] In this example, the reaction temperature was changed from 10–15°C to 30–35°C, while other conditions remained the same as in Example 3-1. Compound 4 was obtained in 45% yield with a purity of 92.3%. The ee value of the product was 93.1%, but after a second recrystallization, the yield was only 33%, and the ee value of the product could be >99.0%.

[0104] Comparative Examples 3-9

[0105] In this comparative example, compound 2 was first reacted with trimethylsilylpropene-magnesium bromide to obtain the product, denoted as compound 9. Compound 9 was then reacted with a borohydride reagent in an ester solvent to undergo a borohydride reduction amination reaction, yielding the product, denoted as compound 10.

[0106]

[0107] Under a nitrogen atmosphere, 340 g of trimethylsilylpropene-magnesium bromide solution was added to a 1 L four-necked flask. The temperature was lowered to 10–15 °C, and 100 mL of tetrahydrofuran solution containing 54.3 g of compound 2 was added dropwise to the system. The temperature was controlled at 10–15 °C, and the reaction was stopped after 2 hours. The reaction was quenched by adding ammonium chloride solution. The mixture was separated, and the organic phase was concentrated until no fraction was distilled to obtain 498 g of compound 9 as an oil. 1 L of ethyl acetate was added, and the temperature was lowered to 0 °C. 464 g of triacetylborohydride was added in portions, and the temperature was controlled at 0 °C. 652 g of trifluoroacetic acid was added dropwise, and the reaction was maintained at 12 hours. The reaction solution was quenched by adding 25% dipotassium hydrogen phosphate solution. The mixture was separated, concentrated, and 187 g of a mixture of compounds 10 was obtained with a purity of 45%. The ee value of the product was 45.4%, and multiple recrystallizations could not yield an ee value >99.0%.

[0108] Example 4: Preparation of Compound 5

[0109]

[0110] 305 g of compound 4 prepared according to Example 3-1 and 1 L of ethyl acetate were added to a 2 L four-necked flask. 262 g of tetrabutylammonium fluoride was added in portions to the system. The reaction was carried out at room temperature for 2 h. 1 L of water was added to the system, and the mixture was stirred and washed. The mixture was separated, and 321 g of trifluoroacetic acid was added to the organic phase. The temperature was raised to 40 °C and the reaction was carried out for 6 h. The temperature was lowered, and 1 L of isopropyl ether was added. The mixture was stirred to disperse and crystallize. The mixture was filtered and dried to obtain 115 g of compound 5 as a white solid. The yield was 80% and the purity was 99%.

[0111] Example 5: Preparation of Compound 7

[0112]

[0113] 115g of compound 5 prepared according to the method of Example 4, 381g of compound 6, and 1L of dichloromethane were added to a 2L four-necked flask and stirred thoroughly. Then, 242g of DIEA and 152g of HOBt were added to the system. 216g of EDCI was added in batches at 10°C and the reaction was maintained at 10°C for 3 hours. 1L of water was added to the system, and the mixture was stirred and washed. The mixture was separated and purified by sand column chromatography to obtain 270g of compound 7 as an oil, with a yield of 76% and a purity of 99.2%.

[0114] A suitable amount of the obtained compound 7 was analyzed for its 1H NMR spectrum. The results were as follows: 1H NMR (CDCl3, 400MHz) δ 7.39-7.28 (m, 5H), 5.47 (s, 1H), 5.41 (s, 1H), 5.18-5.06 (m, 3H), 4.74-4.70 (m, 1H), 4.55-4.51 (m, 1H), 3.79-3.69 (m, 4H), 2.38-2.33 (m, 2H), 2.26-2.18 (m, 3H), 1.43 (s, 9H). Figure 2 This is the corresponding proton spectrum.

[0115] Example 6: Preparation of Compound 8

[0116] Example 6-1

[0117]

[0118] 270g of compound 7 prepared according to the method of Example 5 and 500mL of tetrahydrofuran were added to a 1L four-necked flask. The mixture was stirred thoroughly and the temperature was controlled at 5-10℃. 174g of 9-BBN was added to the system, and the reaction was maintained at 5-10℃ for 5h. 263g of sodium perborate was added to the system in portions, and the reaction was stirred at room temperature for 8h. 500mL of water was added to the system, and the mixture was washed with stirring. The mixture was separated, and the organic phase was purified by sand column chromatography to obtain 168g of compound 8 as an oil, with a yield of 60% and a purity of 99.5%. The ee value of the product was 99.8%.

[0119] Example 6-2

[0120] In this example, the borohydride reagent was changed from 9-BBN to a 9-BBN dimer, and all other conditions were the same as in Example 6-1. Compound 8 was obtained in 57% yield with a purity of 99.1%. The ee value of the product was 99.4%.

[0121] Example 6-3

[0122] In this example, the oxidant was changed from sodium perborate to hydrogen peroxide, while all other conditions remained the same as in Example 6-1. Compound 8 was obtained in 34% yield with a purity of 99.0%. The ee value of the product was 99.3%.

[0123] Example 6-4

[0124] In this embodiment, the equivalent ratio of compound 7, the borohydride reagent, and the oxidizing reagent was changed from 1:2.5:3.0 to 1:2.0:4.0, while all other conditions remained the same as in Example 6-1. Compound 8 was obtained in 55% yield with a purity of 99.3%. The ee value of the product was 99.5%.

[0125] Example 6-5

[0126] In this example, the reaction temperature was changed from 5–10°C to 20–25°C, while all other conditions remained the same as in Example 6-1. Compound 8 was obtained in 53% yield with a purity of 99.0%. The ee value of the product was 99.4%.

[0127] Example 7: AT-406 intermediate compound I a Preparation

[0128] Example 7-1

[0129]

[0130] 168g of compound 8 prepared according to the method of Example 6-1, 16g of palladium on carbon (10w%), and 600mL of methanol were added to a 1L autoclave. The hydrogenation ring-closure reaction was catalyzed under controlled temperature of 50°C and hydrogen (4psi). After 48h, hydrogen absorption automatically stopped. The palladium on carbon catalyst was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure to obtain an off-white solid. Recrystallization yielded compound I. a 70g of white solid, yield 60%, purity 99.2%.

[0131] Take an appropriate amount of the obtained compound I a The proton NMR spectrum was measured, and the results were as follows: ¹H NMR (DMSO, 400 MHz) δ 6.61–6.59 (m, 5H), 4.46–4.33 (m, 3H), 3.64–3.62 (m, 3H), 2.89–2.83 (m, 3H), 2.63 (s, 1H), 2.30–2.28 (m, 1H), 2.07 (s, 1H), 1.88 (s, 1H), 1.74 (s, 1H), 1.61 (s, 1H), 1.58–1.33 (m, 9H). Figure 3 This is the corresponding proton spectrum.

[0132] Example 7-2

[0133] In this example, the hydride was changed from palladium on carbon to palladium hydroxide; all other conditions were the same as in Example 7-1. Recrystallization yielded compound I. a The yield was 58%, and the purity was 99.0%.

[0134] Example 7-3

[0135] In this example, the hydride was changed from palladium on carbon to Raney nickel, and the reaction time was increased from 48 h to 55 h; all other conditions were the same as in Example 7-1. Recrystallization yielded compound I. a The yield was 47%, and the purity was 98.4%.

[0136] Example 7-4

[0137] In this example, the equivalent ratio of compound 7 to the hydrogenating agent was changed from 1:0.1 to 1:0.05, and the reaction time was increased from 48 h to 56 h. All other conditions remained the same as in Example 7-1. Recrystallization yielded compound I. a The yield was 59%, and the purity was 98.9%.

[0138] Example 7-5

[0139] In this example, the reaction pressure was changed from 4 psi to 2 psi, and the reaction time was increased from 48 h to 60 h; all other conditions were the same as in Example 7-1. Recrystallization yielded compound I. a The yield was 55%, and the purity was 98.8%.

[0140] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing an AT-406 intermediate, characterized in that, The AT-406 intermediate, such as compound I a As shown: The preparation method includes the following steps: (1) Compound 1 was reacted with ditert-butyl dicarbonate under the action of a catalyst to carry out the Boc protecting group reaction, and compound 2 was obtained. (2) Compound 2 and ethynyl Grignard reagent were subjected to a Grignard reaction under a nitrogen atmosphere to prepare compound 3; Wherein, R is one of TMS, TES, or TIS; (3) Under a nitrogen atmosphere, compound 3 undergoes a borohydride reduction amination reaction with a borohydride reagent in an ester solvent and an acidic system to prepare compound 4; Wherein, R is one of TMS, TES, or TIS; (4) Compound 4 was first deprotected from the TMS protecting group in polar solvent A, and then deprotected from the Boc protecting group in polar solvent B to obtain compound 5. The polar reagent A is one of tetrabutylammonium fluoride, trifluoroacetic acid, and boron tribromide; The polar reagent B is one of trifluoroacetic acid, hydrogen chloride-ethanol solution, and p-toluenesulfonic acid; (5) Compound 5 was condensed with N-tert-butoxycarbonyl-3-[(benzyloxycarbonyl)amino]-L-alanine under condensing agent conditions to prepare compound 7. (6) Compound 7 was reacted with a borohydride reagent under a nitrogen atmosphere, and then reacted with an oxidant to prepare compound 8; (7) Compound 8 was placed in a hydrogen atmosphere and under hydrogenation catalyst conditions underwent a hydrogenation-reduction ring-closure reaction to obtain compound I. a .

2. The preparation method according to claim 1, characterized in that, The catalyst in step (1) is selected from DMAP, triethylamine, and pyridine.

3. The preparation method according to claim 1, characterized in that, In step (2), the ethynyl Grignard reagent is selected from one of trimethylsilylethynyl magnesium bromide, trimethylsilylethynyl magnesium chloride, triethylsilylethynyl magnesium bromide, and triethylsilylethynyl magnesium chloride; in step (3), the ester solvent is selected from one of ethyl acetate, isopropyl acetate, methyl acetate, and butyl acetate, and the borohydride reagent is selected from one of triacetylborohydride, sodium cyanoborohydride, sodium borohydride, and borane complex.

4. The preparation method according to claim 3, characterized in that, In step (2), the ethynyl Grignard reagent is trimethylsilylethynyl magnesium bromide; in step (3), the ester solvent is ethyl acetate, and the borohydride reagent is sodium triacetylborohydride.

5. The preparation method according to claim 1, characterized in that, In step (5), the condensation reagent is one or more combinations of EDCI / HOBt, T3P, and HATU; in step (6), the borohydride reagent is selected from 9-BBN, 9-BBN dimer, and boranetetrahydrofuran complex; the oxidant is sodium perborate or hydrogen peroxide; and in step (7), the catalyst is selected from palladium on carbon, palladium hydroxide, and Raney nickel.

6. The preparation method according to claim 5, characterized in that, In step (6), the borohydride is 9-BBN and the oxidant is sodium perborate.

7. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound 1 to ditert-butyl dicarbonate and catalyst is 1:1.0-1.5:0.05-0.

2.

8. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of compound 2 to acetylene Grignard reagent is 1:1.2 to 2.0; the reaction temperature in step (2) is -10 to 10℃.

9. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of compound 3 to borohydride reagent is 1:1.2 to 1.8, and the mass ratio of compound 3 to ester solvent is 1:1 to 4; the reaction temperature of step (3) is 0 to 20°C.

10. The preparation method according to claim 1, characterized in that, In step (4), the molar ratio of compound 4 to polar solvent A and polar solvent B is 1:0.9-1.2:2.0-4.

0.

11. The preparation method according to claim 1, characterized in that, In step (6), the molar ratio of compound 6 to borohydride reagent and oxidant is 1:2.0-3.0:3.0-5.0; the reaction temperature in step (6) is -5 to 30°C.

12. The preparation method according to claim 1, characterized in that, In step (7), the mass ratio of compound 7 to catalyst is 1:0.05 to 0.2; and the pressure of the hydrogen atmosphere in step (7) is 1 to 5 psi.

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