Preparation method of ilastrant and salt thereof

Abstract

The invention discloses a method for preparing ilastrant and salts thereof, which can avoid the use of reagents with strong volatility and / or high toxicity such as sodium borohydride / iodine or sodium borohydride / boron trifluoride, acetaldehyde and the like, has the advantages of good process safety, low production cost and simple process operation (including post-treatment), is more suitable for industrial amplification, and is suitable for industrial production. The method has the advantages of obviously improving the product yield and quality, and has a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to an intermediate of elastomeric and a salt thereof and a preparation method. Background Art

[0002] Female breast cancer has surpassed lung cancer to become the most common cancer worldwide in recent years. Breast cancer is also the fifth leading cause of cancer death worldwide. Selective estrogen receptor degraders (SERDs) are one of the three main drugs used in endocrine therapy for breast cancer. They bind to estrogen receptors on the surface of cancer cells, destabilizing them and inducing their degradation through the cell's normal protein degradation machinery. This reduces estrogen receptor levels and inhibits cancer cell growth. They offer a more comprehensive inhibition of estrogen receptor function and may address drug resistance caused by estrogen receptor mutations. Patients receiving SERDs benefit regardless of estrogen receptor α (ESR1) mutation status. In January 2023, the FDA approved elacestrant (elesetron, Orserdu, RAD1901) for postmenopausal women or adult men with advanced or metastatic breast cancer who have ER+, HER2-, or an ESR1 mutation and have progressed after at least one line of endocrine therapy. Elastran is the first oral SERD drug. Compared with fulvestrant or aromatase inhibitors, it has better efficacy, is more convenient to use, and has better safety data. It has been included in the NCCN (2023.V2) guidelines for breast cancer.

[0003] Elastranol, (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, CAS number 722533-56-4, molecular weight 458.64 (C 30 H 38 N2O2). Elastranstran dihydrochloride, CAS number 1349723-93-8, molecular weight 531.56 (C 30 H 40 Cl2N2O2), the structure is as follows:

[0004]

[0005] Currently, there are few reports on the preparation method of elastatin. Patent application CN202080011109.9 of Genken Eisai Co., Ltd. discloses the following preparation route:

[0006]

[0007] Compound (e) and benzaldehyde compound (f) undergo reductive amination in the presence of (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA], followed by reduction with NaBH(OAc)3 to obtain a crude product (g). Product (g) is reduced with NaBH4 / I2 and then post-processed with Na2S2O3 reduction. The product is purified and treated with HCl (MeOH, EtOH, and / or EtOAc) to obtain the dihydrochloride salt of compound 1. This process is relatively demanding, requiring strict dehydration of the solvent using activated molecular sieves and the use of NaBH4 / I2 reduction, making it environmentally unfriendly. Post-processing is complex and tedious, time-consuming, and labor-intensive, making it difficult to scale up industrially.

[0008] Patent application CN202311194779.0 discloses the following preparation route:

[0009]

[0010] Compound II and compound III undergo reductive amination to obtain compound IV. Compound IV is further deprotected to obtain compound V. Compound V is then reductively aminated with acetaldehyde to obtain the target compound, elastostat. This process is difficult to prepare and purify Compound II, resulting in high production costs and a poor fit for industrial scale-up. Subsequent steps utilize acetaldehyde, which is volatile, highly toxic, and environmentally unfriendly. Summary of the Invention

[0011] The present invention overcomes the defects of the prior art and improves the preparation method of elastostat and its salts. The process is simple, safe, environmentally friendly, low in production cost, simple in post-processing, conducive to industrial scale-up, and improves product yield and quality, solving the difficult problems of operation difficulty, environmental protection and production cost in the production process.

[0012] To achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0013] A method for preparing elastostat and its salt (compound of formula V) comprises the following steps:

[0014]

[0015] The compound of formula IV is deprotected and / or further salified under acidic conditions to obtain the compound of formula V.

[0016] wherein PG is a protecting group selected from tert-butyloxycarbonyl, benzyloxycarbonyl, trimethylsilylethoxycarbonyl, benzyl, p-methoxybenzyl, trifluoroacetyl, benzoyl, and p-toluenesulfonyl. In some embodiments, PG is tert-butyloxycarbonyl, benzyloxycarbonyl, or p-toluenesulfonyl.

[0017] The salt is an acid addition salt selected from hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, maleate, acetate, oxalate, and malonate. In some embodiments, the salt is dihydrochloride, hydrobromide, sulfate, methanesulfonate, and p-toluenesulfonate.

[0018] The acidic conditions can be selected from conventional conditions in the art for removing the above-mentioned protecting groups. In some embodiments, the acid is selected from hydrochloric acid, trifluoroacetic acid, or p-toluenesulfonic acid. The deprotection solvent is selected from one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, or dichloromethane.

[0019] In some embodiments, deprotection and further salification are carried out in the presence of an acidic alcohol solution. In some embodiments, deprotection and further salification are carried out in the presence of an alcohol solution of hydrochloric acid, hydrobromic acid or sulfuric acid, wherein the alcohol is selected from one of methanol and ethanol. In some embodiments, deprotection and further salification are carried out in the presence of hydrochloric acid / ethanol.

[0020] The reaction temperature may be between 0°C and 80°C. In some embodiments, the reaction temperature is between 30°C and 60°C. In some embodiments, the reaction temperature is between 40°C and 45°C.

[0021] The amount of acid used is greater than 2 equivalents. In some embodiments, the amount of acid used is 5 to 20 equivalents.

[0022] In some embodiments, the steps include:

[0023]

[0024] Furthermore, a method for preparing elastostat and its salt (compound of formula V) further comprises the following steps:

[0025]

[0026] The compound of formula III is reacted with a reducing agent to obtain the compound of formula IV.

[0027] The reducing agent is NaBH n (OAc) n , wherein n is an integer from 1 to 3, n' is an integer from 1 to 3, and n+n'=4. In some embodiments, NaBH n (OAc) n It is NaBH(OAc)3.

[0028] The solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, dichloroethane, methanol, ethanol, isopropanol, acetonitrile, and toluene. In some embodiments, the solvent is acetonitrile and / or toluene.

[0029] An acidic auxiliary agent may be added or not, and the auxiliary agent is selected from one or more of acetic acid, p-toluenesulfonic acid, and hydrochloric acid. In some embodiments, the auxiliary agent is selected from acetic acid and / or p-toluenesulfonic acid.

[0030] The reaction temperature may be 50° C. to 120° C. In some embodiments, the reaction temperature is 60° C. to 110° C. In some embodiments, the reaction temperature is 80° C. to 110° C.

[0031] The amount of the reducing agent used is greater than 2 equivalents. In some embodiments, the amount of the reducing agent used is 5 to 20 equivalents.

[0032] In some embodiments, the steps include:

[0033]

[0034] Furthermore, a method for preparing elastostat and its salt (compound of formula V) further comprises the following steps:

[0035]

[0036] The compound of formula I and the compound of formula II are aminated under acid catalysis to obtain the compound of formula III.

[0037] The solvent is selected from one or more of tetrahydrofuran, n-heptane, methanol, ethanol, dichloromethane, and acetonitrile. In some embodiments, the solvent is selected from tetrahydrofuran and / or n-heptane.

[0038] The acid catalyst is selected from D-(+)-dibenzoyltartaric acid, acetic acid, citric acid, hydrochloric acid, phosphoric acid, and sulfuric acid. In some embodiments, the acid catalyst is selected from D-(+)-dibenzoyltartaric acid and acetic acid.

[0039] The reaction temperature may be 50° C. to 120° C. In some embodiments, the reaction temperature is 70° C. to 110° C. In some embodiments, the reaction temperature is 80° C. to 110° C.

[0040] The amount of compound II used is 0.9 to 1.5 equivalents. In some embodiments, the amount of compound II used is 1.0 to 1.1 equivalents.

[0041] The amount of the additive acid catalyst is 0.01 to 0.2 equivalents. In some embodiments, the amount of the additive acid catalyst is 0.05 to 0.1 equivalents.

[0042] In some embodiments, the steps include:

[0043]

[0044] Compounds of formula III and IV, which are used as intermediates for preparing elastostat and its salts:

[0045]

[0046] The enantiomeric excess of the compound of formula III or formula IV is >50%. In some embodiments, the enantiomeric excess is >50%>60%, >70%, >80%, >90%, >95%, >98%, or >99%.

[0047] In some embodiments, the compound is Compound BYA, Compound NEB:

[0048] The present invention provides a new synthetic route for elastomeric and its salts, and uses new intermediates. The advantages include: 1) avoiding the use of sodium borohydride / iodine or sodium borohydride / boron trifluoride, thereby improving process safety; 2) avoiding the use of highly volatile and toxic reagents such as acetaldehyde, thereby being environmentally friendly and more suitable for industrial scale-up; 3) low production cost and simple process operation (including post-treatment), thereby being more suitable for industrial scale-up; and 5) significantly improving product yield and quality.

[0049] The original patent application CN202080011109.9, which uses a process essentially equivalent to that of the present invention, exhibits low reaction conversion rates, and even after process optimization, only very low yields are achieved. The present invention, however, significantly improves overall yields, and the final product achieves chemical purity of 99.75%, chiral purity of 99.90%, and impurity content of less than 0.1%. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 The hydrogen spectrum of the intermediate BYA prepared in Example 1-1 is shown;

[0051] Figure 2 The NEB hydrogen spectrum of the intermediate prepared in Example 2-1 is shown;

[0052] Figure 3 The NEB LC-MS spectrum of the intermediate prepared in Example 2-2 is shown;

[0053] Figure 4 The NEB LC-MS spectrum of the intermediate prepared in Example 2-3 is shown;

[0054] Figure 5 The NEB LC-MS spectrum of the intermediate prepared in Example 2-4 is shown;

[0055] Figure 6The NEB LC-MS spectra of the intermediates prepared in Example 2-5 are shown;

[0056] Figure 7 The hydrogen spectrum of the API prepared in Example 3-1 is shown;

[0057] Figure 8 The hydrogen spectrum of compound (g) prepared in Comparative Example 1 is shown;

[0058] Figure 9 The LC-MS spectrum of compound 1 prepared in comparative example 1 is shown; DETAILED DESCRIPTION

[0059] Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific methodology, scheme and reagent described herein, because these can change. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments, and are not intended to limit the scope of the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present invention belongs. Below in conjunction with specific examples, the present invention will be further described. It should be understood that these examples are only for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention.

[0060] Example 1

[0061] Step 1.1: Preparation of intermediate BYA

[0062] Reaction formula:

[0063]

[0064] Example 1-1

[0065] At room temperature, (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (Compound NP) (6.2 g, 23 mmol), tert-butylethyl (4-formylphenethyl)carbamate (Compound EBA) (7.4 g, 25 mmol), D-(+)-dibenzoyltartaric acid (+)-DBTA (0.9 g, 2.3 mmol), tetrahydrofuran (60 mL) and n-heptane (42 mL) were added to the reaction mixture in this order. After the addition was completed, the reaction system was replaced with a nitrogen environment, the reaction solution was heated to 70°C, and the reaction was stirred under temperature control; after 4 hours, the reaction was completed as monitored by TLC, and the reaction system was concentrated under reduced pressure at 40°C until no droplets flowed out, to obtain the target compound tert-butyl-(R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (compound BYA) 12.3 g, yield 100%.

[0066] The hydrogen spectrum data of intermediate BYA (see attached Figure 1 shown): 1 H NMR (400MHz, d6-DMSO): (8.99,s,1H); (8.52,s,1H); (7.82-7.84,m,2H); (7.20-7.32,m,3H); (6.63-6.82,m,5H); (3.77, s,3H); (3.14,s,2H); (2.68-2.81,m,6H); (1.87,s,2H); (1.35,s,9H); (1.01-1.13,m,3H); (0.87~1.02,t,J=7.2Hz,3H).

[0067] Example 1-2

[0068] At room temperature, (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (1.0 g, 3.7 mmol) (Compound NP), tert-butylethyl (4-formylphenethyl)carbamate (0.98 g, 3.5 mmol) (Compound EBA), D-(+)-dibenzoyltartaric acid (+)-DBTA (140 mg, 0.37 mmol), tetrahydrofuran (10 mL) and n-heptane (7 mL) were added in this order. to the reaction flask; after the addition was completed, the reaction system was replaced with a nitrogen environment, the reaction solution was heated to 80° C., and the reaction was stirred at this temperature; after 4 hours, the reaction was completed as monitored by TLC, and the reaction system was concentrated under reduced pressure at 40° C. until no droplets flowed out, to obtain 1.96 g of the target compound tert-butyl-(R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (compound BYA) in a yield of 100%.

[0069] Examples 1-3

[0070] At room temperature, (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (1.0 g, 3.7 mmol) (Compound NP), tert-butylethyl (4-formylphenethyl)carbamate (1.03 g, 3.7 mmol) (Compound EBA), D-(+)-dibenzoyltartaric acid (+)-DBTA (70 mg, 0.185 mmol), and toluene (40 mL) were added to the reaction flask in this order; After completion, the reaction system was replaced with a nitrogen atmosphere, the reaction solution was heated to 110° C. and refluxed, and the reaction was stirred under reflux; after 4 hours, the reaction was completed as monitored by TLC, and the reaction system was concentrated under reduced pressure at 55° C. until no liquid flowed out, to obtain 1.96 g of the target compound tert-butyl-(R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (Compound BYA) in a yield of 100%.

[0071] Examples 1-4

[0072] At room temperature, (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (5.0 g, 18.6 mmol) (Compound NP), tert-butylethyl (4-formylphenethyl)carbamate (5.7 g, 20.5 mmol) (Compound EBA), acetic acid (0.1 g, 1.86 mmol), tetrahydrofuran (50 mL) and n-heptane (35 mL) were added to the reaction flask in this order; after the addition, After completion, the reaction system was replaced with a nitrogen atmosphere, the reaction solution was heated to 70°C, and the reaction was stirred under temperature control; after 4 hours, the reaction was completed as monitored by TLC, and the reaction system was concentrated under reduced pressure at 55°C until no liquid flowed out, to obtain 9.2 g of the target compound tert-butyl-(R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (Compound BYA) in a yield of 93.8%.

[0073] Example 2

[0074] Step 1.2: Preparation of intermediate NEB

[0075] Reaction formula:

[0076]

[0077] Example 2-1

[0078] At room temperature, tert-butyl-(R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (compound BYA) (12.3 g, 23 mmol), acetonitrile (360 mL), acetic acid (24 mL), and sodium acetylborohydride (25.3 g, 115 mmol) were added to a reaction flask in this order; the reaction system was replaced with a nitrogen atmosphere, the reaction solution was heated to 80°C, and the reaction was maintained at this temperature for 16 hours. After the reaction was complete, the reaction system was cooled to 25°C, and a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8-9. The mixture was extracted with ethyl acetate, and the organic phase was washed with water. The organic phase was concentrated under reduced pressure at 40°C until no liquid flowed out, to obtain 12.0 g of the target compound (intermediate NEB) in a yield of 92.3%.

[0079] NEB proton spectrum data of intermediates (see attached) Figure 2 shown): 1 H NMR (400MHz, d6-DMSO): (9.04,s,1H); (7.04-7.16,m,5H); (6.50-6.82,m,5H); (4.38,s,1H); (4.02-4.28,m,2H); (3.71,s,3H); (3.25-3 .53,m,4H); (3.10-3.20,m,2H); (2.60-2.89,m,6H); (1.53-1.76,m,2H); (1.37,s,9H); (1.01-1.13,m,3H); (0.87~1.02,t,J=7.2Hz,3H). LC-MS(ESI): MS(m / z):559.3[M+H] + .

[0080] Example 2-2

[0081] At room temperature, tert-butyl-(R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (compound BYA) (500 mg, 0.95 mmol), acetonitrile (20 mL), p-toluenesulfonic acid (320 mg, 1.9 mmol) and sodium acetylborohydride (2.7 g, 12.8 mmol) were added to a reaction flask in this order; the reaction system was replaced with a nitrogen atmosphere, the reaction solution was heated to 80°C, and the reaction was kept warm for 16 hours. LC-MS showed that the target compound (intermediate NEB) was almost completely converted (MS (m / z): 559.3 [M+H] + )(As attached Figure 3 shown).

[0082] Example 2-3

[0083] At room temperature, tert-butyl-(R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (compound BYA) (500 mg, 0.95 mmol), toluene (20 mL) and sodium acetylborohydride (4.5 g, 25.65 mmol) were added to the reaction flask in this order; the reaction system was replaced with a nitrogen atmosphere, the reaction solution was heated to 110° C., and the reaction was kept warm for 16 hours. LC-MS showed that the target compound (intermediate NEB) was almost completely converted (MS (m / z): 559.3 [M+H] + )(As attached Figure 4 shown).

[0084] Examples 2-4

[0085] At room temperature, tert-butyl-(R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (compound BYA) (500 mg, 0.95 mmol), toluene (20 mL), acetic acid (1 mL) and sodium acetylborohydride (1.8 g, 8.55 mmol) were added to the reaction flask in this order; the reaction system was replaced with a nitrogen atmosphere, the reaction solution was heated to 80°C, and the reaction was kept at this temperature for 8 hours. LC-MS showed that the target compound (intermediate NEB) was almost completely converted (MS (m / z): 559.3 [M+H] + )(As attached Figure 5 shown).

[0086] Examples 2-5

[0087] At room temperature, tert-butyl-(R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (compound BYA) (500 mg, 0.95 mmol), acetonitrile (20 mL), acetic acid (170 mg, 2.85 mmol), p-toluenesulfonic acid (160 mg, 0.95 mmol) and sodium acetylborohydride (3.6 g, 17.1 mmol) were added to a reaction flask in this order; the reaction system was replaced with a nitrogen atmosphere, the reaction solution was heated to 80°C, and the reaction was kept warm for 16 hours. LC-MS showed complete conversion to the target compound (MS (m / z): 559.3 [M+H] + )(As attached Figure 6 shown).

[0088] Example 3

[0089] Step 1.3: Preparation of API

[0090] Reaction formula:

[0091]

[0092] Example 3-1

[0093] At room temperature, tert-butyl (R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (Compound NEB) (12.0 g, 21.5 mmol), ethanol (36 mL), and 30% ethanolic hydrochloride (36 mL) were added sequentially to a reaction flask; the reaction system was heated to 40°C and stirred at this temperature; after 4 hours, the reaction was completed as monitored by TLC and filtered, and the filter cake was rinsed with 10 mL of ethanol; the filter cake was added with 100 mL of 95% ethanol, heated under reflux, and stirred to dissolve; the mixture was cooled to 0°C and stirred at this temperature to precipitate a solid; the mixture was filtered, and the filter cake was rinsed with 10 mL of ethanol; the filter cake was dried under vacuum at 40°C to constant weight; and 6.5 g of the title compound was obtained in a yield of 56.9%, with a chemical purity of 99.75% and a chiral purity of 99.90%.

[0094] API hydrogen spectrum data (as attached Figure 7 shown): 1 H NMR (400MHz, d6-DMSO): (10.40~10.90,m,1H); (8.80-9.10,m,3H); (6.66-7.08,m,8H); (6.36-6.39,m,2H); (4.62-4.67,m,2H); ( 3.49-3.74,m,5H); (2.79-2.90,m,7H); (2.36-2.62,m,2H); (1.28-1.48,m,2H); (1.05~1.09,t,J=7.2Hz,3H); (0.85~0.92,m,3H). LC-MS(ESI): MS(m / z):459.2[M+H-2HCl] + .

[0095] Example 3-2

[0096] At room temperature, tert-butyl (R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (Compound NEB) (1.0 g, 1.8 mmol), ethanol (3 mL) and 30% ethanolic hydrochloride (3 mL) were added sequentially to a reaction flask; the reaction system was heated to 45°C and stirred at this temperature; after 4 hours, the reaction was completed as monitored by TLC, and the mixture was filtered, and the filter cake was rinsed with 1 mL of ethanol. The material was collected to obtain 0.5 g of the title compound in a yield of 52.6%.

[0097] Example 3-3

[0098] At room temperature, tert-butyl (R)-ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (Compound NEB) (2.0 g, 3.6 mmol), ethanol (6 mL), and 30% ethanolic hydrochloride (6 mL) were added sequentially to a reaction flask; the reaction system was heated to 40°C and stirred at this temperature; after 4 hours, the reaction was completed as monitored by TLC, and the mixture was filtered. 20 mL of 95% ethanol was added to the filter cake, heated to reflux, and stirred to dissolve; the mixture was cooled to 0°C and stirred at this temperature to precipitate a solid; the mixture was filtered, and the filter cake was dried in vacuo at 40°C to obtain 0.98 g of the title compound in a yield of 51.6%.

[0099] Comparative Example

[0100] Comparative Example 1

[0101] Original patent CN202080011109.9 synthesis route:

[0102]

[0103] Preparation of compound (g):

[0104] At room temperature, (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound e) (2.0 g, 7.4 mmol), N-ethyl-2-(4-formylphenyl)acetamide (compound f) (1.55 g, 8.9 mmol), D-(+)-dibenzoyltartaric acid (20 mg, 0.07 mmol), tetrahydrofuran (20 mL) and n-heptane (15 mL) were added to the reaction flask in this order; after the addition was completed, the reaction system was replaced with a nitrogen atmosphere, the reaction solution was heated to 70°C, and the reaction was stirred under controlled temperature; after 4 hours, the reaction was completed by TLC monitoring; the reaction system was concentrated under reduced pressure at 40°C until no droplets flowed out to obtain (R,E)-N-ethyl-2- To (4-((2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)imino)methyl)phenyl)acetamide (imine intermediate) (3.2 g, 7.4 mmol) were added tetrahydrofuran (160 mL) and sodium acetylborohydride (16.4 g, 74 mmol), the reaction system was replaced with a nitrogen atmosphere, the reaction solution was heated to 68° C., and the reaction was stirred with temperature control; after 16 hours, the reaction was complete as monitored by TLC; the reaction system was cooled to 25° C., saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8-9, extracted with ethyl acetate, and the layers were separated; the organic phase was washed with water and the layers were separated; the organic phase was concentrated under reduced pressure at 40° C. until no liquid flowed out, to obtain 2.5 g of the target compound (g) in a yield of 71.4%.

[0105] The hydrogen spectrum data of intermediate compound g (such as attached Figure 8 shown): 1 H NMR (400MHz, d6-DMSO): (9.0,s,1H); (7.97,s,1H); (7.11-7.16,m,5H); (6.80-6.83,m,2H); (6.65-6.67,m,1H); (6.50-6.52,m,2H); (4.00-4.04,m,2H); (3.71,s,3H); (3.50-3.53,m,1 H); (3.30-3.33,m,2H); (3.00-3.07,m,2H); (2.85-2.88,m,2H); (2.76-2.78,m,2H); (2.50- 2.53, m, 2H); (1.60 ~ 1.66, m, 2H); (1.16-1.18, t, J = 7.6Hz, 3H); (0.89-0.91, t, J = 7.6Hz, 3H).

[0106] Preparation of compound 1:

[0107] At room temperature, sodium borohydride (0.22 g, 5.25 mmol) and tetrahydrofuran (8 mL) were added to a reaction flask, and the temperature was lowered to -20°C under nitrogen protection. Separately, (R)-N-ethyl-2-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetamide (1.08 g, 2.1 mmol) was dissolved in tetrahydrofuran (6 mL) and added dropwise to the reaction flask at a temperature of -20°C to 0°C. After the addition was complete, iodine (0.58 g, 2.1 mmol) was dissolved in tetrahydrofuran (1 mL) and added dropwise to the reaction flask at a temperature of -20°C to 0°C. After the addition was complete, the reaction system was heated to 65°C and stirred for 20 hours. LC-MS showed that the reaction was incomplete, and the target compound (MS (m / z): 459.3 [M+H]) was obtained. + ), remaining ~30% starting material (MS (m / z): 473.3 [M+H] + )(As attached Figure 9 shown).

[0108] Comparative Example 2

[0109] The sodium borohydride / iodine system in the original synthesis route of patent CN202080011109.9 was replaced with a sodium borohydride / boron trifluoride system:

[0110] At room temperature, sodium borohydride (11.2 g, 296 mmol) and tetrahydrofuran (200 mL) were added to the reaction flask, nitrogen protection, and the temperature was lowered to -20 ° C. Separately, (R)-N-ethyl-2-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetamide (14.0 g, 29.6 mmol) was dissolved in tetrahydrofuran (80 mL) and the temperature was controlled at -20 ° C. ~0 ℃, add dropwise to the reaction flask, control the temperature at -20 ℃ ~ 0 ℃, add boron trifluoride tetrahydrofuran (44 mL) dropwise to the reaction flask; after the addition, heat the reaction system to 40 ℃, keep warm and stir to react; after 4 hours, TLC monitors the completion of the reaction; the reaction system is cooled to 25 ℃, add saturated sodium bicarbonate aqueous solution to adjust the pH to 8-9, extract with ethyl acetate, and separate the liquids; wash the organic phase with water and separate the liquids; the organic phase is concentrated under reduced pressure at 40 ℃ until no droplets flow out, add 260 mL of 95% ethanol to the crude product, heat under reflux and stir to dissolve; cool to 0 ℃, keep warm and stir to precipitate solid; filter, rinse the filter cake with 10 mL of ethanol; dry the filter cake under vacuum at 50 ℃ to constant weight; collect the material to obtain 7.0 g of the target compound with a yield of 45% and a purity of 98%.

[0111] Although the present invention has been described in detail above using general explanations, specific embodiments, and experiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

Claims

1. A method for preparing elastatin and its salt compound of formula V, characterized in that: The steps include: The compound of formula IV is deprotected and / or further salified under acidic conditions to obtain the compound of formula V, wherein PG is a protecting group.

2. The preparation method according to claim 1, characterized in that The PG is selected from one of tert-butyloxycarbonyl, benzyloxycarbonyl, trimethylsilylethoxycarbonyl, benzyl, p-methoxybenzyl, trifluoroacetyl, benzoyl, and p-toluenesulfonyl; and / or the salt is an acid addition salt selected from one of hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, maleate, acetate, oxalate, and malonate.

3. The preparation method according to any one of the preceding claims, characterized in that Further comprising the steps of: The compound of formula III is reacted with a reducing agent to obtain the compound of formula IV.

4. The preparation method according to claim 3, characterized in that The reducing agent is NaBH n (OAc) n , wherein n is an integer of 1-3, n' is an integer of 1-3, and n+n'=4; and / or, the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, dichloroethane, methanol, ethanol, isopropanol, acetonitrile, and toluene; and / or, an acidic auxiliary agent is added or not added, and the auxiliary agent is selected from one or more of acetic acid, p-toluenesulfonic acid, and hydrochloric acid.

5. The preparation method according to any one of the preceding claims, characterized in that Further comprising the steps of: The compound of formula I and the compound of formula II are aminated under acid catalysis to obtain the compound of formula III.

6. The preparation method according to claim 5, characterized in that The acid catalyst is selected from D-(+)-dibenzoyltartaric acid, acetic acid, citric acid, hydrochloric acid, phosphoric acid, and sulfuric acid; and / or the solvent is selected from one or more of tetrahydrofuran, n-heptane, methanol, ethanol, dichloromethane, and acetonitrile.

7. A compound selected from:

8. The compound according to claim 8, which is selected from:

9. The compound according to claim 7 or 8, characterized in that The compound has an enantiomeric excess of >50%, >60%, >70%, >80%, >90%, >95%, >98% or >99%.

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