Process for the preparation of elacrim

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of elacestrant. The preparation method comprises the following steps: step 1, a compound of formula I is subjected to chiral resolution to obtain a compound of formula II; step 2, the compound of formula II is subjected to reductive amination with a compound of formula III to obtain a compound of formula IV, wherein PG is a protecting group; step 3, the compound of formula IV is subjected to protecting group deprotection to obtain a compound of formula V; and step 4, the compound of formula V is subjected to reductive amination with acetaldehyde to obtain the target compound elacestrant. The preparation method of elacestrant provided by the application has the advantages of short synthesis route, high efficiency, low cost, high yield and good application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and particularly to a preparation method of elacestrant. Background Art

[0002] Elacestrant (Chinese name: elacestrant or elacestrant), is an oral selective estrogen receptor degrader (SERD) developed by Radius. On October 20, 2021, Menarini / Radius jointly announced that elacestrant obtained positive results for ER+ / HER2-advanced or metastatic breast cancer patients. On January 27, 2023, the FDA approved Elacestrant (elacestrant, Orserdu) for postmenopausal women or adult men with advanced or metastatic breast cancer with ER+, HER2-, and ESR1 mutations who have progressed after at least one prior endocrine therapy. The molecular weight of Elacestrant is 458.65, and the molecular formula is C 30 H 38 N2O2, and its structural formula is as follows.

[0003]

[0004] Currently, there are few reports on the preparation method of elacestrant. The original research company's patent CN113348163A reported the following synthetic route: starting from 7-benzyloxy-3-bromo-1,2-dihydronaphthalene (CAS: 722536-73-4, compound a), undergoing Miyaura borylation reaction under palladium catalysis, and then undergoing Suzuki-Miyaura coupling reaction with compound c to prepare compound d by "one-pot method". Then, the double bond is reduced by palladium on carbon hydroxide, and the compound f is obtained by hydrolysis with hydrochloric acid. After chiral resolution by forming salt with D-(+)-dibenzoyl tartaric acid, the absolute configuration compound g is obtained, and then reductive amination reaction occurs with compound h, and the carbonyl group is reduced by sodium borohydride to obtain the target product of elacestrant.

[0005]

[0006] However, the above synthetic route has more reaction steps, which is not conducive to the total yield of synthesis and the cost of the process, and limits its wide application in the field of drug synthesis. In short, the research on the preparation method of elacestrant is less at present, and there are still many disadvantages in the existing processes. Therefore, it is of great significance to study a preparation method of elacestrant with high yield, high purity and short synthesis steps. Summary of the Invention

[0007] Aiming at the problems of the prior art, the purpose of the present invention is to provide a preparation method of elacestrant.

[0008] A method for preparing alastracetin includes the following steps:

[0009]

[0010] Step 1: Compound I is chirally resolved to obtain compound II;

[0011] Step 2: Compound II and compound III are reductively aminationd to obtain compound IV, wherein PG is a protecting group;

[0012] Step 3: The protecting group of compound IV is deprotected to obtain compound V;

[0013] Step 4: Compound V is reductively amination with acetaldehyde to obtain the target compound, alasmoid.

[0014] Preferably, in step 1, the resolving agent for chiral resolution is selected from D-(+)-dibenzoyl tartaric acid or L-(-)-di-p-methylbenzoyl tartaric acid;

[0015] And / or, the solvent for chiral resolution is selected from at least one of acetonitrile, dichloromethane, ethyl acetate, acetone, tetrahydrofuran, or 2-methyltetrahydrofuran;

[0016] And / or, the reaction temperature for the chiral resolution is 50-80°C;

[0017] And / or, the molar ratio of the compound of formula I to the resolving agent is 1:0.45 to 0.55.

[0018] Preferably, in step 1, the chiral resolving agent is selected from D-(+)-dibenzoyl tartaric acid. The compound of formula I reacts with D-(+)-dibenzoyl tartaric acid to generate D-(+)-dibenzoyl tartarate, which is dissolved in a solvent and then reacts with a base to obtain the compound of formula II.

[0019] The alkali is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate.

[0020] The solvent used to dissolve the D-(+)-dibenzoyl tartrate is selected from at least one of methanol, ethanol, or water.

[0021] Preferably, in step 1, the solvent for chiral resolution is selected from a mixed solvent of acetonitrile and dichloromethane, the reaction temperature for chiral resolution is 65°C, and the molar ratio of the compound of formula I to the resolving agent is 1:0.5.

[0022] Preferably, in step 2, the protecting group is selected from tert-butoxycarbonyl, benzyloxycarbonyl, benzyl or p-methoxybenzyl;

[0023] And / or, the reducing agent for the reductive amination is selected from at least one of sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride;

[0024] And / or, the reductive amination is carried out in the presence of an auxiliary agent selected from at least one of acetic acid or hydrochloric acid;

[0025] And / or, the solvent for the reductive amination is selected from at least one of methanol, ethanol, tetrahydrofuran, dichloromethane, acetonitrile, or dichloroethane;

[0026] And / or, the reaction temperature for the reductive amination is 40–60°C;

[0027] And / or, the molar ratio of the compound of formula II to the compound of formula III is 1:1 to 2;

[0028] And / or, the molar ratio of the compound of formula II to the reducing agent is 1:1 to 4;

[0029] And / or, the molar ratio of the compound of formula II to the auxiliary is 1:0 to 0.5.

[0030] Preferably, in step 2, the reducing agent and auxiliary agent for the reductive amination are selected from one of the following combinations:

[0031] 1) The reducing agent is sodium triacetoxyborohydride, and no auxiliaries are used.

[0032] 2) The reducing agent is selected from sodium cyanoborohydride, and the auxiliary agent is selected from acetic acid;

[0033] The solvent for the reductive amination is selected from dichloroethane; the reaction temperature for the reductive amination is 45°C; the molar ratio of the compound of formula II to the compound of formula III is 1:1.5; and the molar ratio of the compound of formula II to the reducing agent is 1:1.1.

[0034] Preferably, in step 3, the protecting group is selected from tert-butyloxycarbonyl;

[0035] The deprotection is carried out under the action of an acid, which is selected from hydrochloric acid, trifluoroacetic acid, or p-toluenesulfonic acid;

[0036] And / or, the deprotected solvent is selected from at least one of methanol, 1,4-dioxane, ethyl acetate, tetrahydrofuran, or dichloromethane.

[0037] Preferably, in step 3, the protecting group is selected from benzyloxycarbonyl, benzyl, or p-methoxybenzyl;

[0038] The deprotection is carried out in the presence of a catalyst, which is selected from palladium on carbon or palladium hydroxide on carbon.

[0039] And / or, the deprotection solvent is selected from methanol, ethanol or ethyl acetate.

[0040] Preferably, in step 4, the reducing agent for the reductive amination is selected from sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride;

[0041] And / or, the reductive amination is carried out in the presence of an auxiliary agent selected from at least one of acetic acid or hydrochloric acid;

[0042] And / or, the solvent for the reductive amination is selected from methanol, ethanol, tetrahydrofuran, dichloromethane, acetonitrile, or dichloroethane;

[0043] And / or, the reaction temperature for the reductive amination is 40–60°C;

[0044] And / or, the acetaldehyde is prepared into one of the following solutions and then added to the reaction system: aqueous acetaldehyde solution, tetrahydrofuran acetaldehyde solution, ethanol acetaldehyde solution, isopropanol acetaldehyde solution, or dichloromethane acetaldehyde solution;

[0045] And / or, the molar ratio of the compound of formula V to acetaldehyde is 1:1 to 2;

[0046] And / or, the molar ratio of the compound of formula V to the reducing agent is 1:1 to 4;

[0047] And / or, the molar ratio of the compound of formula V to the auxiliary is 1:0 to 0.5.

[0048] Preferably, in step 4, the reducing agent and auxiliary agent for the reductive amination are selected from one of the following combinations:

[0049] 1) The reducing agent is sodium triacetoxyborohydride, and no auxiliaries are used.

[0050] 2) The reducing agent is selected from sodium cyanoborohydride, and the auxiliary agent is selected from acetic acid;

[0051] The solvent for the reductive amination is selected from dichloroethane; the reaction temperature for the reductive amination is 45°C; the acetaldehyde is prepared as a 40 wt.% acetaldehyde-tetrahydrofuran solution and then added to the reaction system; the molar ratio of compound V to acetaldehyde is 1:2; the molar ratio of compound V to reducing agent is 1:1.05.

[0052] This invention presents a novel synthetic route for the preparation of ellaxizone and optimizes the process conditions for each reaction step. The synthetic route of this invention involves only four steps, which improves process efficiency, reduces production costs, and increases the overall yield. Therefore, this invention has excellent application prospects.

[0053] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0054] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0055] The reagents and raw materials used in the following examples are all commercially available products.

[0056] Example 1:

[0057]

[0058] First step reaction:

[0059] Compound I (120 g, 0.4 mol) and acetonitrile / dichloromethane (1.2 L, v / v = 3 / 1) were added to a reaction flask and stirred until dissolved. Then, D-(+)-dibenzoyl tartrate (71.6 g, 0.2 mol) was added and stirred until homogeneous. The mixture was heated to 65 °C and refluxed for 3 h. After slow cooling to room temperature, a solid precipitated out. The solid was filtered, and the filter cake was washed twice with dichloromethane (0.4 L). The filter cake was then dispersed evenly in dichloromethane (0.5 L) and refluxed for 1 h. The mixture was then filtered and washed again. The above operation was repeated once more. The final filter cake was dried under vacuum to obtain D-(+)-dibenzoyl tartrate of compound II.

[0060] The D-(+)-dibenzoyl tartrate of compound II was dissolved in water / methanol (1.2 L, v / v = 5:1). After stirring until dissolved, 4 L of 25% sodium bicarbonate aqueous solution was added, and the reaction was stirred at room temperature for 2 h. A solid precipitated out. The solid was filtered, and the filter cake was washed twice with water. The pH of the filtrate was adjusted to ≥8 with sodium bicarbonate solution, and a solid precipitated out again. The solid was filtered and washed, and the filter cakes from the two filtrations were combined. The filter cakes were washed twice with water (0.2 L) and n-heptane (0.2 L), respectively, and dried under vacuum at 50 °C to obtain compound II (58.3 g, 49% yield). LC-MS (ESI) m / z = 298.2 [M+H] +

[0061] Second step reaction:

[0062] Compound II (58.3 g, 0.196 mol) and methanol (0.6 L) were added to a reaction flask and stirred until dissolved. Compound III (53.9 g, 0.216 mol) and acetic acid (5 mL, 88 mmol) were then added. The mixture was heated to 45 °C and reacted for 2 h. Sodium cyanoborohydride (24.6 g, 0.392 mol) was then added, and the reaction was continued for 4 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was allowed to return to room temperature, and the reaction was quenched with saturated sodium bicarbonate solution. Ethyl acetate (0.4 L × 2) was added for extraction. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound IV (93.2 g, 89.6% yield). LC-MS (ESI) m / z = 531.3 [M + H] +

[0063] Third step reaction:

[0064] Compound IV (93.2 g, 0.176 mol) was added to a reaction flask, followed by 0.4 L of 1,4-dioxane. After stirring and dissolving, 0.2 L of 12 M HCl was added, and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, dissolved in water, and then extracted with ethyl acetate (0.2 L × 2) to remove the organic phase. The aqueous phase was then adjusted to pH 7 by adding saturated sodium bicarbonate solution, followed by extraction with ethyl acetate (0.2 L × 2). The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound V (70.9 g, 93.6% yield). LC-MS (ESI) m / z = 431.3 [M + H] +

[0065] Fourth step reaction:

[0066] Compound V (70.9 g, 0.165 mol) and methanol (0.6 L) were added to a reaction flask and stirred until dissolved. Then, 50 wt.% acetaldehyde-ethanol solution (17.9 g, 0.203 mol) was added, and the mixture was heated to 45 °C and reacted for 1 h. Sodium cyanoborohydride (32 g, 0.51 mol) and acetic acid (4 mL, 70 mmol) were added, and the reaction was maintained at this temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was brought back to room temperature, and the reaction was quenched with saturated sodium bicarbonate solution. Ethyl acetate (0.5 L × 2) was added for extraction. The combined organic phases were washed twice with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude ellastatin (72 g).

[0067] The crude product was dissolved in ethanol (0.8 L), and 30% hydrogen chloride ethanol solution (0.2 L) was added. After stirring for 1 h, the mixture was concentrated under reduced pressure. Then, ethyl acetate (0.9 L) was added and stirred for 1 h. The precipitated solid was filtered, and the filter cake was washed with ethyl acetate (0.1 L). The filter cake was dissolved in water, and the pH was adjusted to 8 with 4 M NaOH solution. Then, it was extracted with ethyl acetate (0.6 L × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The above operation was repeated twice with the residue. Finally, the organic phase was concentrated under reduced pressure to obtain pure leprastran (67.3 g, 88.9% yield, 97.2% purity). 1H NMR(400MHz,Chloroform-d)0.94-1.09(m,6H),1.65-1.84(m,2H),2.38-2.46(m,2H),2.66-2.89(m,8H),2.88-2.94(m,2H),3.62-3.69(m,1H ),3.80(s,3H),3.94-4.02(m,2H),6.56-6.64(m,2H),6.70-6.78(m,2H),6.94-7.02(m,3H),7.14-7.18(m,3H).LC-MS(ESI)m / z=459.3[M+H]+

[0068] Example 2:

[0069]

[0070] First step reaction:

[0071] Compound I (120 g, 0.4 mol) and acetonitrile / dichloromethane (1.2 L, v / v = 3 / 1) were added to a reaction flask and stirred until dissolved. Then, L-(-)-dibenzoyl tartaric acid (75.2 g, 0.21 mol) was added and stirred until homogeneous. The mixture was heated to 65 °C and refluxed for 3 h. After slow cooling to room temperature, a solid precipitated. The solid was filtered, and the filter cake was washed twice with dichloromethane (0.2 L). The filtrate was collected and washed twice with saturated sodium bicarbonate and twice with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (53.5 g, 45% yield). LC-MS (ESI) m / z = 298.2 [M+H] +

[0072] Second step reaction:

[0073] Compound II (53.5 g, 0.18 mol) and dichloroethane (0.6 L) were added to a reaction flask and stirred until dissolved. Compound III (67.3 g, 0.27 mol) was then added, and the mixture was heated to 45 °C and reacted for 2 h. Subsequently, sodium triacetoxyborohydride (42 g, 0.198 mol) was added, and the reaction was continued for 4 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was allowed to return to room temperature, and the reaction was quenched with saturated ammonium chloride aqueous solution. Ethyl acetate (0.4 L × 2) was added for extraction. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound IV (89.5 g, 93.7% yield). LC-MS (ESI) m / z = 531.3 [M + H] +

[0074] Third step reaction:

[0075] Compound IV (89.5 g, 0.169 mol) was added to a reaction flask, followed by the addition of dichloromethane (0.6 L) and stirring to dissolve. Trifluoroacetic acid (0.2 L) was then added, and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, dissolved in water, and then extracted with ethyl acetate (0.2 L × 2) to remove the organic phase. A saturated sodium bicarbonate solution was added to the aqueous phase to adjust the pH to 7, followed by extraction with ethyl acetate (0.4 L × 2). The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound V (67.7 g, 93.1% yield). LC-MS (ESI) m / z = 431.3 [M + H] +

[0076] Fourth step reaction:

[0077] Compound V (67.7 g, 0.157 mol) and dichloroethane (0.6 L) were added to a reaction flask and stirred until dissolved. Then, 40 wt.% acetaldehyde-tetrahydrofuran solution (34.6 g, 0.314 mol) was added, and the mixture was heated to 45 °C and reacted for 1 h. Next, sodium triacetoxyborohydride (35 g, 0.165 mol) was added, and the reaction was maintained at this temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was brought back to room temperature, and the reaction was quenched with saturated ammonium chloride aqueous solution. Ethyl acetate (0.5 L × 2) was added for extraction. The combined organic phases were washed twice with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude ellastatin (71 g).

[0078] The crude product was dissolved in ethanol (0.8 L), and 30% hydrogen chloride ethanol solution (0.2 L) was added. After stirring for 1 h, the mixture was concentrated under reduced pressure. Then, ethyl acetate (0.9 L) was added and stirred for 1 h. The precipitated solid was filtered, and the filter cake was washed with ethyl acetate (0.1 L). The filter cake was dissolved in water, and the pH was adjusted to 8 with 4 M NaOH solution. Then, it was extracted with ethyl acetate (0.4 L × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The above operation was repeated twice with the residue. Finally, the organic phase was concentrated under reduced pressure to obtain pure leprastran (64.4 g, 89.4% yield, 98.9% purity). 1 H NMR(400MHz,Chloroform-d)0.94-1.09(m,6H),1.65-1.84(m,2H),2.38-2.46(m,2H),2.66-2.89(m,8H),2.88-2.94(m,2H),3.62-3.69(m,1 H),3.80(s,3H),3.94-4.02(m,2H),6.56-6.64(m,2H),6.70-6.78(m,2H),6.94-7.02(m,3H),7.14-7.18(m,3H).LC-MS(ESI)m / z=459.3[M+H] +

[0079] Example 3: Scale-up Production

[0080]

[0081] First step reaction:

[0082] Compound I (12 kg, 40 mol) and acetonitrile / dichloromethane (120 L, v / v = 3 / 1) were added to a reaction flask and stirred until dissolved. Then, D-(+)-dibenzoyl tartaric acid (7.16 kg, 20 mol) was added and stirred until homogeneous. The mixture was heated to 65 °C and refluxed for 3 h. After slow cooling to room temperature, a solid precipitated out. The solid was filtered, and the filter cake was washed twice with dichloromethane (40 L). The filter cake was then dispersed evenly in dichloromethane (50 L) and refluxed for 1 h. The mixture was then filtered and washed again. The above operation was repeated once more. The final filter cake was dried under vacuum to obtain D-(+)-dibenzoyl tartaric acid salt of compound II.

[0083] The D-(+)-dibenzoyl tartrate of compound II was dissolved in water / methanol (120 L, v / v = 5:1). After stirring until dissolved, 400 L of 25% sodium bicarbonate aqueous solution was added, and the mixture was stirred at room temperature for 2 h. A solid precipitated out. The solid was filtered, and the filter cake was washed twice with water. The pH of the filtrate was adjusted to ≥8 with sodium bicarbonate solution, and a solid precipitated out again. The solid was filtered and washed, and the filter cakes from the two filtrations were combined. The filter cakes were washed twice with water (40 L) and n-heptane (40 L), respectively, and dried under vacuum at 50 °C to obtain compound II (5.71 kg, 48% yield).

[0084] Second step reaction:

[0085] Compound II (5.71 kg, 19.2 mol) and dichloroethane (60 L) were added to a reaction flask and stirred until dissolved. Compound III (4.69 kg, 28.8 mol) was then added, and the mixture was heated to 45 °C and reacted for 2 h. Subsequently, sodium triacetoxyborohydride (4.47 kg, 21.1 mol) was added, and the reaction was continued for 6 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was allowed to return to room temperature, and the reaction was quenched with saturated ammonium chloride solution. Ethyl acetate (40 L × 2) was added for extraction. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound IV (9.34 kg, 91.7% yield).

[0086] Third step reaction:

[0087] Compound IV (9.34 kg, 17.6 mol) was added to a reaction flask, followed by the addition of dichloromethane (60 L) and stirring to dissolve it. Trifluoroacetic acid (20 L) was then added, and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, dissolved in water, and then extracted with ethyl acetate (20 L × 2) to remove the organic phase. A saturated sodium bicarbonate solution was added to the aqueous phase to adjust the pH to 7, followed by extraction with ethyl acetate (40 L × 2). The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound V (6.88 kg, 90.8% yield).

[0088] Fourth step reaction:

[0089] Compound V (6.88 kg, 16 mol) and dichloroethane (55 L) were added to a reaction flask and stirred until dissolved. Then, 40 wt.% acetaldehyde-tetrahydrofuran solution (3.52 kg, 32 mol) was added, and the mixture was heated to 45 °C and reacted for 1 h. Next, sodium triacetoxyborohydride (3.56 kg, 16.8 mol) was added, and the reaction was maintained at this temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was brought back to room temperature, and the reaction was quenched with saturated ammonium chloride aqueous solution. Ethyl acetate (50 L × 2) was added for extraction. The combined organic phases were washed twice with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude ellastatin (7.1 kg).

[0090] The crude product was dissolved in ethanol (80 L), and 20 L of 30% hydrogen chloride ethanol solution was added. After stirring for 1 h, the solution was concentrated under reduced pressure. Then, ethyl acetate (90 L) was added and stirred for 1 h. The precipitated solid was filtered, and the filter cake was washed with ethyl acetate (10 L). The filter cake was dissolved in water, and the pH was adjusted to 8 with 6M NaOH solution. The solution was then extracted with ethyl acetate (40 L × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The above operation was repeated twice with the residue. Finally, the organic phase was concentrated under reduced pressure to obtain pure leprastran (6.46 kg, 88.1% yield, 98.7% purity).

[0091] Screening of Synthesis Conditions in Comparative Examples 1-4

[0092] The synthesis method of Comparative Example 14-7-4 is the same as that of Example 1, except that the reaction conditions for the first, second, and fourth steps are changed, as shown in Table 1.

[0093] Table 1. Comparison of Examples under Different Reaction Conditions for the First Step Reaction

[0094]

[0095] Table 2 Comparison of Examples under Different Reaction Conditions in the Second Step Reaction

[0096]

[0097] Table 3. Comparison of Examples under Different Reaction Conditions in Step 4

[0098]

[0099] As can be seen from the above comparative experimental data, the process conditions selected in Examples 1 and 2 can achieve better yields and are the preferred processes.

[0100] As can be seen from the above embodiments, the ellastatin preparation method provided by the present invention has a short synthetic route, and has the advantages of high efficiency, low cost and high yield, and has good application prospects.

Claims

1. A process for the preparation of Elacridar, characterized in that, Comprising the following steps: Step 1, chiral resolution of the compound of formula I to obtain the compound of formula II; Step 2, reductive amination of the compound of formula II with the compound of formula III to obtain the compound of formula IV, wherein PG is a protecting group selected from tert-butyloxycarbonyl; Step 3, deprotection of the protecting group of the compound of formula IV to obtain the compound of formula V; Step 4, reductive amination of the compound of formula V with acetaldehyde to obtain the target compound Irasposag. In step 1, the resolving agent of the chiral resolution is selected from D-(+)-dibenzoyl tartaric acid or L-(-)-di-p-toluoyl tartaric acid; In step 2, the reducing agent of the reductive amination is selected from sodium cyanoborohydride, and the reductive amination is carried out in the presence of an auxiliary agent selected from acetic acid; In step 4, the reducing agent of the reductive amination is selected from sodium cyanoborohydride, and the reductive amination is carried out in the presence of an auxiliary agent selected from acetic acid.

2. The production method according to claim 1, characterized by, In step 1, the solvent of the chiral resolution is selected from at least one of acetonitrile, dichloromethane, ethyl acetate, acetone, tetrahydrofuran or 2-methyltetrahydrofuran; And / or, the reaction temperature of the chiral resolution is 50-80℃; And / or, the ratio of the compound of formula I to the resolving agent is 1:0.45-0.55 in mole ratio.

3. The preparation method according to claim 2, characterized in that, In step 1, the resolving agent of the chiral resolution is selected from D-(+)-dibenzoyl tartaric acid, and the compound of formula I reacts with D-(+)-dibenzoyl tartaric acid to form D-(+)-dibenzoyl tartaric acid salt dissolved in a solvent, and then reacts with a base to obtain the compound of formula II; The base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate; The solvent for dissolving the D-(+)-dibenzoyl tartaric acid salt is selected from at least one of methanol, ethanol or water.

4. The production method according to claim 2, characterized by, In step 1, the solvent of the chiral resolution is a mixed solvent of acetonitrile and dichloromethane, the reaction temperature of the chiral resolution is 65℃, and the ratio of the compound of formula I to the resolving agent is 1:0.5 in mole ratio.

5. The production method according to claim 1, characterized by, In step 2, the solvent of the reductive amination is selected from at least one of methanol, ethanol, tetrahydrofuran, dichloromethane, acetonitrile or dichloroethane; And / or, the reaction temperature of the reductive amination is 40-60℃; And / or, the ratio of the compound of formula II to the compound of formula III is 1:1-2 in mole ratio; And / or, the ratio of the compound of formula II to the reducing agent is 1:1-4 in mole ratio; And / or, the ratio of the compound of formula II to the auxiliary agent is 1:0-0.5 in mole ratio.

6. The production method according to claim 5, characterized by, In step 2, the reducing agent and the auxiliary agent of the reductive amination are selected from one of the following combinations: 1) the reducing agent is selected from sodium triacetoxyborohydride, and no auxiliary agent is used, 2) the reducing agent is selected from sodium cyanoborohydride, and the auxiliary agent is selected from acetic acid; The solvent of the reductive amination is dichloroethane; the reaction temperature of the reductive amination is 45℃; the ratio of the compound of formula II to the compound of formula III is 1:1.5 in mole ratio; and the ratio of the compound of formula II to the reducing agent is 1:1.1 in mole ratio.

7. The production method according to claim 1, characterized by, In step 3, the deprotection is carried out in the presence of an acid selected from hydrochloric acid, trifluoroacetic acid or p-toluenesulfonic acid; and / or, the solvent for the deprotection is at least one selected from methanol, 1,4-dioxane, ethyl acetate, tetrahydrofuran or dichloromethane.

8. The production method according to claim 1, characterized by, In step 4, the solvent for the reductive amination is selected from methanol, ethanol, tetrahydrofuran, dichloromethane, acetonitrile or dichloroethane; and / or, the reaction temperature for the reductive amination is 40-60°C; and / or, the acetaldehyde is added into the reaction system after being formulated into one of the following solutions: acetaldehyde aqueous solution, acetaldehyde tetrahydrofuran solution, acetaldehyde ethanol solution, acetaldehyde isopropanol solution or acetaldehyde dichloromethane solution; and / or, the ratio of the compound of formula V to acetaldehyde is 1:1-2 in mole ratio; and / or, the ratio of the compound of formula V to the reducing agent is 1:1-4 in mole ratio; and / or, the ratio of the compound of formula V to the auxiliary agent is 1:0-0.5 in mole ratio.

9. The production method according to claim 8, characterized by, In step 4, the reducing agent and auxiliary agent for the reductive amination are selected from one of the following combinations: 1) the reducing agent is selected from sodium triacetoxyborohydride, and no auxiliary agent is used, 2) the reducing agent is selected from sodium cyanoborohydride, and the auxiliary agent is selected from acetic acid; the solvent for the reductive amination is selected from dichloroethane; the reaction temperature for the reductive amination is 45°C; the acetaldehyde is added into the reaction system after being formulated into 40 wt.% acetaldehyde-tetrahydrofuran solution; the ratio of the compound of formula V to acetaldehyde is 1:2 in mole ratio; and the ratio of the compound of formula V to the reducing agent is 1:1.05 in mole ratio.

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