Romidepsin intermediate and preparation method thereof

Abstract

The invention provides a romidepsin intermediate and a preparation method thereof, and relates to the technical field of medicine preparation. The preparation method of the romidepsin intermediate comprises the following steps: reacting an initial substance under the action of a first base catalyst to obtain a substance A; reacting the substance A with a substance B under the action of a second base catalyst to obtain a substance C; oxidizing the substance C with an oxidant to obtain a substance D; reacting the substance D with 3-(triphenylmethylthio) propionaldehyde under the action of a third base catalyst to obtain a substance E; performing hydrolysis reaction on the substance E under the action of a fourth base catalyst to obtain a substance F; and performing deprotection on the substance F under a first acid condition to obtain the romidepsin intermediate G. The romidepsin intermediate prepared by the preparation method disclosed by the invention is relatively high in yield.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and specifically relates to a romidepsin intermediate and a preparation method thereof. Background Art

[0002] The prior art discloses that cancer has become another major disease that endangers human health after cardiovascular and cerebrovascular diseases. According to statistics, there will be about 20 million new cancer cases and about 10 million deaths worldwide in 2020. Therefore, researching and discovering low-toxic and high-efficiency tumor treatment drugs has important commercial value.

[0003] In 2009, romidepsin (FK228) was approved by the FDA for the treatment of cutaneous T-cell lymphoma. It has very good inhibitory activity and selectivity against histone deacetylase and tumor cells, and low toxicity to normal cells. The unique structure and good pharmacological activity of romidepsin have aroused the interest of scientists, and several research groups have completed its total synthesis.

[0004] Romidepsin is a cyclopentyl histone deacetylase inhibitor with a unique macrolide structure. The compound (3S,4E)-3-hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid is the key active structure of romidepsin and is also the most important key intermediate in the synthesis of romidepsin.

[0005] CN104529842 discloses a synthetic route for the compound (3S, 4E)-3-hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid. It is reported that a racemic compound is obtained by aldol condensation of acrolein and tert-butyl acetate, and then purified on a vinyl acetate silica gel column after treatment with lipase PS and 4A molecular sieve to obtain (3R)-3-hydroxy-4-pentenoic acid tert-butyl ester, and then catalyzed with (trityl)thio-1-butene and Grubbs reagent to obtain an intermediate, and then hydrolyzed to obtain the product. This route uses lipase PS and 4A molecular sieve to purify the chiral, the yield is low, and it needs to pass through a column, the cost is high, and it is difficult to industrialize. In addition, the yield of the relatively expensive Grubbs reagent is only 62%, and the cost of this route is even higher, making it difficult to industrialize.

[0006]

[0007] Therefore, providing a method for preparing a romidepsin intermediate with a higher yield has become a technical problem that needs to be solved urgently by those skilled in the art. Summary of the invention

[0008] 1. Technical issues to be resolved

[0009] In view of the deficiencies in the prior art, the present invention provides a romidepsin intermediate and a preparation method thereof, which solves the technical problem that the yield of the romidepsin intermediate prepared by the prior preparation method is low.

[0010] (II) Technical solution

[0011] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0012] In a first aspect, the present invention provides a method for preparing a romidepsin intermediate, and the synthesis route of the romidepsin intermediate is as follows:

[0013]

[0014] Wherein, R1 in the starting material, material A, material C, material D, and material E is selected from one of a chain alkyl group and a cyclic alkyl group; X in the starting material and material A is one of chlorine, bromine, and iodine; and R2 is selected from any one of thiazoles;

[0015] The specific steps include:

[0016] The starting material reacts under the action of a first base catalyst to obtain a substance A;

[0017] Substance A reacts with substance B under the action of a second base catalyst to obtain substance C;

[0018] Substance C is oxidized by an oxidant to obtain substance D;

[0019] Substance D reacts with 3-(triphenylmethylthio)propionaldehyde in the presence of a third base catalyst to obtain substance E;

[0020] Substance E is hydrolyzed under the action of a fourth base catalyst to obtain substance F;

[0021] Substance F is deprotected under the first acid solution condition to obtain romidepsin intermediate G.

[0022] Preferably, the synthesis process of the substance A comprises: under nitrogen protection, mixing the starting material, the first reaction solvent and the first base catalyst evenly, causing a substitution reaction to obtain substance A;

[0023] Wherein, the first base catalyst is selected from any one of sodium hydroxide, triethylamine, and pyridine; preferably, the first base catalyst is selected from triethylamine;

[0024] The molar ratio of substance A to the first base catalyst is 1:0.5-5, preferably, the molar ratio of substance A to the first base catalyst is 1:1.3;

[0025] The first reaction solvent is selected from dichloromethane, tetrahydrofuran, and ethyl acetate, preferably dichloromethane;

[0026] The R2 is selected from any one of 2-methyl-1,3,4-thiadiazole, benzothiazole, and 5-phenyltetrazolyl.

[0027] Preferably, the synthesis process of the substance C comprises: under a nitrogen atmosphere, adding substance A, substance B, a phase transfer catalyst and a second base catalyst into a second reaction solvent and heating the solvent to a feeding temperature to react to obtain substance C;

[0028] The second reaction solvent is selected from toluene, N,N-dimethylacetamide, N,N-dimethylacetamide, preferably N,N-dimethylacetamide;

[0029] The second base catalyst is selected from any one of sodium hydroxide, sodium carbonate, potassium carbonate and triethylamine. Preferably, the second base catalyst is selected from sodium bicarbonate;

[0030] The molar ratio of substance B to the second base catalyst is 1:0.5-5, preferably, the molar ratio of substance B to the second base catalyst is 1:1.2;

[0031] The feeding temperature is 80-130°C, preferably 100-120°C;

[0032] The reaction time is 1 to 24 hours, preferably 5 to 7 hours;

[0033] The phase transfer catalyst is selected from tetrabutylammonium fluoride, tetrabutylammonium bromide, polyethylene glycol, preferably tetrabutylammonium bromide.

[0034] Preferably, the synthesis process of the substance D comprises: taking substance C and a third catalyst, adding them into a third reaction solvent and cooling the solvent to a feeding temperature, adding an oxidant dropwise, reacting at a low temperature, and obtaining substance D;

[0035] Wherein, the oxidant is selected from one or more of 30% hydrogen peroxide, 70% tert-butyl hydroperoxide, and m-chloroperbenzoic acid, preferably 30% hydrogen peroxide;

[0036] The third catalyst is one or more of sodium molybdate, sodium tungstate, and ammonium molybdate tetrahydrate, preferably ammonium molybdate tetrahydrate;

[0037] The molar ratio of the substance C to the third catalyst is 1:0.01-0.5, preferably, the molar ratio of the substance C to the third catalyst is 1:0.05;

[0038] The molar ratio of the substance C to the oxidant is 1:1 to 20, preferably, the molar ratio of the substance C to the oxidant is 1:5;

[0039] The temperature of the low temperature reaction is 0 to 50°C, preferably 20 to 30°C;

[0040] The third reaction solvent is selected from any one of methanol, ethanol, dichloromethane and ethyl acetate. Preferably, the third reaction solvent is selected from methanol.

[0041] Preferably, the synthesis process of substance E comprises the following steps:

[0042] Under a nitrogen atmosphere, substance D is mixed with 3-(triphenylmethylthio)propanal, a fourth reaction solvent and a third base catalyst, and the mixture is stirred and cooled to a reaction temperature to allow a condensation reaction to occur. The reaction is monitored until the raw material point disappears, thereby obtaining compound E;

[0043] The fourth reaction solvent is selected from toluene, tetrahydrofuran, 1,4-dioxane, preferably tetrahydrofuran;

[0044] The third base catalyst is selected from any one of sodium methoxide, potassium tert-butoxide, and lithium bis(trimethylsilyl)amide. Preferably, the third base catalyst is potassium tert-butoxide;

[0045] The molar ratio of substance D to the third base catalyst is 1:0.5-3, preferably, the molar ratio of substance D to the third base catalyst is 1:1.5;

[0046] The reaction temperature is -80 to 40°C; preferably, the reaction temperature is -70 to 0°C.

[0047] Preferably, the synthesis process of the substance F comprises: taking substance E and a fifth reaction solvent, stirring and cooling to a reaction temperature, dripping an aqueous solution of a fourth base catalyst, and monitoring the reaction until the raw material point disappears, to obtain compound F;

[0048] The fifth reaction solvent is selected from one or more of tetrahydrofuran, acetonitrile, and 1,4-dioxane. Preferably, the fifth reaction solvent is selected from tetrahydrofuran;

[0049] The fourth base catalyst is selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide. Preferably, the fourth base catalyst is selected from sodium hydroxide;

[0050] The molar ratio of substance E to the fourth base catalyst is 1:0.5-3, preferably, the molar ratio of substance E to the fourth base catalyst is 1:1.5;

[0051] The concentration of the fourth base catalyst is 0.5 to 3 mol / L, preferably, the concentration of the fourth base catalyst is 1 mol / L;

[0052] The reaction temperature is -10 to 10°C, preferably, the reaction temperature is 0 to 10°C.

[0053] Preferably, the synthesis process of the substance G comprises: taking compound F and a sixth reaction solvent, stirring and cooling, adding a first acid solution after cooling, and performing an acidification deprotection reaction to obtain compound G;

[0054] The sixth reaction solvent is selected from one or more of dichloromethane hydrochloride, ethyl acetate, and butyl acetate. Preferably, the sixth reaction solvent is dichloromethane;

[0055] The first acid solution is a hydrochloric acid aqueous solution, the concentration of the hydrochloric acid aqueous solution is 0.5 to 3 mol / L, preferably, the concentration of the hydrochloric acid aqueous solution is 1 mol / L;

[0056] The deprotection reaction temperature is 0-40°C, preferably, the deprotection reaction temperature is 5-10°C.

[0057] Preferably, the R1 is selected from one of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Preferably, the R1 is selected from C1 to C4 alkyl.

[0058] Preferably, at least one of the following conditions is also met:

[0059] The R2 is benzothiazole;

[0060] The X is chlorine.

[0061] On the other hand, the present invention provides a romidepsin intermediate, a compound G prepared by the preparation method described in the first aspect, and its structural formula is as follows:

[0062]

[0063] (III) Beneficial effects

[0064] The present invention provides a romidepsin intermediate and a preparation method thereof. Compared with the prior art, the present invention has the following beneficial effects:

[0065] The preparation method of the romidepsin intermediate of the present invention comprises the following steps: a starting material reacts under the action of a first base catalyst to obtain a substance A; A reacts with a substance B under the action of a second base catalyst to obtain a substance C; substance C is oxidized by an oxidant to obtain a substance D, and then reacts with 3-(tritylthio)propionaldehyde under the action of a third base catalyst to obtain a substance E; substance E is hydrolyzed under the action of a fourth base catalyst to obtain a substance F, and substance F is deprotected under the first acid condition to obtain a romidepsin intermediate G. The method has easy-to-obtain raw materials, is environmentally friendly, has a novel route, a short synthesis route, and has a high yield and low cost for the prepared romidepsin intermediate. DETAILED DESCRIPTION

[0066] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0067] The embodiments of the present application provide a romidepsin intermediate and a preparation method thereof, thereby solving the technical problem that the ee value of the romidepsin intermediate prepared by the existing preparation method is small, and achieving the technical effect of high chiral selectivity and high chiral purity of the prepared romidepsin intermediate.

[0068] The technical solution in the embodiment of the present application is to solve the above technical problems, and the overall idea is as follows:

[0069] The currently disclosed synthetic routes of the compound (3S, 4E)-3-hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid also include the following two.

[0070] (1) CN103601742B reports that triphenylmethanol is used as a raw material, reacted with Lawesson's reagent to obtain triphenylthiol, and then subjected to acrolein addition and Wittig reaction with Ph3=CHCHO to obtain an aldehyde compound, and finally subjected to aldol condensation with Evans auxiliary and hydrolysis to obtain the product. This route uses Ph3=CHCHO to Wittig directly to produce the aldehyde, and the reaction yield is low. The Evans ligand is expensive and difficult to store. In addition, the chiral alcohol prepared has a low chiral selectivity and an ee value (enantiomeric purity) of only 80%. The chiral selectivity is low, and the post-treatment requires column chromatography, which is costly and difficult to industrialize.

[0071]

[0072] (2) World patent WO 2017068596 reported the construction of an E-configuration double bond using 3-(tritylthio)propanal and Wittig reagent Ph3=CHCO2Et, which was reduced to alcohol by DIBAL-H, oxidized to aldehyde by manganese dioxide, and then condensed to chiral alcohol by Evans auxiliary, and finally hydrolyzed to product acid by lithium hydroxide. This route has a relatively long synthesis process. The use of DIBAL-H reduction is a dangerous process in industrialization. The use of Evans auxiliary to make chiral alcohol has an ee value of only 80%, and the chiral selectivity is low. Column chromatography or separation is also required, which is costly and difficult to industrialize.

[0073]

[0074] The invention provides a method for preparing a romidepsin intermediate, comprising the following steps: a starting material reacts under the action of a first base catalyst to obtain a substance A; A reacts with a substance B under the action of a second base catalyst to obtain a substance C; substance C is oxidized by an oxidant to obtain a substance D, and then reacts with 3-(triphenylmethylthio) propionaldehyde under the action of a third base catalyst to obtain a substance E; substance E is hydrolyzed under the action of a fourth base catalyst to obtain a substance F, and substance F is deprotected under the first acid condition to obtain a romidepsin intermediate. The romidepsin intermediate prepared by the method has a large ee value and high chiral purity.

[0075] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with specific implementation methods.

[0076] Example 1

[0077] This embodiment provides a method for preparing a romidepsin intermediate (3S, 4E)-3-hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid, and the synthetic route is as follows:

[0078]

[0079] The specific steps include:

[0080] S1. Synthesis of substance A

[0081] The reaction equation is as follows:

[0082]

[0083] In a 1000mL four-necked round-bottom flask, 150g (0.9mol) of ethyl S-4-chloro-3-hydroxybutyrate, 118.5g (1.17mol) of triethylamine and 400mL of dichloromethane were added in sequence. Under nitrogen protection, the temperature was lowered to 3°C, and 117g (1.07mol) of trimethylsilyl chloride was added dropwise. The reaction was stirred for 4h. Samples were taken for TLC (developing solvent: petroleum ether: ethyl acetate = 1: 1v / v) to detect complete conversion of the raw materials. 200mL of water was added for quenching, and the mixture was washed twice with 200mL of water to obtain a dichloromethane solution. The dichloromethane was concentrated to obtain 190.2g of oily substance A with a detection purity of 98.6% and a yield of 88.5%.

[0084] S2. Synthesis of substance C

[0085] The reaction equation is as follows:

[0086]

[0087] In a 1000mL four-necked round-bottom flask, 150g of oily substance A (0.63mol), 105.3g (0.63mol) of substance B, 2.03g of TBAB (6.3mmol), 63.5g of sodium bicarbonate (0.756mol) and 450mL of DMF were added and stirred in sequence, and the mixture was protected by nitrogen and heated to 100°C. The reaction was maintained for 7 hours, and a sample was taken for TLC (developing solvent was petroleum ether: ethyl acetate = 1:1 v / v) to detect that the raw material conversion was complete, cooled to room temperature, quenched with 200mL of water, extracted with 400mL of ethyl acetate, and the organic layer was washed with 300mL of water for 3 times. The organic layer was concentrated to obtain 221.9g of substance C oily substance, with a detection purity of 99.2% and a yield of 95.3%.

[0088] S3. Synthesis of substance D

[0089] The reaction equation is as follows:

[0090]

[0091] 177.4g of substance C (0.48mol), 640mL of methanol, 16.0g of sodium bicarbonate, 0.19mol, and 29.7g of ammonium molybdate tetrahydrate (0.024mol) were put into a 2000mL reaction bottle, stirred, cooled to 0°C, and 272g of 30% hydrogen peroxide (2.4mol) was added dropwise. After the addition was completed, the mixture was reacted at 20°C for 8h, and a large amount of off-white color precipitated. The off-white solid was filtered to obtain a purity of 99.2%. The solid was dried at 55°C for 8 hours to obtain 185.2g of a dry substance D with a yield of 96.1%.

[0092] S4. Synthesis of substance E

[0093] The reaction equation is as follows:

[0094]

[0095] 0.378 mol of 3-(tritylthio)propanal 125.7 g, 144.6 g of substance D (0.36 mol), and 500 mL of tetrahydrofuran were put into a 1000 mL reaction bottle, replaced with nitrogen, protected with nitrogen, cooled to -70°C with stirring, added with 60.6 g of potassium tert-butoxide (0.54 mol), maintained at -70°C, reacted for 4 hours, sampled for TLC (developing solvent: petroleum ether: ethyl acetate = 2: 1 v / v) to detect complete conversion of the raw materials, added with 300 mL of saturated ammonium chloride to quench, warmed to room temperature, concentrated tetrahydrofuran, added with 500 mL of ethyl acetate, and then washed with 200 mL of water for 3 times to pH 7, added with 100 g of anhydrous sodium sulfate to dry the organic layer, filtered to remove the desiccant, concentrated ethyl acetate to obtain an off-white solid with a detection purity of 99.4%, dried at 55°C with air for 8 hours, and dried to obtain 165.3 g of a dry product of substance E with a yield of 88.5%.

[0096] S5. Synthesis of substances F and G

[0097] The reaction equation is as follows:

[0098]

[0099] 140 g of substance E (0.27 mol) and 640 mL of tetrahydrofuran were added into a 2000 mL reaction bottle, stirred and cooled to 0°C, 405 mL (0.405 mol) of 1 mol / L sodium hydroxide aqueous solution was added dropwise, the temperature was controlled at 20°C, hydrolyzed for 3 hours, and samples were taken for TLC (developing solvent: petroleum ether: ethyl acetate = 1:2 v / v) to detect complete conversion of the raw materials, tetrahydrofuran was concentrated to dryness to obtain substance F, 300 mL of dichloromethane was added, the temperature was cooled to 5°C, 1 m ol / L hydrochloric acid 1L, stirred for 4 hours, detected pH was 2, sampled for TLC (developing solvent is petroleum ether: ethyl acetate = 1: 2v / v) to detect complete conversion of raw materials, extracted 5 times with 300mL of dichloromethane, combined dichloromethane, washed dichloromethane once with 200mL of saturated brine, concentrated dichloromethane to obtain an off-white solid, HPLC detection purity of 99.5%, dried to obtain 106.8g of dry product of substance G, enantiomeric purity of 99.3%, high chiral purity, yield of 94.5%.

[0100] Example 2

[0101] This embodiment provides a method for preparing (3S, 4E)-3-hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid, which specifically comprises the following steps:

[0102] S1. Synthesis of substance A

[0103] The reaction equation is as follows:

[0104]

[0105] In a 1000mL four-necked round-bottom flask, 177.3g (0.9mol) of methyl S-4-bromo-3-hydroxybutyrate, 92.5g (1.17mol) of pyridine and 300mL of tetrahydrofuran were added in sequence. The mixture was protected by nitrogen and cooled to 3°C. 117g (1.07mol) of trimethylsilyl chloride was added dropwise. The mixture was stirred for 4h. A sample was taken for TLC (developing solvent: petroleum ether: ethyl acetate = 1:1 v / v) to detect complete conversion of the raw materials. 200mL of water was added to quench the mixture. 200mL of dichloromethane was added, the organic layer was separated, and the organic layer was washed twice with 200mL of water to obtain a dichloromethane solution. The dichloromethane was concentrated to obtain 212.2g of oily substance A with a detection purity of 97.8% and a yield of 87.6%.

[0106] S2. Synthesis of substance C

[0107] The reaction equation is as follows:

[0108]

[0109] In a 1000mL four-necked round-bottom flask, 169.6g of oily substance A (0.63mol), 83.3g (0.63mol) of substance B, 1.65g of tetrabutylammonium fluoride (6.3mmol), 80.1g of sodium carbonate (0.756mol) and 300mL of toluene were added in sequence with stirring, protected by nitrogen, and heated to 120°C for reaction for 8 hours. Samples were taken for TLC (developing solvent: petroleum ether: ethyl acetate = 1: 1v / v) to detect complete conversion of the raw materials, cooled to room temperature, quenched with 200mL of water, and the organic layer was separated. The organic layer was washed three times with 300mL of water, and the organic layer was concentrated to obtain 191.0g of an oily substance with a purity of 99.0% and a yield of 94.6% as detected.

[0110] S3. Synthesis of substance D

[0111] The reaction equation is as follows:

[0112]

[0113] 153.8g of substance C (0.48mol), 500mL of ethanol, 16.0g of sodium bicarbonate (0.19mol), and 1.03g of sodium molybdate (0.005mol) were put into a 2000mL reaction bottle, stirred, cooled to 0°C, and 309g of 70% tert-butyl hydroperoxide (2.4mol) were added dropwise. After the addition was completed, the mixture was reacted at room temperature at 30°C overnight, and a large amount of off-white color precipitated. The off-white solid was obtained by filtration, and the purity was 99.0%. The solid was dried at 55°C for 8 hours, and 161.6g of dry product was obtained with a yield of 95.5%.

[0114] S4. Synthesis of substance E

[0115] The reaction equation is as follows:

[0116]

[0117] 0.378 mol of 3-(tritylthio)propanal, 125.7 g, 133.2 g of substance D (0.378 mol), and 400 mL of 1,4-dioxane were put into a 1000 mL reaction bottle, replaced with nitrogen, protected with nitrogen, cooled to 0°C with stirring, and 10.3 g of sodium methoxide (0.19 mol) was added. The reaction was maintained for 7 hours, and a sample was taken for TLC (developing solvent was petroleum ether: ethyl acetate = 2: 1 v / v) to detect that the raw material conversion was complete. 300 mL of saturated ammonium chloride was added to quench, the temperature was raised to room temperature, 1,4-dioxane was concentrated, 500 mL of ethyl acetate was added, and 200 mL of water was added. The ethyl acetate was washed with water 3 times until the pH was 7, 100 g of anhydrous sodium sulfate was added to dry the organic layer, the desiccant was filtered out, and the ethyl acetate was concentrated to obtain an off-white solid with a detection purity of 99.1%. The solid was dried at 55°C with air blowing for 8 hours, and 168.1 g of a dry product was obtained by drying with a yield of 88.1%.

[0118] S5. Synthesis of substances F and G

[0119] The reaction equation is as follows:

[0120]

[0121] 136 g of substance E (0.27 mol) and 500 mL of acetonitrile were added into a 2000 mL reaction bottle, stirred and cooled to -5°C, 280 mL (0.14 mol) of 0.5 mol / L lithium hydroxide aqueous solution was added dropwise, the temperature was controlled at 30°C, hydrolyzed for 6 hours, and a sample was taken for TLC (developing solvent was petroleum ether: ethyl acetate = 1: 2 v / v) to detect complete conversion of the raw material. The acetonitrile was concentrated to dryness to obtain substance F, 300 mL of ethyl acetate was added, the temperature was lowered to 10°C, 500 mL of 3 mol / L hydrochloric acid was added dropwise, stirred for 4 hours, and the pH was detected to be 1. A sample was taken for TLC (developing solvent was petroleum ether: ethyl acetate = 1: 2 v / v) to detect complete conversion of the raw material, 300 mL of ethyl acetate was extracted 5 times, the ethyl acetate was combined, the ethyl acetate was washed once with 200 mL of saturated brine, and the ethyl acetate was concentrated to obtain an off-white solid with a detection purity of 99.2%. The dry product 104.1 g was obtained by drying, the enantiomeric purity was 99.1%, and the yield was 92.1%.

[0122] Example 3

[0123] This embodiment provides a method for preparing (3S, 4E)-3-hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid, which specifically comprises the following steps:

[0124] S1. Synthesis of substance A

[0125] The reaction equation is as follows:

[0126]

[0127] In a 1000mL four-necked round-bottom flask, 232g (0.9mol) of ethyl S-4-chloro-3-hydroxybutyrate, 40g (1.0mol) of sodium hydroxide and 200mL of ethyl acetate were added in sequence. Under nitrogen protection, the temperature was lowered to 0°C, and 116.2g (1.07mol) of trimethylsilyl chloride was added dropwise. The reaction was stirred for 2h. A sample was taken for TLC (developing solvent: petroleum ether: ethyl acetate = 1:1 v / v) to detect complete conversion of the raw materials. 200mL of water was added to quench the mixture. The organic layer was separated and washed twice with 200mL of water to obtain an ethyl acetate solution. The ethyl acetate was concentrated to obtain 259.2g of an oily substance A with a detection purity of 98.7% and a yield of 87.2%.

[0128] S2. Synthesis of substance C

[0129] The reaction equation is as follows:

[0130]

[0131] In a 1000mL four-necked round-bottom flask, 208.1g of oily substance A (0.63mol), 105.3g (0.63mol) of substance B, 2.53g of polyethylene glycol (6.3mmol), 76.5g of triethylamine (0.756mol) and 400mL of DMAC were added and stirred in sequence, and the mixture was protected by nitrogen and heated to 100°C. The reaction was maintained for 5 hours, and a sample was taken for TLC (developing solvent was petroleum ether: ethyl acetate = 1:1 v / v) to detect that the raw material was completely converted, cooled to room temperature, quenched with 200mL of water, extracted with 400mL of ethyl acetate, and the organic layer was washed with 300mL of water 3 times. The organic layer was concentrated to obtain 219.6g of substance C oily substance, with a detection purity of 99.4% and a yield of 94.3%.

[0132] S3. Synthesis of substance D

[0133] The reaction equation is as follows:

[0134]

[0135] 177.4g of substance C (0.48mol), 500mL of ethyl acetate, 16.0g of sodium bicarbonate (0.19mol), and 7.05g of sodium tungstate (0.024mol) were put into a 2000mL reaction bottle, stirred, cooled to 5°C, and 828.3g of 50% m-chloroperbenzoic acid (2.4mol) were added dropwise. After the addition was completed, the mixture was reacted at 30°C for 4h, and a large amount of off-white color precipitated. The off-white solid was obtained by filtration, and the purity was 99.0%. The solid was dried at 55°C for 8 hours to obtain 182.5g of dry substance D with a yield of 94.7%.

[0136] S4. Synthesis of substance E

[0137] The reaction equation is as follows:

[0138]

[0139] 0.378 mol of 3-(tritylthio)propanal, 125.7 g, 144.6 g of substance D (0.36 mol), and 400 mL of acetonitrile were put into a 1000 mL reaction bottle, replaced with nitrogen, protected with nitrogen, cooled to -30°C with stirring, added with 60.6 g of lithium bis(trimethylsilyl)amide (0.5 mol), maintained at -30°C, reacted for 6 hours, sampled for TLC (developing solvent: petroleum ether: ethyl acetate = 2: 1 v / v) to detect complete conversion of the raw material, added with 300 mL of saturated ammonium chloride to quench, warmed to room temperature, concentrated acetonitrile, added with 300 mL of ethyl acetate, separated the organic layer, added with 200 mL of water to wash the ethyl acetate 3 times until the pH was 7, added with 100 g of anhydrous sodium sulfate to dry the organic layer, filtered to remove the desiccant, concentrated the ethyl acetate to obtain an off-white solid with a purity of 99.0%, dried at 55°C with air for 8 hours, and dried to obtain 163.2 g of a dry product of substance E with a yield of 87.4%.

[0140] S5. Synthesis of substances F and G

[0141] The reaction equation is as follows:

[0142]

[0143] 140 g of substance E (0.27 mol) and 500 mL of 1,4-dioxane were added into a 2000 mL reaction bottle, stirred and cooled to 0°C, 405 mL (0.405 mol) of 1 mol / L potassium hydroxide aqueous solution was added dropwise, the temperature was controlled at 25°C, and hydrolyzed for 4 hours. Samples were taken for TLC (developing solvent: petroleum ether: ethyl acetate = 1:2 v / v) to detect complete conversion of the raw materials, 1,4-dioxane was dried to obtain substance F, 400 mL of butyl acetate was added, and the temperature was cooled to 25°C. The mixture was warmed to 10°C, 1 L of 1 mol / L hydrochloric acid was added dropwise, and the mixture was stirred for 5 hours. The pH value was detected to be 1. A sample was taken for TLC (developing solvent: petroleum ether: ethyl acetate = 1:2 v / v) to detect complete conversion of the raw materials. The mixture was extracted twice with 300 mL of butyl acetate, and the organic layers were combined. The organic layers were washed once with 200 mL of saturated brine, and the dichloromethane was concentrated to obtain an off-white solid with a detection purity of 99.2%. The solid was dried to obtain 105.7 g of a dry product of substance G with an enantiomeric purity of 99.1% and a yield of 93.5%.

[0144] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0145] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a romidepsin intermediate, characterized in that: The romidepsin intermediate synthesis route is as follows: Wherein, R1 in the starting material, material A, material C, material D, and material E is selected from one of a chain alkyl group and a cyclic alkyl group; X in the starting material and material A is one of chlorine, bromine, and iodine; and R2 is selected from any one of thiazoles; The specific steps include: The starting material reacts under the action of a first base catalyst to obtain a substance A; Substance A reacts with substance B under the action of a second base catalyst to obtain substance C; Substance C is oxidized by an oxidant to obtain substance D; Substance D reacts with 3-(triphenylmethylthio)propionaldehyde in the presence of a third base catalyst to obtain substance E; Substance E is hydrolyzed under the action of the fourth base catalyst to obtain substance F; Substance F is deprotected under the first acid solution condition to obtain romidepsin intermediate G.

2. The method for preparing a romidepsin intermediate according to claim 1, characterized in that: The synthesis process of the substance A comprises: under nitrogen protection, taking the starting material, the first reaction solvent and the first base catalyst and mixing them evenly, causing a substitution reaction to obtain the substance A; Wherein, the first base catalyst is selected from any one of sodium hydroxide, triethylamine, and pyridine; preferably, the first base catalyst is selected from triethylamine; The molar ratio of substance A to the first base catalyst is 1:0.5-5, preferably, the molar ratio of substance A to the first base catalyst is 1:1.3; The first reaction solvent is selected from dichloromethane, tetrahydrofuran, and ethyl acetate, preferably dichloromethane; The R2 is selected from any one of 2-methyl-1,3,4-thiadiazole, benzothiazole, and 5-phenyltetrazolyl.

3. The method for preparing a romidepsin intermediate according to claim 1, characterized in that: The synthesis process of the substance C comprises: in a nitrogen atmosphere, taking substance A, substance B, a phase transfer catalyst and a second base catalyst into a second reaction solvent and heating the solvent to a feeding temperature to react to obtain substance C; The second reaction solvent is selected from toluene, N,N-dimethylacetamide, N,N-dimethylacetamide, preferably N,N-dimethylacetamide; The second base catalyst is selected from any one of sodium hydroxide, sodium carbonate, potassium carbonate and triethylamine. Preferably, the second base catalyst is selected from sodium bicarbonate; The molar ratio of substance B to the second base catalyst is 1:0.5-5, preferably, the molar ratio of substance B to the second base catalyst is 1:1.2; The feeding temperature is 80-130°C, preferably 100-120°C; The reaction time is 1 to 24 hours, preferably 5 to 7 hours; The phase transfer catalyst is selected from tetrabutylammonium fluoride, tetrabutylammonium bromide, polyethylene glycol, preferably tetrabutylammonium bromide.

4. The method for preparing a romidepsin intermediate according to claim 1, characterized in that: The synthesis process of the substance D comprises: taking the substance C and the third catalyst, adding them into the third reaction solvent and cooling them to the feeding temperature, dropping the oxidant, reacting at low temperature, and obtaining the substance D; Wherein, the oxidant is selected from one or more of 30% hydrogen peroxide, 70% tert-butyl hydroperoxide, and m-chloroperbenzoic acid, preferably 30% hydrogen peroxide; The third catalyst is one or more of sodium molybdate, sodium tungstate, and ammonium molybdate tetrahydrate, preferably ammonium molybdate tetrahydrate; The molar ratio of the substance C to the third catalyst is 1:0.01-0.5, preferably, the molar ratio of the substance C to the third catalyst is 1:0.05; The molar ratio of the substance C to the oxidant is 1:1 to 20, preferably, the molar ratio of the substance C to the oxidant is 1:5; The temperature of the low temperature reaction is 0 to 50°C, preferably 20 to 30°C; The third reaction solvent is selected from any one of methanol, ethanol, dichloromethane and ethyl acetate. Preferably, the third reaction solvent is selected from methanol.

5. The method for preparing a romidepsin intermediate according to claim 1, characterized in that: The synthesis process of substance E comprises the following steps: Under a nitrogen atmosphere, substance D is mixed with 3-(triphenylmethylthio)propanal, a fourth reaction solvent and a third base catalyst, and the mixture is stirred and cooled to a reaction temperature to allow a condensation reaction to occur. The reaction is monitored until the raw material point disappears, thereby obtaining compound E; The fourth reaction solvent is selected from toluene, tetrahydrofuran, 1,4-dioxane, preferably tetrahydrofuran; The third base catalyst is selected from any one of sodium methoxide, potassium tert-butoxide, and lithium bis(trimethylsilyl)amide. Preferably, the third base catalyst is potassium tert-butoxide; The molar ratio of substance D to the third base catalyst is 1:0.5-3, preferably, the molar ratio of substance D to the third base catalyst is 1:1.5; The reaction temperature is -80 to 40°C; preferably, the reaction temperature is -70 to 0°C.

6. The method for preparing a romidepsin intermediate according to claim 1, characterized in that: The synthesis process of the substance F comprises: taking substance E and a fifth reaction solvent, stirring and cooling to a reaction temperature, dropping an aqueous solution of a fourth base catalyst, and monitoring the reaction until the raw material point disappears, thereby obtaining compound F; The fifth reaction solvent is selected from one or more of tetrahydrofuran, acetonitrile, and 1,4-dioxane. Preferably, the fifth reaction solvent is selected from tetrahydrofuran; The fourth base catalyst is selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide. Preferably, the fourth base catalyst is selected from sodium hydroxide; The molar ratio of substance E to the fourth base catalyst is 1:0.5-3, preferably, the molar ratio of substance E to the fourth base catalyst is 1:1.5; The concentration of the fourth base catalyst is 0.5 to 3 mol / L, preferably, the concentration of the fourth base catalyst is 1 mol / L; The reaction temperature is -10 to 10°C, preferably, the reaction temperature is 0 to 10°C.

7. The method for preparing a romidepsin intermediate according to claim 1, characterized in that: The synthesis process of the substance G comprises: taking compound F and a sixth reaction solvent, stirring and cooling, adding a first acid solution after cooling, and performing an acidification and deprotection reaction to obtain compound G; The sixth reaction solvent is selected from one or more of dichloromethane hydrochloride, ethyl acetate, and butyl acetate. Preferably, the sixth reaction solvent is dichloromethane; The first acid solution is a hydrochloric acid aqueous solution, the concentration of the hydrochloric acid aqueous solution is 0.5 to 3 mol / L, preferably, the concentration of the hydrochloric acid aqueous solution is 1 mol / L; The deprotection reaction temperature is 0-40°C, preferably, the deprotection reaction temperature is 5-10°C.

8. The method for preparing a romidepsin intermediate according to claim 1, characterized in that: The R1 is selected from one of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Preferably, the R1 is selected from C1 to C4 alkyl.

9. The method for preparing a romidepsin intermediate according to claim 1, characterized in that: At least one of the following conditions is also met: The R2 is benzothiazole; The X is chlorine.

10. A romidepsin intermediate, characterized in that: The compound G prepared by the preparation method according to any one of claims 1 to 9 has the structural formula as shown below:

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