WO2015131355A1

WO2015131355A1 - Preparation of natural product histone deacetylase inhibitor thailandepsin b

Info

Publication number: WO2015131355A1
Application number: PCT/CN2014/072925
Authority: WO
Inventors: 程义强; 杨思遥; 王鹏
Original assignee: 清安医药科技武汉有限公司
Priority date: 2014-03-05
Filing date: 2014-03-05
Publication date: 2015-09-11

Abstract

A compound of formula I is an intermediate in a method for preparing a natural product histone deacetylase inhibitor Thailandepsin B. The method comprises the following steps: 1) adding an elemental iodine into a mixed solvent of dichloromethane and methanol to obtain a solution A; 2) dissolving TDP-23 into the mixed solvent of dichloromethane and methanol to obtain a solution B; 3) adding the solution B into the solution A to perform a reaction; and 4) after the completion of the reaction, subjecting the obtained product to an aqueous phase-organic phase separation, and after the organic phase has been dried, obtaining the TDP-B.

Description

The invention relates to a chemical synthesis preparation method of a natural product of microorganisms, in particular to a chemical synthesis preparation method of a natural product histone deacetylase inhibitor, Tyrandopin B, and an intermediate thereof. BACKGROUND OF THE INVENTION The natural product histone deacetylase inhibitor, Thai l and eps in B ₍ TDP-B), is a newly discovered natural product compound having anticancer effects. The compound and its pharmaceutical use are disclosed in research papers (Wang C, Menkes LM, Doughty LB, He M, Wang D, eyer-Almes FJ and Cheng YQ (201 1 } Thailandepsins: bacterial products with potent histone deacetylase inhibition activities and broad- Journal of Natural Products 74:2031-2038. ) and US Patent Application (Chen Y-Q and Wang C. Hi stone deacetylase inh ibi tors and uses thereof. US Patent Ap l i i i i n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n In the case of Juqian, Tyrande Sustain B is generally prepared by biological fermentation, but the expression level of the compound in natural bacteria is very low, which is improved after the medium composition is improved, but the yield is very low. The production requirements cannot be met, so the yield of the compound is very low and the cost is high.

The technical problem to be solved by the present invention is as follows: In the prior art, the natural product histone deacetylase inhibitor, Tyrandopin B, is prepared by a biological fermentation method, and has low yield and high cost.

In order to solve the above technical problems, the present invention provides a chemical synthesis puncturing method of the natural product histone deacetylase inhibitor Tyrandopin B.

The present invention provides a compound having the structure of the following formula, which is an intermediate in the chemical synthesis preparation method of the natural product histone deacetylase inhibitor Tylloprein B.

Wherein R ¹ is hydrogen, a silane group or an alkoxy group; R ² is triphenylmethyl, p-methoxybenzyl, 2 trimethylsilyl)ethyl, or 9-fluorenylmethyl;

R ³ is: triphenylmethyl, p-methoxy 2-(indolyl)methyl, or 9-fluorenylmethyl. Preferably, the above compound has the following structure:

TDP-23 The present invention provides a method for preparing a natural product histone deacetylase inhibitor, Tyrandopin B, characterized in that the structure of Tyrandein B is as shown in the formula TDP-B, and includes the following Steps:

TDP-23 TDP-B

1), the iodine element is added to a mixed solvent of dichloromethane and methanol to obtain a solution A:

2), TDP-23 is dissolved in a mixed solvent of dichloromethane and methanol to obtain a solution B;

3), solution B is added to solution A, and the reaction is carried out;

4) After the reaction is completed, the obtained product is separated from the aqueous phase and the organic phase, and the organic phase is dried to obtain TDP-B. As a preferred embodiment, the molar ratio of the iodine element in the solution A to the TDP-23 in the solution B in the step 3) is 3-20:1. As a preferred technical solution, the volume ratio of dichloromethane to methanol in the mixed solvent of the steps 2) and 2) is between 1 and 20:1. The preferred technical solution is as follows: Step 4) The aqueous solution of sodium thiosulfate is quenched, the saturated sodium chloride solution is added, the liquid phase is separated, the aqueous phase is extracted with dichloromethane, the organic phase is combined, and the organic phase is dried over anhydrous sodium sulfate. After purification, TDP-:B is specifically obtained. Specifically, the method for preparing the natural product histone deacetylase inhibitor tyramupin B of the present invention comprises the following steps:

No face to earn organic solvents

TDP~35

CPh

TDP-38

HO SCPh- _;

OH O NHBoc

BOC deprotection reagent

TDP-25 ^ 3⁄4t -»NH - SCPh, BOC deprotection reagent iv eO HO ¹ HO'

缩合 condensation reaction solvent

NHBoc 舦 bond condensing agent, / NHBoc

[3⁄4 . or Bu: 0 Me0 ₂ CX >

TDP - 2δ

Inorganic alkali solution

HO! o

o

Organic solvents

HC1⁄2C

Ph _3⁄4 CS

TDP-27 TDP-18 TDP-19

TDP-23 TDP-

1. Compound TDP- 36

1 } The compound TDP-34 and the compound TDP-7 are dissolved in a solvent, added 4-is separated, concentrated and dried, and purified to obtain the compound TDP-35; 2) The compound TDP-35 is dissolved in an organic solvent, and an aqueous solution of an inorganic alkali is added. After the reaction is completed, the pH is adjusted to 3, and the organic phase is extracted, and after washing and drying, TDP-36 is obtained;

2, the synthesis of TDP-27:

1) The compound TDP-]0 is reacted with a Boc deprotecting reagent, and after completion of the reaction, TDP-11 is obtained; 2) the compound TDP-il is dissolved in a condensation reaction solvent capable of forming a peptide bond, and the temperature is cooled to -^ by an ice bath. ^ ^ , adding TDP-25, a peptide bond condensing agent, i-hydroxybenzotriazole or 1-hydroxy-7-azobenzotriazole, and an alkaline inorganic salt or an organic base, after the reaction, the obtained organic After phase purification and drying, TDP 26 is obtained;

3) The TDP-26 is reacted with the Boc deprotecting reagent to obtain TDP-27 after the reaction:

3, Ί !) Ρ-Ι3 synthesis: 1) The compound TDP-27 is formed in a condensation reaction solvent which can form a peptide bond, and the temperature is cooled to -10~25 Γ in an ice bath.

TDP-36, peptide bond condensing agent, 1-hydroxybenzoxazole or 1-hydroxy-7-azobenzotriazole, and basic inorganic salt or organic base. After the reaction, the obtained organic phase is purified and dried. After that, it is TDP 18;

2) The compound TDP-18 is dissolved in an organic solvent, and an inorganic alkali aqueous solution is added. After the reaction is completed, the pH is adjusted to 1 to 3, and the phase is extracted. After washing and drying, TDP 19 is obtained; 3) 2-methyl- 6-nitrobenzoic anhydride, dichloromethane and 4-diaminopyridine, mixed and dissolved to obtain a mixture

T; TDP-19 is dissolved in dichloromethane to obtain a mixture of hydrazine; the mixture is added to the mixture ,, after completion of the reaction to obtain TDP-23;

4) a. Iodine is added to a mixed solvent of dichloromethane and methanol to obtain solution A; b. TDP-23 is dissolved in a mixed solvent of dichloromethane and methanol to obtain solution B; c. Solution B is added to solution A. In the reaction, d. After the reaction is completed, the obtained product is separated from the aqueous phase and the organic phase, and the organic phase is dried to obtain TDP-B. The preferred embodiment is that the organic solvent described in 1) of the first step is dichloromethane. The preferred embodiment is that the organic solvent in the step 2) is tetrahydrofuran, the aqueous solution of the inorganic alkali is an aqueous lithium hydroxide solution, and the molar ratio of lithium hydroxide to TDP-35 is 1:1 to 20:1. The preferred embodiment is that the Boc deprotecting reagent in the step i) is trifluoroacetic acid, and the molar ratio of the TOP-10 to the trifluoroacetic acid is 2:1 to 100:1. As a preferred technical solution, the condensation reaction solvent capable of forming a peptide bond in 2) of the step 2 is hydrazine, hydrazine-dimethylformamide, dichloromethane or acetonitrile, and the peptide bond condensing agent is i-ethyl. 3-dimethylaminopropyl)carbodiimide Hydrochloride, hydrazine, Ν'-dicyclohexylcarbodiimide, 2 7-azobenzotriazole) - hydrazine, hydrazine, hydrazine, Ν'-tetramethylurea hexafluorophosphate, benzo Triazolyl-1-yloxytris(dimethylamino)phosphorus iron hexafluorophosphate, 3 (diethoxyphosphoryloxy)-1,2,3 benzotriazine-4-ketone, 0-benzotriazole - hydrazine, hydrazine, hydrazine, Ν'-tetradecylurea tetrafluoroboric acid, benzoxazole hexafluorophosphate-1 -yl-oxy: tripyrrolidinyl or bis (2- Oxo-3-oxazolidinyl)phosphoric acid chloride; the basic inorganic salt is sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate or potassium phosphate, the organic base is: triethylamine, diiso Propylethylamine or pyridine, wherein TDP-]l:T:DP-25:peptide bond condensing agent: 1-hydroxybenzoxazole or 1-hydroxy-7-azobenzindole: nitrogen 3⁄4 basic inorganic The molar ratio of the salt or the organic base is: 1 : 1 -2: 1 -3: 1 -3: 1-5: The Boc deprotecting reagent in step 3) is trifluoroacetic acid, the TOP-26 and trifluoroacetate The molar ratio of acetic acid is from 2:1 to 100:1. As a preferred technical solution, the condensation reaction solvent capable of forming a peptide bond in 1) of the step 3 is hydrazine, hydrazine-dimethylformamide, dichloromethane or acetonitrile, and the peptide bond condensing agent is 1-ethyl. - (3-Dimethylaminopropyl)carbodiimide hydrochloride, hydrazine, Ν'-dicyclohexylcarbodiimide, 2-(7-azobenzidine 3⁄4)- Ν, Ν, Ν ',Ν'-tetramethylurea hexafluorophosphate, benzopyrene: azole- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 3-(diethoxyphosphoryloxy) -1,2,3-benzotriazin-4-one, 0-benzotriazolium, anthracene, Ν', Ν'tetrazyl urea tetrafluoroboric acid, hexafluorophosphate benzotriazole 1 - yl-oxytripyridinyl or bis(2-oxo-3-oxazolyl)phosphoryl chloride: the basic inorganic salt is sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate or Potassium phosphate, the organic base is triethylamine, diisopropylethylamine or pyridine, wherein TDP-27: TDP-36: peptide bond condensing agent: hydroxybenzotriazole or 1-hydroxy 7-azobenzene And the triazole: the molar ratio of the basic inorganic salt or the organic base is: 1 : 1 -2: 1 -3: 1 -3: 1-5. As a preferred technical solution, the organic solvent in the step 2) is tetrahydrofuran, acetonitrile, dioxane or acetone, the aqueous solution of the inorganic alkali is an aqueous solution of lithium hydroxide, and the molar ratio of lithium hydroxide to TDP 18 is hi to 20: 1. The preferred technical scheme, the molar ratio of TDP-19, 2-methyl-6-nitrobenzoic anhydride and 4-dimethylaminopyridine in 3) of step 3 is as follows: 1: 2-5:2- 10 is the preferred technical solution, the volume ratio of dichloromethane to methanol in the mixed solvent of dichloromethane and methanol in steps 4 and 4 of step 3 is 1 20:1; The molar ratio of iodine element to TDP-23 in solution B is 3-20:1; step d is quenched by adding aqueous solution of sodium thiosulfate, saturated brine is added, liquid is separated, and the aqueous phase is extracted with dichloromethane. The organic phase was combined, and the organic phase was dried over anhydrous sodium sulfate and purified to afford TDP-B. The fraud is the preferred technical solution, and the preparation method of TDP 25 is as follows:

TDP-24 TDP-25 In the above formula, M is an alkali metal, and the specific steps are as follows: TDP-24 is mixed with water, and a god or a combination thereof of an alkali metal carbonate or hydrogencarbonate is added, and then di-tert-butyl dicarbonate is added. After the reaction, Get TDP-25. Preferably, one or a combination of the alkali metal carbonate or hydrogencarbonate is a hydrogencarbonate pin, a potassium hydrogencarbonate, a mixture of sodium hydrogencarbonate and sodium carbonate, or a mixture of sodium hydrogencarbonate and potassium carbonate. Preferably, one or a combination of the alkali metal carbonates or hydrogencarbonates is uranium hydrogencarbonate, molar ratio TDP-24: hydrogencarbonate pin: di-tert-butyl dicarbonate = 1: i~5: l~3. As a preferred technical solution, the preparation method of TDP-34 is as follows:

The TDP-34 specifically includes the following steps _{: the} compound TDP-33 is added to methanol, and the temperature is lowered to 0 Torr to 5 Torr in an ice bath, and thionyl chloride is added thereto, and the temperature is raised to reflux. After completion of the reaction, the compound TDP-34 is obtained. Preferably, the molar ratio of thionyl chloride to TDP-33 in step 1) is from 1 to 20:1.

The invention can achieve the following technical effects:

The invention provides a chemical synthesis method of a natural product histone deacetylase inhibitor, Tyrandopin B, which is a new method proposed for the first time, which is known for small molecular raw materials and intermediates. The synthesis overcomes the shortcomings of the biological fermentation method, and the yield can reach 71%, which increases the yield of the compound and reduces the production cost. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a nuclear magnetic resonance spectrum of TDP 23.

Figure 2 shows the infrared spectrum of TDP-23.

Figure 3 shows the nuclear magnetic resonance spectrum of TDP B.

Figure 4 shows the nuclear magnetic spectrum of TDP B. The following embodiments are provided to better illustrate the present invention, and those skilled in the art can better understand and understand the present invention by the embodiments. However, the scope of the protection and claims of the present invention is not limited to the examples provided.

The synthetic route of TDP-B in the embodiment of the present invention is specifically as follows -

TriSH CM P ^P^CHCOoEt D!BAL

Ph ₃ CS,

C Q COOEt

TEA

TDP-01 TDP-S01 TOP -02 TDP~S02 TDP-03 TDP-S03

92% 54% 99%

Dess- artin TOP -06

Ph ₃ CS, H Ph ₃ CS

S

CH ₂ 3⁄4 * TiCi4, DiPEA, DCrvi

TDP-S04 TDP~S05

TDP-04 66% TDP-05 75% TDP-07

TDP-33

CPh ₃

TDP-36

TDP-11 69% for 2 ste s TDP-26

TDP-23 TDP-B Step 1 (TDP-SOI) Synthesis of TDP-02

In a 500 ml round bottom flask, trityl mercaptan (50 g, 181 mmol) and dichloromethane (200 mi) were added, and with stirring, triethylamine (27.66 ml) and TDP-01 (13.29 ml) were added. After the addition, the reaction was carried out at room temperature for 4 h. The reaction mixture was concentrated to dryness EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

TDP-02 nuclear magnetic data:

IH NR (400 MHz, CDC13) δ 9,59 (t, J - 1.3 Hz, IH), 7.48-7,40 (m, 6H), 7,35― 7.27 (nx 7H), 7.24 (ddd, J = 8,4, 2.5, 1.3 Hz, 3H), 2.53 - 2.46 (m, 2H), 2.42 - 2,34 (m, 2H). Step 2 (TDP-S02) Synthesis of TDP-03

TDP-02 (23.8 g, 71.6 mmol) and dichloromethane (85 ml) were added to a 250 ml round bottom flask, stirred until fully dissolved, and (:triphenylphosphene) ethyl acetate (34.8 g, 100.2) Mmo!), stir the reaction at room temperature for 3 h. The reaction was stopped, n-hexane (850 mi) was added to the reaction mixture, and the mixture was stirred for 5 mm, filtered, and evaporated to dryness. Rate: 54%.

TDP-03 nuclear magnetic data -

1H NMR (400 MHz, CDC13) δ 7.47 (dt, 1 --- --- 3,5, 2,1 Hz, 6H), 7.36 7.29 (m, 6H), 7,29 -

7.22 (m, 3H), 6.82 (dt, J = 15.6, 6.8 Hz, 1H), 5.76 (dt, J = 15.6, 1.5 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2,39 - 2.31 (m, 2H), 2.23 (q, J 7.2 Hz, 2H), 1 , 31 (t, J - 7.1 Hz, 3H), Step 3 (TDP-S03) Synthesis of TDP-04

TDP-03 (18 g, 44.7 mmol) and tetrahydrofuran (312 ml) were placed in a 1 000 ml round bottom flask and cooled to -78 °C with a sm. When the internal temperature drops below -70 ,, diisobutylaluminum hydride (L5M in toluene) (89.5 ml) is added dropwise, and the temperature is not higher than -70 Torr. After the completion of the dropwise addition, the reaction was transferred to a low-temperature bath - 30 ° C reaction 2, 5 hb - 30' underarm was added dropwise with methanol for 54 mi, and then 324 mi of saturated sodium potassium tartrate solution was added, and vigorously stirred at room temperature. After stirring, the reaction mixture was concentrated, EtOAc EtOAc (EtOAc m. Yield

99%, HPLC purity: 95.i8%, used directly in the next step.

TDP-04 nuclear magnetic data:

1H NMR (400 MHz, CDC13) δ 7.44 (dt, J = 3.2, 2.0 Hz, 6H), 7,34-7,7 (m, 7H), 7.26―

7.20 fm, 3H), 5.61 - 5.55 (m, 2H), 4.06 (d, J :: 4.8 Hz, 2H), 2.27 (dd, J::: 11.0, 4.0 Hz, 2H),

2.14 (ddd, J = 12.9, 8.L 5.3 Hz, 2H). Step 4 (TDP S04) Synthesis of TDP-05

In a 1000 ml round bottom flask, add Ή] Ρ - 04 (20.6 g, 57.2 mmo!) and chloroform (260 mi), stir until completely dissolved, cool to 0 Torr in ice bath, add hydrogen carbonate pin (20.4 g, 243.2 mmol) and Dess Martin oxidized ij (33.9 g, 80.1 mmol), after the addition was completed, stirring at 0 ° C for 30 min, removing the ice bath, stirring the reaction at room temperature for ih, stopping the reaction, adding 1 cm thick in the Buchner funnel The reaction solution was filtered through silica gel to remove insoluble material. The filter cake was washed with 1000 ml of ethyl acetate. The filtrate was washed with a 20% sulphurous acid pin solution (300 mi * 3 times), washed with 300 ml of saturated brine, dried with anhydrous uranyl sulfate, and concentrated under reduced pressure to hexanes, eluted with petroleum ether: ethyl acetate = 4:1 Column purified product 3.5g, Yield: 66%.

TDP-05 nuclear magnetic data:

1H N (400 MHz, CDC13) δ 9,45 (d, J - 7.8 Hz, 1H), 7.48 - 7.41 (m, 6H), 7.35 - 7,28 (m, 7H), 7.25 (dd, j = 8.3 , 6.2 Hz, 3H), 6.66 (dt, J = 15.6, 6.4 Hz, IH), 6.00 (dd, J = 15.6, 7.8 Hz, 1H), 2, 42 2.28 (m, 4H). Step 6 (TDP-S06) Synthesis of TDP-21

TDP 20 (11.9 g, 101.58 mm oi) and sodium borohydride (9.6 g, 253.95 mmol) were added to a 1 000 ml round bottom flask. Under a nitrogen atmosphere, tetrahydrofuran (200 ml) was added, stirred, and iodine (45.1) was added at room temperature. g, 177.76 mmol) in tetrahydrofuran solution 90 ml, dropwise for 4 h.

The addition was heated to reflux for 16 h. The reaction solution was cooled to a ffi ice-bath, and 25 ml of methanol was slowly added, and the mixture was concentrated under reduced pressure, and the volatile matter was evaporated, and 90 ml of 20% aqueous sodium hydroxide solution was added, and the mixture was heated to reflux for 3 hours. It was extracted with ethyl acetate (40 ml * 3 times), washed with 8 ml of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give a crude product 16 g (about 9 g of pure product) and used directly in the next step.

TDP-21 magnetic data:

1H N (400 MHz, CDC13) δ 3.86 (dd, J 1 1.5, 3.3 Hz, IH), 3,64 (dd, J - 11 , 4, 9, 2 Hz, 】 H), 3.13 - 2.99 fm, 1 H), 1.94 (dq, J::: 13.6, 6.9 Hz, 1H), 1.07 (d, j == 6.8 Hz, 3H), 1.02 (d, J::: 6.8 Hz, 3H). Step 7 (TDP) S07) Synthesis of TDP-22

Potassium hydroxide (25.2 g, 450 mmol) and water (450 ml) were added to a lOOOmi round bottom flask, stirred, and then TDP-21 (9 g, 90 mmol) and carbon disulfide (34.2 g, 450 mol). The oil bath temperature was set to 100 ° C and refluxed for 2 μh, and the product was found to be 91.6% by HPLC. After the reaction was stopped, a large amount of solid was precipitated, and a product having a wet weight of 12.7 g was filtered, and the filtrate was extracted with dichloromethane (200 ml), concentrated to dryness under reduced pressure, and combined with petroleum ether; :: 8:1 eluent was purified by column to obtain 10 g of product, two-step yield: 62'1⁄2.

TDP-22 nuclear magnetic data:

1 H NMR (400 MHz, CDC13) δ 8.09 (s, 1 H), 4.69 (t, j == 9.1 Hz, 1 H), 4.38 (dd, J::: 9.1, 6.7 Hz, 1H), 3, 84 (dt, J = 8.5, 6.7 Hz, 1H), 1,83 (dq, J = 13.5, 6.7 Hz, IH), 0.99 (d, J = 6.7 Hz, 3H), 0.94 (cL J === 6.8 Hz, 3H). Step 8 (TDP-S08) Synthesis of TDP-06

Sodium (60%) (1.9 g, 76.8 mmol) and anhydrous tetrahydrofuran (60 mi) were hydrogenated in a 250 ml three-necked flask, and the mixture was cooled with nitrogen and cooled to 0 hr. TDP-22 (10,3 g, 64 ramoO force il to 100 ml: three-necked flask, ventilated, nitrogen-protected, dissolved in 60 ml of anhydrous tetrahydrofuran, and the solution was added dropwise to a suspension of sodium hydride in THF. after the dropwise addition of the solution, was added dropwise acetyl chloride cool (6.0 g, _76.8mmol)? after complete addition, the ice bath was stirred lOmiii, then the ice bath removed and the reaction temperature for 16h. dilute hydrochloric acid was added dropwise under ice-IN ( I50mi), liquid separation, the aqueous phase was extracted with ethyl acetate (70mi*2 times), then washed with 35ml of saturated brine, dried with anhydrous uranyl sulfate, and dried, with eluent petroleum ether: ethyl acetate ==8 :1 Purification by column, 9.4 g of product was obtained, yield: 72%.

Step 5 (TDP S08) Synthesis of TDP 07

TDP-06 (6.4 g, 31.42. mmoi) was added to a 500 ml three-necked flask, dissolved in anhydrous dichloromethane (100 ml), dissolved in nitrogen, three times in air, and cooled to 0 Torr in an ice bath. The titanium tetrachloride (3.72 ml) was dissolved in 35 ml of anhydrous dichloromethane, and the solution was slowly added dropwise to the above reaction mixture, and stirred for 15 min. After cooling with a thousand ice-acetone bath to -78 V, diisopropylethylamine (4.38 g, 33.92 mmoi) was slowly added dropwise, and after the addition was completed, the mixture was stirred at -78 ° C for 2 h. TDP-05 (6.4 g, 17,85 mmoi) was dissolved in 50 ml of anhydrous dichloromethane, and slowly added dropwise to the above reaction solution, and the reaction was stirred for 4 hours. The reaction was concentrated under reduced pressure, and the residue was evaporated. EtOAc EtOAc EtOAc EtOAc EtOAc Purified by column with petroleum ether; ethyl acetate: :::8: ield 7.5 g, yield: 75%.

TDP-07 nuclear magnetic data:

1H NMR (400 MHz, CDC13) δ 7.43 (d, j == 7.3 Hz, 6H), 7.31 (t, j :: 7.6 Hz, 6H), 7.23 (t, j :: 7.2 Hz, 3H), 5.66― 5,57 (m, 1H), 5.48 (dd, J = 15.5, 6.0 Hz, 1H), 5,15 (t, J = 7.0 Hz, 1H),

4.59 (s, IH), 3.59 (dd, J :: 17.6, 3.0 Hz, 1H), 3.50 fdd, j::: 11.5, 7.9 Hz, 1H), 3.31 (dd, J 17.6. 8.7 Hz, IH), 3.02 (d, J = 11.5 Hz, IH), 2,38 (dq, J = 13,6, 6,8 Hz, IH), 2.24 (i, J = 7.5 Hz, 2H) _: 2.12 fdd, j :: 14.1, 6,9 Hz, 2H), 1.09 (t, j 5.8 Hz, 3H), 1.00 (i, J::: 5.8 Hz, 3H). Step 9 (TDP-S09) Synthesis of TDP-34

In a 2000 ml round bottom flask, add TDP 33 (18 g, 138 mm oi), methanol (1000 ml), cool to ΟΓ 5 ° C in an ice bath, and add thionyl chloride (75 ml, 7.2 eq) dropwise. After the addition was completed, the system was warmed to reflux, and the reaction was refluxed for 4 hours, the heating was stopped, and methanol and excess chlorination were distilled off under reduced pressure, and vacuum was applied for 2 hours to obtain crude product: 23.06 g, crude yield: 115% , used directly in the next step.

TDP-34 nuclear magnetic data - 1H NMR (400 MHz, DMSO) δ 8.74 (s, 3H), 3.94 (t, J = 6,2 Hz, 1H), 3.74 (s, 3H), 1.82 (dd, J 8.3, 6.0 Hz, 2H), 1,45― 1,20 (ra, 4H), 0.87 (t, J 6,9 Hz, 3H). Step 10 (TDP-S10) Synthesis of TDP-35

In a 250 ml round bottom flask, add TDP-34 (5.8 g, 27 mniol), TDP- 07 (7,6 g, 13.5 mmol), dichloromethane (B8 ml), stir and dissolve, add 4-two Methylaminopyridine (3.6 g, 29.7 mmoi), after the addition is completed, the reaction is stirred, and after 5 hours of reaction, TLC is detected (petroleum ether: ethyl acetate 2:1), the reaction of the starting material is completed, the reaction is stopped, and silica gel is added to the reaction system. After concentration to dryness under reduced pressure, the residue was purified by column eluting with petroleum ether: ethyl acetate = 4 _: 1, and then with petroleum ether: ethyl acetate:: 2:1. 6.1 g product, yield: 83%.

TDP-35 nuclear magnetic data:

1H NMR (400 MHz, CDC13) δ 7.43 (dt, J = 3.4, 2.2 Hz, 6H), 7,34 - 7,26 (m, 6H), 7.26 - 7.19 (m, 3H), 6,42 (d , J - 7,9 Hz, 1H), 5.66 - 5,54 (m, 1H), 5,44 (dd, J - 15.4, 6.2 Hz, 1H), 4.60 (td, J = 7.8, 5.4 Hz, 1H ), 4.44 (dd, J = 11.4, 6.3 Hz, 1H), 3.75 (d, J = 4,8 Hz, 3H), 3.49 (s, IH), 2,47― 2.32 (m, 2H), 2.24 ( Dd, J - 11.3, 4.1 Hz, 2H), 2,14- 2.06 (m, 2H), 1.92 - 1.81 (m, IH), 1.68 (tdd, J = 9.7, 8.5, 5.4 Hz, IH), 1.41 - 1,24 (m, 5H), 0.92 (t, J = 7.0 Hz, 3H). Step 11 (TDP-Sli) Synthesis of TDP-36

In a 100 ml round bottom flask, add TDP-35 (6.1 g, 11,2 mmol), tetrahydrofuran (40 ml), stir and dissolve, then cool in an ice bath, slowly add 58 ml of 0.5 Μ aqueous lithium hydroxide solution at room temperature. Stir for 2h, TLC (petroleum ether: ethyl acetate:: 2:1), the reaction of the starting material was complete, the reaction was stopped, the reaction was adjusted with 6N diluted hydrochloric acid and extracted with ethyl acetate (50ml*3 times), combined The organic phase was washed with brine (50 ml*2×), dried over anhydrous sodium sulfate. Step 12 (TDP-S12) Synthesis of TDP-25

To a 500 ml round bottom flask was added TDP-24 (18.5 g, 51 mmol) of 185 185 η1 water, and sodium hydrogencarbonate (8.56 g, 102 mmol) and di-tert-butyl dicarbonate (16,7 g, 76.4 mmol), after the addition was completed, the reaction was stirred at 45 °C for 20 h. After HPLC, after the reaction of the raw materials was completed, the temperature was lowered to room temperature, and the reaction liquid was washed with diethyl ether (150 m!*3). After the washing was completed, the aqueous phase was adjusted with IN diluted hydrochloric acid: ==4, with ethyl acetate (150 mi*3) The organic phase is extracted, washed with 90 ml of saturated brine, dried over anhydrous sodium sulfate, evaporated, evaporated, evaporated, evaporated, evaporated. step.

Step 13 (TDP-S13) Synthesis of TDP-09

Dissolve TDP-08 (12g, 48.9 mmol) in 183mi tetrahydrofuran, cool to 0 °C in ice bath, add The carbonyl bis 3⁄4azole (7.53 g, 46, 46 mmol) was stirred, and the mixture was stirred at room temperature for 1.5 h, and then added to the monomethyl malonate potassium salt (6.86 g, 44 mmol), anhydrous magnesium chloride (11.6 g, 122.29 mmol). The system was transferred to a 45 ° C oil bath to stir the reaction overnight (〖4h), the system was filtered, and the filtrate was concentrated to dryness (40 Ό), then dissolved in 300 ml of ethyl acetate and washed with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of saturated brine. Drying over anhydrous sodium sulfate, and eluent eluting with petroleum ether: ethyl acetate = 8:1 to give s.

Step 14 (TDP-S14) Synthesis of TDP-10

Steps

TDP-10 (8.6 g, 29.9 mm oi) was dissolved in 125 m! methanol, and the dry ice-acetone bath was cooled to -78 Torr, potassium borohydride (5.69 g, 104, 65 mm oi) was added, and the reaction was stirred at this temperature for 0.5 h. Change to ice bath reaction until the conversion of raw materials is complete (about lh), slowly add 125mi water to the system in dry ice acetone bath, adjust pH=4 with 6N diluted hydrochloric acid, spin off methanol, and extract with ethyl acetate (50ml*) 3 times), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate Lg, yield: 82%.

TDP-10 nuclear magnetic data:

1H Li R—(400 MHz, CDC13) δ 4,44 (d, J - 9.1 Hz, 1H), 3.91 (d, J - 9,9 Hz, IH), 3.72 (s, 3H), 3.70 - 3.59 ( m, IH), 3.23 (s, IH), 2.63 (d, J = 16.3 Hz, 1H), 2.49 (dd, j = 16.5, 9.0 Hz, IH), 1,99– 1.85 (m, IH), 1.52 ― 1,40 (m, I OH), 1.35 (dt, J 14,0, 7,0 Hz, IH), 1.24 (dt, J - 13.8, 5.9 Hz, IH), 0.93 (dd, J = 9.2, 5.5 Hz, 3H:), 0.88 (t, J = 6.9 Hz, 3H). Step 15 (TDP-S 15) Synthesis of TDP-1

In a 250mi round bottom flask, TDP-10 (3.5 g, 12.11 mm oi), dichloromethane (35 ml, 10 3⁄41), trifluoroacetic acid (7 ml, 2 Vol) was added dropwise, and the reaction was stirred for 2 hours. , TLC detection (petroleum ether: ethyl acetate = 4:1, sulfomolybdic acid coloring λ raw material reaction completed, concentrated under reduced pressure to remove dichloromethane and excess fluoroacetic acid, with toluene twice, oil pump vacuum 30mi «, used directly in the next step.

Step 16 (TDP-S16) Synthesis of TDP-26

In a 50mi round bottom flask, TDP-11 (13 g, 6.9 mmol), hydrazine, hydrazine-dimethylformamide (30 ml) were added, stirred and dissolved, and the ice bath was lowered to 0 ° C, and TDP- was added in sequence. 25 (3.8 g, 8,2 mmol,), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.6 g, 13.8 mmol), 1-hydroxybenzotriene Azole (1.8 g, 13,8 mmol), sodium bicarbonate (3,36 g, 41.4 mmol). After the addition was completed, the reaction was stirred for 20 h, TLC ( petroleum ether: ethyl acetate::==2:1), After the completion of the reaction, 120 ml of water and 40 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred for about 5 Torr, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (40 ml*3 times), and the organic phase was combined, washed with 40 ml of water, and washed with 40 ml of saturated brine. , Dry over anhydrous sodium sulfate, concentrate to a solution of 5,3 g of crude material, purified by column (washing) 1 part petroleum ether: ethyl acetate = 4: i) 3 g of product obtained, total yield of two oximes: 69%.

TDP-26 nuclear magnetic data:

1H NMR (400 MHz, CDC13) δ 7.45 (d, J = 7.6 Hz, 6H), 7.31 (dd, j = 13.9, 6.1 Hz, 7H), 7,24 (t, J - 7.2 Hz, 3H), 6.04 (s, 1H), 4,75 (s, 1H), 3.93 (dt, J 19.3, 6.6 Hz, 2H), 3,72 (dd, J = 13.1, 6.5 Hz, 1H), 3.68 (s, 3H: ), 3,27 (d, J = 4.1 Hz, 1H), 3.11 (q, J = 7.3 Hz, 1H), 2.69 (dd, J

13.0, 7.0 Hz, 1H), 2,64― 2.55 (m, 2H), 2.44 (dd, J - 16.9, 8,9 Hz, IH), 1.94 (d, J - 4,2 Hz, 1H), 1.62 (d, J = 25.1 Hz, 3H), 1.45 - 1.40 (m, lOH), 1.31 - 1.20 (m, 3H), 1.19 - 1.09 (m, IH), 0.96 - 0,78 (m, 7H), step Seventeen C TDP-S17) Synthesis of TDP-27

In a 250 ml round bottom flask, TDP-26 (3.7 g, 5,8 mm oi), dichloromethane (37 ml, iOV l) was added, and hydrazine fluoride (7.4 ml, 2 Vol) was added dropwise, and the reaction was stirred. After 6 hours, the reaction was detected by HPLC, and the starting material was completely reacted. Product: 67% (HPLC), concentrated under reduced pressure to remove dichloromethane and excess trifluoroacetic acid, toluene was taken twice, and the oil pump sleeve was vacuumed for 30 min, directly 3⁄4 in the next .

Step 18 (TDP-S) 8) Synthesis of TDP-18

In a 500 ml round bottom flask, TDP-27 (3,6 g, 6.7 nimol), hydrazine, hydrazine-dimethylformamide (40 mi) were added, stirred and dissolved, and the ice bath was lowered to 0 Torr, and TDP- was added in sequence. 36 (4.0 g,7,5 mnioi), i-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (2.6 g, I3.4mmoI), 1-hydroxybenzo:triazole ( L8 g, 13.4 nimol), sodium hydrogencarbonate (3.4 g, 40.2 mmol), after the addition is completed, the reaction is stirred for 16 h, HPLC detection, after the completion of the reaction of the starting materials, 200 ml of water and 50 mi of ethyl acetate are added to the reaction solution, and stirred for about 10 min. After the liquid separation, the aqueous phase was extracted with ethyl acetate (50 ml * 3 times), and the organic phase was combined, washed with 30 ml of water, 30 ml of brine, dried over anhydrous sodium sulfate, Purification (first with eluent petroleum ether: ethyl acetate = 2: 1 flush, then K dichloromethane; alcohol = 30: 1 eluent) 6 g of product, two-step total yield: 85% .

TDP-I8 nuclear magnetic data:

IH NMR (400 MHz, CDC13) δ 7.49 - 7,37 (m, 12H), 7.35 - 7.26 (ni, 13H), 7,23 (dt, J = 14.6, 7.3 Hz, 6H), 7.00 (d, J ::: 7.5 Hz, IH), 6.1 1 (t, J::: 7.8 Hz, 2H), 5.54 - 5.42 (m, IH), 5.36 (dd, J = 15,4, 6.3 Hz, IH), 4.36 (s, IH), 4.23 (dd, J = 11.9, 8.4 Hz, IH), 4.07 (dd, J = 13,4, 6.9 Hz, IH), 4.02 - 3.91 (m, 2H), 3.66 (s, 3H ), 3.34 (s, IH), 3.15 - 2.99 (m, IH), 2.65 (ddcl J :: 22,3, 14,6, 4.7 Hz, 2H), 2.53― 2.32 (ni, 3H), 2,29 ― 2.21 (m, 3H), 2.09 (dd, J = 13.7, 6.3 Hz, 2H), 1,91 (d, J = 3,4 Hz, 1H), 1.73 (s, 3H), 1.29 (dd, J = 14.1, 6.6 Hz, 7H), 1.20- 1.11 (m, IH), 0 , 90 (tt, J - 7.2, 3.4 Hz, 10H). Step 19 (TDP-S19) Synthesis of TDP-19

In a 250 ml round bottom flask, add TDP-18 (6 g, 5.7 mmol), tetrahydrofuran (60 ml), stir and dissolve, then cool to 5' ^: C in an ice bath, slowly add 57 μL of lithium hydroxide solution, drop After the addition was completed, the Ibu TLC was stirred at room temperature (petroleum ether: ethyl acetate:: 2:1), the reaction of the starting material was complete, the reaction was stopped, and the reaction mixture was adjusted to pH = 2 with 6N diluted hydrochloric acid, and then extracted with ethyl acetate ( 40 ml * 4 times), the organic phase was combined, dried with anhydrous sulfuric acid, dried under reduced pressure and concentrated to dryness (40 Ό) to give 6.3 g of crude product, and purified by column to yield 3 g of product, yield: 51%.

TDP-I9 nuclear magnetic data:

IH NMR (400 MHz, CDC13) δ 7.41 (dd, J = 17.4, 7.6 Hz, 12H), 7.35 - 7.25 (ni, 14H), 7,25 — 7.11 (m, 6H), 6.36 (d, J :: :: 8.8 Hz, 2H), 5,45 (dd, J:::13.9, 7,7 Hz, IH), 5.35 (dd, J - 16.1, 6.6 Hz, IH), 4.36 (s, IH), 4.21 (s, IH), 4.10 (d, J = 5.7 Hz, IH), 4.03 (s, IH), 3.92 (s, IH), 3.09 (s, IH), 2.75 (dd, J - 12.4, 7.4 Hz, 2H), 2,60 (d, J - 14,0 Hz, IH), 2.45 (dd, J 15.9, 8.6 Hz, 2.H), 2,36 (d, J = 10.9 Hz, IH), 2.30 - -- 2.20 (m, 3H), 2.09 (t, J = 6,7 Hz, 3H), 1.92 (s, IH), 1,81 (s, IH), 1,61 (s, IH), 1, 39― 1.26 (m, 9H), 1,17 (dd, J - 13.9, 6.6 Hz, IH), 0,98― 0.76 (m, 10H), Step 20 (TDP-S20) Synthesis of TDP-23

Add 2-methyl-6-nitrobenzoic anhydride ( 1.89 g, 5,5 mmol), dichloromethane (750 ml), and add 4-dimethyl at room temperature in a 5 L Ξ:neck flask. Aminopyridine ( 1.76 g, 14.68 mmol), dissolved by stirring;

TDP-]9 (3.8 g, 3.67 mmol), dichloromethane (3000 ml) was added to a 3000 ml Erlenmeyer flask, dissolved, and slowly added to the above reaction solution dropwise, dropwise for 16 h, after the addition was completed. After 6 h of reaction, HPLC detection, starting material: 77%, product: 17%, additional 2-methyl-6-nitrobenzene anhydride (0.5 eq, 630 mg), and then reacted for 18 h, the reaction was stopped, and steam was evaporated under reduced pressure. In addition to the solvent, purification by column (eluent dichloropurine: methanol: := 80:1) gave 790 mg of pure product, yield: 21%.

The nuclear magnetic resonance spectrum of TDP-23 is shown in Figure I. The data is as follows:

IH NMR (400 MHz, CDC13) δ 7.45 - 7,34 (m, 13H), 7.31 - 7.27 (m, lOH), 7.24 - 7.16 (m, 7H), 7.03 - 6,91 (m, 2H), 5.99 (d, J = 6.6 Hz, IH), 5.67― 5.56 (m, 1H), 5.55-5,45 (m, IH), 5.34 (dd, J == 15,4, 6.7 Hz, IH), 4.36― .4.24 (m, IH), 4.21 (dd, J::: 13.7, 7.3 Hz, IH), 3.48 (d, j = 33,1 Hz, 2H), 3.25-3,07 (m, 2H), 2.62 2,31 (m, 5H), 2.24 2.14 (m, 2H), 2,11 1.97 (m, 2H), 1.86 - 1.70 (m, 2H), 1.60 - 1.49 (m, IH), 1.39 - 1.28 (m , 5H), 1.19 - 1.07 (m, IH), 0.89 0,91 (m, 9H),

The infrared spectrum of TDP-23 is shown in Figure 2.

IR: 3646, 3296, 2927, 2857, 1731, 1670, 1540, 1454, 1391, 700, 645 cm

- 23 is structured as follows:

TBP-23

Step 21 (TDP-S21) Synthesis of TDP-B

At room temperature, in a 2000mi round bottom flask, add iodine (li g, 4, 4mmoi), dichloromethane: alcohol (731ml: 73.1ml) mixed solvent, and slowly add TDP- slowly and slowly. 23 (450 mg, 0.44 mmol) of methylene chloride: methanol (450 ml: 45 ml), the mixture was added for 3 h, and after the addition was completed, the reaction was stopped for 30 min, the reaction was stopped, and 112 ml of an aqueous solution of sodium thiosulfate was added, followed by addition of 56 ml of saturated After the mixture is stirred for about 10 minutes, the mixture is separated and the aqueous phase is extracted with dichloromethane (100m!*3 times). The organic phase is combined, dried over anhydrous sodium sulfate and concentrated to s. Batch No.: 13039059) Combined, purified by preparative thin layer chromatography to give 290 mg, yield: 71%, HPLC purity: 98, 9%.

The TDP-B nuclear magnetic resonance spectrum is shown in Figure 3, and the nuclear magnetic resonance spectrum data -

IH NMR (400 MI-lz, CDC13) δ 7.26 (s, 1H), 6.74 (d, J - 9.5 Hz, 1H), 6.47 (d, J 】 2,7 Hz, IH), 5.95 (d, J = 3.4 Hz, IH), 5.69 (d, J = 153 Hz, IH), 5.52 (s, IH), 4.96 (td, J = 8.7, 3.5 Hz, IH), 4,66 (s, IH), 4.26― 4,14 (ra,)H), 3.47 (s, IH), 3.37 (dd, J 13,2, 7.0 Hz, IH), 3.29 - 3.03 (m, 2H), 3.02 - 2.83 (m, 2H), 2.75 (dd, J = 11,2, 9,0 Hz, 4H), 2.62 (d, J = 13.3 Hz, IH), 2,50 (dd, J 24.3, 11.3 Hz, IH), 2,18 - 2 , ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 50 - 1.37 (m, 4H), 1,34 - 1.19 (m, 4H), 1.03 --- 0.76 (m, 10H).

TDP-B nuclear magnetic carbon spectrum, see Figure 4

According to the control, the map and research paper of TDP-B synthesized in this example (Wang C, Menkes LM, Doughty LB, He M, Wang D, Meyer-Almes FJ and Cheng YQ (2011) Thailandepsins: bacterial products with potent hisione deacetylase Inhibition activities and broad-spectrum antiproliferative activities. Journal of Natural Products 74: 2031-2038.) The reported patterns are consistent.

Claims

A compound characterized by having the following structure:

Wherein R ¹ is hydrogen, silane or alkoxy;

R ² is triphenylmethyl, p-methoxybenzyl, 2-(:trimethylsilyl; I, or 9-fluorenylmethyl;

R ^j is triphenylmethyl, p-methoxybenzyl, 2-(trimethylsilyl)ethyl, or 9-fluorenylmethyl _t

2. A compound according to claim 1 which has the structure _:

HO ^{1 1} ■ \,

0 厶

Ph ₃ CS

TDP 23

3. A method for preparing a natural product histone deacetylase inhibitor, Tyrandopin B, characterized in that the structure of Depusum B is as shown by the formula TDP-B, and comprises the following steps: S

TOP -23 TDP-B

:), the iodine element is added to a mixed solvent of dichloromethane and methanol to obtain a solution A;

3), solution B is added to solution A to carry out the reaction;

4) After the reaction is completed, the obtained product is subjected to aqueous phase separation and phase separation, and the organic phase is dried to obtain TDP-B.

4. The method according to claim 3, wherein the molar ratio of the iodine element in the solution A to the TDP-23 in the solution B in the step 3) is from 3 to 20:1.

The method according to claim 3, wherein the volume ratio of dichloromethane to methanol in the mixed solvent of dichloromethane and methanol in steps 1) and 2) is from 1 to 20:1.

6. The method according to claim 3, wherein step 4) adding an aqueous solution of a thiosulfate pin to quench the reaction, adding a saturated brine, separating the liquid, extracting the aqueous phase with methylene chloride, and combining the organic phases. The organic phase is dried over anhydrous sodium sulfate, and after purification, TDP-B is obtained. It is characterized in that it comprises the following steps;

Inorganic alkali solution organic solvent

HO ^-SCPh _:i

0 ΟΗ O hJHBoc

BOC deprotection reagent

TDP-25 „ - SCPh, BOC Deprotection Reagent

Jt

ivleO Ϊ HO ¹ condensation reaction solvent

HBoc ."C0 ₂ iVie 舦 bond condensing agent, , 0 NHBoc

TDP-10 TDP-11 alkaline inorganic or organic base

TDP-27 TDP-1S TDP-19

TDP TDP-B i, compound TDP- 36

1 } The compound TDP-34 and the compound TDP-7 are dissolved in an organic solvent, 4-dimethylamino P-pyridinium is added, and after the reaction, it is separated, concentrated and dried to obtain a compound TDP-35; 2) a compound TDP-35 is dissolved in an organic solvent, and an inorganic alkali aqueous solution is added. After the reaction is completed, the pH is adjusted to Bu 3, and the organic phase is extracted, and after washing and drying, TDP-36 is obtained;

2, the synthesis of TDP-27:

1) reacting the compound TDP-]0 with Boc deprotecting reagent, and after completion of the reaction, obtaining TDP-11;

2) Dissolve the compound TDP-i l in a condensation reaction solvent capable of forming a peptide bond, cool to -10 to 25 Torr in an ice bath, add TDP-25, a peptide bond condensing agent, 1-hydroxybenzotriazole or 1- Hydroxy-7-azobenzotriazole, and a basic inorganic salt or an organic base, after the reaction, the obtained organic phase is purified and dried to obtain TDP 26;

3. Synthesis of TDP-B:

1) The compound TDP-27 is subjected to a condensation reaction solvent capable of forming a peptide bond, and the temperature is lowered to -10 to 25 Torr in an ice bath, and TDP-36, a peptide bond condensing agent, 1-hydroxybenzotriazole or 1-hydroxy-7 is added. - azobenzotriazole, and a basic inorganic salt or an organic base, after the reaction, the obtained organic phase is purified, after drying, is TDP 18; 2) The compound TDP-i8 is dissolved in an organic solvent, and an inorganic alkali aqueous solution is added. After the reaction is completed, the pH is adjusted to ~3, and the organic phase is extracted, and after washing and drying, TDP-19 is obtained;

3) taking 2-methyl-6-nitrobenzoic anhydride, methylene chloride and 4-dimethylaminopyridine, mixed and dissolved to obtain a mixture A; taking TDP 19 dissolved in dichloromethane, to obtain a mixture B; Mixture B is added to the mixture A, and after completion of the reaction, TDP-23 is obtained;

4) a. Iodine is added to a mixed solvent of dichloromethane and methanol to obtain a solution A: b. TDP-23 is dissolved in a mixed solvent of dichloromethane and methanol to obtain a solution B; c. Solution B is added to solution A. Medium, reaction; d. After the reaction is completed, the obtained product is separated from the aqueous phase and the organic phase, and the organic phase is dried to obtain TDP-B.

8. The method according to claim 7, wherein the organic solvent in 1) of step 1 is methylene chloride.

The method according to claim 7, wherein the organic solvent in 2) of the first step is tetrahydrofuran, and the aqueous solution of the inorganic alkali is an aqueous solution of lithium hydroxide, a molar ratio of lithium hydroxide to TDP-35. It is 1:1 to 20:1.

10. The method according to claim 7, wherein the Boc deprotecting reagent in step 2) is trifluoroacetic acid, and the molar ratio of the TOP-10 to trifluoroacetic acid is 2:1-100. :1. The method according to claim 7, wherein the condensation reaction solvent capable of forming a peptide bond in 2) of the step 2 is hydrazine, hydrazine-dimethylformamide, dichloromethane or acetonitrile. The peptide bond condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, hydrazine, Ν'-dicyclohexylcarbodiimide, 2-(7-azo Benzotriazole)-Ν,Ν,Ν',Ν'-tetramethylphosphonium hexafluorophosphate, benzopyrene: azole-]-yloxy: tris(dimethylamino)phosphonium hexafluoro Phosphate, 3-(diethoxyphosphoryloxy)-i,2,3-benzotriazin-4-one, 0-benzotriazole, hydrazine, Ν', Ν'tetrazyl urea Tetrafluoroboric acid, benzotriazole hexyl fluorotriphenyl- 1 -yloxytripyridyl β alkyl or bis(2-oxo-3-oxazolyl)phosphoryl chloride; the basic inorganic salt is carbonic acid Sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate or potassium phosphate, the organic base is triethylamine, diisopropylethylamine or pyridine, wherein T:DP-11:TDP-25: peptide bond condensing agent : 1-hydroxybenzotriazole or 1-hydroxy-7-azobenzotriazole: The molar ratio of basic inorganic salt or organic base is: 1 :1-2:1-3:1-3:1 5; The Boc deprotecting reagent in step 3 of step 2 is a king fluoroacetic acid, and the molar ratio of the cerium-26 to the trifluoroacetic acid is 2:1 to 100:1. The method according to claim 7, wherein the condensation reaction solvent capable of forming a peptide bond in 1) of step 3 is hydrazine, hydrazine-dimethylformamide, dichloromethane or acetonitrile. The peptide bond condensing agent is 1-ethyl-(3 dimethylaminopropyl) carbodiimide hydrochloride, hydrazine, Ν'-dicyclohexylcarbodiimide, 2-(7-azobenzo) Triazole)- Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate, benzotriazole-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 3- ( Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-one, 0-benzo:triazole-Tsi,N,N',N'-tetramethylureatetrafluoro Boric acid, benzohexafluorophosphate: triazol-1-yl-oxypyrrolidinyl or bis(2-oxo-3-oxazolyl)phosphoryl chloride; The basic inorganic salt is sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate or potassium phosphate, and the organic base is triethylamine, diisopropylethylamine or pyridine, wherein TDP-27: TDP- 36: service bond condensing agent: 1-hydroxybenzotriazole or 1-hydroxy-7-azobenzoxazole: The molar ratio of basic inorganic salt or organic base is: 1 :1-2: 1-3: 1-3: 1-5.

The method according to claim 7, wherein the organic solvent in the step 2) is tetrahydrofuran, acetonitrile, dioxane or acetone, and the aqueous solution of the inorganic alkali is an aqueous lithium hydroxide solution, and is oxidized. The molar ratio of lithium to TDP-18 is: 1 to 20: 1.

The method according to claim 7, wherein the molar ratio of TDP-19, 2-methyl-6-nitrobenzoic anhydride and 4-dimethylaminopyridine in 3) of step 3 is; : 2-5: 2-10.

The method according to claim 7, wherein the volume ratio of dichloromethane to methanol in the mixed solvent of dichloromethane and methanol in the steps a and b of the step 4) is 1-20: 1 ; The molar ratio of the iodine element in the solution A to the TDP-23 in the solution B is 3 - 20:1 in step c: the step d is quenching the aqueous solution of sodium thiosulfate, adding saturated brine, and separating the liquid. The aqueous phase is extracted with dichloromethane, and the organic phase is combined. The organic phase is dried over anhydrous sodium sulfate and purified to give TDP-:B.

16. The method according to claim 7, wherein the preparation method of TDP-25 is as follows:

TDP-24 TDP-25 In the above formula, M is an alkali metal. The specific steps are as follows: TDP-24 is mixed with water, one or a combination of alkali metal carbonates or hydrogencarbonates is added, and then di-dicarbonate is added. Butyl ester, after the reaction, TDP-25 is obtained.

17. The method according to claim 16, wherein one or a combination of the alkali metal carbonate or hydrogencarbonate is sodium hydrogencarbonate, potassium hydrogencarbonate, hydrogen carbonate pin and carbonated pin. a mixture or a mixture of uranium hydrogencarbonate and potassium carbonate.

18. The method according to claim 16, wherein one or a combination of the alkali metal carbonate or hydrogencarbonate is sodium hydrogencarbonate, and the molar ratio is TDP-24: sodium hydrogencarbonate: two Di-tert-butyl carbonate: = 1:] ~ 5: 1 to 3.

19. The method according to claim 7, wherein the method of preparing the TDP 34 is as follows; Oo

!j SOC3⁄4 J!

He 八, , · ·, *· ο' ', ■

ΝΗ, ^{Μβ0Η 1} ΝΗ,

TDP-33 specifically includes the following steps: Compound TDP 33 is added to the alcohol, cooled to 0O~5 °C in an ice bath, thionyl chloride is added, and the temperature is raised to reflux. After the reaction, the compound TDP-34 is obtained.

20. The method according to claim 19, wherein the molar ratio of thionyl chloride to TDP-33 in step 1) is from 1 to 20:1.