Preparation method of LATS inhibitor VT02956

Abstract

The invention relates to a preparation method of an LATS inhibitor VT02956, and belongs to the technical field of medicines and chemistry. The invention provides a preparation method of an LATS inhibitor VT02956, and the reaction is as follows: # imgabs0 #, in which R1 is selected from one of trityl (Trt), 2-tetrahydropyranyl (THP) and tertiary butyl (tBu); comprising the following steps: step 7, obtaining a compound 11 from a compound 9 and a compound 10 under the action of Pd (PPh3) 4, CuI and organic alkali; and 8, reacting the compound 11 with a deprotection reagent to obtain a compound 12. The method has the advantages of high yield, high purity, simple operation, low energy consumption, good selectivity, good reproducibility, effective cost reduction, and suitableness for industrial production, and has good market value and profound practical significance.

Description

Technical Field

[0001] The invention relates to a preparation method of a LATS inhibitor VT02956, and belongs to the technical field of medicine and chemistry. Background Art

[0002] Breast cancer (BC) is the most common malignancy in women, accounting for a quarter of all cancer incidence and more than 15% of mortality in women worldwide. Therefore, drugs targeting advanced breast cancer associated with mutant ERα represent a major unmet medical need.

[0003] VT02956 is a novel LATS inhibitor (IC50: LATS1 is 0.76nM, LATS2 is 0.52nM) with the following structure:

[0004]

[0005] VT02956 inhibits the growth and ESR1 expression of ER breast cancer cell lines and patient-derived tumor organoids by targeting the Hippo signaling pathway. The combination with the CDK4 / 6 inhibitor Palbociclib inhibits MCF-7 cell growth more strongly than either treatment alone, and the two inhibitors show a combined effect. VT02956 showed superior effects over 4-OHT and Fulvestrant in inhibiting breast cancer cells with hotspot mutations in hormone therapy resistance, including ESR1-Y537S and ESR1-D538G, representing a potential treatment for hormone-resistant breast cancer.

[0006] However, there is no report on the preparation of VT02956 in the prior art, and therefore, there is an urgent need for a method for synthesizing the compound of formula 12 that is economical, fast, easy to operate, simple to post-process, high in yield and high in purity.

[0007] The present invention provides a preparation method of a LATS inhibitor VT02956, which does not require the use of dangerous reagents such as oxidants, explosives, and flammables, and has the advantages of being economical and fast, easy to operate, simple to post-process, high conversion rate, and high atomic utilization rate, and is suitable for industrial production. Therefore, it has good market value and far-reaching practical significance. Summary of the invention

[0008] In view of the above technical background, the present invention provides a method for preparing a LATS inhibitor VT02956, which has the advantages of simple operation, high yield, good selectivity, high conversion rate, short time consumption, reduced cost, and is conducive to industrial production.

[0009] The first aspect of the present invention provides a method for preparing LATS inhibitor VT02956, the reaction is as follows:

[0010]

[0011] Wherein, R1 is selected from one of trityl (Trt), 2-tetrahydropyranyl (THP), and tert-butyl (tBu);

[0012] The following steps are involved:

[0013] Step 7: Compound 9 and compound 10 are reacted with Pd(PPh3)4, CuI and an organic base to obtain compound 11;

[0014] Step 8: Compound 11 reacts with a deprotection agent to obtain compound 12.

[0015] As a further improvement of the present invention, including but not limited to, the organic base in step 7 is selected from one of triethylamine, n-butylamine, N,N-diisopropylethylamine (DIPEA), and ethanolamine, preferably n-butylamine.

[0016] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 9, compound 10 and organic base in step 7 is 1:(1.5-8):(2-15), preferably 1:(2-8):(3-12).

[0017] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 7, CuI and Pd(PPh3)4 in step 7 is 1:(0.02-1):(0.02-0.8), preferably 1:(0.05-1):(0.05-0.5).

[0018] As a further improvement of the present invention, including but not limited to, the reaction solvent in step 7 is selected from one of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,4-dioxane, toluene, and tetrahydrofuran, preferably one of DMF, DMSO, and DMA.

[0019] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 7 is 70-120°C, preferably 80-110°C.

[0020] As a further improvement of the present invention, including but not limited to, the reaction time of step 7 is 1 to 6 hours, preferably 2 to 5 hours.

[0021] As a further improvement of the present invention, in certain embodiments, after the reaction of step 7 is completed, the crude product of the compound of formula 11 is obtained by washing with water, extracting with an organic solvent, separating the liquids, drying, and concentrating; the crude product can be optionally further purified to obtain a pure product of the compound of formula 11.

[0022] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane.

[0023] As a further improvement of the present invention, in certain embodiments, the crude product can be further subjected to column chromatography to obtain a pure product of the compound of formula 11, and the column chromatography eluent is, for example, dichloromethane:methanol=50:1.

[0024] As a further improvement of the present invention, including but not limited to, the deprotection reagent in step 8 is selected from one or more of trifluoroacetic acid, hydrochloric acid, ethyl hydrochloride, dioxane hydrochloride, methanol hydrochloride, and ethanol hydrochloride, preferably trifluoroacetic acid.

[0025] As a further improvement of the present invention, including but not limited to, a solvent may be optionally added in step 8, and the solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, dioxane, and ethyl acetate; preferably at least one of dichloromethane, dichloroethane, chloroform, methanol, and ethyl acetate.

[0026] As a further improvement of the present invention, including but not limited to, the volume of the deprotection reagent in step 8 is 1.5 to 20 times, preferably 2 to 18 times, the mass of compound 11.

[0027] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 8 is 0 to 40°C, preferably 0 to 35°C.

[0028] As a further improvement of the present invention, including but not limited to, the reaction time of step 8 is 0.5 to 6 hours, preferably 1 to 5 hours.

[0029] As a further improvement of the present invention, the compound 10 protected by trityl (Trt), 2-tetrahydropyranyl (THP), or tert-butyl (tBu) is more stable than the reaction using alkynol or 3-phenyl-1-propyne without a protecting group, and has good selectivity, high yield, and high purity.

[0030] As a further improvement of the present invention, the present invention uses Pd(PPh3)4, which has good reaction selectivity and reproducibility, less impurities, and is easy to post-process compared to using other palladium catalysts. Especially when using PdCl2 and Pd(dppe)Cl2, the reaction is very complicated and there is almost no target product.

[0031] As a further improvement of the present invention, when the inorganic base potassium carbonate is used in step 7, the compound of formula 11 is not obtained and the reaction is very complicated. When n-butylamine is used, the reaction is very clean, the selectivity is good, no isomers and halogen impurities are produced, the yield is high, and it is conducive to industrial production.

[0032] The second aspect of the present invention provides a method for preparing a key intermediate compound of formula 9 of VT02956, the reaction is as follows:

[0033]

[0034] The steps include:

[0035] Step 4: Compound 5 reacts with ammonium acetate to generate compound 6;

[0036] Step 5: Compound 6 is reacted in the presence of a chlorinating agent and a base to obtain compound 7;

[0037] Step 6: Compound 7, compound 8 and a base react in an organic solvent to obtain compound 9;

[0038] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 5 to ammonium acetate in step 4 is 1:(12-25), preferably 1:(13-22).

[0039] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 4 is 80-160°C, preferably 85-150°C.

[0040] As a further improvement of the present invention, including but not limited to, the reaction time of step 4 is 0.5 to 6 hours, preferably 1 to 5 hours.

[0041] As a further improvement of the present invention, in certain embodiments, after the reaction of step 4 is completed, the reaction solution is directly poured into water, and then extracted with an organic solvent, separated, dried, and spin-dried to obtain a crude product, and the crude product can be optionally slurried with methanol to obtain a pure compound of formula 6.

[0042] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane.

[0043] As a further improvement of the present invention, when ammonium formate is used in step 4 of the present invention, only a small amount is the target product, and the by-products occupy the main peaks. When ammonium acetate is used, LCMS shows that only one main peak is the target product, and the inventors found that the reaction of step 4 deteriorates after adding a solvent. Therefore, the present invention does not need to add a solvent, is simple to operate, simple to post-process, has high purity, and is suitable for industrial production.

[0044] As a further improvement of the present invention, including but not limited to, the chlorination agent in step 5 is selected from phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, preferably phosphorus oxychloride.

[0045] As a further improvement of the present invention, including but not limited to, the base in step 5 is selected from one of N,N-diisopropylethylamine, triethylamine, diethylamine or pyridine.

[0046] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 6 to the base in step 5 is 1:(0.05-2), preferably 1:(0.05-1).

[0047] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 5 is 80-140°C, preferably 80-130°C.

[0048] As a further improvement of the present invention, including but not limited to, the reaction time in step 5 is 1 to 8 hours, preferably 1 to 5 hours.

[0049] As a further improvement of the present invention, the use of phosphorus oxychloride in step 5 of the present invention is significantly better than the use of thionyl chloride in the prior art. When thionyl chloride is used, there are problems such as incomplete reaction, generation of by-products and slow reaction. The above problems are avoided by using the method of the present invention.

[0050] As a further improvement of the present invention, including but not limited to, the base in step 6 is selected from one or more of triethylamine, diethylamine, n-butylamine, DIPEA, pyridine, 4-dimethylaminopyridine (DMAP), sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, preferably one or more of triethylamine, diethylamine, n-butylamine, DIPEA, pyridine, 4-dimethylaminopyridine (DMAP).

[0051] As a further improvement of the present invention, including but not limited to, the organic solvent in step 6 is selected from one of halogenated hydrocarbons, alcohols, nitriles, and ether solvents, preferably one of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, and dioxane; more preferably dichloromethane, dichloroethane, and chloroform.

[0052] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 7, compound 8 and base in step 6 is 1:(0.9-1.2):(1-5), preferably 1:(1-1.2):(1-3).

[0053] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 6 is 0-40°C, preferably 10-35°C.

[0054] As a further improvement of the present invention, including but not limited to, the reaction time in step 6 is 5 to 20 hours, preferably 6 to 18 hours.

[0055] As a further improvement of the present invention, in certain embodiments, after the reaction in step 6 is completed, water is added to quench the reaction, and the reaction is extracted with an organic solvent, separated, dried, and concentrated to obtain a crude product of the compound of formula 9; the crude product may be further purified to obtain a pure product of the compound of formula 9;

[0056] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane.

[0057] As a further improvement of the present invention, in certain embodiments, the crude product can be further subjected to column chromatography to obtain a pure product of the compound of formula 9, and the column chromatography eluent is, for example, dichloromethane:methanol=50:1.

[0058] The third aspect of the present invention provides a method for preparing a VT02956 intermediate compound of formula 5, the reaction is as follows:

[0059]

[0060] The specific steps include:

[0061] Step 1: Compound 1 reacts with an acyl chloride reagent in an organic solvent to obtain compound 2;

[0062] Step 2: Compound 2 and compound 3 are reacted in the presence of a base and an organic solvent to obtain compound 4;

[0063] Step 3: Compound 4 is cyclized in the presence of a dehydrating agent to obtain compound 5;

[0064] As a further improvement of the present invention, including but not limited to, the acyl chloride reagent in step 1 is selected from any one of dichloroxythionyl chloride, oxalyl chloride, and POCl3.

[0065] As a further improvement of the present invention, including but not limited to, the organic solvent in step 1 is selected from one or more of halogenated hydrocarbons, aromatic hydrocarbons, and nitrile solvents, preferably dichloromethane (DCM), dichloroethane, chloroform, toluene, xylene, ether, acetonitrile, and more preferably one or more of dichloromethane, dichloroethane, and chloroform.

[0066] As a further improvement of the present invention, including but not limited to, dimethylformamide (DMF) may be optionally added as a catalyst in step 1, preferably 1 to 10 drops of DMF are added.

[0067] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 1 is 0 to 40°C, preferably 0 to 35°C.

[0068] As a further improvement of the present invention, including but not limited to, the reaction time of step 1 is 1 to 8 hours, preferably 2 to 5 hours.

[0069] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 1 to acyl chloride reagent in step 1 is 1:(1.5-5), preferably 1:(2-4).

[0070] As a further improvement of the present invention, including but not limited to, the base in step 2 is selected from one of triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, and potassium carbonate, preferably one of triethylamine, diisopropylamine, and N,N-diisopropylethylamine.

[0071] As a further improvement of the present invention, including but not limited to, the organic solvent in step 2 is selected from one or more of halogenated hydrocarbons, aromatic hydrocarbons, ketones, ethers, and ester solvents, preferably one or more of dichloromethane, dichloroethane, chloroform, toluene, xylene, acetone, tetrahydrofuran (THF), dioxane, ethyl acetate, and butyl acetate; more preferably one or more of dichloromethane, dichloroethane, chloroform, toluene, xylene, acetone, and tetrahydrofuran (THF).

[0072] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 3, compound 2 and base in step 2 is 1:(1-2):(1-2), preferably 1:(1-1.5):(1-1.5).

[0073] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 2 is 0 to 40°C, preferably 0 to 35°C.

[0074] As a further improvement of the present invention, including but not limited to, the reaction time of step 2 is 2 to 24 hours, preferably 5 to 16 hours.

[0075] As a further improvement of the present invention, including but not limited to, the dehydration reagent in step 3 is selected from one of acetic anhydride and trifluoroacetic anhydride, preferably acetic anhydride.

[0076] As a further improvement of the present invention, including but not limited to, the reaction time of step 3 is 1 to 8 hours, preferably 1 to 5 hours.

[0077] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 3 is 130-160°C, preferably 130-150°C.

[0078] The fourth aspect of the present invention provides a compound having the following structural formula:

[0079]

[0080] Wherein, R1 is selected from one of trityl (Trt), 2-tetrahydropyranyl (THP), and tert-butyl (tBu).

[0081] The fifth aspect of the present invention provides a method for preparing VT02956, which includes the method for preparing the LATS inhibitor VT02956 provided by the first aspect above, or the method for preparing the key intermediate compound of formula 9 of VT02956 provided by the second aspect above, or the method for preparing the VT02956 intermediate compound of formula 5 provided by the third aspect of the present invention above, or the compound of formula 5, formula 6, formula 7, formula 9, or formula 11 described in the fourth aspect.

[0082] Beneficial technical effects of the present invention:

[0083] 1. Through hundreds of creative efforts, the present invention synthesized a new intermediate of VT02956 and proposed a feasible preparation method of VT02956, which is the first route for the compound and fills the gap in the preparation of the compound.

[0084] 2. The inventors found that the compound 10 protected by trityl (Trt), 2-tetrahydropyranyl (THP), or tert-butyl (tBu) in step 7 is more stable, has good selectivity, high yield, and high purity compared to the reaction using alkynol or 3-phenyl-1-propyne without a protecting group; the inventors also found that the reaction using Pd(PPh3)4 in step 7 has good selectivity and reproducibility, less impurities, and is easy to post-process compared to the reaction using other palladium catalysts, especially when using PdCl2 and Pd(dppe)Cl2, the reaction is very complicated and there is almost no target product; and when the inorganic base potassium carbonate is used in step 7, the compound of formula 11 is not obtained, and the reaction is very complicated, but when n-butylamine is used, the reaction is very clean, has good selectivity, no isomers and halogen-dropping impurities are produced, and has a high yield, which is conducive to industrial production.

[0085] 3. When ammonium formate is used in step 4 of the present invention, only a small amount of the target product is obtained, and the by-products account for the main peaks. When ammonium acetate is used, LCMS shows that only one main peak is the target product, and the inventors found that the reaction of step 4 deteriorates after adding a solvent. Therefore, step 4 of the present invention does not need to add a solvent, is simple to operate, simple to post-process, has high purity, and is suitable for industrial production.

[0086] 4. The use of phosphorus oxychloride in step 5 of the present invention is significantly better than the use of thionyl chloride in the prior art. When thionyl chloride is used, there are problems such as incomplete reaction, generation of by-products and slow reaction. The method of the present invention avoids the above problems, has high purity and high yield, and is suitable for industrial production.

[0087] 5. More importantly, the present invention has finally determined suitable protecting groups, palladium catalysts, bases, aminating agents, chlorinating agents, solvents, etc., as well as creative deprotecting agents and important process parameters of Sonogashira coupling reaction, such as the selection of palladium catalysts using Pd(PPh3)4, and the determination of the reaction temperature and time using organic bases, etc. through hundreds of creative labors. On this basis, creative purification technology is further used for purification, so that the present invention provides a compound of formula 12 that can be prepared under a variety of different conditions.

[0088] 6. The route proposed in the present invention is simple to operate, has no harsh reaction conditions, is conducive to industrial scale-up production, and therefore has good market value and far-reaching practical significance.

[0089] 7. The method of the present invention not only has high yield and high purity, but also has simple operation, low energy consumption, good selectivity, good reproducibility, effectively reduces costs, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Figure 1 The HNMR spectrum of compound 12 prepared in Example 8 of the present invention;

[0091] Figure 2 The HNMR spectrum of compound 11 prepared in Example 7 of the present invention;

[0092] Figure 3 LCMS spectrum of compound 9 prepared in Example 6 of the present invention;

[0093] Figure 4 This is the LCMS spectrum of the reaction solution of Comparative Example 1 of the present invention;

[0094] Figure 5 It is the LCMS spectrum of the reaction solution of Comparative Example 4 of the present invention. DETAILED DESCRIPTION

[0095] The present invention will be further described below in conjunction with specific examples. It should be understood that the following detailed description of the technical solution of the present invention with examples will help to further understand the advantages and effects of the technical solution of the present invention, and the examples do not limit the protection scope of the present invention, which is determined by the claims.

[0096] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers.

[0097] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0098] Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers and used without further treatment.

[0099] Embodiment 1:

[0100]

[0101] Pyridine-4-carboxylic acid (30 g, 243.6 mmol) was dissolved in DCM (70 mL), 3 drops of DMF were added, and then oxalyl chloride (92.7 g, 731 mmol, 3 eq) was slowly added in an ice-water bath, and the reaction was carried out at room temperature for 3 h. Then the white solid (34.49 g, 243.6 mmol) was directly evaporated to dryness and directly used in the next step.

[0102] Embodiment 2:

[0103]

[0104] 2-amino-3-bromobenzoic acid (52.6 g, 243.6 mmol) was added to the reaction bottle, DCM (500 mL) was added, triethylamine (24.61 g, 243.6 mmol, 1 eq) was added, and then the product of the previous step (34.49 g, 243.6 mmol, 1 eq) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was basically completed, the reaction was turbid, and it was directly filtered, and the solid obtained by filtration was slurried with ethanol, and filtered to obtain an orange-yellow solid (22.5 g, 70 mmol, Y: 28.78%), LC-MS: 321 (M+1).

[0105] Embodiment 3:

[0106]

[0107] The compound of formula 4 (22.5 g, 70 mmol) was dissolved in acetic anhydride (220 mL, 33 eq) and refluxed at 150 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature. A large amount of solids would precipitate during the cooling process of the reaction solution. The solids were filtered and slurried with methanol to obtain a yellow solid (17.51 ​​g, 57.4 mmol) with a yield of 82%. LC-MS: 305 (M+1).

[0108] Embodiment 4:

[0109]

[0110] The compound of formula 5 (17.51 ​​g, 57.4 mmol) and ammonium acetate (70.7 g, 920 mmol, 16 eq) were placed in a bottle and stirred at 140°C for 2 h. After the reaction was completed, the reaction solution was directly poured into water, and then extracted with dichloromethane, separated, dried, and spin-dried to obtain a crude product, which was slurried with methanol to obtain a yellow solid (15.15 g, 50.1 mmol, purity: 100%), with a yield of 87.4%, LC-MS: 302 (M+1).

[0111] Embodiment 5:

[0112]

[0113] The compound of formula 6 (15.15 g, 50.1 mmol) was dissolved in phosphorus oxychloride (160 mL, 34 eq), and N,N-diisopropylethylamine (1 mL, 5.74 mmol, 0.11 eq) was added. The reaction was carried out at 110°C for 2 h. After the reaction was completed, the reaction was quenched with ice water, and the pH was adjusted to neutral. The mixture was extracted with ethyl acetate, separated, dried, concentrated to dryness, filtered, and concentrated under reduced pressure. A yellow solid (12.26 g, 38.2 mmol) was obtained by silica gel column chromatography (dichloromethane: methanol = 100: 1) with a yield of 76.2%.

[0114] LC-MS: 320 (M+1).

[0115] Embodiment 6:

[0116]

[0117] The compound of formula 7 (12.26 g, 38.2 mmol) was dissolved in 1,2-dichloroethane (1000 mL), and triethylamine (5.79 g, 57.2 mmol, 1.5 eq) and 4-(Boc-aminomethyl)piperidine (8.19 g, 38.2 mmol) were added. The reaction was allowed to react overnight at room temperature. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The crude product was separated, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 50:1) to obtain a yellow solid (12.24 g, 24.5 mmol, purity: 97.71%, LCMS spectrum as shown below): Figure 3 Yield: 64%, LC-MS: 498 (M+1).

[0118] Embodiment 7:

[0119]

[0120] The compound of formula 9 (12.24 g, 24.6 mmol) was added to a sealed tube and dissolved with N,N-dimethylformamide (80 mL). Then, n-butylamine (17.96 g, 245.6 mmol, 10 eq) and 2-(2-propyn-1-oxy)tetrahydro-2H-pyran (17.21 g, 191.1 mmol, 5 eq) were added. After passing argon for 10 minutes, cuprous iodide (933 mg, 4.9 mmol, 0.2 eq) and tetrakistriphenylphosphine palladium (2.83 g, 2.5 mmol, 0.1 eq) were added. After passing argon for another 15 minutes, the mixture was transferred to a 90°C oil pan and reacted for 3 h. After the reaction was completed, the mixture was washed with water, extracted with ethyl acetate, separated, dried, and concentrated to obtain a crude product. A yellow solid (6.83 g) was obtained by silica gel column chromatography (dichloromethane: methanol = 50:1). 12.2mmol, purity: 100%) yield 49.9%, LC-MS: 557 (M+1), 1 H-NMR spectrum Figure 2 shown.

[0121] HNMR(DMSO):8.75(d,2H),8.38(d,2H),7.95-8.00(t,2H),7.59-7.64(dd,1H),6.93(t,1H),5.10(t,1H),4.57-4.68(q,2H ),4.45(d,2H),3.80-3.86(t,1H),3.55(q,1H),3.25(t,2H),3.90(t,2H),1.73-1.83(5H),1.52-1.62(5H),1.38(s,10H).

[0122] Embodiment 8:

[0123]

[0124] The compound of formula 11A (6.83 g, 12.3 mmol) was dissolved in dichloromethane (120 mL), and then trifluoroacetic acid (30 mL, 32 eq) was added to react at room temperature for three hours. After the reaction was completed, saturated sodium bicarbonate was added and then ethyl acetate was added for extraction. The solid was dissolved in dichloromethane and methanol, and the organic phases were combined and evaporated to dryness. The product was purified by liquid phase inversion preparation to obtain a yellow solid (3.55 g, 9.5 mmol, purity: 100%) with a yield of 77.6%. LC-MS: 373 (M+1). 1 H-NMR spectrum Figure 1 shown.

[0125] HNMR(DMSO):8.77(dd,2H),8.39(dd,2H),7.93-7.98(d,2H),7.51(t,1H),4.48(s,4H),3 .25(d,2H),2.92(t,1H),2.53(s,1H),1.82-1.92(t,2H),1.62(s,1H),1.36-1.41(q,2H).

[0126] Comparative Example 1:

[0127]

[0128] The compound of formula 9 (1 g, 24.6 mmol) was added to a sealed tube and dissolved with N,N-dimethylformamide (10 mL). Then, triethylamine (667 mg, 6.59 mmol, 3 eq) and propargyl alcohol (952 mg, 16.98 mmol, 7.7 eq) were added. After passing argon for 10 minutes, cuprous iodide (40 mg, 210.03 umol, 0.1 eq) and palladium dichloride (60 mg, 338.36 umol, 0.15 eq) were added. After passing argon for another 15 minutes, the mixture was transferred to an oil pan at 80°C and reacted for 2 h. LCMS detection showed that the reaction was complicated, no raw material remained and no target product was produced. The LCMS spectrum was as follows: Figure 4 shown.

[0129] Comparative Example 2:

[0130]

[0131] The compound of formula 9 (100 mg g, 219.41 umol) was added to a sealed tube and dissolved with DMF (5 mL). Then potassium carbonate (41 mg, 296.7 umol, 1.5 eq) and propargyl alcohol (33 mg, 588.6 umol, 2.7 eq) were added. After passing argon for 10 minutes, cuprous iodide (4 mg, 21 umol, 0.1 eq) and Pd(PPh3)4 (20 mg, 17.34 umol, 0.08 eq) were added. After passing argon for another 15 minutes, the mixture was transferred to an oil pan at 80 ° C and reacted for 24 hours. TLC detection showed that the reaction was complicated and no raw materials remained.

[0132] Comparative Example 3:

[0133]

[0134] The compound of formula 9 (500 mg, 1.1 mmol) was added to a sealed tube and dissolved with DMF:ETOH=3:1 (15 mL), and then potassium carbonate (230 mg, 1.66 mmol, 1.5 eq) and 3-phenyl-1-propyne (140 mg, 1.21 mmol, 1.1 eq) were added. After passing argon for 10 minutes, cuprous iodide (20 mg, 105.01 umol, 0.1 eq) and palladium dichloride (40 mg, 225.6 umol, 0.2 eq) were added, and argon was passed for another 15 minutes. The mixture was transferred to a 60°C oil pan overnight. TLC detected that the reaction was relatively complicated and no raw material remained.

[0135] Comparative Example 4:

[0136]

[0137] The compound of formula 9 (50 mg, 100.32 umol) was added to a sealed tube, dissolved with n-butylamine (10 mL), and 2-(2-propyn-1-oxy)tetrahydro-2H-pyran (70 mg, 499.36 umol, 5 eq) was added. After passing argon for 10 minutes, cuprous iodide (6 mg, 30.45 umol, 0.3 eq) and tetrakistriphenylphosphine palladium (12 mg, 10.38 umol, 0.1 eq) were added. After passing argon for another 15 minutes, the mixture was transferred to a 90°C oil pan and reacted for 3 hours. LCMS detection showed that the reaction was relatively complicated and no raw materials remained. LCMS showed that 22.8% of the target product was produced with a retention time of 2.149. The LCMS spectrum was as follows: Figure 5 shown.

[0138] Comparative Example 5:

[0139]

[0140] The compound of formula 9 (1 g, 2.01 mmol) was added to a sealed tube and dissolved with DMF (15 mL). Then, triethylamine (667 mg, 6.59 mmol, 3.3 eq) and 2-(2-propyn-1-oxy)tetrahydro-2H-pyran (925 mg, 6.60 mmol, 3.3 eq) were added. After passing argon for 10 minutes, cuprous iodide (40 mg, 210.03 umol, 0.1 eq) and palladium dichloride (60 mg, 338.36 umol, 0.17 eq) were added. After passing argon for another 15 minutes, the mixture was transferred to a 100°C oil pan and reacted for 2 h. After the reaction was completed, TLC detection showed that the reaction was relatively mixed and there was no main point.

[0141] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing a LATS inhibitor VT02956, characterized in that: The reaction is as follows: Wherein, R1 is selected from one of trityl, 2-tetrahydropyranyl, and tert-butyl; The following steps are involved: Step 7: Compound 9 and compound 10 are reacted with Pd(PPh3)4, CuI and an organic base to obtain compound 11; Step 8: Compound 11 reacts with a deprotection agent to obtain compound 12.

2. The preparation method according to claim 1, characterized in that: The compound of formula 9 is prepared by the following method, and the reaction is as follows: The steps include: Step 4: Compound 5 reacts with ammonium acetate to generate compound 6; Step 5: Compound 6 is reacted in the presence of a chlorinating agent and a base to obtain compound 7; Step 6: Compound 7, compound 8 and a base react in an organic solvent to obtain compound 9.

3. The preparation method according to claim 2, characterized in that: The compound of formula 5 is prepared by the following method, and the reaction is as follows: The specific steps include: Step 1: Compound 1 reacts with an acyl chloride reagent in an organic solvent to obtain compound 2; Step 2: Compound 2 and compound 3 are reacted in the presence of a base and an organic solvent to obtain compound 4; Step 3: Compound 4 is cyclized in the presence of a dehydrating agent to give compound 5.

4. The preparation method according to claim 3, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The acyl chloride reagent in step 1 is selected from any one of thionyl chloride, oxalyl chloride and POCl3; (2) the organic solvent in step 1 is selected from one or more of halogenated hydrocarbons, aromatic hydrocarbons, and nitrile solvents, preferably dichloromethane, dichloroethane, chloroform, toluene, xylene, ether, and acetonitrile, and more preferably one or more of dichloromethane, dichloroethane, and chloroform; (3) in step 1, DMF is optionally added as a catalyst, preferably 1 to 10 drops of DMF is added; (4) The reaction temperature of step 1 is 0 to 40° C., preferably 0 to 35° C.; (5) The reaction time of step 1 is 1 to 8 hours, preferably 2 to 5 hours; (6) In step 1, the molar ratio of compound 1 to the acyl chloride reagent is 1:(1.5-5), preferably 1:(2-4); (7) The base in step 2 is selected from one of triethylamine, N,N-diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, and potassium carbonate, preferably one of triethylamine, diisopropylamine, and N,N-diisopropylethylamine; (8) The organic solvent in step 2 is selected from one or more of halogenated hydrocarbons, aromatic hydrocarbons, ketones, ethers, and ester solvents, preferably one or more of dichloromethane, dichloroethane, chloroform, toluene, xylene, acetone, tetrahydrofuran, dioxane, ethyl acetate, and butyl acetate; more preferably one or more of dichloromethane, dichloroethane, chloroform, toluene, xylene, acetone, and tetrahydrofuran; (9) In step 2, the molar ratio of compound 3, compound 2 and base is 1:(1-2):(1-2), preferably 1:(1-1.5): (1～1.5)； (10) The reaction temperature of step 2 is 0 to 40°C, preferably 0 to 35°C; (11) The reaction time of step 2 is 2 to 24 hours, preferably 5 to 16 hours; (12) The dehydrating agent in step 3 is selected from acetic anhydride and trifluoroacetic anhydride, preferably acetic anhydride; (13) The reaction time of step 3 is 1 to 8 hours, preferably 1 to 5 hours; (14) The reaction temperature of step 3 is 130-160°C, preferably 130-150°C.

5. The preparation method according to claim 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) In step 4, the molar ratio of compound 5 to ammonium acetate is 1:(12-25), preferably 1:(13-22); (2) The reaction temperature of step 4 is 80 to 160° C., preferably 85 to 150° C.; (3) The reaction time of step 4 is 0.5 to 6 hours, preferably 1 to 5 hours; (4) After the reaction of step 4 is completed, the reaction solution is directly poured into water, and then extracted with an organic solvent, separated, dried, and spin-dried to obtain a crude product, and the crude product can be optionally slurried with methanol to obtain a pure compound of formula 6; (5) The chlorination agent in step 5 is selected from phosphorus oxychloride, phosphorus pentachloride, and phosphorus trichloride, preferably phosphorus oxychloride; (6) The base in step 5 is selected from N,N-diisopropylethylamine, triethylamine, diethylamine or pyridine; (7) In step 5, the molar ratio of compound 6 to the base is 1:(0.05-2), preferably 1:(0.05-1); (8) The reaction temperature of step 5 is 80 to 140° C., preferably 80 to 130° C.; (9) The reaction time in step 5 is 1 to 8 hours, preferably 1 to 5 hours.

6. The preparation method according to claim 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The base in step 6 is selected from one or more of triethylamine, diethylamine, n-butylamine, DIPEA, pyridine, DMAP, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, preferably one or more of triethylamine, diethylamine, n-butylamine, DIPEA, pyridine, and DMAP; (2) The organic solvent in step 6 is selected from one of halogenated hydrocarbons, alcohols, nitriles, and ether solvents, preferably one of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, and dioxane; more preferably dichloromethane, dichloroethane, and chloroform; (3) In step 6, the molar ratio of compound 7, compound 8 and base is 1:(0.9-1.2):(1-5), preferably 1:(1-1.2): (1～3)； (4) The reaction temperature of step 6 is 0 to 40° C., preferably 10 to 35° C.; (5) The reaction time in step 6 is 5 to 20 hours, preferably 6 to 18 hours; (6) After the reaction in step 6 is completed, water is added to quench the reaction, and the mixture is extracted with an organic solvent, separated, dried, and concentrated to obtain a crude product of the compound of formula 9; the crude product may be further purified to obtain a pure product of the compound of formula 9.

7. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The organic base in step 7 is selected from one of triethylamine, n-butylamine, N,N-diisopropylethylamine and ethanolamine, preferably n-butylamine; (2) In step 7, the molar ratio of compound 9, compound 10 and the organic base is 1:(1.5-8):(2-15), preferably 1: (2～8)：(3～12)； (3) In step 7, the molar ratio of compound 7, CuI and Pd(PPh3)4 is 1:(0.02-1):(0.02-0.8), preferably 1: (0.05～1)：(0.05～0.5)； (4) The reaction solvent in step 7 is selected from one of DMF, DMA, NMP, DMSO, 1,4-dioxane, toluene, and tetrahydrofuran, preferably one of DMF, DMSO, and DMA; (5) The reaction temperature of step 7 is 70 to 120° C., preferably 80 to 110° C.; (6) The reaction time of step 7 is 1 to 6 hours, preferably 2 to 5 hours; (7) After the reaction of step 7 is completed, the mixture is washed with water, extracted with an organic solvent, separated, dried, and concentrated to obtain a crude product of the compound of formula 11; the crude product may be further purified to obtain a pure product of the compound of formula 11.

8. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) the deprotection reagent in step 8 is selected from one or more of trifluoroacetic acid, hydrochloric acid, ethyl hydrochloride, dioxane hydrochloride, methanol hydrochloride, and ethanol hydrochloride, preferably trifluoroacetic acid; (2) In step 8, a solvent is optionally added, the solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, dioxane, and ethyl acetate; preferably at least one of dichloromethane, dichloroethane, chloroform, methanol, and ethyl acetate; (3) The volume of the deprotection reagent in step 8 is 1.5 to 20 times, preferably 2 to 18 times, the mass of compound 11; (4) The reaction temperature of step 8 is 0 to 40° C., preferably 0 to 35° C.; (5) The reaction time of step 8 is 0.5 to 6 hours, preferably 1 to 5 hours.

9. A compound having the following structure: in, R1 is selected from one of trityl, 2-tetrahydropyranyl and tert-butyl.

10. A method for preparing VT02956, characterized in that: It is prepared by the method of claim 1, 2 or 3, or prepared by the compound of claim 9.

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