A method for preparing a lats inhibitor vt02956

Abstract

The application relates to a preparation method of a LATS inhibitor VT02956 and belongs to the technical fields of medicines and chemistry. The application provides a preparation method of the LATS inhibitor VT02956, and the reaction is as follows: wherein R1 is selected from one of triphenylmethyl (Trt), 2-tetrahydropyranyl (THP) and t-butyl (tBu); and the method comprises the following steps: step 7: compounds 9 and 10 are reacted under the action of Pd (PPh3) 4, CuI and an organic base to obtain compound 11; and step 8: compound 11 is reacted with a deprotection reagent to obtain compound 12. The application has the advantages of high yield, high purity, simple operation, low energy consumption, good selectivity, good reproducibility, cost reduction, suitability for industrial production, good market value and far-reaching practical significance.

Description

TECHNICAL FIELD

[0001] The application relates to a preparation method of LATS inhibitor VT02956 and belongs to the technical field of medicines and chemistry. BACKGROUND

[0002] Breast cancer (BC) is the most common malignancy in women, accounting for one-fourth of all cancer types worldwide and more than 15% of female mortality, thus drugs for advanced breast cancer associated with mutant ERa represent an unmet major medical need.

[0003] VT02956 is a new LATS inhibitor (IC50: 0.76 nM for LATS1 and 0.52 nM for LATS2), and the structure is as follows:

[0004]

[0005] VT02956 inhibits the growth of ER breast cancer cell lines and patient-derived tumor organoids and ESR1 expression by targeting the Hippo signaling pathway. And the combination of CDK4 / 6 inhibitor Palbociclib is stronger than the use of any one of the treatments alone to inhibit MCF-7 cell growth, and the two inhibitors show a combination effect. VT02956 shows better effect than 4-OHT and fulvestrant in inhibiting breast cancer cells with hormone therapy resistance hotspot mutations (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 synthesis method of the compound of formula 12, which is economic and fast, simple to operate, simple to post-treat, high in yield and high in purity.

[0007] The application provides a preparation method of LATS inhibitor VT02956, which does not need to use oxidizing agents, explosives and flammable substances, has the advantages of being economic and fast, simple to operate, simple to post-treat, high in conversion rate and high in atomic utilization rate, is suitable for industrial production, and therefore has good market value and far-reaching practical significance. SUMMARY

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

[0009] The application provides a preparation method of LATS inhibitor VT02956, which has the advantages of simple operation, high yield, good selectivity, high conversion rate, short time consumption, reduced cost and advantages of industrial production.

[0010] The application provides a preparation method of LATS inhibitor VT02956, which has the advantages of simple operation, high yield, good selectivity, high conversion rate, short time consumption, reduced cost and advantages of industrial production.

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

[0012] comprising the following steps:

[0013] Step 7: Compound 9 and compound 10 are reacted in the presence of Pd(PPh3)4, CuI and an organic base to obtain compound 11.

[0014] Step 8: Compound 11 is reacted with a deprotection reagent to obtain compound 12.

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

[0016] As a further improvement of the present application, including but not limited to, the molar ratio of compound 9, compound 10 and the 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 application, 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 application, 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, tetrahydrofuran, preferably one of DMF, DMSO, DMA.

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

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

[0021] As a further improvement of the present application, in some embodiments, after the completion of step 7, the reaction mixture is washed with water, extracted with an organic solvent, separated, dried, and concentrated to obtain a crude compound of formula 11; the crude compound of formula 11 can be further purified to obtain a pure compound of formula 11.

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

[0023] As a further improvement of the present application, in some embodiments, the crude product mentioned above is optionally further purified by column chromatography to obtain pure product of compound of formula 11, and the eluent of column chromatography is, for example, dichloromethane:methanol=50:1.

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

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

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

[0027] As a further improvement of the present application, including but not limited to, the reaction temperature in step 8 is 0-40℃, preferably 0-35℃.

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

[0029] As a further improvement of the present application, the compound 10 protected by triphenylmethyl (Trt), 2-tetrahydropyranyl (THP), and tert-butyl (tBu) is more stable, has better selectivity, higher yield, and higher purity than the reaction using acetylene alcohol without protection group or 3-phenyl-1-propyne.

[0030] As a further improvement of the present application, the use of Pd(PPh3)4 has better reaction selectivity, better reproducibility, less impurities, and easy post-treatment than the use of other palladium catalysts, especially when PdCl2 and Pd(dppe)Cl2 are used, the reaction is very messy, and there is almost no target product.

[0031] As a further improvement of the present application, step 7 does not obtain compound of formula 11 when inorganic base potassium carbonate is used, and the reaction is very messy, while the reaction is very clean when n-butylamine is used, has good selectivity, no isomer and halogen loss impurities are produced, and has high yield, which is conducive to industrial production.

[0032] The second aspect of the present application provides a method for preparing a key intermediate of VT02956, i.e. a compound of formula 9, as shown in the following reaction:

[0033]

[0034] comprising the following steps:

[0035] Step 4: reacting compound 5 with ammonium acetate to obtain compound 6;

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

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

[0038] As a further improvement of the present application, 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 application, 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 application, including but not limited to, the reaction time of step 4 is 0.5-6h, preferably 1-5h.

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

[0042] As a further improvement of the present application, 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 application, when ammonium formate is used in step 4 of the present application, only a small amount of the target product is obtained, and the by-products account for the main peak, while when ammonium acetate is used, LCMS shows only one main peak which is the target product, and the present inventors have found that the reaction of step 4 becomes poor after the addition of a solvent, therefore the present application does not need to add a solvent, and is simple in operation, simple in post-treatment, high in purity and suitable for industrial production.

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

[0045] As a further improvement of the present application, 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 application, including but not limited to, the molar ratio of compound 6 and base in step 5 is 1:(0.05-2), preferably 1:(0.05-1).

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

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

[0049] As a further improvement of the present application, the use of phosphorus oxychloride in step 5 of the present application is significantly superior to the use of thionyl chloride in the prior art, which has the problems of incomplete reaction and by-product generation, and slow reaction. The use of the method of the present application avoids the above problems.

[0050] As a further improvement of the present application, 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 application, including but not limited to, the organic solvent in step 6 is selected from one of halogenated hydrocarbons, alcohols, nitriles, ether solvents, preferably one of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, dioxane; more preferably dichloromethane, dichloroethane, chloroform.

[0052] As a further improvement of the present application, 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 application, including but not limited to, the reaction temperature in step 6 is 0-40℃, preferably 10-35℃.

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

[0055] As a further improvement of the present application, in some embodiments, after the reaction of step 6 is completed, water is added to quench 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 is optionally further purified to obtain a pure product of the compound of formula 9.

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

[0057] As a further improvement of the present application, in some embodiments, the crude product is optionally further purified by 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 application provides a method for preparing a compound of formula 5, which is an intermediate of VT02956, and the reaction is as follows:

[0059]

[0060] Specifically comprising the following steps:

[0061] Step 1: reacting compound 1 with an acylating agent in an organic solvent to obtain compound 2;

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

[0063] Step 3: ring-closing compound 4 in the presence of a dehydrating agent to obtain compound 5;

[0064] As a further improvement of the present application, including but not limited to, the acylating agent in step 1 is selected from any one of thionyl chloride, oxalyl chloride, POCl3.

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

[0066] As a further improvement of the present application, including but not limited to, dimethylformamide (DMF) is optionally added in step 1 for catalysis, preferably 1-10 drops of DMF are added.

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

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

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

[0070] As a further improvement of the present application, 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, potassium carbonate, preferably one of triethylamine, diisopropylamine, N,N-diisopropylethylamine.

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

[0072] As a further improvement of the present application, 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 application, including but not limited to, the reaction temperature of step 2 is 0-40℃, preferably 0-35℃.

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

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

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

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

[0078] The fourth aspect of the present application provides a compound, the structural formula of which is as follows:

[0079]

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

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

[0082] The present application has the beneficial technical effects:

[0083] 1. Through thousands of times of creative labor, the present application synthesizes a novel intermediate of VT02956, proposes a feasible preparation method of VT02956, which is the first route of the compound, and fills the gap in the preparation of the compound.

[0084] 2. The present inventors find that, in step 7, the compound 10 protected by trityl (Trt), 2-tetrahydropyranyl (THP) or tert-butyl (tBu) is more stable than the alkyne alcohol without a protecting group or 3-phenyl-1-propyne, and has good selectivity, high yield and high purity; meanwhile, the present inventors also find that, in step 7, the use of Pd(PPh3)4 has good reaction selectivity, good reproducibility, few impurities and easy post-treatment compared with other palladium catalysts; especially when PdCl2 and Pd(dppe)Cl2 are used, the reaction is very impure, and almost no target product is obtained; and when inorganic potassium carbonate is used in step 7, no compound of formula 11 is obtained, and the reaction is very impure, but when n-butylamine is used, the reaction is very clean, has good selectivity, no isomer and halogen loss impurities are generated, and has high yield, which is conducive to industrial production.

[0085] 3. In step 4 of the present application, only a small amount of target product is obtained when ammonium formate is used, and the by-product accounts for the main peak; when ammonium acetate is used, LCMS shows that only one main peak is the target product; and the present inventors find that the reaction becomes poor after the solvent is added in step 4, so the solvent does not need to be added in step 4 of the present application, which is simple to operate, simple to post-treat, has high purity and suitable for industrial production.

[0086] 4. In step 5 of the present application, the use of phosphorus oxychloride is obviously superior to the use of thionyl chloride in the prior art; when thionyl chloride is used, the reaction is incomplete and by-products are generated, and the reaction is slow; the method of the present application avoids the above problems, has high purity, high yield and is suitable for industrial production.

[0087] 5、More importantly, the present application through hundreds of times of creative labor, eventually determined the appropriate protecting group, palladium catalyst, base, amination reagent, chloro reagent, solvent, etc., as well as the creative deprotection reagent and the important process parameters of Sonogashira coupling reaction, for example, the palladium catalyst is selected to use Pd(PPh3)4, and the use of organic base to adjust the reaction temperature and time determination, etc. On this basis, further using the creative purification technology for purification, so that the present application provides can be prepared under a variety of different conditions to form the compound of formula 12 of the present application.

[0088] 6、The route provided by the present application is simple to operate, has no harsh reaction conditions, is conducive to industrial scale production, and thus has good market value and far-reaching practical significance.

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

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

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

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

[0093] Figure 4 LCMS spectrum of the reaction liquid of Comparative Example 1 of the present application;

[0094] Figure 5 LCMS spectrum of the reaction liquid of Comparative Example 4 of the present application. DETAILED DESCRIPTION

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

[0096] The experimental methods in the following examples not marked with specific conditions are usually according to the conventional conditions or according to the conditions suggested by the manufacturers.

[0097] The raw materials or reagents used in the examples are commercially available, except specifically stated.

[0098] Unless otherwise indicated, the reagents were used as received without purification. All solvents were purchased from commercial suppliers and used without further purification.

[0099] Example 1:

[0100]

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

[0102] Example 2:

[0103]

[0104] 2-Amino-3-bromobenzoic acid (52.6 g, 243.6 mmol) was added to a reaction flask, DCM (500 mL) was added, then triethylamine (24.61 g, 243.6 mmol, 1 eq) was added, followed by the product of previous step (34.49 g, 243.6 mmol, 1 eq), the reaction was carried out at room temperature overnight. The reaction was almost complete, the reaction was turbid, it was directly filtered, the solid obtained by filtration was slurried in ethanol, filtered to get orange yellow solid (22.5 g, 70 mmol, Y: 28.78%), LC-MS: 321 (M+1).

[0105] Example 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 was cooled to room temperature, a large amount of solid was precipitated during the cooling process, filtered, the solid was slurried in methanol to get yellow solid (17.51 g, 57.4 mmol), yield 82%, LC-MS: 305 (M+1).

[0108] Example 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 charged into a bottle and stirred at 140 °C for 2 h. After the reaction was completed, the reaction solution was directly poured into water, then extracted with dichloromethane, separated, dried, and concentrated to obtain a crude product, which was slurried with methanol to obtain a yellow solid (15.15 g, 50.1 mmol, purity: 100%), yield 87.4%, LC-MS: 302 (M+1).

[0111] Example 5:

[0112]

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

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

[0115] Example 6:

[0116]

[0117] The compound of formula 7 (12.26 g, 38.2 mmol) was dissolved in 1,2-dichloroethane (1000 mL), triethylamine (5.79 g, 57.2 mmol, 1.5 eq), 4-(Boc-aminomethyl)piperidine (8.19 g, 38.2 mmol) were added, and the reaction was carried out at room temperature overnight. After the reaction was completed, the reaction was quenched with water and extracted with dichloromethane, separated, dried, and concentrated to obtain a crude product, which 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 in Figure 3

[0118] Example 7:

[0119]

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

[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] Example 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, and it was reacted at room temperature for three hours, and after the reaction was completed, saturated sodium bicarbonate was added, and then it was extracted with ethyl acetate, and the solid was dissolved with dichloromethane and methanol, and the organic layers were combined and evaporated, and it was purified by liquid reverse phase preparative purification to obtain a yellow solid (3.55 g, 9.5 mmol, purity: 100%) at a yield of 77.6%, LC-MS: 373 (M+1), 1 The H-NMR spectrum is shown in Figure 1

[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 taken in a sealed tube, dissolved in 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 gas 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, and argon gas was passed for another 15 minutes, and it was transferred to an 80 °C oil bath for 2 h of reaction, and LCMS detection showed that the reaction was heterogeneous, no starting material was left and no target product was produced, and the LCMS spectrum is shown in Figure 4

[0129] Comparative Example 2:

[0130]

[0131] The compound of formula 9 (100 mg g, 219.41 umol) was taken in a sealed tube, dissolved in 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 gas 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, and argon gas was passed for another 15 minutes, and it was transferred to an 80 °C oil bath for 24 h of reaction, TLC detection showed that the reaction was heterogeneous, no starting material was left.

[0132] Comparative Example 3:

[0133]

[0134] ​Compound of formula 9 (500 mg, 1.1 mmol) was taken in a sealed tube, dissolved in DMF: ETOH = 3: 1 (15 mL), 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 gas for 10 min, cuprous iodide (20 mg, 105.01 umol, 0.1 eq) and palladium dichloride (40 mg, 225.6 umol, 0.2 eq) were added, again argon gas was passed for 15 min, then it was transferred to 60 °C oil bath overnight, TLC detection showed that the reaction was heterogeneous, no starting material was left.

[0135] Comparative Example 4:

[0136]

[0137] Compound of formula 9 (50 mg, 100.32 umol) was taken in a sealed tube, dissolved in n-butylamine (10 mL), then 2-(2-propyn-l-oxy)tetrahydro-2H-pyran (70 mg, 499.36 umol, 5 eq) was added, after passing argon gas for 10 min, cuprous iodide (6 mg, 30.45 umol, 0.3 eq) and tetrakis triphenyl phosphine palladium (12 mg, 10.38 umol, 0.1 eq) were added, again argon gas was passed for 15 min, then it was transferred to 90 °C oil bath for 3 h, LCMS detection showed that the reaction was heterogeneous, no starting material was left, 22.8% of the target product was produced, retention time was 2.149, LCMS spectrum was shown as Figure 5

[0138] Comparative Example 5:

[0139]

[0140] Compound of formula 9 (1 g, 2.01 mmol) was taken in a sealed tube, dissolved in DMF (15 mL), then triethylamine (667 mg, 6.59 mmol, 3.3 eq) and 2-(2-propyn-l-oxy)tetrahydro-2H-pyran (925 mg, 6.60 mmol, 3.3 eq) were added, after passing argon gas for 10 min, cuprous iodide (40 mg, 210.03 umol, 0.1 eq) and palladium dichloride (60 mg, 338.36 umol, 0.17 eq) were added, again argon gas was passed for 15 min, then it was transferred to 100 °C oil bath for 2 h, after the reaction was completed, TLC detection showed that the reaction was heterogeneous, no main point.

[0141] ​The foregoing description of the embodiments has been presented for the purpose of illustration and description. It is not intended to be exhaustive or to limit the application to the precise form disclosed. Modifications and variations are possible in light of the above teachings or can be acquired from practice of the application. As well, the description is presented in the context of the preferred embodiments as a number of alternatives. It is not intended to limit the application to the precise form described.

Claims

1. A process for the preparation of LATS inhibitor VT02956, characterized by, The reaction is as follows: wherein R1 is selected from one of triphenylmethyl, 2-tetrahydropyranyl, tert-butyl; The method comprises the following steps: Step 7: Compound 9 and compound 10 are reacted under the action of Pd(PPh3)4, CuI and an organic base to obtain compound 11; Step 8: Compound 11 is reacted with a deprotection reagent to obtain compound 12.

2. The production method according to claim 1, characterized by, The compound of formula 9 is prepared by the following method, and the reaction is as follows: The method comprises the following steps: Step 4: Compound 5 is reacted with ammonium acetate to obtain compound 6; Step 5: Compound 6 is reacted in the presence of a chlorinating reagent and a base to obtain compound 7; Step 6: Compound 7, compound 8 and a base are reacted 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 method comprises the following steps: Step 1: Compound 1 is reacted with an acylating reagent in an organic solvent to obtain compound 2; Step 2: Compound 2 is reacted with compound 3 in the presence of a base and an organic solvent to obtain compound 4; Step 3: Compound 4 is ring-closed in the presence of a dehydrating reagent to obtain compound 5.

4. The production method according to claim 3, characterized by, The preparation method meets one or more of the following conditions: (1) The acylating 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; (3) DMF is added in step 1 for catalysis; (4) The reaction temperature in step 1 is 0-40°C; (5) The reaction time in step 1 is 1-8 h; (6) The molar ratio of compound 1 to the acylating reagent in step 1 is 1:(1.5-5); (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; (8) The organic solvent in step 2 is selected from one or more of halogenated hydrocarbons, aromatic hydrocarbons, ketones, ethers and ester solvents; (9) The molar ratio of compound 3, compound 2 and the base in step 2 is 1:(1-2):(1-2); (10) The reaction temperature in step 2 is 0-40°C; (11) The reaction time in step 2 is 2-24 h; (12) The dehydrating reagent in step 3 is selected from one of acetic anhydride and trifluoroacetic anhydride; (13) The reaction time in step 3 is 1-8 h; (14) The reaction temperature in step 3 is 130-160°C.

5. The preparation method according to claim 4, characterized in that, The preparation method meets one or more of the following conditions: (1) The organic solvent in step 1 is selected from dichloromethane, dichloroethane, chloroform, toluene, xylene, diethyl ether and acetonitrile; (2) 1-10 drops of DMF are added in step 1 for catalysis; (3) The reaction temperature in step 1 is 0-35°C; (4) The reaction time in step 1 is 2-5 h; (5) The molar ratio of compound 1 to the acylating reagent in step 1 is 1:(2-4); (6) The base in step 2 is selected from one of triethylamine, diisopropylamine and N,N-diisopropylethylamine; (7) the organic solvent in step 2 is selected from one or more of dichloromethane, dichloroethane, chloroform, toluene, xylene, acetone, tetrahydrofuran, dioxane, ethyl acetate, butyl acetate; (8) the molar ratio of compound 3, compound 2 and base in step 2 is 1:(1-1.5):(1-1.5); (9) the reaction temperature of step 2 is 0-35℃; (10) the reaction time of step 2 is 5-16 h; (11) the dehydrating reagent of step 3 is selected from acetic anhydride; (12) the reaction time of step 3 is 1-5 h; (13) the reaction temperature of step 3 is 130-150℃.

6. The preparation method according to claim 2, characterized in that, The preparation method meets one or more of the following conditions: (1) the molar ratio of compound 5 and ammonium acetate in step 4 is 1:(12-25); (2) the reaction temperature of step 4 is 80-160℃; (3) the reaction time of step 4 is 0.5-6 h; (4) after the reaction of step 4 is completed, the reaction solution is directly poured into water, then extracted with an organic solvent, separated, dried, and rotary evaporated to obtain a crude product, the crude product is slurried with methanol to obtain a pure compound of formula 6; (5) the chlorinating reagent in step 5 is selected from phosphorus oxychloride, phosphorus pentachloride, and phosphorus trichloride; (6) the base in step 5 is selected from one of N,N-diisopropylethylamine, triethylamine, diethylamine, or pyridine; (7) the molar ratio of compound 6 and base in step 5 is 1:(0.05-2); (8) the reaction temperature of step 5 is 80-140℃; (9) the reaction time of step 5 is 1-8 h.

7. The production method according to claim 6, characterized by, The preparation method meets one or more of the following conditions: (1) the molar ratio of compound 5 and ammonium acetate in step 4 is 1:(13-22); (2) the reaction temperature of step 4 is 85-150℃; (3) the reaction time of step 4 is 1-5 h; (4) the chlorinating reagent in step 5 is selected from phosphorus oxychloride; (5) the molar ratio of compound 6 and base in step 5 is 1:(0.05-1); (6) the reaction temperature of step 5 is 80-130℃; (7) the reaction time of step 5 is 1-5 h.

8. The preparation method according to claim 2, characterized in that, The preparation method meets 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, and sodium tert-butoxide; (2) the organic solvent in step 6 is selected from one of a halogenated hydrocarbon, an alcohol, a nitrile, and an ether; (3) the molar ratio of compound 7, compound 8 and base in step 6 is 1:(0.9-1.2):(1-5); (4) the reaction temperature of step 6 is 0-40℃; (5) the reaction time of step 6 is 5-20 h; (6) after the reaction of step 6 is completed, water is added to quench and extracted with an organic solvent, separated, dried, and concentrated to obtain a crude compound of formula 9; the crude product is further purified to obtain a pure compound of formula 9.

9. The production method according to claim 8, characterized by, The preparation method meets one or more of the following conditions: (1) the base of step 6 is selected from one or more of triethylamine, diethylamine, n-butylamine, DIPEA, pyridine, DMAP; (2) the organic solvent of step 6 is selected from one of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, dioxane; (3) the molar ratio of compound 7, compound 8 and base in step 6 is 1:(1-1.2):(1-3); (4) the reaction temperature of step 6 is 10-35℃; (5) the reaction time of step 6 is 6-18h.

10. The method of claim 1, wherein, The preparation method meets one or more of the following conditions: (1) the organic base in step 7 is selected from one of triethylamine, n-butylamine, N,N-diisopropyl ethylamine, ethanolamine; (2) the molar ratio of compound 9, compound 10 and organic base in step 7 is 1:(1.5-8):(2-15); (3) the molar ratio of compound 7, CuI and Pd(PPh3)4 in step 7 is 1:(0.02-1):(0.02-0.8); (4) a solvent is added in step 7, and the solvent is selected from one of DMF, DMA, NMP, DMSO, 1,4-dioxane, toluene, tetrahydrofuran; (5) the reaction temperature of step 7 is 70-120℃; (6) the reaction time of step 7 is 1-6h; (7) after the reaction of step 7 is completed, water washing, organic solvent extraction, liquid separation, drying and concentration are performed to obtain a crude product of compound 11; the crude product is further purified to obtain a pure product of compound 11.

11. The method of claim 10, wherein, The preparation method meets one or more of the following conditions: (1) the organic base in step 7 is selected from n-butylamine; (2) the molar ratio of compound 9, compound 10 and organic base in step 7 is 1:(2-8):(3-12); (3) the molar ratio of compound 7, CuI and Pd(PPh3)4 in step 7 is 1:(0.05-1):(0.05-0.5); (4) the solvent in step 7 is selected from one of DMF, DMSO, DMA; (5) the reaction temperature of step 7 is 80-110℃; (6) the reaction time of step 7 is 2-5h.

12. The method of claim 1, wherein, The preparation method meets 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, hydrochloric acid ethyl acetate, hydrochloric acid dioxane, hydrochloric acid methanol, hydrochloric acid ethanol; (2) a solvent is 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, ethyl acetate; (3) the volume of the deprotection reagent in step 8 is 1.5-20 times the mass of compound 11; (4) the reaction temperature of step 8 is 0-40℃; (5) the reaction time of step 8 is 0.5-6h.

13. The method of claim 12, wherein, The preparation method meets one or more of the following conditions: (1) the deprotection reagent in step 8 is trifluoroacetic acid; (2) the solvent in step 8 is selected from at least one of dichloromethane, dichloroethane, chloroform, methanol, ethyl acetate; (3) the volume of the deprotection reagent in step 8 is 2-18 times the mass of compound 11; (4) the reaction temperature in step 8 is 0-35℃; (5) the reaction time in step 8 is 1-5 h.

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

15. A process for the preparation of VT02956, characterized by, VT02956 is prepared using the method of claim 1 or 2 or 3.

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