Synthesis method of benzodihydropyran compound with aziridine structure fragment

Abstract

A synthesis method of benzodihydropyran compound II with aziridine structure fragments comprises following steps: 1, preparing compound II-6 by using compound II-5 as reaction raw material, namely # imgabs 0 #, 2, preparing compound II-7 by reacting compound II-6 with alkali for cyclization, namely # imgabs 1 #, 3, and reacting compound II-7 with intermediate HO-Rw to obtain compound II, namely # imgabs 2 #.

Description

Technical Field

[0001] The present invention relates to the synthesis and preparation of benzodihydropyran compounds of aziridine structural fragments, in particular to the synthesis of a class of compounds with similar structures disclosed in WO2021068952, and belongs to the technical field of organic synthesis. Background Art

[0002] AST-3424 is an AKR1C3 enzyme-activated DNA alkylating agent prodrug that has entered Phase II clinical trials in both China and the United States (China's registered clinical trials are CTR20201915, CTR20201908, CTR20191399, and CTR20191371, and the United States' registered clinical trials are NCT04315324 and NCT03592264). It is specifically activated by the AKR1C3 enzyme that is highly expressed in various tumors to release DNA alkylating agents and thus exert anti-tumor effects.

[0003] This type of compound was first disclosed in patent applications WO2016145092 and WO2017087428. This type of compound I is based on a nitrobenzyl skeleton and is connected to a drug structure fragment T via a linking group to form:

[0004]

[0005] By substituting different substituents -X at the ortho position of the nitro group on the nitrobenzyl skeleton 10 -A, linker group, and drug structure T (such as AST2660) are combined to obtain AKR1C3 enzyme-activated anti-tumor prodrug molecules with different activities.

[0006] The above application discloses the following two synthetic routes of TH2870 (racemate of AST-3424):

[0007]

[0008]

[0009] Improved synthetic route based on synthetic route 1

[0010] The above two routes are not much different. Both of them first form a nitrobenzyl skeleton-drug precursor structure (Br-IPM) intermediate from a nitrobenzyl skeleton, then form a nitrobenzyl skeleton-drug structure (AST2660) intermediate through an Ag2O ring closure reaction, and finally react with a substituted group compound to generate the final product.

[0011] On this basis, patent application WO2021068952 discloses a similar mechanism of AKR1C3 enzyme-activated DNA alkylating agent prodrug II, which replaces the nitrobenzyl skeleton with a nitro-substituted chroman structure:

[0012]

[0013] And disclosed a new synthetic route:

[0014]

[0015] This synthetic route is quite different from the above synthetic routes 1 and 2. It first forms a nitro-substituted chroman skeleton-substituted group intermediate from a nitro-substituted chroman skeleton, and then connects it to a drug precursor structure Br-IPM to form a nitro-substituted chroman skeleton-substituted group-drug precursor structure (Br-IPM) intermediate, and finally forms the final product through Ag2O reaction ring closure. Summary of the invention

[0016] In order to synthesize new nitro-substituted chroman-structured AKR1C3 enzyme-activated DNA alkylating agent prodrugs, the applicant designed a series of compounds similar to structure II. The structural variations of these compounds are in the Rw substituent, but they have a common nitro-substituted chroman skeleton-drug structure (AST2660), so the compound synthesis route considers using the above-mentioned synthesis route 1 (including the improved route of synthesis route 1) similar to synthesis route 1'.

[0017]

[0018] However, due to the inconsistency of the chemical structure of the final product, the reaction activity of the intermediate obtained is different from that of the original intermediate. In the process of preparing II-7 from intermediate II-6, the Ag2O used in synthesis route 1 cannot be successfully ring-closed to obtain the final aziridine structure intermediate II-7 or the purity of the prepared intermediate is reduced. After many experiments, it was found that if a base is used instead of Ag2O, the reaction can be successfully completed and a higher purity final aziridine structure intermediate II-7 can be obtained.

[0019] The following technical solutions are provided.

[0020] A method for synthesizing chromanoid compounds II having an aziridine structural fragment,

[0021]

[0022] The process includes:

[0023] Process 1, using compound II-5 as a reaction raw material to prepare compound II-6, namely

[0024]

[0025] Step 2: Compound II-6 reacts with a base to prepare compound II-7, namely

[0026]

[0027] Process 3: Compound II-7 reacts with the intermediate HO-Rw to obtain compound II, namely

[0028]

[0029] Wherein, the definition of Rw is as described in the claims of patent application PCT / CN2020 / 120281, publication number WO2021068952A1, and the synthesis preparation method of the specific compound is also described in the above application, and is specifically defined as:

[0030] Rw is

[0031] R1 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted with 1, 2 or 3 R a replaced by;

[0032] Each R a are independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl;

[0033] R2 is H or C 1-6 alkyl;

[0034] Or R1 and R2 are linked together to form a 4-6 membered heterocycloalkyl group, wherein the 4-6 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R b replaced by;

[0035] Each R b are independently H, F, Cl, Br, I, -CN, -OH, -NH2, -OCH3, -OCH2CH3, -CH3 or -CH2CH3;

[0036] R3 is H, F, Cl, Br, I, -OH, -NH2, C 1-3 Alkoxy or C 1-3 alkyl;

[0037] Or R2 and R3 are connected together to make the structural unit for

[0038] T1 is -(CR c R d ) m -or-(CR c R d ) n -O-;

[0039] m is 1, 2 or 3;

[0040] n is 1 or 2;

[0041] T2 is N or CH;

[0042] R c and R d Each independently is H, F, C 1-3 Alkyl or C 1-3 Alkoxy;

[0043] R4, R5 and R6 are each independently H, F, Cl, Br, I, C 1-3 Alkyl or C 1-3 Alkoxy;

[0044] T is N or CH;

[0045] R7 and R8 are each independently H, F, Cl, Br or I;

[0046] R9 and R 10 Each independently is H, F, Cl, Br, I, -CN or

[0047] The 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl groups each contain 1, 2, 3 or 4 heteroatoms independently selected from N, -O- and -S-;

[0048] L is a leaving group,

[0049] X in the II-6 compound is selected from Cl and Br, and two Xs are the same element.

[0050] Regarding compounds of structure II, the entire text of patent application PCT / CN2020 / 120281, publication number WO2021068952A1 is hereby introduced as part of the specification of this application.

[0051] Leaving groups are leaving groups, which refer to moieties that can be displaced under nucleophilic displacement conditions well known in the art. Leaving groups include, but are not limited to, halo and -OSO2-R, wherein R is an optionally substituted alkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl, and typical leaving groups include -F, -Br, -Cl, and -OTs, -OMs, OTf.

[0052] OTs is a toluenesulfonate ester with the structural formula p-CH3-C6H4-SO2O-; OMs is a methylsulfonate ester with the structural formula -OSO2CH3; OTf is a trifluoromethanesulfonate ester with the structural formula -OSO2CF3.

[0053] Process 1: There are many methods for preparing compound II-6 using compound II-5 as a reaction raw material, which are specifically recorded in the corresponding prior art documents:

[0054]

[0055] For the specific operation process, please refer to patent applications WO2016145092 and WO2017087428.

[0056] The specific reaction raw materials, reaction conditions and solvents need to be adjusted according to the different structures of the reaction raw material compound II-5.

[0057] Alternatively, POCl3 or POBr3, 2-bromoethylamine or 2-chloroethylamine or their hydrohalides or a mixture thereof can be used to react with compound II-5 to generate compound II-6.

[0058] As a preference, in some embodiments, the operation of process one includes:

[0059] Add compound II-5 and organic amine to POCl3 or POBr3, control the temperature at -50 to -10°C during the addition, and control the temperature at -50 to -10°C after the addition is completed to react;

[0060] After the reaction is completed, the reaction system is cooled to -50 to -10°C, and then 2-bromoethylamine or 2-chloroethylamine or its hydrohalide or a mixture of the three is added in batches, and the temperature is controlled at -50 to -10°C during the addition process;

[0061] After the addition is completed, the organic amine is added, and the temperature is controlled at -50 to -10°C during the addition, and the reaction is carried out at -50 to -10°C.

[0062] After the reaction is completed, post-treatment is carried out and purification steps are performed to obtain compound II-6 product.

[0063] The organic amine is selected from aliphatic chain amines or cyclic chain amines with 1 to 6 carbon atoms, including primary amines and secondary amines, preferably diethylamine, triethylamine, etc. which are liquid at room temperature.

[0064] As a preference, in certain embodiments, the solvent for the above process 1 reaction is dichloromethane:

[0065] POCl3 or POBr3 is prepared as a dichloromethane solution with a concentration of not more than 0.1g / ml, compound II-5 and organic amine are prepared as a dichloromethane solution with a concentration of not more than 0.15g / ml, 2-bromoethylamine or 2-chloroethylamine or its hydrohalide or a mixture of the three is prepared as a solution or suspension, and the organic amine is prepared as a dichloromethane solution with a concentration of not more than 0.20g / ml.

[0066] 2-bromoethylamine or 2-chloroethylamine or its hydrohalide salt or a mixture thereof includes the following:

[0067] 2-bromoethylamine alone, 2-chloroethylamine alone;

[0068] 2-chloroethylamine hydrochloride alone, 2-chloroethylamine hydrobromide alone, 2-bromoethylamine hydrochloride alone, 2-bromoethylamine hydrobromide alone;

[0069] Various situations in which the above 6 single-purpose materials are mixed.

[0070] As a preferred embodiment, the molar ratio of a compound II-5, POCl3 or POBr3, 2-bromoethylamine or 2-chloroethylamine or its hydrohalide salt or a mixture of the three is 1:1.2-1.8:2-5.

[0071] In fact, the reaction can also be carried out by using other ratios for feeding. After the reaction of the above ratios is completed, the post-processing and purification are relatively simple and quick.

[0072] In the above ratio, if it is a mixture, the amount of 2-bromoethylamine or 2-chloroethylamine or its hydrohalide salt or the mixture of the three is the sum of the amounts of the materials in the mixture.

[0073] As a preferred embodiment, the amount of compound II-5 should be monitored to determine whether the reaction is complete. When compound II-5 reacts to more than 95%, 2-bromoethylamine or 2-chloroethylamine or its hydrohalide salt or a mixture of the three is added.

[0074] As a recommendation, HPLC can be used to monitor the remaining amount of compound II-5. A simple and easy way is to take a sample at the beginning of the reaction to detect the integrated area of ​​the signal peak corresponding to II-5, where the area is defined as 1; take a sample at the monitoring time point to detect the integrated area of ​​the signal peak corresponding to II-5. If the detected integrated area is less than 0.05, it can be considered that the reaction is complete, and 2-bromoethylamine or 2-chloroethylamine or its hydrohalide salt or a mixture of the three can be added. Of course, other methods can also be used for detection, such as 1 H-NMR, LC-MS or quantitative TLC (quantitative thin layer chromatography), ordinary TLC.

[0075] Step 2: Compound II-6 reacts with a base to prepare compound II-7, namely

[0076]

[0077] Compared with the prior art using Ag2O for ring-closing reaction, using alkali ring-closing in process 2 can successfully complete the reaction of process 2.

[0078] According to the experimental data of AST-3424 stability at different pH values ​​in WO2021 / 008520 (see Table 3 of the application text), the applicant speculates that this type of compound containing an aziridine structure may have poor stability in an acidic environment, but strong stability in an alkaline environment. Ag2O is generally prepared by reacting AgNO3, so when added to the reaction system, the system will become slightly acidic, so the II-7 compound may decompose, resulting in the applicant's inability to successfully complete the reaction of process 2 using Ag2O.

[0079] The base here is in a broad sense, including strong base, weak acid salts, alkali metal hydroxides, nucleophilic organic amines (organic bases), sodium alcoholates or potassium alcoholates, etc. The added base should be in excess, generally 2-5 times the amount of the reactant II-7.

[0080] Specific operations include:

[0081] A base is added to compound II-6, and the temperature is controlled at -5 to 5°C during the addition.

[0082] The base is preferably selected from K2CO, Cs2CO3, K3PO4, NaOH, KOH, DBU, NaHMDS (sodium hexamethyldisilazide), KHMDS (hexamethyldisilazide potassium), t-BuOK, t-BuONa.

[0083] Preferably, compound II-6 is formulated as a THF, dioxane, acetone, acetonitrile, or DMF solution at no more than 1.0 g / ml.

[0084] In certain embodiments, the base is formulated as THF, dioxane, acetone, acetonitrile, DMF, or an aqueous solution.

[0085] Further, in certain embodiments, when X in compound II-6 is Br, the base is selected from NaOH, which is prepared as a 1 mol / L aqueous solution; the molar ratio of compound II-6 to the base is 1:2.0-2.2.

[0086] Process 3: Compound II-7 reacts with the intermediate HO-Rw to obtain compound II, namely

[0087]

[0088] Preferably, in some embodiments, the specific operations of process three include:

[0089] After the DMF solution of compound II-7 and intermediate HO-Rw is cooled to -5 to 5°C, Cs2CO3 is added and the temperature is controlled within the range of -5 to 5°C for the reaction.

[0090] More preferably, the molar ratio of compound II-7, intermediate HO-Rw and Cs2CO3 is 1:1.1-1.5:10-20.

[0091] Considering that Cs2CO3 is in solid powder form, in certain embodiments, it is prepared as a DMF solution.

[0092] Preferably, compound II is selected from

[0093]

[0094] In some embodiments, Compound II is selected from:

[0095]

[0096] In certain embodiments, compound II is selected from the following structural compounds

[0097] The synthesis method includes

[0098]

[0099] Process 1:

[0100] Add dichloromethane to the reaction vessel, cool to -30±10°C, add POCl3, add the mixed solution of raw material 1 and triethylamine in dichloromethane, raise the temperature to -25±10°C after the addition is complete, and react for 3-5 hours;

[0101] When the content of raw material 1 is monitored to be lower than 5%, the reaction system is cooled to -30±10°C, and 2-bromoethylamine hydrobromide is added in batches, and the temperature is controlled at -30±10°C during the addition process;

[0102] After the addition is completed, a solution of triethylamine in dichloromethane is added dropwise. After the addition is completed, the reaction system is heated to -20±10°C and reacted for 12-20 hours to obtain intermediate 2.

[0103]

[0104] Process 2:

[0105] Add intermediate 2 and THF to the reaction vessel, cool the reaction solution to 0±10°C, add NaOH aqueous solution, and react for 10-18 hours after the addition is complete to obtain intermediate 3.

[0106]

[0107] Process three:

[0108] Add intermediate 3, 3-hydroxy-N,N-dimethylbenzamide and DMF to the reaction container, cool the reaction solution to 0±10°C, add Cs2CO3 or Cs2CO3 DMF solution, and react for 18-30 hours to obtain the target compound II.

[0109] Preferably, in process 1, the molar ratio of raw material 1, POCl3 or POBr3, 2-bromoethylamine or 2-chloroethylamine or its hydrohalide salt or a mixture thereof is 1:1.5:4.

[0110] In process 2, the concentration of NaOH aqueous solution is 1 mol / L, and the molar ratio of intermediate 2 to NaOH is 1:2.1.

[0111] In process three, the molar ratio of compound intermediate 3, 3-hydroxy-N,N-dimethylbenzamide and Cs2CO3 is 1:1.3:16.

[0112] Summary of the beneficial effects of the invention

[0113] The new compound of structural formula II uses base to close the ring with II-6 to generate the key intermediate II-7, and then II-7 is reacted with different HO-Rw to synthesize benzodihydropyran compounds with different structures. Through this synthetic route, the key intermediate II-7 can react with HO-Rw with different structures to quickly and cost-effectively synthesize target compounds with different structures, thereby accelerating the screening of potential AKR1C3 enzyme-activated DNA alkylating agent prodrugs.

[0114] The new synthetic route and benzodihydropyran compounds overcome the problem that the key intermediate II-7 is difficult to synthesize using Ag2O in the prior art. On this basis, the key intermediate II-7 reacts with HO-Rw of different structures to prepare the final target product quickly, at low cost and with high yield.

[0115] Although the reaction can be carried out using silver oxide, it has the following shortcomings in the subsequent large-scale production process:

[0116] In terms of economic cost, on the one hand, silver oxide is expensive, and the silver chloride or silver bromide generated by the reaction is easy to adhere to the surface of silver oxide, causing the silver oxide to be inactivated, which further increases the amount of silver oxide used, making the cost of the reaction materials high. On the other hand, the final product needs to control silver ions, but silver ions are not easy to remove, and the process of removing silver ions is complicated and costly;

[0117] In terms of process operation, on the one hand, the silver chloride or silver bromide generated by the reaction is easy to adhere to the surface of silver oxide, causing the silver oxide to be inactivated and requiring replacement and addition of new silver oxide in the middle of the process, which is cumbersome; in particular, the silver oxide powder is heavy and easy to sink to the bottom in the reactor, and cannot fully contact with the reaction materials, thus affecting the reaction speed. On the other hand, the silver oxide ring closure generally needs to be heated to the solvent reflux, and the reaction time is relatively long. DETAILED DESCRIPTION

[0118] The present invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0119] The experimental methods in the following examples are all conventional methods unless otherwise specified. The medicinal materials, reagents, etc. used are all commercially available products unless otherwise specified.

[0120] The following Take the synthesis preparation process as an example to illustrate in detail.

[0121]

[0122] Raw material 1 was synthesized by the method described in WO2021068952. The HPLC method was a conventional C18 column, acetonitrile / water mobile phase, and UV238nm or 254nm ultraviolet detector.

[0123] Synthesis of intermediate 2

[0124] Add 10ml of dichloromethane to the reaction bottle, cool to about -30℃ under nitrogen protection, add POCl3 (0.89g, 5.8mmol), and then slowly drop the mixed solution of raw material 1 (0.83g, 3.9mmol), triethylamine (1.38g, 13.7mmol) and 10ml of dichloromethane. After the drop is complete, warm to about -25℃, react for 4.5h, take samples for monitoring, the content of raw material 1 is less than 5%. Cool the reaction solution to about -30℃, add 2-bromoethylamine hydrobromide (3.19g, 0.0156mol) in batches, add triethylamine (1.97g, 19.5mmol) dissolved in 10ml of dichloromethane slowly, drop after the drop is complete, warm the reaction solution to about -20℃, react for 16h, and stop the reaction. The mixture was washed with water three times, 30 ml each time, and the organic phase was collected. 10 g of anhydrous Na2SO4 was added and dried for 2 h. The mixture was filtered and concentrated to dryness under reduced pressure. The mixture was purified by normal phase preparative liquid chromatography to obtain 0.75 g of intermediate 2 product with a purity of 84% (HPLC, 254 nm). 1H-NMR(400MHz,DMSO-d6)δ7.65(d,J=11.5Hz,1H),7.56(d,J=6.3Hz,1H),5.3 5(dt,J=9.3,4.9Hz,1H),5.09(tt,J=11.5,7..0Hz,2H),4.38(ddd,J=11.3,5. 8,3.7Hz,1H),4.21(ddd,J=11.7,9.1,3.4Hz,1H),3.47(t,J=6.7Hz,3H),3.1 6(ddq,,J=13.7,10.2,6.9Hz,4H), 2.21(tddd,J=14.4,11.1,7.0,3.1Hz,2H).

[0125] Synthesis of intermediate 3 (ring closure using NaOH solution)

[0126] Add intermediate 2 (0.35 g, 0.7 mmol) and 5 ml THF to the reaction flask. Under nitrogen protection, cool the reaction solution to about 0°C, then slowly drop 1.5 ml 1 mol / L NaOH solution. After the dropwise addition, react for 4 h, stop the reaction, extract the reaction solution twice with ethyl acetate, 10 ml each time, combine all organic phases, add 15 ml saturated brine to wash the organic phase, collect the organic phase, add anhydrous Na2SO4 to dry for 2 h, filter, concentrate to dryness under reduced pressure, separate and purify on a silica gel column (ethyl acetate / ethanol = 100 / 5) to collect the product, and obtain 100 mg of intermediate 3 with a purity of 95% (HPLC, 254 nm). 1 H-NMR (400MHz, CDCl3) δ7.54(d,J=6.1Hz,1H),7.45(d,J=10.8Hz,1H),5.61(dt,J =8.3, 4.3Hz, 1H), 4.35 (dddd, J = 15.9, 11.4, 8.6, 4.5Hz, 2H), 2.39–2.18 (m, 10H).

[0127] Synthesis of intermediate 3 (cyclization using silver oxide)

[0128] Add intermediate 2 (0.82g, 1.6mmol) and 40ml THF to the reaction bottle, add triethylamine (0.17g, 1.7mmol) and silver oxide (3.74g, 16.1mmol) under nitrogen protection, and then heat to 40℃, react for 15h (samples were taken at 3, 4, 6, and 8 hours during the reaction, and the reaction was complete), then stop the reaction, filter, concentrate to dryness under reduced pressure, separate and purify on a silica gel column (ethyl acetate / ethanol = 100 / 5), collect the product, and obtain 480mg of intermediate 3 with a purity of 91% (HPLC, 254nm).

[0129] Synthesis of target compound II

[0130] Add intermediate 3 (0.10 g, 0.29 mmol), 3-hydroxy-N, N-dimethylbenzamide (0.63 g, 3.8 mmol) and 2 ml DMF to the reaction flask. Under nitrogen protection, cool to about 0 ° C, add cesium carbonate (1.52 g, 4.7 mmol), react for 24 hours, and stop the reaction. Add 10 ml of water to the reaction solution, extract the reaction solution with ethyl acetate three times, 10 ml each time, combine the organic phases, add 20 ml of saturated brine to wash the organic phase, collect the organic phase, add 5 g of anhydrous Na2SO4 and dry for 2 hours. Filter and concentrate the organic phase, and purify the crude product by normal phase preparative liquid phase to obtain 0.03 g of compound with a purity of 96% (HPLC, 254 nm) and a yield of 30%. 1 H-NMR (400MHz, CDCl3) δ7.48(s,1H),7.38(t,J=7.9Hz,1H),7.30(s,1H),7.15(dt,J=7.7,1.3Hz,1H),7.04(ddd,J=8.3,2.6,1.0Hz,1H),6 .98(dd,J=2.5,1.5Hz,1H),5.58(dt,J=8.2,4.2Hz,1H),4.45–4.29(m,2H),3.03(d,J=48.3Hz,6H),2.35–2.29(m,2H),2.21–2.08(m,8H).

[0131] Repeat the above operation. The following are the experimental results of different batches. The specific results are shown in the following table.

[0132]

[0133] The experimental results of different batches showed that the reaction time in the step of converting intermediate 2 to intermediate 3 was about 4 hours.

Claims

1. A method for synthesizing chromanoid compounds II having an aziridine structural fragment, The process includes: Process 1, using compound II-5 as a reaction raw material to prepare compound II-6, namely Step 2: Compound II-6 reacts with a base to prepare compound II-7, namely Process 3: Compound II-7 reacts with the intermediate HO-Rw to obtain compound II, namely in, Rw is R1 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted with 1, 2 or 3 R a replaced by; Each R a are independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl; R2 is H or C 1-6 alkyl; Or R1 and R2 are linked together to form a 4-6 membered heterocycloalkyl group, wherein the 4-6 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R b replaced by; Each R b are independently H, F, Cl, Br, I, -CN, -OH, -NH2, -OCH3, -OCH2CH3, -CH3 or -CH2CH3; R3 is H, F, Cl, Br, I, -OH, -NH2, C 1-3 Alkoxy or C 1-3 alkyl; Or R2 and R3 are connected together to make the structural unit for T1 is -(CR c R d ) m -or-(CR c R d ) n -O-; m is 1, 2 or 3; n is 1 or 2; T2 is N or CH; R c and R d Each independently is H, F, C 1-3 Alkyl or C 1-3 Alkoxy; R4, R5 and R6 are each independently H, F, Cl, Br, I, C 1-3 Alkyl or C 1-3 Alkoxy; T is N or CH; R7 and R8 are each independently H, F, Cl, Br or I; R9 and R 10 Each independently is H, F, Cl, Br, I, -CN or The 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl groups each contain 1, 2, 3 or 4 heteroatoms independently selected from N, -O- and -S-; L is a leaving group, X in the II-6 compound is selected from Cl and Br, and two Xs are the same element.

2. The synthesis method according to claim 1, wherein compound II is selected from The definition of the variables is as in claim 1.

3. The synthesis method according to claim 1, wherein the specific operations of process 1 include: Add compound II-5 and organic amine to POCl3 or POBr3, control the temperature at -50 to -10°C during the addition, and control the temperature at -50 to -10°C after the addition is completed to react; After the reaction is completed, cool the reaction system to -50 to -10°C and add 2-bromoethylamine or 2-chloroethylamine or its hydrohalide salt or a mixture of the three in batches, and control the temperature at -50 to -10°C during the addition process; After the addition is completed, the organic amine is added, and the temperature is controlled at -50 to -10°C during the addition, and the reaction is carried out at -50 to -10°C.

4. The synthesis method according to claim 3, wherein The solvent for the entire reaction is dichloromethane, POCl3 or POBr3 is prepared as a dichloromethane solution with a concentration of not more than 0.1g / ml, compound II-5 and organic amine are prepared as a dichloromethane solution with a concentration of not more than 0.15g / ml, 2-bromoethylamine or 2-chloroethylamine or its hydrohalide or a mixture of the three is prepared as a solution or suspension, and the organic amine is prepared as a dichloromethane solution with a concentration of not more than 0.20g / ml.

5. The synthesis method according to claim 3, wherein In the reaction, the molar ratio of the reactants, compound II-5, POCl3 or POBr3, 2-bromoethylamine or 2-chloroethylamine or its hydrohalide salt or a mixture of the three is 1::1.2-1.8:2-5.

6. The synthesis method according to claim 3, wherein When the reaction of compound II-5 reaches 95% or more, 2-bromoethylamine or 2-chloroethylamine or its hydrohalide or a mixture of the three is added.

7. The synthesis method according to claim 1, wherein The specific operations of process 2 include: Add a base to compound II-6, and control the temperature at -5 to 5°C during the addition process. Wherein compound II-6 is prepared as a THF, dioxane, acetone, acetonitrile, DMF solution of no more than 1.0 g / ml, The base is selected from K2CO3, Cs2CO3, K3PO4, NaOH, KOH, DBU, NaHMDS, KHMDS, t-BuOK, t-BuONa, Bases were prepared as THF, dioxane, acetone, acetonitrile, DMF or aqueous solutions.

8. The synthesis method according to claim 7, wherein When X in compound II-6 is Br, the base is selected from NaOH, which is prepared as a 1 mol / L aqueous solution, and the molar ratio of compound II-6 to the base is 1:2.0-2.

2.

9. The synthesis method according to claim 1, wherein The specific operations of process three include: After the DMF solution of compound II-7 and intermediate HO-Rw is cooled to -5 to 5°C, Cs2CO3 is added and the temperature is controlled within -5 to 5°C to react. The molar ratio of compound II-7, intermediate HO-Rw and Cs2CO3 is 1:1.1-1.5:10-20.

10. The synthesis method according to claim 9, wherein Cs2CO3 was prepared as a DMF solution.

11. The synthesis method according to claim 1, wherein compound II is selected from the following structural compounds The synthesis method includes Process 1: Add dichloromethane to the reaction vessel, cool to -30±10°C, add POCl3, add the mixed solution of raw material 1 and triethylamine in dichloromethane, raise the temperature to -25±10°C after the addition is complete, and react for 3-5 hours; When the content of raw material 1 is monitored to be lower than 5%, the reaction system is cooled to -30±10°C, and 2-bromoethylamine hydrobromide is added in batches, and the temperature is controlled at -30±10°C during the addition process; After the addition is completed, a solution of triethylamine in dichloromethane is added dropwise. After the addition is completed, the reaction system is heated to -20±10°C and reacted for 12-20 hours to obtain intermediate 2. Process 2: Add intermediate 2 and THF to the reaction vessel, cool the reaction solution to 0±10°C, add NaOH aqueous solution, and react for 10-18 hours after the addition is complete to obtain intermediate 3. Process three: Add intermediate 3, 3-hydroxy-N,N-dimethylbenzamide and DMF to the reaction container, cool the reaction solution to 0±10°C, add Cs2CO3 or Cs2CO3 DMF solution, and react for 18-30 hours to obtain the target compound II.

12. The synthesis method according to claim 11, In process 1, the molar ratio of raw material 1, POCl3 or POBr3, 2-bromoethylamine or 2-chloroethylamine or its hydrohalide salt or a mixture of the three is 1:1.5:

4. In process 2, the concentration of NaOH aqueous solution is 1 mol / L, and the molar ratio of intermediate 2 to NaOH is 1:2.

1. In process three, the molar ratio of compound intermediate 3, 3-hydroxy-N,N-dimethylbenzamide and Cs2CO3 is 1:1.3:16.

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