Synthesis method of compound with aziridine phosphate structure

Abstract

The invention provides a synthesis method of a compound with an aziridine phosphate structure, in particular to a synthesis method for generating a compound with a bicyclic aziridine structure from a compound containing a phosphamide structure through a ring closing reaction, and the method can be carried out by using various inorganic strong bases, strong base weak acid salts and organic bases under corresponding solvents and reaction conditions. Compared with a traditional method using Ag2O or n-butyllithium (BuLi) as a catalytic reagent, the method has the obvious advantages of being high in conversion rate, few in by-products, easy and convenient to operate, low in cost and the like.

Description

Technical Field

[0001] The invention relates to a synthesis method of a phosphoric acid aziridine structure compound, in particular to a ring-closing synthesis reaction of a phosphoramide structure compound to generate a bicyclic aziridine structure compound through ring-closing, 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. It contains a bicyclic aziridine structure.

[0003] This type of compound was first disclosed in patents WO2016145092 and WO2017087428, which disclosed the following two synthetic routes of TH2870 (racemic form of AST-3424):

[0004]

[0005] Synthetic route 1

[0006]

[0007] Based on the improvement of synthetic route 1, synthetic route 2

[0008] The ring-closing reaction of the phosphoramide structure in both synthetic routes 1 and 2 is carried out with the participation of Ag2O.

[0009] In addition, the following preparation process is disclosed in patent WO2020172506:

[0010]

[0011] Synthetic route 3

[0012]

[0013] Synthetic route 4

[0014] The ring-closing reaction of the phosphoramide structure in synthetic routes 3 and 4 is also carried out with the participation of Ag2O.

[0015] AST-3424 or its racemic isomer TH2870 are compounds containing a bicyclic aziridine structure, and the relevant preparation processes are to use the corresponding phosphoramide structure compound to close the ring with the participation of Ag2O to generate a bicyclic aziridine structure.

[0016] Patent WO2016210175A1, corresponding to Chinese application CN108024974A, discloses a series of hypoxia-activated antitumor compounds. Taking the compounds in synthetic routes 5 and 6 as examples, when the phosphoramide structure compounds are ring-closed to generate the corresponding bicyclic aziridine structure compounds, it is carried out with the participation of Ag2O.

[0017]

[0018] Synthetic route 5

[0019]

[0020] Synthetic route 6

[0021] The series of compounds disclosed in patent WO2021068952A1 are similar to AST-3424. They are DNA alkylating agent prodrugs activated by the AKR1C3 enzyme, which are specifically activated by the AKR1C3 enzyme highly expressed in a variety of tumors to release DNA alkylating agents and then exert anti-tumor effects. They contain a bicyclic aziridine structure. Taking its compound 1 synthesis method as an example, Ag2O is also used to participate in the ring-closing reaction from the phosphoramide structure to the bicyclic aziridine structure: Compound 1-12 (80 mg, 120.44 μmol) was dissolved in THF (6 ml), and silver oxide (279.11 mg, 1.2 mmol) was added. The mixed solution was stirred at 60 degrees Celsius for 14 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (separation column: Waters Xbridge (specification: C18150×50 mm, particle size: 10 μm); mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; elution gradient: 17%-47%, 10 minutes) to obtain compound 1.

[0022]

[0023] Synthetic route 7

[0024] The compounds disclosed in patent WO2022057838A1 are similar in structure to the compounds in patent WO2021068952A1, and both have the same mechanism of action on tumors as compound AST-3424. They are AKR1C3 enzyme-activated prodrugs and contain a bicyclic aziridine structure.

[0025]

[0026] Synthetic route 8

[0027] The above-mentioned synthetic routes 1-4 are the synthetic methods related to AST-3424, in which the compounds containing phosphoramide structures disclosed therein are all subjected to ring-closing reactions using Ag2O as a catalytic reagent to generate corresponding bicyclic aziridine structure compounds, which are the key steps in the synthesis of AKR1C3 enzyme-activated prodrug compounds.

[0028] The above-mentioned synthetic routes 5 and 6 also use Ag2O as a catalytic reagent to carry out a ring-closing reaction to generate the corresponding bicyclic aziridine structure compound, which is a key step in the synthesis of oxygen-deficient (nitrogen) activated prodrug compounds. The reaction requires to be carried out under the protection of Ar atmosphere, which is extremely inconvenient in actual operation.

[0029] The above-mentioned synthetic routes 7 and 8 prepare analogues of AST-3424, which are nitrobicyclic compounds formed by cyclization with the side chain oxygen atom and sharing two carbon atoms with the phenyl group on the basis of the nitrobenzyl monocyclic ring. The synthetic route also uses Ag2O reagent to carry out the ring-closing reaction to generate the corresponding bicyclic aziridine structure compound. The reaction is carried out at 60-70°C and the bicyclic aziridine structure compound is prepared through a ring-closing synthesis reaction for 12-14 hours. The reaction temperature is relatively high and the time is relatively long.

[0030] In summary, in the application of the above-mentioned ring-closing reaction using Ag2O as a reagent, although the reaction can be carried out, it has the following shortcomings in the subsequent large-scale production process:

[0031] 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;

[0032] 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. Summary of the invention

[0033] In order to explore the method of ring-closing compounds containing phosphoramide structures to generate corresponding bicyclic aziridine structure compounds and further optimize the synthesis process of AST-3424 and its similar drugs, the inventor consulted relevant literature. The literature Chem Inform Abstract: Phosphorylated Nitrogen Mustards. Cyclization and Ring Opening of Phosphoric and Phosphonic N-(2-Chloroethyl)amides (DOI: 10.1002 / chin.199352236) discloses the following phosphoric acid aziridine cyclization process:

[0034]

[0035] The above-mentioned process route uses n-butyl lithium as a catalytic reagent to generate a bicyclic aziridine structure compound, but also generates a large amount of monocyclic aziridine structure byproducts. Chloride ions have a significant effect on the cyclization reaction catalyzed by NBu4Br and the cleavage reaction of (VI) with lithium chloride; under the action of chlorine, the bicyclic aziridine structure compound will be cleaved into a monocyclic aziridine structure and an acyclic amide structure compound, and the cyclization rate will gradually decrease with the extension of the reaction time.

[0036] In the reaction of a series of phosphoramide compounds in the above-mentioned prior art to generate bicyclic aziridine structure compounds through ring-closing reaction, Ag2O or n-butyl lithium (BuLi) is mostly used as a catalytic reagent, which has a series of problems such as high energy consumption, long reaction cycle, strict environmental conditions requiring argon atmosphere protection, excessive monocyclic by-products, and low conversion rate.

[0037] Based on this, the inventors changed the catalytic reagent and solvent of the ring-closing reaction and controlled the material ratio and concentration. Under relatively mild conditions and through convenient operations, phosphoramide compounds with similar structures were subjected to a ring-closing reaction to generate high-yield bicyclic aziridine structure compounds. Moreover, the purity of the obtained series of bicyclic aziridine structure compounds can meet the requirements of industrial quality.

[0038] The inventors unexpectedly discovered that the above objectives can be achieved by using alkaline substances instead of Ag2O or n-butyllithium (BuLi).

[0039] In particular, the inventors have summarized the rules for different solvents and material mass or volume ratios corresponding to different alkaline substances through a large number of experiments, and provided an environmentally friendly and convenient method for synthesizing corresponding bicyclic aziridine structure compounds from typical phosphoramide structure compounds through ring-closing reactions. This method is expected to reduce costs and waste generation when the process is used on a large scale.

[0040] The alkaline substances here are broad in meaning, referring to substances that have the ability to provide electrons or accept protons. According to the characteristics of the substances, they are divided into organic bases and inorganic bases; according to the strength of the alkalinity of the substances, they are divided into strong bases and weak bases. Common ones include strong bases such as NaOH and KOH; strong bases and weak acid salts such as K2CO3, Cs2CO3, and K3PO4; organic bases such as DBU, NaHMDS / KHMDS, t-BuONa / t-BuOK, and TMG.

[0041] To this end, the applicant proposes the following technical solution for the synthesis method.

[0042] The synthesis method of the aziridine phosphate structure compound II having the following formula:

[0043]

[0044] Wherein, the base is selected from one or more of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal dihydrogen phosphates, and organic bases, and the organic base does not include n-butyl lithium;

[0045] The solvent is selected from one or more of acetone, DMF, THF and acetonitrile;

[0046] R t is a cyclic or chain group containing C, H and at least one of O, N, and halogen atoms, and -O- and R t The C or N atoms in are directly connected;

[0047] X and Y are each independently selected from halogen, OMs, OTs or ONs.

[0048] When the above-mentioned base or solvent is selected from multiple types, they will not produce chemical reactions with each other or have no adverse effects on the ring-closing reaction.

[0049] The base here is in a broad sense, including strong base and weak acid salts, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal dihydrogen phosphates, nucleophilic organic amines (organic bases), sodium alcoholates, potassium alcoholates, etc.

[0050] Alkali metals refer to metal elements of the first main group in the periodic table, such as Li, Na, K, Rb, Cs, and Fr. Alkali metal hydroxides refer to substances that can form alkaline substances with hydroxides, such as LiOH, NaOH, KOH, and CsOH. Alkali metal carbonates refer to carbonates formed by the above-mentioned alkali metal ions and carbonate ions, such as Na2CO3, K2CO3, and Cs2CO3. Alkali metal bicarbonates refer to bicarbonates formed by the above-mentioned alkali metal ions and bicarbonate ions, such as NaHCO3, KHCO3, and CsHCO3. Similarly, alkali metal phosphates include Na3PO4, K3PO4, and the like. Alkali metal dihydrogen phosphates include Na2HPO4, K2HPO4, and the like.

[0051] Strong base weak acid salt refers to the salt formed by the reaction of a strong base and a weak acid. The type of strong base weak acid salt can be selected according to the actual situation, as long as the strong base weak acid salt can be hydrolyzed to obtain weak acid hydrogen ions. For example, the acid radical ion in the above-mentioned strong base weak acid salt can be a borate ion (B4O7 2- ), carbonate ions (CO3 2- ), sulfite ion (SO3 2- ) and silicate ions (SiO3 2- ), the strong base ion in the above-mentioned strong base and weak acid salt can be sodium ion (Na+), potassium ion (K+), etc.

[0052] Optionally, the pKa value of the organic base is greater than or equal to 11.

[0053] Optionally, the base is selected from one or more of NaOH, KOH, CsOH, Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, CsHCO3, Na3PO4, Na2HPO4, K3PO4, K2HPO4, DBU, NaHMDS, KHMDS, t-BuOK, t-BuONa, and TMG.

[0054] Optionally, the halogen is selected from F, Cl, Br, I, preferably F.

[0055] The chemical name of DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene, and its molecular formula is C9H 16 N2, the structural formula is

[0056]

[0057] NaHMDS, sodium bis(trimethylsilyl)amide, also known as sodium hexamethyldisilazide, has the following structure:

[0058]

[0059] KHMDS, potassium bis(trimethylsilyl)amide, also known as potassium hexamethyldisilanediazide, has the following structure:

[0060]

[0061] t-BuONa and t-BuOK are potassium tert-butoxide and potassium tert-butoxide, respectively, and their structures are as follows:

[0062]

[0063] The chemical name of TMG is 1,1,3,3-tetramethylguanidine, also known as tetramethylguanidine. Its structure is as follows:

[0064]

[0065] In the above ring-closing reaction, X and Y are leaving groups, which are known in the art as leaving groups, and refer to moieties that can be replaced under nucleophilic replacement conditions. Leaving groups include (but are not limited to) halogen groups and -OSO2-R, wherein R is an alkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl group that is optionally substituted, and typical leaving groups include -F, -Cl, -Br, and -OMs, -OTs, -ONs, -OTf.

[0066] OMs is a methylsulfonate group, i.e. -OSO2CH3;

[0067] OTs is p-toluenesulfonate, i.e. p-CH3-C6H4-SO2-O-;

[0068] ONs is p-nitrobenzenesulfonate group, i.e. -O-SO2-C6H4-NO2-p.

[0069] OTf is a trifluoromethanesulfonate group, i.e. -OSO2CF3.

[0070] In the above reaction, R in Formula I and Formula II t It has the structure of the following formula (1):

[0071]

[0072] wherein X, Y, and Z are each independently H, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 、-NR 13 COR 14 ;

[0073] R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 、-NR 13 COR 14 ;

[0074] R w Halogen or Among them, X 10 It is O, S, SO or SO2.

[0075] Preferably, halogen is F; A is C6-C 10 Aryl, 5-15 membered heteroaryl, -N=CR 1 R 2 or

[0076] In some embodiments, R 1 , R 2 Each independently represents H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 、-NR 13 COR 14 .

[0077] In some embodiments, R3 is C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic ring or Z-substituted heterocyclic ring, 5-15 membered heteroaryl or Z-substituted heteroaryl, 7-15 membered condensed ring or Z-substituted condensed ring;

[0078] R4 is hydrogen, a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a mercapto group, an amine group, OTs, OMs, a C1-C6 alkyl group or a Z-substituted alkyl group, a C2-C6 alkenyl group or a Z-substituted alkenyl group, a C2-C6 alkynyl group or a Z-substituted alkynyl group, a C3-C8 cycloalkyl group or a Z-substituted cycloalkyl group, a C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, ether of 1-6 carbon atoms or alkoxy of 1-6 carbon atoms substituted by Z, -CONR 6 R 7 、-SO2NR 6 R 7 、-SO2R 6 、-OCOO-R 6 、-COOR 6 、-NR 6 COR 7、-OCOR 6 、-NR 6 S02R 7 、-NR 6 SO2NR 6 R 7 Or R2 and the atoms on the R1 group to which it is bonded together form a 7-15 membered condensed ring or a Z-substituted condensed ring;

[0079] R 6 and R 7 Each of them is independently hydrogen, cyano or isocyano, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, or R 6 , R 7 The group together with the atom to which it is bonded forms a 5-7 membered heterocyclic group or a Z-substituted 5-7 membered heterocyclic group;

[0080] The Z substituent is a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a thiol group, an amine group, OTs, OMs, a C1-C3 alkyl group or a substituted alkyl group, a C1-C3 alkoxy group or a substituted alkoxy group, a C2-C3 alkenyl group or a substituted alkenyl group, a C2-C3 alkynyl group or a substituted alkynyl group, a C3-C8 cycloalkyl group or a substituted cycloalkyl group, an aromatic ring, a heterocyclic ring, a heteroaromatic ring and a condensed ring or a substituted aromatic ring, a heterocyclic ring, a heteroaromatic ring and a condensed ring, and the substitution is monosubstitution or geminal disubstitution;

[0081] R 13 , R 14 are independently H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl or ether.

[0082] Preferably, R t Select from the following structures:

[0083]

[0084] In the above reaction, R in Formula I and Formula II t It has the structure of the following formula (2):

[0085] in,

[0086] The three Ys are independently C or O;

[0087] R s Is halogen or

[0088] Preferably, one of the three Ys is O, and the others are C;

[0089] Halogen is F;

[0090] X 10 O, S, SO or SO2;

[0091] R v Definition: R as described in the claims of patent application PCT / CN2020 / 120281 and publication number WO2021068952A1 w The synthesis and preparation methods of specific compounds are also recorded in the above-mentioned application, and the full text of the patent is hereby introduced into the present application.

[0092] R w The definition is as follows:

[0093] R w for

[0094] 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;

[0095] Each R a are independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl;

[0096] R2 is H or C 1-6 alkyl;

[0097] 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;

[0098] Each R b are independently H, F, Cl, Br, I, -CN, -OH, -NH2, -OCH3, -OCH2CH3, -CH3 or -CH2CH3;

[0099] R3 is H, F, Cl, Br, I, -OH, -NH2, C 1-3 Alkoxy or C 1-3 alkyl;

[0100] Or R2 and R3 are connected together to make the structural unit for

[0101] T1 is -(CR c R d ) m -or-(CR c R d ) n -O-;

[0102] m is 1, 2 or 3;

[0103] n is 1 or 2;

[0104] T2 is N or CH;

[0105] R c and R d Each independently is H, F, C 1-3 Alkyl or C 1-3 Alkoxy;

[0106] R4, R5 and R6 are each independently H, F, Cl, Br, I, C 1-3 Alkyl or C 1-3 Alkoxy;

[0107] T is N or CH;

[0108] R7 and R8 are each independently H, F, Cl, Br or I;

[0109] R9 and R 10 Each independently is H, F, Cl, Br, I, -CN or

[0110] The 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl each contain 1, 2, 3 or 4 heteroatoms independently selected from N, -O- and -S-.

[0111] Preferably, R t Selected from the following structures:

[0112]

[0113] In the above reaction, R in Formula I and Formula II t It has the structure of the following formula (3):

[0114] in,

[0115] R1, R2, R3, C xThe definition is as recorded in the claims of patent application PCT / CN2020 / 114519 and publication number WO2021120717A1, and the synthesis and preparation methods of specific compounds are also recorded in the above-mentioned applications, which are hereby introduced into the present application in their entirety.

[0116] R1, R2, R3, C x The specific definition is as follows:

[0117] Cx is a 5-10 membered aromatic ring or aromatic heterocyclic ring, aliphatic heterocyclic ring or cycloalkane, which shares two carbon atoms with the nitrobenzene ring to form a condensed ring structure;

[0118] R1 is connected to any backbone atom of the Cx ring and is selected from hydrogen, halogen atoms, cyano or isocyano, hydroxyl, thiol, amine, OTs, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, 1-6 carbon atom alkoxy or Z-substituted 1-6 carbon atom alkoxy, -CONR 6 R 7 、-SO2NR 6 R 7 、-SO2R 6 、-OCOO-R 6 、-COOR 6 、-NR 6 COR 7 、-OCOR 6 、-NR 6 S02R 7 、-NR 6 SO2NR 6 R 7 ,

[0119] R2 and R3 are each independently hydrogen, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, or R2, R3 and the benzylic carbon atom to which they are bonded together form a 3-6 membered ring;

[0120] The group can replace the hydrogen atom at any position on the condensed ring carbon atom, and the number of substitutions is 1;

[0121] The Z substituent is a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a mercapto group, an amine group, a C1-C3 alkyl group or a substituted alkyl group, a C1-C3 alkoxy group or a substituted alkoxy group, a C2-C3 alkenyl group or a substituted alkenyl group, a C2-C3 alkynyl group or a substituted alkynyl group, or a C3-C8 cycloalkyl group or a substituted cycloalkyl group;

[0122] R 6 , R 7 Each is independently hydrogen, C1-C6 alkyl or Z-substituted C1-C6 alkyl, C2-C6 alkenyl or Z-substituted C2-C6 alkenyl, C2-C6 alkynyl or Z-substituted C2-C6 alkynyl, C3-C8 cycloalkyl or Z-substituted C3-C8 cycloalkyl, C6-C 10 Aryl or Z substituted C6-C 10 aryl, 4-15 membered heterocyclic group or 4-15 membered heterocyclic group substituted by Z, 5-15 membered heteroaryl or 5-15 membered heteroaryl substituted by Z, or R 6 , R 7 Together with the atoms to which it is bonded, it forms a 5-7 membered heterocyclic group or a Z-substituted 5-7 membered heterocyclic group.

[0123] Preferably, R t Select from the following structures:

[0124]

[0125] In the above reaction, R in Formula I and Formula II t It has the structure of the following formula (4):

[0126] wherein L is independently selected from H, -CH3, -CH2CH3 or -CF3.

[0127] Preferably, R t Select from the following structures:

[0128]

[0129] In the above reaction, R in Formula I and Formula II t It can also be the following structure:

[0130]

[0131] In the above reaction, when R t When the structure is formula (1), the compound of formula II is selected from the following structural compounds:

[0132]

[0133] as well as as well as

[0134]

[0135]

[0136] as well as

[0137]

[0138]

[0139]

[0140] and

[0141]

[0142] In the above reaction, when R t When the structure is formula (2), the compound of formula II is selected from the following structural compounds:

[0143]

[0144]

[0145] In the above reaction, when R t When the structure is formula (3), the compound of formula II is selected from the following structural compounds:

[0146]

[0147] In the above reaction, when R t When the structure is formula (4), the compound of formula II is selected from the following structural compounds:

[0148]

[0149] In the above reaction, the compound of formula II is selected from the following structural compounds:

[0150]

[0151] For the above-mentioned synthesis method, the base is selected from NaOH, KOH or a combination of the two, which includes the following reaction steps: after the compound I and the solvent are stirred to dissolve, the temperature is lowered to -10°C to 10°C, and the alkaline solution is slowly added dropwise. After the addition is completed, the solution is kept warm and stirred continuously until the reaction is complete.

[0152] Preferably, the ratio of the volume amount (ml:mmol) of the solvent to the compound I is 3-5:1, preferably 4:1; or

[0153] The solvent is THF; or

[0154] The base is configured as THF, dioxane, acetone, acetonitrile, DMF or an aqueous solution, preferably an aqueous solution of NaOH and / or KOH, and the concentration thereof is 0.5-1 mol / L; or

[0155] The volume amount (ml:mmol) ratio of the alkaline solution to the compound I is 1.8-3.5:1, preferably 2.2:1; or

[0156] The temperature is cooled to -5°C to 5°C; or

[0157] The dropwise addition time of the base is 0.8 to 1.2 h, preferably 1.0 h.

[0158] 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.

[0159] In the above ratio, if the base is a mixture of NaOH and KOH, the amount of the substance providing alkalinity OH in the mixture is the same as the amount of the substance providing OH in single NaOH or KOH.

[0160] For the above-mentioned synthesis method, the base is selected from K2CO3, Cs2CO3, K3PO4 or any combination thereof, which includes the following reaction steps: at room temperature, compound I and solvent are stirred to dissolve, then a base is added, the reaction temperature is controlled at -15°C to 70°C, and stirring is performed until the reaction is complete.

[0161] Preferably, the ratio of the volume amount (ml:mmol) of the solvent to the compound I is 4-5:1, preferably 4.5:1; or

[0162] The molar ratio of the base to compound I is 3-5:1; or

[0163] The base is configured as THF, dioxane, acetone, acetonitrile, DMF or an aqueous solution; or

[0164] The reaction temperature is -15°C to 50°C, preferably -5°C to 50°C; or

[0165] After the reaction was completed, the solid salt was filtered out through diatomaceous earth and concentrated to obtain compound II.

[0166] For the above-mentioned synthesis method, the base is selected from DBU, NaHMDS, KHMDS, t-BuOK, t-BuONa or any combination thereof, which comprises the following reaction steps: after the compound I and the solvent are stirred to dissolve, the temperature is lowered to -10°C-5°C, the base is added dropwise, and the reaction temperature is maintained at -10°C-5°C and stirring is continued until the reaction is complete.

[0167] Preferably, the ratio of the volume amount (ml:mmol) of the solvent to the compound I is 4-5:1, preferably 4.5:1; or

[0168] The solvent is selected from THF and / or DMF; or

[0169] The molar ratio of the base to compound I is 2-4:1, preferably 2-3:1; or

[0170] The base is configured as THF, dioxane, acetone, acetonitrile, DMF or an aqueous solution; or

[0171] The reaction temperature is -10°C to 0°C, preferably -5°C to 0°C.

[0172] In the above-mentioned synthesis reaction, the following post-treatment steps may also be included: adding saturated brine to the reaction system, extracting the aqueous phase with ethyl acetate, combining the organic phases, and then washing the organic phases with saturated brine, collecting the organic phases, adding a desiccant to dry, filtering and concentrating to dryness, separating and purifying with a silica gel column or recrystallizing to obtain a refined product of compound II.

[0173] Preferably, the ratio of the volume amount (ml:mmol) of the saturated salt water added to the reaction system to the compound I is 2.5-5:1, preferably 3:1; or

[0174] Extract the aqueous phase twice with ethyl acetate, each time using ethyl acetate in a ratio of ethyl acetate to the volume amount of compound I (ml:mmol) of 2.5-8:1, preferably 3:1; or

[0175] The amount of saturated brine used for washing the organic phase is such that the ratio of the volume amount (ml:mmol) of saturated brine to compound I is 2.5-5:1, preferably 3:1. DETAILED DESCRIPTION

[0176] 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.

[0177] The experimental methods in the following examples are conventional methods unless otherwise specified. The medicinal materials, reagents, etc. used are commercially available products unless otherwise specified.

[0178] The present invention uses the following abbreviations:

[0179] THF Tetrahydrofuran DMF N,N-Dimethylformamide Acetone acetone DBU <![CDATA[1,8-Diazabicyclo[5.4.0]undec-7-ene; Molecular formula: C9H 16 N2]]> NaHMDS Sodium bis(trimethylsilyl)amide, sodium hexamethyldisilazide KHMDS Potassium bis(trimethylsilyl)amide, potassium hexamethyldisilazide t-BuONa Sodium tert-butoxide t-BuOK Potassium tert-butoxide OMs <![CDATA[Methylsulfonate group; -OSO2CH3]]> OTs <![CDATA[p-toluenesulfonate group; p-CH3-C6H4-SO2-O-]]> ONs <![CDATA[p-Nitrophenylsulfonate group; -O-SO2-C6H4-NO2-p]]>

[0180] Purity was determined by HPLC and the percentage of the target compound was calculated by area normalization method.

[0181] Example 1: Ring-closing reaction with strong bases such as NaOH or KOH

[0182] 1.1 When X and Y are both Br, the following ring-closure reaction is carried out:

[0183]

[0184] At room temperature, the substrate (Compound I, 10 mmol) and 40 ml of THF were added to the reaction flask. After stirring to dissolve, the temperature was lowered to -5 to 5 ° C. 22 ml of 1 mol / L KOH or NaOH aqueous solution was slowly added dropwise for 1 hour. After the addition, the reaction was continued with stirring for 1 to 2 hours. After the reaction was complete, 30 ml of saturated brine was added to the reaction flask. The aqueous phase was extracted twice with 30 ml of ethyl acetate. The organic phases were combined and washed with 30 ml of saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Compound II was obtained after separation and purification on a silica gel column.

[0185] R t Selected from the following structures:

[0186]

[0187] The corresponding base, compound II structure and its amount, yield and purity are shown in Table 1, and the NMR data is shown in the last part of the specification.

[0188] Table 1: Reaction yield, yield and purity data of compound II

[0189]

[0190]

[0191] 1.2 When R t for When, on the basis of the experimental method in 1.1, the amount of base, the amount of solvent, and the reaction temperature were changed, and other operating conditions remained unchanged. After post-treatment, compound II, i.e. compound number M1, was obtained. Its amount, yield, and purity data are shown in Table 2.

[0192] Table 2: Reaction yield, yield and purity data of compound II at different base dosage, solvent dosage and reaction temperature

[0193]

[0194] Example 2: Ring-closing reaction with strong base and weak acid salt such as K2CO3, Cs2CO3, K3PO4

[0195] 2.1 When X and Y are both Br, the following ring-closure reaction is carried out:

[0196]

[0197] At room temperature, 10 mmol of compound I (substrate) and 45 ml of solvent were added to the reaction bottle. After stirring until dissolved, 40 mmol of a strong base and a weak acid salt were added, and the reaction temperature was controlled to react at a certain temperature. After the reaction was complete, the solid salt was filtered out with diatomaceous earth, and the crude product of compound II was obtained by concentration, and the crude product was separated and purified by silica gel column to obtain compound II.

[0198] R t Selected from the following structures:

[0199]

[0200] Different strong bases, weak acid salts, different solvents, and different reaction temperatures were used to carry out the corresponding ring-closing reactions. t The amount, yield and purity of compound II after column chromatography purification corresponding to the structure are shown in Table 3. The NMR data of each compound can be found in the last part of the specification.

[0201] Table 3: The yield, yield and purity data of each ring-closure reaction under different reaction conditions

[0202]

[0203]

[0204] 2.2 When X and Y are both ONs, the following ring-closing reaction is carried out:

[0205]

[0206] On the basis of the experimental method in 2.1, different bases of strong base and weak acid salt, different solvent selection, and different reaction temperature were used to carry out the corresponding ring-closing reaction. t The amount, yield and purity of compound II after column chromatography purification corresponding to the structure are shown in Table 4. The NMR data of each compound can be found in the last part of the specification.

[0207] Table 4: When X and Y are both ONs, the yield, yield and purity data of each ring-closure reaction under different reaction conditions

[0208]

[0209] Note: Room temperature is 25°C.

[0210] Example 3: Ring-closing reaction with organic bases such as DBU, NaHMDS, KHMDS, t-BuOK, and t-BuONa

[0211] When X and Y are both Br, the following ring-closure reaction is carried out:

[0212]

[0213] Add 10 mmol of compound I (substrate) and 45 ml of solvent into a reaction flask, stir until dissolved, cool to -5°C to 0°C, add 25 mmol of an organic base, maintain -5°C to 0°C and continue stirring to react; after the reaction is complete, add 30 ml of saturated brine to the reaction flask, then extract twice with 30 ml of ethyl acetate, combine the organic phases; then extract the organic phase with 30 ml of saturated brine, then dry with anhydrous sodium sulfate, filter and concentrate to dryness, separate and purify on a silica gel column or recrystallize to obtain compound II.

[0214] R t Selected from the following structures:

[0215]

[0216] Different organic bases were used to carry out the corresponding ring-closing reactions. t The amount, yield and column chromatography purity of different compounds II corresponding to the structure are shown in Table 5. The NMR data of each compound can be found in the last part of the specification.

[0217] Table 5: The yield, yield and purity data of the ring-closure reaction under different organic base reaction conditions

[0218]

[0219] In the above embodiments 1 to 3, different R t The structures correspond to different compounds II (compounds M1-M11). The NMR data of the synthesized compounds M1-M11 are as follows:

[0220] Compound M1 1 H-NMR (400MHz, CDCl3): δ8.07(t,J=8.0Hz,1H),7.41-7.29(m,2H),5.74–5.63(m,1H),2.27–2.07(m,8H),1.63(d,J=6.6Hz,3H).

[0221] Compound M2 1 H-NMR (400MHz, Chloroform-d): δ7.92(d,J=8.5Hz,1H),7.40–7.33(m,1H),7.25–7.13(m,2H),7.09 –6.95(m,3H),5.62–5.42(m,1H),2.97(d,J=41.0Hz,6H),2.15–1.91(m,8H),1.52(d,J=6.5Hz,3H).

[0222] Compound M3 1 H-NMR (400MHz, Chloroform-d): δ8.15 (dd, J=8.4, 7.3Hz, 1H), 7.61–

[0223] 7.37(m,2H),5.84(dq,J=10.2,6.2Hz,1H),2.40–2.10(m,8H).

[0224] Compound M4 1 H-NMR (400MHz, Chloroform-d): δ8.06 (d, J=8.4Hz, 1H), 7.51 (ddt, J=6.9, 5.3, 1.6Hz, 2H), 7.48–7.40 (m, 2H), 7.34(d,J=1.8Hz,1H),7.21–7.09(m,2H),6.95–6.79(m,2H),5.78(dq,J=10.1,6.2Hz,1H),2.30–2.05(m,8H).

[0225] Compound M5 1 H-NMR (400MHz, Chloroform-d) δ: 8.02 (d, J=8.4Hz, 1H), 7.50 (ddd, J=8.8, 5.3, 1.6Hz, 2H), 7.40 (t, J=8.6Hz, 1H), 7.31 (dd, J=8.5, 1.8 Hz,1H),7.22(d,J=1.7Hz,1H),7.14(t,J=8.7Hz,2H),6.92–6.78(m,2H),5.93–5.44(m,1H),2.22–2.05(m,8H),1.62(d,J=6.5Hz,3H).

[0226] Compound M6 1 H-NMR (400MHz, Chloroform-d): 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).

[0227] Compound M7 1H-NMR (400MHz, Chloroform-d) δ: 7.48 (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, 1 H),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).

[0228] Compound M8 1 H-NMR (400MHz, Chloroform-d) δ: 8.54–8.46 (m, 1H), 8.21 (dd, J = 12.4, 8.1Hz, 1H ),7.97(d,J=8.0Hz,1H),7.84–7.67(m,2H),6.67(dq,J=11.6,5.8Hz,1H),2.31–

[0229] 2.10(m,4H),2.08–2.04(m,1H),2.01–1.88(m,3H).

[0230] Compound M9 1 H-NMR (400MHz, Chloroform-d) δ: 8.54–8.46 (m, 1H), 8.21 (dd, J=12.4, 8.1Hz, 2H ),7.97(d,J=8.0Hz,1H),7.84–7.67(m,2H),6.67(dq,J=11.6,5.8Hz,1H),2.31–

[0231] 2.10(m,4H),2.08–2.04(m,1H),2.01–1.88(m,3H).

[0232] Compound M10 1 H-NMR (400MHz, Chloroform-d) δ: 7.23 (s, 1H), 5.20 (d, J = 7.7Hz, 2H), 4.09 (d, J = 1.2Hz, 3H), 2.28–2.14 (m, 8H).

[0233] Compound M11 1 H-NMR (400MHz, Chloroform-d) δ: 3.51 (dt, J=7.5, 3.6Hz, 2H), 2.83–

[0234] 2.58(m,2H),2.43–2.15(m,8H),1.82–1.59(m,6H),1.32–1.17(m,1H).

[0235] The above embodiments describe the basic principles or main features or advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments, and the above embodiments and descriptions only describe the principles or main features or advantages of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the claims for protection.

Claims

1. A method for synthesizing a compound II having the following formula: in, The base is selected from one or more of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal dihydrogen phosphates, and organic bases, and the organic base does not include n-butyl lithium; The solvent is selected from one or more of acetone, DMF, THF and acetonitrile; R t is a cyclic or chain group containing C, H and at least one of O, N, and halogen atoms, and -O- and R t The C or N atoms in are directly connected; X and Y are each independently selected from halogen, OMs, OTs or ONs.

2. The synthesis method according to claim 1, wherein The base is selected from one or more of NaOH, KOH, CsOH, Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, CsHCO3, Na3PO4, Na2HPO4, K3PO4, K2HPO4, DBU, NaHMDS, KHMDS, t-BuOK, t-BuONa, and TMG; the halogen is selected from F, Cl, Br, and I, and is preferably F.

3. The synthetic method according to claim 1, wherein R in Formula I and Formula II t It has the structure of the following formula (1): in, X, Y, and Z are each independently H, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 、-NR 13 COR 14 ; R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 、-NR 13 COR 14 ; R w Halogen or Among them, X 10 It is O, S, SO or SO2.

4. The synthesis method according to claim 3, wherein Halogen is F; A is C6-C 10 Aryl, 5-15 membered heteroaryl, -N=CR 1 R 2 or 5. The synthesis method according to claim 4, wherein R 1 , R 2 Each independently represents H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 、-NR 13 COR 14 ; R3 is C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic ring or Z-substituted heterocyclic ring, 5-15 membered heteroaryl or Z-substituted heteroaryl, 7-15 membered condensed ring or Z-substituted condensed ring; R4 is hydrogen, a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a mercapto group, an amine group, OTs, OMs, a C1-C6 alkyl group or a Z-substituted alkyl group, a C2-C6 alkenyl group or a Z-substituted alkenyl group, a C2-C6 alkynyl group or a Z-substituted alkynyl group, a C3-C8 cycloalkyl group or a Z-substituted cycloalkyl group, a C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, ether of 1-6 carbon atoms or alkoxy of 1-6 carbon atoms substituted by Z, -CONR 6 R 7 、-SO2NR 6 R 7 、-SO2R 6 、-OCOO-R 6 、-COOR 6 、-NR 6 COR 7 、-OCOR 6 、-NR 6 S02R 7 、-NR 6 SO2NR 6 R 7 Or R2 and the atoms on the R1 group to which it is bonded together form a 7-15 membered condensed ring or a Z-substituted condensed ring; Preferably, R 13 , R 14 are independently H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl or ether. Preferably, R 6 and R 7 Each of them is independently hydrogen, cyano or isocyano, C1-C6 alkyl or Z-substituted alkyl, C2-C6 alkenyl or Z-substituted alkenyl, C2-C6 alkynyl or Z-substituted alkynyl, C3-C8 cycloalkyl or Z-substituted cycloalkyl, C6-C 10 Aryl or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, C1-C6 alkoxy or Z-substituted C1-C6 alkoxy, or R 6 , R 7 The group together with the atom to which it is bonded forms a 5-7 membered heterocyclic group or a Z-substituted 5-7 membered heterocyclic group; Preferably, the Z substituent is a halogen atom, a cyano group or an isocyano group, a hydroxyl group, a thiol group, an amine group, OTs, OMs, a C1-C3 alkyl group or a substituted alkyl group, a C1-C3 alkoxy group or a substituted alkoxy group, a C2-C3 alkenyl group or a substituted alkenyl group, a C2-C3 alkynyl group or a substituted alkynyl group, a C3-C8 cycloalkyl group or a substituted cycloalkyl group, an aromatic ring, a heterocyclic ring, a heteroaromatic ring and a condensed ring or a substituted aromatic ring, a heterocyclic ring, a heteroaromatic ring and a condensed ring, and the substitution is monosubstitution or geminal disubstitution.

6. The synthesis method according to claim 3, wherein R t for 7. The synthesis method according to claim 1, wherein R in Formula I and Formula II t It has the structure of the following formula (2): in, The three Ys are independently C or O; R s Is halogen or 8. The synthesis method according to claim 7, wherein One of the three Ys is O, and the rest are C; Halogen is F; X 10 O, S, SO or SO2; R v Definition: R as described in the claims of patent application PCT / CN2020 / 120281 and publication number WO2021068952A1 w .

9. The synthesis method according to claim 8, wherein R t for 10. The synthesis method according to claim 1, wherein R in Formula I and Formula II t It has the structure of the following formula (3): in, R1, R2, R3, C x The definition of is as recorded in the claims of patent application PCT / CN2020 / 114519 and publication number WO2021120717A1.

11. The synthesis method according to claim 10, wherein R t for 12. The synthesis method according to claim 1, wherein R in Formula I and Formula II t It has the structure of the following formula (4): in, L is each independently selected from H, -CH3, -CH2CH3 or -CF3.

13. The synthesis method according to claim 12, wherein R t for 14. The synthesis method according to claim 1, wherein R in Formula I and Formula II t for 15. The synthesis method according to claim 1, wherein When R t When the structure is formula (1), the compound of formula II is selected from the following structural compounds: as well as as well as as well as and When R t When the structure is formula (2), the compound of formula II is selected from the following structural compounds: When R t When the structure is formula (3), the compound of formula II is selected from the following structural compounds: When R t When the structure is formula (4), the compound of formula II is selected from the following structural compounds:

16. The synthesis method according to any one of claims 1 to 15, wherein: The base is selected from NaOH, KOH or a combination of the two, and the reaction comprises the following steps: after the compound I and the solvent are stirred and dissolved, the temperature is lowered to -10°C to 10°C, and the base solution is slowly added dropwise. After the addition is completed, the solution is kept warm and stirred continuously until the reaction is complete.

17. The synthesis method according to claim 16, wherein The ratio of the volume amount (ml:mmol) of the solvent to the compound I is 3-5:1, preferably 4:1; or The solvent is THF; or The base is configured as THF, dioxane, acetone, acetonitrile, DMF or an aqueous solution, preferably an aqueous solution of NaOH and / or KOH, and the concentration thereof is 0.5-1 mol / L; or The volume amount (ml:mmol) ratio of the alkaline solution to the compound I is 1.8-3.5:1, preferably 2.2:1; or The temperature is cooled to -5°C to 5°C; or The dropwise addition time of the base is 0.8 to 1.2 h, preferably 1.0 h.

18. The synthesis method according to any one of claims 1 to 15, wherein: The base is selected from Na2CO3, K2CO3, Cs2CO3, Na3PO4, K3PO4 or any combination thereof, and comprises the following reaction steps: at room temperature, after the compound I and the solvent are stirred to dissolve, a base is added, the reaction temperature is controlled at -15°C to 70°C, and stirring is performed until the reaction is complete.

19. The synthesis method according to claim 18, wherein The ratio of the volume amount (ml:mmol) of the solvent to the compound I is 4-5:1, preferably 4.5:1; or The molar ratio of the base to compound I is 3-5:1; or The base is configured as THF, dioxane, acetone, acetonitrile, DMF or an aqueous solution; or The reaction temperature is -15°C to 50°C, preferably -5°C to 50°C; or After the reaction was completed, the solid salt was filtered out through diatomaceous earth and concentrated to obtain compound II.

20. The synthesis method according to any one of claims 1 to 15, wherein: The base is selected from DBU, NaHMDS, KHMDS, t-BuOK, t-BuONa, TMG or any combination thereof, and comprises the following reaction steps: after the compound I and the solvent are stirred to dissolve, the temperature is lowered to -10°C-5°C, the base is added dropwise, and the reaction temperature is maintained at -10°C-5°C and stirring is continued until the reaction is complete.

21. The synthesis method according to claim 20, wherein: The ratio of the volume amount (ml:mmol) of the solvent to the compound I is 4-5:1, preferably 4.5:1; or The solvent is selected from THF and / or DMF; or The molar ratio of the base to compound I is 2-4:1, preferably 2-3:1; or The base is configured as THF, dioxane, acetone, acetonitrile, DMF or an aqueous solution; or The reaction temperature is -10°C to 0°C, preferably -5°C to 0°C.

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