Naphthyridinone derivative and preparation method therefor

Abstract

The present disclosure relates to a naphthyridinone derivative and a preparation method therefor. Specifically, the present disclosure relates to a method for preparing the compound as represented by formula 4a or a salt thereof. The preparation method has the advantages of a mild reaction, suitability for industrial production, etc.

Description

A naphthidone derivative and its preparation method Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to the preparation of a naphthidinone derivative and its preparation method. Background Technology

[0002] Poly(ADP-ribose) polymerase 1 (PARP1), first reported over 50 years ago, has since been found to play crucial roles in DNA repair, maintaining genome integrity, and regulating various metabolic and signal transduction processes. PARP1 catalyzes the transfer of ADP-ribose residues from NAD+ to target substrates, constructing a poly(ADP-ribose) (PAR) chain. The formation and clearance of PAR chains occur in almost all eukaryotic cells.

[0003] ADP-ribosylation is a post-translational modification of proteins widely present in various physiological and pathological processes. It refers to the binding of one or more ADP-ribose units to a specific site on a protein under the catalysis of an enzyme. PARP1 is the first member of the PARP superfamily, which consists of proteins homologous to PARP1 and currently has 17 members, four of which (PARP1, PARP2, PARP5A, and PARP5B) can synthesize PAR chains. Most other enzymes in the family can only construct a single ADP-ribose unit and are therefore classified as mono(ADP-ribosyl)ases (MARs).

[0004] This disclosure provides a novel method for preparing PARP inhibitors, which has advantages such as mild reaction and suitability for industrial production. Summary of the Invention

[0005] Firstly, this disclosure provides a method for preparing a compound or its salt as shown in Formula 4a, which has advantages such as mild reaction and suitability for industrial production. It includes reacting a compound or its salt as shown in Formula 3a in the presence of a basic substance and a carbene reagent to form a compound or its salt as shown in Formula 4a.

[0006] in,

[0007] R1 is selected from halogen, C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkylene 3-6 membered cycloalkyl, wherein C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6The alkylene group (3-6 membered cycloalkyl group) may optionally be replaced by one or more substituents selected from halogen, hydroxyl, or cyano groups;

[0008] R2 is selected from an amino protecting group;

[0009] R3 is selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)OC 1-6 Alkyl, -O-aryl, -CHO, wherein the C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)OC 1-6 The alkyl and -O-aryl groups may be optionally replaced by one or more substituents selected from halogens, hydroxyl groups, and cyano groups;

[0010] R4 is selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0011] X is selected from halogen, C 1-6 Alkoxy, -O-aryl.

[0012] In some embodiments, such as the preparation method described in the first aspect, the alkaline substance is selected from at least one of K2CO3, CsF, and Cs2CO3.

[0013] In some embodiments, such as the preparation method described in the first aspect, the alkaline substance is selected from a combination of CsF and Cs2CO3.

[0014] In some embodiments, such as the preparation method described in the first aspect, the alkaline substance is selected from K2CO3.

[0015] In some embodiments, such as the preparation method described in the first aspect, the carbene reagent is selected from 1,3-dimethylimidazole chloride, 1,3-dicyclohexylimidazole chloride, 1,3-bis(2,4,6-trimethylphenyl)imidazole chloride, 1,3-bis(2,6-diisopropylphenyl)imidazole onium chloride, and 1,3-bis(4-trimethoxyphenyl)dimethylimidazole chloride.

[0016] In some embodiments, such as the preparation method described in the first aspect, the carbene reagent is selected from 1,3-dimethylimidazole chloride, 1,3-dicyclohexylimidazole chloride, and 1,3-bis(4-trimethoxyphenyl)dimethylimidazole chloride.

[0017] In some embodiments, such as the preparation method described in the first aspect, the amino protecting group is selected from Bn (benzyl), PMB (p-methoxybenzyl), DMB (2,4-dimethoxybenzyl), Tr (triphenylmethyl), Me (methyl), SEM (trimethylsilylethoxymethyl), BOM (benzylchloromethyl ether), and MOM (chloromethyl methyl ether).

[0018] In some embodiments, such as the preparation method described in the first aspect, the amino protecting group is selected from Bn (benzyl), PMB (p-methoxybenzyl), and Me (methyl).

[0019] In some embodiments, such as the preparation method described in the first aspect, the amino protecting group is selected from PMB (p-methoxybenzyl).

[0020] In some embodiments, such as the preparation method described in the first aspect, R1 is selected from C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 alkylene 3-6 membered cycloalkyl, wherein C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 The alkylene group (3-6 membered cycloalkyl group) may be optionally replaced by one or more substituents selected from halogen, hydroxyl, or cyano groups.

[0021] In some embodiments, such as the preparation method described in the first aspect, R1 is selected from C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkylene, 3-6 membered cycloalkyl.

[0022] In some embodiments, such as the preparation method described in the first aspect, R1 is selected from methyl, ethyl, propyl, cyclopropyl, and methylenecyclopropyl.

[0023] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from halogens, C 1-6 Alkyl, C 1- 6-alkoxy, -O-aryl, -CHO, wherein C 1-6 Alkyl, C 1-6 The alkoxy and -O-aryl groups may be optionally replaced by one or more substituents selected from halogens, hydroxyl groups, and cyano groups.

[0024] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from halogens, C 1-6 Alkyl, -C(O)OC 1-6 Alkyl group, -CHO.

[0025] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from halogens, C 1-6 Alkyl group, -CHO.

[0026] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from halogens, halogenated C, etc. 1- 6-alkyl, hydroxy-C 1-6 Alkyl group, -CHO.

[0027] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from halogens, halogenated C, etc. 1- 6-alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Alkoxy, -O-aryl, -CHO.

[0028] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from halogens.

[0029] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from C 1-6 alkyl.

[0030] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from -C(O)OC 1-6 alkyl.

[0031] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from -CHO.

[0032] In some embodiments, such as the preparation method described in the first aspect, R3 is selected from halogens and -CHO.

[0033] In some embodiments, such as the preparation method described in the first aspect, R4 is selected from hydrogen, C 1-6 alkyl.

[0034] In some embodiments, such as the preparation method described in the first aspect, X is selected from halogens.

[0035] In some embodiments, such as the preparation method described in the first aspect, X is selected from C 1-6 Alkoxy, -O-aryl.

[0036] In some embodiments, such as the preparation method described in the first aspect, X is selected from F, Cl, Br, I, methoxy, and -OPh.

[0037] In some embodiments, such as the preparation method described in the first aspect, R1 is selected from ethyl; R2 is selected from PMB (p-methoxybenzyl); R3 is selected from halogen; X is selected from halogen; and R4 is selected from hydrogen.

[0038] In some embodiments, such as the preparation method described in the first aspect, R1 is selected from ethyl; R2 is selected from PMB (p-methoxybenzyl); R3 is selected from Br; X is selected from Cl; and R4 is selected from hydrogen.

[0039] In some embodiments, such as the preparation method described in the first aspect, the molar ratio of the compound represented by formula 3a to the basic substance is 1:1 to 1:10.

[0040] In some embodiments, such as the preparation method described in the first aspect, the molar ratio of the compound represented by formula 3a to the basic substance is 1:1 to 1:5.

[0041] In some embodiments, such as the preparation method described in the first aspect, the molar ratio of the compound represented by formula 3a to the basic substance is 1:2 to 1:5.

[0042] In some embodiments, such as the preparation method described in the first aspect, the molar ratio of the compound represented by formula 3a to the carbene reagent is 1:0.01-1:5.

[0043] In some embodiments, such as the preparation method described in the first aspect, the molar ratio of the compound represented by formula 3a to the carbene reagent is 1:0.05-1:3.

[0044] In some embodiments, such as the preparation method described in the first aspect, the molar ratio of the compound represented by formula 3a to the carbene reagent is 1:0.1-1:1.

[0045] In some embodiments, such as the preparation method described in the first aspect, the preparation method is carried out in a solvent, said solvent including but not limited to one or more of toluene, xylene, dimethylacetamide, chlorobenzene, and 1,4-dioxane.

[0046] In some embodiments, this disclosure also provides a method for preparing a compound or a salt thereof as shown in Formula 4b, comprising the step of removing the protecting group R2 from the compound or a salt thereof shown in Formula 4a.

[0047] In some implementations, the conditions / operations for removing the amino protecting group are described in Greene & Wuts, eds., *Protecting Groups in Organic Synthesis*, 3rd edition, 1999, and related content is incorporated herein for illustration.

[0048] In some embodiments, the present disclosure includes a method for preparing a compound or a salt thereof as shown in Formula 4b, including the preparation method described in the first aspect.

[0049] In some embodiments, a method for preparing a compound or a salt thereof as shown in Formula 4b according to the present disclosure includes preparing a compound or a salt thereof as shown in Formula 4a according to the preparation method described in the first aspect.

[0050] In some embodiments, this disclosure also provides a method for preparing a PARP inhibitor, comprising using a compound of formula 4a or 4b or a salt thereof as one of the starting materials.

[0051] In some embodiments, a method for preparing a PARP inhibitor according to this disclosure includes using a compound of formula 4a or 4b or a salt thereof as one of the raw materials, wherein the compound of formula 4a or 4b or a salt thereof is prepared according to the foregoing preparation method.

[0052] In some embodiments, a method for preparing a PARP inhibitor as described in this disclosure includes the steps of preparing a compound of formula 4a or a salt thereof by the aforementioned preparation method and / or the steps of preparing a compound of formula 4b or a salt thereof by the aforementioned preparation method.

[0053] In some embodiments, the method for preparing a PARP inhibitor described in this disclosure, wherein R3 is selected from halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl group, -CHO.

[0054] In some embodiments, the method for preparing a PARP inhibitor is described, wherein R3 is selected from -CHO.

[0055] In some embodiments, the present disclosure describes a method for preparing a PARP inhibitor, wherein the compound represented by formula 4a or a salt thereof is prepared as described in the first aspect.

[0056] In some embodiments, the method for preparing a PARP inhibitor described in this disclosure is wherein the compound represented by formula 4b or a salt thereof is prepared as described above.

[0057] In some embodiments, the PARP inhibitors described in this disclosure are selected from...

[0058] Secondly, this disclosure also provides a method for preparing a compound or a salt thereof as shown in formula 7a, comprising reacting a compound or a salt thereof as shown in formula 4a or 4b with a compound or a salt thereof as shown in formula 6a.

[0059] R5 is selected from an amino protecting group or hydrogen.

[0060] In some embodiments, the method for preparing a compound of formula 7a or a salt thereof as described in this disclosure, wherein R5 is selected from an amino protecting group.

[0061] In some embodiments, the method for preparing a compound of Formula 7 or a salt thereof as described in this disclosure, wherein R5 is selected from PMB (p-methoxybenzyl).

[0062] In some embodiments, the method for preparing a compound of formula 7a or a salt thereof as described in this disclosure, wherein R5 is selected from hydrogen.

[0063] In some embodiments, the amino protecting group is selected from Bn (benzyl), PMB (p-methoxybenzyl), DMB (2,4-dimethoxybenzyl), Tr (triphenylmethyl), Me (methyl), SEM (trimethylsilylethoxymethyl), BOM (benzylchloromethyl ether), and MOM (chloromethyl methyl ether).

[0064] In some embodiments, a method for preparing a compound of formula 7a or a salt thereof as described in this disclosure includes the preparation method described in the first aspect.

[0065] In some embodiments, the present disclosure describes a method for preparing a compound of formula 7a or a salt thereof, wherein the compound of formula 4a or 4b or a salt thereof is prepared according to the foregoing preparation method.

[0066] This disclosure also provides a method for preparing a compound of formula 8a or a pharmaceutically acceptable salt thereof, comprising the step of removing the protecting group R5 from the compound of formula 7a or a salt thereof.

[0067] In some embodiments, this disclosure also provides a method for preparing a compound or a salt thereof as shown in Formula 7, comprising reacting a compound or a salt thereof as shown in Formula 4a or 4b with a compound or a salt thereof as shown in Formula 6.

[0068] R5 is selected from an amino protecting group or hydrogen.

[0069] In some embodiments, the method for preparing a compound of Formula 7 or a salt thereof as described in this disclosure, wherein R5 is selected from an amino protecting group.

[0070] In some embodiments, the method for preparing a compound of Formula 7 or a salt thereof as described in this disclosure, wherein R5 is selected from PMB (p-methoxybenzyl).

[0071] In some embodiments, the method for preparing a compound of Formula 7 or a salt thereof as described in this disclosure, wherein R5 is selected from hydrogen.

[0072] This disclosure also provides a method for preparing a compound as shown in Formula 8 or a pharmaceutically acceptable salt thereof, comprising the step of removing the protecting group R5 from the compound as shown in Formula 7 or a salt thereof.

[0073] Thirdly, this disclosure also provides a method for preparing a compound or a salt thereof as shown in formula 5a, comprising reacting a compound or a salt thereof as shown in formula 4a or 4b in the presence of alkyllithium to form a compound or a salt thereof as shown in formula 5a.

[0074] in,

[0075] R3 is selected from halogens;

[0076] R1, R2, and R3 are as defined in the first aspect.

[0077] In some embodiments, such as the preparation method described in the third aspect, the alkyl lithium is selected from n-butyllithium and tert-butyllithium.

[0078] In some embodiments, such as the preparation method described in the third aspect, a Grignard reagent is further included. In some specific embodiments, the Grignard reagent is selected from isopropyl magnesium chloride.

[0079] In some implementations, such as the preparation method described in the third aspect, the reaction temperature is not lower than -20°C.

[0080] In some embodiments, such as the preparation method described in the third aspect, the molar ratio of alkyllithium to Grignard reagent is 5:1 to 1:1.

[0081] In some embodiments, such as the preparation method described in the third aspect, the molar ratio of alkyllithium to Grignard reagent is 3:1 to 1:1.

[0082] In some embodiments, such as the preparation method described in the third aspect, the molar ratio of alkyllithium to Grignard reagent is 3:1 to 2:1.

[0083] Fourthly, this disclosure also provides a method for preparing the compound shown in formula 2a or a salt thereof, wherein the compound shown in formula 1a or a salt thereof reacts with acrylic acid in the presence of phosphorus oxychloride to form the compound shown in formula 2a or a salt thereof, wherein R1, R2, R3, and R4 are as defined in the first aspect.

[0084] This disclosure also provides a method for preparing the compound shown in formula 2a or a salt thereof, wherein the compound shown in formula 1a or a salt thereof reacts with acryloyl chloride to form the compound shown in formula 2a or a salt thereof, wherein R1, R2, R3, and R4 are as defined in the first aspect.

[0085] This disclosure also provides a compound or a salt thereof shown in formula 3a, including the step of protecting the compound or a salt thereof shown in formula 2a with a protecting group.

[0086] Fifthly, this disclosure also provides a compound or a salt thereof, the compound being selected from...

[0087] The compound or its salt according to the fifth aspect serves as an intermediate. More specifically, it serves as an intermediate for the preparation of PARP inhibitors. Furthermore, it serves as an intermediate for the preparation of the compound or its salt shown in Formula 7a or Formula 7.

[0088] On the other hand, the preparation method described in this disclosure also includes one or more steps such as filtration, concentration, column chromatography purification and drying.

[0089] The terms "formation" and "conversion" in this disclosure do not specifically refer to a single-step conversion reaction between two substrates; they can be single-step or multi-step reactions between two substrates. If the intermediate contains a protecting group, the intermediate undergoes a step of deprotection before reacting with the corresponding substrate to obtain the target product.

[0090] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0091] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, and isopropyl. Alkyl groups may be optionally substituted or unsubstituted.

[0092] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be replaced at any usable connection point.

[0093] The term "aryloxy group" refers to -O-aryl, where aryl is defined as a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryloxy group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable junction.

[0094] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted, and when substituted, the substituent can be replaced at any usable connection point.

[0095] The term “heterocycloalkyl” refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 6 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.

[0096] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0097] The term "hydroxyl group" refers to the -OH group.

[0098] The term "carboxyl group" refers to -C(O)OH.

[0099] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0100] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0101] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently replaced by the corresponding number of substituents. When the substituent is a ketone or an oxo (i.e., =O), two (2) hydrogen atoms on the atom are replaced.

[0102] When the functional group of this disclosure is substituted, the substituent is preferably one or more of the following groups: halogen, oxo, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 cycloalkyl.

[0103] "Amino protecting group" is a suitable group known in the art for amino protection. Suitable protecting groups, their introduction, and removal methods are described in Greene & Wuts, *Protecting Groups in Organic Synthesis*, 3rd edition, 1999. Preferably, the amino protecting group can be (C1-C2). 10 Alkyl or aromatic acyl group, such as formyl, acetyl, benzoyl, etc.; can be (C1-C6 alkyl or C1-C6 alkyl). 10 (aryl)sulfonyl; or (C1-C6 alkoxy or C1-C6) 10 Aryloxy)carbonyl, such as Boc or Cbz; can also be substituted or unsubstituted alkyl, such as triphenylmethyl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn). Detailed Implementation

[0104] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0105] Example

[0106] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0107] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0108] Waters ACQuity UPLC-QD / SQD (Manufacturer: Waters, MS Model:

[0109] waters ACQuity Qda Detector / waters SQ Detector) THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0110] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 liquid chromatograph.

[0111] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0112] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0113] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0114] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0115] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0116] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0117] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0118] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0119] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0120] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0121] Example 1: Preparation of N-(5-bromo-2-chloropyridin-3-yl)-2-methylenebutyramide (compound 2)

[0122] 70g of compound 1,2-ethylacrylic acid and 29.5g of POCl3 were dissolved in 140mL of pyridine and 420mL of dichloromethane. The mixture was cooled to -10℃, and 47.5g of POCl3 was slowly added dropwise while keeping the internal temperature below 10℃. After the addition was complete, the internal temperature was kept at 10℃ for the reaction. The reaction was monitored by TLC until it was complete.

[0123] 30 mL of methanol was added to the reaction system while maintaining the internal temperature at 10 °C. The mixture was concentrated under reduced pressure until no obvious droplets fell. The concentrate was dissolved in 1 L of toluene, washed twice with 500 mL of 20% citric acid aqueous solution, and the organic phase was concentrated to dryness to give 75 g of compound 2, with a yield of 88%.

[0124] 1 H NMR (400MHz, DMSO-d6): 9.77 (s, 1H), 8.44 (d, J = 2.4Hz, 1H), 8.33 (d, J = 2.4Hz, 1H), 5.91 (s, 1H), 5.55 (s, 1H), 2.37 (m, 2H), 1.05 (t, J = 7.6Hz, 3H).

[0125] Example 2 Preparation of N-(5-bromo-2-chloropyridin-3-yl)-N-(4-methoxybenzyl)-2-methylenebutyramide (compound 3)

[0126] 64 g of compound 2 was dissolved in 500 mL of toluene, and 45 g of PMBCl and 7 g of TBAI (tetrabutylammonium iodide) were added. The internal temperature was lowered to 0 °C, and 288 mL of 1.0 M KHMDS (bis(trimethylsilyl)aminopotassium) solution was slowly added dropwise. The reaction was allowed to proceed for 2 h. After quenching the system with 300 mL of water, the mixture was separated. The aqueous phase was extracted once with 500 mL of toluene. The organic phases were combined, concentrated, and separated by column chromatography to obtain 72 g of compound 3, with a yield of 80%.

[0127] 1 H NMR(400MHz, DMSO-d6):8.48(d,J=2.4Hz,1H),8.03(s,1H),7.13(d,J=8.4Hz,2H),6.83(d,J=8.8 Hz,2H),5.11(s,1H),4.99(s,2H),4.69(s,1H),3.70(s,3H),2.22(m,2H),0.94(t,J=7.2Hz,3H).

[0128] Example 3 Preparation of 7-bromo-3-ethyl-1-(4-methoxybenzyl)-1,5-naphthyl-2(1H)-one (compound 4)

[0129] 20 g (49.0 mmol, 1.0 eq.) of compound 3 was dissolved in 100 mL of toluene, and 20 g of potassium carbonate (147 mmol, 3.0 eq.) and 6.4 g of 1,3-dimethylimidazolium chloride (49.0 mmol, 1.0 eq.) were added. Under nitrogen purging protection, the mixture was heated to 120 °C for 2 hours, and the reaction was monitored by HPLC until complete. The reaction mixture was washed twice with 100 mL of ethyl acetate, filtered, concentrated, separated by column chromatography, and dried under vacuum to give 12.6 g of compound 4, with a yield of 70%.

[0130] 1 H NMR(400MHz, DMSO-d6),8.57(d,J=1.6Hz,1H),8.10(d,J=1.2Hz,1H),7.81(s,1H),7.16(d,J=8 .8Hz,2H),6.88(d,J=8.8Hz,2H),5.48(s,2H),3.70(s,3H),2.63(m,2H),1.22(t,J=7.2Hz,3H).

[0131] Example 4 Preparation of 7-ethyl-5-(4-methoxybenzyl)-6-oxo-5,6-dihydro-1,5-naphthidine-3-carboxaldehyde (compound 5)

[0132] 1.0 g (2.69 mmol, 1.0 eq.) of compound 4 was dissolved in 20 mL of THF, cooled to -10 °C, and 1.4 mL of 1.0 M isopropyl magnesium chloride was added, followed by stirring for 30 min. Then, 1 mL of 2.5 M n-butyllithium was added, and the mixture was stirred for 30 min. Finally, 0.3 g of DMF was added, and the mixture was heated to room temperature and stirred for 3 h. The solution was quenched with 10 mL of water, extracted twice with 10 mL of EA, dried, and concentrated. The crude product was separated by column chromatography to give 644 mg of compound 5, with a yield of 75%.

[0133] 1 H NMR (400MHz, DMSO-d6): 10.14(s,1H),8.95(d,J=1.6Hz,1H),8.24(d,J=0.8Hz,1H),7.92(s,1H),7.19 (d,J=8.8Hz,2H),6.88(d,J=8.8Hz,2H),5.53(s,2H),3.70(s,3H),2.67(m,2H),1.24(t,J=7.2Hz,3H).

[0134] Example 5 Preparation of (R)-3-((7-ethyl-5-(4-methoxybenzyl)-6-oxo-5,6-dihydro-1,5-naphthyl-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridyl[3,2-e][1,4]oxazolidin-9-carboxamide (compound 7)

[0135] 500 mg (1.55 mmol, 1.0 eq.) of compound 5 and 500 mg (1.90 mmol, 1.2 eq.) of compound 6 were dissolved in 10 mL of dichloromethane, and 300 mg of triethylamine (2.96 mmol, 2.0 eq.) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was cooled to 0 °C, and 600 mg of sodium triacetoxyborohydride (2.83 mmol, 1.8 eq.) was added. The mixture was then slowly heated to room temperature. The reaction was quenched with 10 mL of 5% sodium bicarbonate aqueous solution, and the organic phase was concentrated under reduced pressure after separation. The crude product was subjected to column chromatography to give 570 mg of compound 7, in 65% yield.

[0136] 1H NMR (400MHz, DMSO-d6): 8.42 (m, 2H), 7.85 (m, 2H), 7.82 (s, 1H), 7.43 (d, J = 8.8Hz, 1H), 7. 17(d,J=8.4Hz,2H),6.87(d,J=8.8Hz,2H),5.50(m,2H),4.93(d,J=13.6Hz,1H),4.74(d,J =14.0Hz,1H),3.86(m,1H),3.68(m,2H),3.64(s,3H),3.41(s,1H),3.18(m,2H),2.83(d, J=4.8Hz,3H),2.68(m,1H),2.64(m,2H),2.58(m,2H),2.40(m,2H),1.24(t,J=7.2Hz,3H).

[0137] Example 6 Preparation of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazazepone-9-carboxamide (compound 8)

[0138] 100 mg (0.176 mmol, 1.0 eq.) of compound 7 was dissolved in 1 mL of trifluoroacetic acid, and 0.2 mL of trifluoromethanesulfonic acid was added. The mixture was stirred at 25 °C for 18 hours. The reaction solution was directly concentrated, and the crude product was purified by column chromatography to give 67 mg of compound 8, with a yield of 85%.

[0139] Example 7 Preparation of 7-bromo-3-ethyl-1-(4-methoxybenzyl)-1,5-naphthyl-2(1H)-one (compound 4)

[0140] 1.0 g of compound 3 was dissolved in 10 mL of toluene, and 320 mg of 1,3-dimethylimidazolium chloride (as shown in Table 1) was added. Under nitrogen purging protection, the mixture was heated to 120 °C for 4 hours, and the reaction was monitored by HPLC until complete. The reaction mixture was washed twice with 10 mL of ethyl acetate, filtered, and the crude product was concentrated and separated by column chromatography. Compound 4 was dried under vacuum.

[0141] Table 1

[0142] Example 8 Preparation of N-(5-bromo-2-chloropyridin-3-yl)-2-methylenebutyramide (compound 2)

[0143] In a 30L reactor, compound 1 was dissolved in 4L of acetonitrile, and 1.35kg of pyridine was added. The mixture was stirred and dissolved, and the internal temperature was controlled at 10℃. 570g of 2-ethylacryloyl chloride was slowly added dropwise, and the internal temperature was controlled at <30℃. The addition was completed in 30 minutes. After the addition was completed, the mixture was stirred for 1 hour, and 500mL of ethanol was added dropwise to quench the reaction.

[0144] After the reaction solution was concentrated, it was pulped at room temperature for 2 hours, filtered to obtain a white product, and dried by blowing air at room temperature to finally obtain 960g of compound 2, with a yield of 87%.

[0145] Example 9 Preparation of N-(5-bromo-2-chloropyridin-3-yl)-N-(4-methoxybenzyl)-2-methylenebutyramide (compound 3)

[0146] 920g of compound 2 was dissolved in 5L of acetonitrile, 662g of potassium carbonate and 110g of tetrabutylammonium iodide were added, and 523g of PMBCl was slowly added dropwise over 10 minutes. The mixture was then heated to 45°C and mechanically stirred for 18 hours.

[0147] Filter the mixture, wash the filter cake with 1L of acetonitrile, combine the filtrates and concentrate under reduced pressure, add 4L of ethanol to completely dissolve the filtrate, transfer it to a 10L reactor, heat to 45°C, add 3L of water dropwise over 30 minutes, keep warm and stir for 1 hour, then allow it to cool naturally to room temperature, and stir overnight to allow crystals to precipitate.

[0148] The mixture was filtered, the filter cake was washed with 1L of water, and dried at 45°C for 18 hours to obtain 1.2kg of compound 3, with a yield of 92%.

[0149] Example 10 Preparation of 7-bromo-3-ethyl-1-(4-methoxybenzyl)-1,5-naphthyl-2(1H)-one (compound 4)

[0150] 600g of potassium carbonate, 900g of anhydrous sodium sulfate, and 20L of xylene were placed in a 30L reactor and dispersed evenly. The mixture was heated to 130℃, purged with nitrogen three times, and protected. 80g of 1,3-dimethylimidazole chloride was added. 600g of compound 3 was dissolved in 4L of xylene, and the solution was added dropwise to the reaction system. The addition was completed over 20 minutes. Timing was started when the temperature inside the reaction system reached 130℃. The reaction was carried out for 4 hours, and the reaction was monitored by HPLC until it was complete.

[0151] The system was cooled to room temperature, filtered, and the filter cake was washed with 5 L of ethyl acetate. The combined organic phases were concentrated under reduced pressure until almost no liquid dripped. 2 L of ethanol was added to dissolve the compound, and 2 L of water was added to stir and crystallize for 2 h. The mixture was filtered and dried at 50 °C for 18 h to obtain 410 g of compound 4, with a yield of 75%.

Claims

1. A method for preparing a compound of formula 4a or a salt thereof, comprising reacting a compound of formula 3a or a salt thereof in the presence of a basic substance and a carbene reagent to form a compound of formula 4a or a salt thereof. in, R1 is selected from halogen, C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkylene 3-6 membered cycloalkyl, wherein C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 The alkylene group (3-6 membered cycloalkyl group) may optionally be replaced by one or more substituents selected from halogen, hydroxyl, or cyano groups; R2 is selected from an amino protecting group; R3 is selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)OC 1-6 Alkyl, -O-aryl, -CHO, wherein the C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)OC 1-6 The alkyl and -O-aryl groups may be optionally replaced by one or more substituents selected from halogens, hydroxyl groups, and cyano groups. R4 is selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 alkyl; X is selected from halogen, C 1-6 Alkoxy, -O-aryl.

2. The preparation method according to claim 1, wherein the alkaline substance is selected from at least one of K2CO3, CsF and Cs2CO3, preferably K2CO3.

3. The preparation method according to claim 1 or 2, wherein the carbene reagent is selected from 1,3-dimethylimidazole chloride, 1,3-dicyclohexylimidazole chloride, 1,3-bis(2,4,6-trimethylphenyl)imidazole chloride, 1,3-bis(2,6-diisopropylphenyl)imidazole onium chloride, and 1,3-bis(4-trimethoxyphenyl)dimethylimidazole chloride.

4. The preparation method according to any one of claims 1-3, wherein the amino protecting group is selected from Bn (benzyl), PMB (p-methoxybenzyl), DMB (2,4-dimethoxybenzyl), Tr (triphenylmethyl), Me (methyl), SEM (trimethylsilylethoxymethyl), BOM (benzylchloromethyl ether), and MOM (chloromethyl methyl ether).

5. The preparation method according to any one of claims 1-4, wherein the molar ratio of the compound shown in formula 3a to the basic substance is 1:1-1:10, preferably 1:1-1:5, and more preferably 1:2-1:

5.

6. The preparation method according to any one of claims 1-5, wherein the molar ratio of the compound shown in formula 3a to the carbene reagent is 1:0.01-1:5, preferably the molar ratio of the compound shown in formula 3a to the carbene reagent is 1:0.05-1:3, and more preferably the molar ratio of the compound shown in formula 3a to the carbene reagent is 1:0.1-1:

1.

7. A method for preparing a compound of formula 4b or a salt thereof, comprising the steps of preparing a compound of formula 4a or a salt thereof according to any one of claims 1-6, and the step of removing the protecting group R2 from the compound of formula 4a or the salt thereof.

8. A method for preparing a PARP inhibitor, comprising the steps of preparing a compound of formula 4a or a salt thereof according to any one of claims 1-6 and / or preparing a compound of formula 4b or a salt thereof according to the method of claim 7.

9. A method for preparing a compound of formula 7a or a salt thereof, comprising the steps of preparing a compound of formula 4a or a salt thereof according to any one of claims 1-6 and / or preparing a compound of formula 4b or a salt thereof according to the method of claim 7, and reacting the compound of formula 4a or 4b or a salt thereof with a compound of formula 6a or a salt thereof. in, R5 is selected from R2 or hydrogen.

10. The preparation method according to claim 9, wherein the compound of formula 7a or a salt thereof is selected from the compound of formula 7 or a salt thereof. in, R5 is selected from R2 or hydrogen.

11. A compound or a salt thereof, wherein the compound is selected from...

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