Preparation method for phthalazinone PRMT5 inhibitor and intermediate thereof

Abstract

The present invention provides a preparation method for a phthalazinone PRMT5 inhibitor (formula (S)) and an intermediate thereof. The method involves a novel reaction route, mild reaction conditions, simple operation, high reaction yield, high product purity and convenient work-up, and is suitable for industrial production.

Description

A method for preparing a phthalazinone PRMT5 inhibitor and its intermediates Technical Field

[0001] This invention relates to a method for preparing a pharmaceutical compound, specifically a method for preparing a phthalazinone PRMT5 inhibitor and its intermediates, belonging to the field of medicinal chemistry technology. Background Technology

[0002] Protein arginine methyltransferases (PRMTs) catalyze protein arginine methylation, an important post-translational modification that uses S-adenosylmethionine (SAM) as a methyl donor to methylate the nitrogen atom of the protein arginine side chain. Based on the arginine methylation state, the nine identified human PRMTs (PRMT1 and PRMT9) are further subdivided into types I, II, and III. Type I PRMTs catalyze the formation of monomethylarginine (MMA) and asymmetric dimethylarginine (aDMA), including PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8; type II PRMTs catalyze the formation of MMA and symmetric dimethylarginine (sDMA), including PRMT5 and PRMT9; and type III PRMTs catalyze the formation of MMA, including PRMT7.

[0003] In MTAP-deficient cells, methylthioadenosine (MTA) accumulates excessively, forming the PRMT5-MTA complex with PRMT5. This partially inhibits PRMT5 enzyme activity, leading to increased cell proliferation sensitivity to PRMT5 deficiency or loss of activity. Therefore, MTAP deficiency reduces PRMT5 methylation activity, making cells selectively dependent on PRMT5 activity. In MTAP-deficient cancers, the synergistic inhibition of PRMT5 activity by MTA could provide therapeutic benefits for various cancers.

[0004] Therefore, it is necessary to develop new MTA-synergistic PRMT5 inhibitors that can inhibit PRMT5 activity in the presence of elevated MTA concentrations, especially in MTAP-deficient cells.

[0005] WO2024008176A1 discloses a compound (S) belonging to the PRMT5-MTA inhibitors.

[0006] The preparation method of the compound of formula (I) described in the patent has the following disadvantages: many reaction conditions are not conducive to production scale-up, the intermediates have poor stability, multiple steps require column purification, purification is difficult, the final product requires SFC resolution, and the overall yield is low; it is not only costly but also difficult to achieve large-scale production. Summary of the Invention

[0007] This invention provides a method for preparing compound P', comprising the following reaction:

[0008] Wherein, PG is a protecting group selected from Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Pht (phthaloyl), Fmoc (methoxycarbonyl), and trifluoroacetyl (Tfa);

[0009] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from [1,1'-bis(dicyclohexylphosphine)ferrocene]palladium(II) dichloride, allylpalladium(II) chloride dimer, di-bis[(1,2,3)-1-phenyl-2-propene]palladium, Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(PPh3)4, Pd2(dba)3, Pd(TFA)2, Pd(MeCN)2Cl 2、 At least one of Pd(PhCN)2Cl2 and PdCl2[P(Cy)3]2, preferably [1,1'-bis(dicyclohexylphosphine)ferrocene]palladium(II) dichloride;

[0010] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of potassium phosphate, potassium fluoride, cesium fluoride, potassium acetate, sodium acetate, potassium pentovane, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydrogen phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, pyridine, piperidine, 2,6-dimethylpyridine, imidazole, morpholine, triethylamine, 4-dimethylaminopyridine, and N,N-diisopropylethylamine, preferably at least one of potassium phosphate and potassium carbonate.

[0011] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of 2-methyltetrahydrofuran, water, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, tert-amyl alcohol, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, 1,4-dioxane, methyl tert-butyl ether, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably 2-methyltetrahydrofuran / water or toluene / water;

[0012] Optionally, in some embodiments, the reaction temperature is 30–100°C, preferably 55±5°C.

[0013] This invention provides a compound R 0The preparation method includes the following reaction:

[0014] Wherein, PG is a protecting group selected from Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Pht (phthaloyl), Fmoc (methoxycarbonyl), and trifluoroacetyl (Tfa);

[0015] Optionally, in some embodiments, the reaction is carried out in the presence of an acid selected from at least one of benzenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid monohydrate, preferably at least one of benzenesulfonic acid and hydrochloric acid;

[0016] Optionally, in some embodiments, the reaction is carried out in the presence of a resolving agent selected from at least one of Boc-D phenylalanine, Boc-L phenylalanine, D-tartaric acid, L-tartaric acid, D-di-p-methylbenzoyl tartaric acid, L-di-p-methylbenzoyl tartaric acid, D-mandelic acid, BOC-D-proline, L-camphorsulfonic acid, D-camphorsulfonic acid, BOC-D-phenylglycine, BOC-D-alanine, and (S)-2-(6-methoxy-2-naphthyl)propionic acid, preferably Boc-D phenylalanine. The present invention provides a method for preparing compound S, comprising the following reaction:

[0017] Optionally, in some embodiments, the reaction is carried out in the presence of an alkali selected from at least one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and ammonia water, preferably at least one of potassium carbonate and ammonia water.

[0018] This invention provides a method for preparing compound I', comprising the following reaction:

[0019] Wherein, R and R' are leaving groups; selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl, -Br, -I, and R1 is an alkyl group;

[0020] Optionally, in some embodiments, the reaction is carried out in the presence of isobutyl chloroformate;

[0021] Optionally, in some embodiments, the reaction solvent for the reaction is selected from at least one of tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, 2-methyltetrahydrofuran, cyclopentyl methyl ether, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of tetrahydrofuran and acetonitrile;

[0022] Optionally, in some embodiments, the reaction temperature is -20 to 50°C, preferably 10 ± 5°C.

[0023] This invention provides a method for preparing compound H', comprising the following reaction:

[0024] Wherein, R and R' are leaving groups; selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl, -Br, and R1 is an alkyl group;

[0025] Optionally, in some embodiments, the hydrazine is selected from hydrazine hydrate;

[0026] Optionally, in some embodiments, the reaction solvent is selected from at least one of methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, tert-amyl alcohol, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of ethanol, isopropanol, and n-propanol.

[0027] This invention provides a method for preparing compound G', comprising the following reaction:

[0028] Wherein, R and R' are leaving groups selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl and -Br, and R1 is an alkyl group;

[0029] Optionally, in some embodiments, the reaction is carried out in the presence of N,N-dimethylformamide dimethyl acetal (DMF-DMA);

[0030] Optionally, in some embodiments, the reaction is carried out in the presence of an acid selected from at least one of p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and sulfuric acid, preferably p-toluenesulfonic acid.

[0031] This invention provides a method for preparing compound F', comprising the following reaction:

[0032] Wherein, R and R' are leaving groups selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl and -Br, and R1 is an alkyl group;

[0033] Optionally, in some embodiments, the reaction is carried out in the presence of an acid selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid monohydrate, preferably at least one of hydrochloric acid and sulfuric acid.

[0034] This invention provides a method for preparing compound J', comprising the following reaction:

[0035] Wherein, X is a halogen, R and R' are leaving groups selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl and -Br, and R1 is an alkyl group;

[0036] Optionally, in some embodiments, the reaction is carried out in the presence of potassium phthalimide;

[0037] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of N,N-dimethylformamide, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, toluene, acetonitrile, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of N,N-dimethylformamide and N-methylpyrrolidone;

[0038] Optionally, in some embodiments, the reaction temperature is -20 to 50°C, preferably 10 ± 5°C.

[0039] This invention provides a method for preparing compound K', comprising the following steps:

[0040] Wherein, R and R' are leaving groups selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl and -Br, and R1 is an alkyl group;

[0041] Optionally, in some embodiments, the reaction is carried out in the presence of a reducing agent selected from at least one of hydrazine, hydrazine hydrate, methylamine, diethylamine, hydrochloric acid, and sulfuric acid, preferably at least one of hydrazine hydrate and hydrochloric acid;

[0042] Optionally, in some embodiments, the reaction solvent for the reaction is selected from at least one of methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, tert-amyl alcohol, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of ethanol and n-propanol;

[0043] Optionally, in some embodiments, the reaction temperature is 20-100°C, preferably 70-75°C.

[0044] This invention provides a method for preparing compound L', comprising the following steps:

[0045] Wherein, R and R' are leaving groups selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl and -Br, wherein R1 is an alkyl group; PG is a protecting group selected from Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Pht (phthalyl), Fmoc (tetrafluoroacetyl), and trifluoroacetyl (Tfa);

[0046] Optionally, in some embodiments, PG is a Boc protecting group, and the reaction is carried out in the presence of di-tert-butyl dicarbonate;

[0047] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, pyridine, piperidine, 2,6-dimethylpyridine, imidazole, morpholine, triethylamine, 4-dimethylaminopyridine, and N,N-diisopropylethylamine, preferably at least one of triethylamine and N,N-diisopropylethylamine;

[0048] Optionally, in some embodiments, the reaction solvent for the reaction is selected from at least one of ethyl acetate, isopropyl acetate, acetone, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of N,N-dimethylformamide and tetrahydrofuran;

[0049] Optionally, in some embodiments, the reaction temperature is 0-60°C, preferably 20±5°C.

[0050] This invention provides a method for preparing compound M', comprising the following reaction:

[0051] Wherein, R and R' are leaving groups selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl and -Br, wherein R1 is an alkyl group; PG is a protecting group selected from Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Pht (phthalyl), Fmoc (tetrafluoroacetyl), and trifluoroacetyl (Tfa);

[0052] Optionally, in some embodiments, the reaction is carried out in the presence of potassium trifluoro(vinyl)borate;

[0053] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from palladium acetate, allyl palladium(II) chloride dimer, di-bis[(1,2,3)-1-phenyl-2-propene]palladium, PdCl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(PPh3)4, Pd2(dba)3, Pd(TFA)2, Pd(MeCN)2Cl 2、 At least one of Pd(PhCN)2Cl2 and PdCl2[P(Cy)3]2, preferably palladium acetate;

[0054] Optionally, in some embodiments, the reaction is carried out in the presence of a ligand selected from at least one of 1,1'-bis(diisopropylphosphine)ferrocene, Ph3P, RuPhos, SPhos, DavePhos, XPhos, BrettPhos, XantPhos, Cy-cBRIDP, CataCixum PtB, dppf, dppb, and Ad2nBuP, preferably 1,1'-bis(diisopropylphosphine)ferrocene;

[0055] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of potassium carbonate, anhydrous potassium carbonate, potassium fluoride, cesium fluoride, potassium acetate, sodium acetate, lithium acetate, potassium pivalate, sodium pivalate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, pyridine, piperidine, 2,6-dimethylpyridine, imidazole, morpholine, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1,8-diazacyclo[5,4,0]undecene-7, 1,5,7-triazabicyclo[4,4,0]decene-5-ene, preferably at least one of anhydrous potassium carbonate and potassium phosphate;

[0056] Optionally, in some embodiments, the reaction solvent for the reaction is selected from at least one of dioxane, water, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, tert-amyl alcohol, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of dioxane, N-methylpyrrolidone, 2-methyltetrahydrofuran, and water;

[0057] Optionally, in some embodiments, the reaction temperature is 50-100°C, preferably 75-85°C.

[0058] This invention provides a method for preparing compound N', comprising the following reaction:

[0059] Wherein, R is a leaving group selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl, -Br, and R1 is an alkyl group; PG is a protecting group selected from Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Pht (phthalyl), Fmoc (tetrafluoroacetyl), and trifluoroacetyl (Tfa);

[0060] Optionally, in some embodiments, the reaction is carried out in the presence of pinacol diboronate or pinacol vinylboronate;

[0061] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from tris(dibenzylacetone)dipalladium, palladium acetate, allylpalladium(II) chloride dimer, di-bis[(1,2,3)-1-phenyl-2-propene]dipalladium, PdCl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(PPh3)4, Pd(TFA)2, Pd(MeCN)2Cl 2、 At least one of Pd(PhCN)2Cl2 and PdCl2[P(Cy)3]2, preferably at least one of tris(dibenzylacetone)palladium and palladium acetate;

[0062] Optionally, in some embodiments, the reaction is carried out in the presence of a ligand selected from at least one of 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl, Ph3P, RuPhos, SPhos, DavePhos, CPhos, BrettPhos, XantPhos, Cy-cBRIDP, CataCixum PtB, dppf, dppb, and Ad2nBuP, preferably 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl;

[0063] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of potassium acetate, sodium acetate, ammonium acetate, potassium propionate, potassium pivalate, triethylamine, tetramethylguanidine, and N,N-diisopropylethylamine, preferably at least one of potassium acetate and potassium pivalate.

[0064] Optionally, in some embodiments, the reaction solvent for the reaction is selected from at least one of dioxane, ethanol, isopropanol, n-propanol, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of dioxane and N,N-dimethylacetamide;

[0065] Optionally, in some embodiments, the reaction temperature is 60-120°C, preferably 90±5°C.

[0066] This invention provides a method for preparing compound B, comprising the following reaction:

[0067] Wherein, R is a leaving group selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl, -Br, and R1 is an alkyl group;

[0068] The reaction was carried out in the presence of bromine;

[0069] Optionally, in some embodiments, the reaction solvent for the reaction is selected from at least one of acetic acid, water, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably acetic acid / water;

[0070] Optionally, in some embodiments, the reaction temperature is -10 to 50°C, preferably 10 to 20°C.

[0071] This invention provides a method for preparing compound C, comprising the following reaction:

[0072] Wherein, R is a leaving group selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl, -Br, and R1 is an alkyl group;

[0073] The reaction was carried out in the presence of iodomethane;

[0074] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, pyridine, piperidine, 2,6-dimethylpyridine, imidazole, morpholine, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1,8-diazacyclo[5,4,0]undecene-7, and 1,5,7-triazabicyclo[4,4,0]decene-5-ene, preferably at least one of potassium carbonate and sodium carbonate;

[0075] Optionally, in some embodiments, the reaction solvent is selected from at least one of N,N-dimethylformamide, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of N,N-dimethylformamide and acetonitrile;

[0076] Optionally, in some embodiments, the reaction temperature is -10 to 50°C, preferably 25 ± 5°C.

[0077] This invention provides a method for preparing compound D', comprising the following reaction:

[0078] Wherein, R is a leaving group selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl, -Br, and R1 is an alkyl group;

[0079] The reaction is carried out in the presence of CuCN / NaCN or potassium cyanide;

[0080] Optionally, in some embodiments, the reaction is carried out in the presence of a diazotizing agent / acid, wherein the diazotizing agent is selected from at least one of sodium nitrite and tert-butyl nitrite, preferably sodium nitrite; and the acid is selected from at least one of hydrochloric acid, sulfuric acid, and phosphoric acid, preferably at least one of hydrochloric acid and sulfuric acid.

[0081] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of sodium bicarbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, and potassium hydroxide, preferably at least one of sodium bicarbonate and potassium bicarbonate.

[0082] Optionally, in some embodiments, the reaction solvent is selected from at least one of water, acetone, 4-methyl-2-pentanone, tetrahydrofuran, acetonitrile, acetic acid, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably water;

[0083] Optionally, in some embodiments, the reaction temperature is -10 to 80°C, preferably 25±5°C.

[0084] This invention provides a method for preparing compound E', comprising the following reaction:

[0085] Wherein, R is a leaving group selected from halogens, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens, more preferably from -Cl, -Br, and R1 is an alkyl group;

[0086] Optionally, in some embodiments, the reaction is carried out in the presence of a reducing agent selected from at least one of lithium borohydride, sodium borohydride, potassium borohydride, and lithium aluminum hydride, preferably at least one of lithium borohydride and sodium borohydride;

[0087] Optionally, in some embodiments, the reaction solvent is selected from at least one of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, and ethylene glycol dimethyl ether, preferably at least one of methanol and tetrahydrofuran;

[0088] Optionally, in some embodiments, the reaction temperature is -10 to 50°C, preferably 25 ± 5°C.

[0089] This invention also provides a method for preparing a compound by sequentially combining the above-described reaction steps, for example:

[0090] Methods for preparing compound S include P'→R 0 →Step S;

[0091] The preparation methods of compound S include N'→P'→R 0 →Step S;

[0092] The preparation methods of compound S include M'→N'→P'→R 0 →Step S;

[0093] The preparation methods of compound S include L'→M'→N'→P'→R 0 →Step S;

[0094] The preparation methods of compound S include K'→L'→M'→N'→P'→R 0 →Step S;

[0095] The preparation method of compound N' includes the steps of L'→M'→N';

[0096] The preparation method of compound N' includes the steps of K'→L'→M'→N';

[0097] The preparation method of compound N' includes the steps of J'→K'→L'→M'→N';

[0098] The preparation method of compound N' includes the steps of I'→J'→K'→L'→M'→N';

[0099] The preparation method of compound N' includes the steps of H'→I'→J'→K'→L'→M'→N';

[0100] The preparation method of compound I' includes the steps of G'→H'→I';

[0101] The preparation method of compound I' includes the steps of F'→G'→H'→I';

[0102] The preparation method of compound I' includes the steps of E'→F'→G'→H'→I';

[0103] The preparation method of compound I' includes the steps of D'→E'→F'→G'→H'→I';

[0104] The preparation method of compound I' includes the steps of C'→D'→E'→F'→G'→H'→I';

[0105] The preparation method of compound I' includes the steps of B'→C'→D'→E'→F'→G'→H'→I';

[0106] The preparation method of compound I' includes the steps of A'→B'→C'→D'→E'→F'→G'→H'→I';

[0107] The preparation method of compound F' includes the steps of D'→E'→F';

[0108] The preparation method of compound F' includes the steps of C'→D'→E'→F';

[0109] The preparation method of compound F' includes the steps of B'→C'→D'→E'→F';

[0110] The preparation method of compound F' includes the steps of A'→B'→C'→D'→E'→F';

[0111] The preparation method of compound E' includes the steps of C'→D'→E';

[0112] The preparation method of compound E' includes the steps of B'→C'→D'→E';

[0113] The preparation method of compound E' includes the steps of A'→B'→C'→D'→E'.

[0114] This invention also provides a method for preparing compound O, comprising the following reaction:

[0115] Optionally, in some embodiments, the reaction is carried out in the presence of N-iodosuccinimide;

[0116] Optionally, in some embodiments, the reaction is carried out in the presence of an acid selected from at least one of trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, preferably trifluoroacetic acid;

[0117] Optionally, in some embodiments, the reaction solvent for the reaction is selected from at least one of acetonitrile, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of acetonitrile and dimethyl sulfoxide;

[0118] Optionally, in some embodiments, the reaction temperature is 30-100°C, preferably 65-75°C.

[0119] This invention provides a method for preparing compound O-6, comprising the following reaction:

[0120] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from bis(di-tert-butyl-4-dimethylaminophenylphosphine)palladium chloride, bis-bis[(1,2,3)-1-phenyl-2-propene]palladium, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(PPh3)4, Pd2(dba)3, Pd(TFA)2, Pd(MeCN)2Cl 2、At least one of Pd(PhCN)2Cl2, PEPPSI-iPr, PdCl2[P(Cy)3]2, allyl palladium(II) chloride dimer and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, preferably bis(di-tert-butyl-4-dimethylaminophenylphosphine)palladium chloride;

[0121] Optionally, in some embodiments, the reaction is carried out in the presence of a reaction promoter selected from at least one of potassium fluoride, potassium carbonate, anhydrous potassium carbonate, potassium fluoride, cesium fluoride, potassium acetate, sodium acetate, lithium acetate, potassium pivalate, sodium pivalate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, pyridine, piperidine, 2,6-dimethylpyridine, imidazole, morpholine, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1,8-diazacyclo[5,4,0]undecene-7, 1,5,7-triazabicyclo[4,4,0]decene-5-ene, preferably at least one of potassium fluoride and sodium carbonate;

[0122] Optionally, in some embodiments, the reaction solvent for the reaction is selected from at least one of dioxane, 2-methyltetrahydrofuran, water, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, tert-amyl alcohol, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, methyl tert-butyl ether, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of dioxane / water and 2-methyltetrahydrofuran / water;

[0123] Optionally, in some embodiments, the reaction temperature is 30-90°C, preferably 60-70°C.

[0124] This invention provides a method for preparing compound O-4, comprising the following reaction:

[0125] The reaction is carried out in the presence of iodine;

[0126] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of lithium diisopropylamino, lithium tetramethylpiperidine, lithium bis(trimethylsilylamino), sodium bis(trimethylsilylamino), and potassium bis(trimethylsilylamino), preferably lithium diisopropylamino;

[0127] Optionally, in some embodiments, the reaction solvent for the reaction is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, and N-methylpyrrolidone, preferably tetrahydrofuran;

[0128] Optionally, in some embodiments, the reaction temperature is -80 to 20°C, preferably -70 to -60°C.

[0129] This invention provides a method for preparing compound O-3, comprising the following reaction:

[0130] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1,8-diazacyclo[5,4,0]undecene-7, and 1,5,7-triazabicyclo[4,4,0]decene-5-ene, preferably at least one of cesium carbonate and potassium carbonate;

[0131] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of N,N-dimethylformamide, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, tert-amyl alcohol, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, methyl tert-butyl ether, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, cyclobutane sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably at least one of N,N-dimethylformamide and N-methylpyrrolidone.

[0132] Optionally, in some embodiments, the reaction temperature is 30-100°C, preferably 55-60°C.

[0133] This invention also provides a method for preparing a compound by sequentially combining the reaction steps of the above-mentioned compound O, for example:

[0134] The preparation method of compound O includes the steps of O-4→O-6→O;

[0135] The preparation method of compound O includes the steps of O-3→O-4→O-6→O;

[0136] The preparation method of compound O includes the steps of O-1→O-3→O-4→O-6→O;

[0137] A method for preparing compound O-6, comprising the steps of O-3→O-4→O-6;

[0138] The preparation method of compound O-6 includes the steps of O-1→O-3→O-4→O-6;

[0139] The preparation method of compound O-4 includes the steps of O-1→O-3→O-4.

[0140] The present invention also provides the following compounds E, F, G, H, I, J, K, L, M, N, O-3, O-4 or salts thereof:

[0141] Definitions of abbreviations and key terms in this invention:

[0142] Technical effects of the present invention:

[0143] 1. The starting materials are inexpensive and readily available, the operation is simple, the intermediates have good stability, high purity, high yield, and are environmentally friendly. The entire synthesis process uses crystallization purification and does not use silica gel column chromatography or other preparative chromatographic methods. The process is highly robust, the product quality is more controllable, and it is suitable for large-scale industrial production.

[0144] 2. The chirality of the key axis can be chemically resolved, and the yield can be improved through a strategy of continuous desiccation and re-resolution, thereby reducing production costs. Detailed Implementation

[0145] The present invention will be further described in detail below with reference to embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art in accordance with the disclosure of the present invention shall fall within the protection scope of the present invention.

[0146] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers in the following solvents: deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD). Tetramethylsilane (TMS) was used as the internal standard.

[0147] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0148] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0149] 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 0.15mm-0.20mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4mm-0.5mm.

[0150] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0151] Example 1: Preparation of compound S

[0152] (R)-2-(4-(4-(aminomethyl)-1-oxo-8-vinyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazole-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile

[0153] (R)-2-(4-(4-(aminomethyl)-1-oxo-8-vinyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile

[0154] Step 1: 2-Amino-3-bromo-5-chlorobenzoic acid (B)

[0155] 2-amino-3-bromo-5-chlorobenzoic acid(B)

[0156] Add 50 kg of compound A, acetic acid (10 V), and water (2 V) sequentially to a reaction vessel, maintaining the temperature at 10–20 °C, and then add bromine (1.12 eq.) dropwise. After the addition is complete, allow the reaction to proceed at room temperature for 5–7 hours. Take a sample for HPLC control; if the content of compound A is less than 0.5%, the reaction is stopped.

[0157] Water (8V) was added to the reaction solution, and the temperature was lowered to 0–5°C. The mixture was filtered to obtain the crude product. The crude product was dissolved in methyl tert-butyl ether (8V). The organic phase was washed once each with sodium thiosulfate (4V) solution and sodium chloride solution (4V). After concentrating the organic phase, ethyl acetate (1V) and n-heptane (3V) were added and stirred for about 2 hours. The mixture was then cooled to 0–10°C, filtered, and dried under vacuum to obtain compound B, with a yield of 85%.

[0158] Step 2: Methyl 2-amino-3-bromo-5-chlorobenzoate (C)

[0159] methyl 2-amino-3-bromo-5-chlorobenzoate(C)

[0160] N,N-dimethylformamide (5V), 20 kg of compound B, and potassium carbonate (1.3 eq) were added to a reaction vessel, and the mixture was stirred and cooled to 5±5℃. The temperature was maintained at 5±5℃, and iodomethane (1.1 eq) was added dropwise. After the addition was complete, the temperature was raised to 25±5℃ and the reaction was carried out for approximately 6 hours. After the reaction was monitored by TLC, water (10V) was added to quench the dissolution reaction. The aqueous phase was extracted twice with methyl tert-butyl ether (10V). The combined organic phases were washed twice with saturated sodium chloride solution (5V), concentrated under reduced pressure, and n-heptane (2V) was added. The mixture was stirred for approximately 1 hour, filtered, and dried under vacuum to obtain compound C, with a yield of 90%.

[0161] Step 3: Methyl 3-bromo-5-chloro-2-cyanobenzoate (D)

[0162] methyl 3-bromo-5-chloro-2-cyanobenzoate(D)

[0163] Reaction: Purified water (1.3V) and concentrated hydrochloric acid (4eq) were added to reactor 1. 10kg of compound A was added with stirring. The temperature was lowered to 0-5℃, and controlled at 0±5℃. An aqueous solution of NaNO2 (1.1eq of NaNO2 dissolved in 1V of water) was added dropwise. The reaction proceeded for approximately 3 hours. After the reaction was complete, water (3V), NaHCO3 (7eq), CuCN (1.1eq), and NaCN (1.6eq) were added to reactor 2. The mixture was stirred and heated to 60℃, controlled at 55±5℃. The reaction solution from reactor 1 was dropwise added to reactor 2. After the addition was complete, the mixture was kept at 55±5℃ and stirred for approximately 1 hour.

[0164] Post-processing: Cool to 20±5℃, add 5V of purified water to the reaction solution, extract the aqueous phase twice with ethyl acetate (10V), combine the organic phases, wash twice with sodium chloride solution (5V), concentrate the organic phase to obtain crude product, recrystallize the crude product with ethyl acetate (1V) and n-heptane (4V), filter, and vacuum dry to obtain compound D, yield 45%.

[0165] 1 H NMR (400MHz, DMSO) δ8.41(d,1H),8.10(d,1H),3.93(s,3H).

[0166] LCMS m / z = 275.9 [M+H] +

[0167] Step 4: 2-Bromo-4-chloro-6-(hydroxymethyl)benzonitrile (E)

[0168] 2-bromo-4-chloro-6-(hydroxymethyl)benzonitrile(E)

[0169] Lithium borohydride (3.5 eq) and methanol (10 V) were added to the reaction vessel, and the temperature was controlled at 10-20 °C. 10 kg of compound D was added in portions, and the mixture was stirred at 25 ± 5 °C for approximately 2 h after the addition was complete. After the reaction was complete, a 10% ammonium chloride aqueous solution was added to the reaction solution to quench the reaction. The aqueous phase was extracted twice with ethyl acetate (8 V). The combined organic phases were washed with saturated sodium chloride solution, and the organic phase was concentrated to obtain crude compound E, which was directly used in the next reaction. The crude product yield was 100%.

[0170] LCMS m / z = 247.9 [M+H] +

[0171] Step 5: 7-Bromo-5-chloroisobenzofuran-1(3H)-one (F)

[0172] 7-bromo-5-chloroisobenzofuran-1(3H)-one(F)

[0173] 10 kg of crude compound E and concentrated hydrochloric acid (10V) were added to a reaction vessel, and the mixture was stirred and heated to 90-100°C for approximately 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and stirred for approximately 1 hour, then filtered. The filter cake was washed with water and n-heptane, and dried to obtain compound F, with a yield of 80%.

[0174] 1 H NMR (400MHz, DMSO) δ7.95(d,1H),7.83(d,1H),5.35(s,2H).

[0175] LCMS m / z = 249.0 [M+H] +

[0176] Step 6: 7-Bromo-5-chloro-3-((dimethylamino)methylene)isobenzofuran-1(3H)-one (G)

[0177] 7-bromo-5-chloro-3-((dimethylamino)methylene)isobenzofuran-1(3H)-one(G)

[0178] 500.00 g of compound F, 38.46 g of p-toluenesulfonic acid monohydrate (0.1 eq), and 2500 mL of DMF-DMA (5V) were added to a 5 L reactor. After addition, the temperature was raised to 90 °C and maintained at 90 ± 5 °C for about 5 h. After the reaction was complete, the reaction solution was concentrated until no obvious fractions were observed. It was then distilled twice with 1500 mL of ethyl acetate. After distillation, 1500 mL of ethyl acetate (3V) was added to the concentrate, and 1000 mL of an aqueous solution of 8.89 g of NaOH (0.11 eq) (2V) was added with stirring. The mixture was stirred at room temperature for 1 h, filtered, and the filter cake was washed successively with 500 mL of purified water (1V) and 500 mL of n-hexane (1V). The filter cake was collected and vacuum dried (50 °C) for 16 h, yielding 563.90 g of product, with a yield of 92.2%.

[0179] LCMS m / z = 303.9 [M+H] +

[0180] Step 7: 8-Bromo-6-chloro-4-((dimethylamino)methyl)phthalazine-1(2H)-one (H)

[0181] 8-bromo-6-chloro-4-((dimethylamino)methyl)phthalazin-1(2H)-one(H)

[0182] 463.51 g of compound G, 2320 mL of anhydrous ethanol, and 124.71 g of hydrazine hydrate (1.3 eq) were added to a 5 L reactor. The temperature was controlled at 50 ± 5 °C, and the mixture was stirred for about 1 h. The temperature was then raised to reflux, and the reaction was stirred for about 26 h. After the reaction was completed, the temperature was lowered to 5 ± 5 °C, and the mixture was kept at 5 ± 5 °C and stirred for 2 h. The mixture was filtered, and the filter cake was washed once with 500 mL (1V) of ethanol. The filter cake was then dried under vacuum (50 °C) for 16 h to obtain 443.21 g of compound H, with a yield of 91.4%.

[0183] 1 H NMR (400MHz, DMSO) δ12.63(s,1H),8.19(dd,2H),3.59(s,2H),2.19(s,6H).

[0184] LCMS m / z = 318.0 [M+H] +

[0185] Step 8: 8-Bromo-6-chloro-4-(chloromethyl)phthalazine-1(2H)-one (I)

[0186] 8-bromo-6-chloro-4-(chloromethyl)phthalazin-1(2H)-one(I)

[0187] 6.64 L of tetrahydrofuran (15V) and 443.10 g of compound H were added to a 20 L reactor and stirred to dissolve. Under N2 protection, the mixture was cooled to -10 °C, and 286.81 g of isobutyl chloroformate (1.5 eq) was added dropwise while maintaining the temperature at -15 to -10 °C. After the addition was complete, the temperature was raised to 10 °C and the reaction was carried out for about 4 h. After the reaction was complete, the reaction solution was cooled to -10 °C, and 6.64 L of 1N dilute hydrochloric acid (15V) was added dropwise while maintaining the temperature at -10±5 °C. After the addition was complete, the temperature was raised to 10 °C and maintained at 10±5 °C with stirring for 2 h. 2.21 L of purified water (5V) was added to the reaction solution, and the mixture was maintained at 5±5 °C with stirring for 1 h. The mixture was filtered, and the filter cake was washed with 880 mL of purified water (2V). The filter cake was collected and vacuum dried (50 °C) to obtain 306.10 g of compound I, with a yield of 71%.

[0188] 1 H NMR (400MHz, DMSO) δ12.80(s,1H),8.20(dd,2H),5.10(s,2H).

[0189] LCMS m / z = 309.0 [M+H] +

[0190] Step 9: 2-((5-bromo-7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindole-1,3-dione (J)

[0191] 2-((5-bromo-7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione(J)

[0192] Add 57.71 g of potassium phthalimide (1.5 eq) to a 5 L reactor. Under N2 protection, add 640 ml of N,N-dimethylformamide (10 V). Cool to -15 °C, and control the temperature between -15 and -10 °C. Add 64 g of compound I (1.0 eq) in 5 batches. After the addition is complete, raise the temperature to about 10 °C and react for about 4 h. After the reaction is complete, control the internal temperature at 5 ± 5 °C and add 640 ml of purified water (10 V). Keep warm and stir for 1 h. Filter, wash the filter cake with 128 mL of purified water (2 V), add the filter cake to 640 ml of anhydrous ethanol and slurry at 5 ± 5 °C for 2 h. Filter, collect the filter cake and vacuum dry (50 °C). 80.7 g of compound J was obtained, yield 92.8%.

[0193] LCMS m / z = 418.0 [M+H] +

[0194] Step 10: 4-(aminomethyl)-8-bromo-6-chlorophthalazine-1(2H)-one (K)

[0195] 4-(aminomethyl)-8-bromo-6-chlorophthalazin-1(2H)-one(K)

[0196] 80.66 g of compound J (1 eq), 1.21 L of anhydrous ethanol (15 V), and 19.30 g of hydrazine hydrate (2 eq) were added to a 2 L reactor. The mixture was heated to an internal temperature of 70–75 °C and reacted for approximately 2 h. After the reaction was complete, the mixture was cooled to an internal temperature of 5 ± 5 °C and stirred for 2 h. The mixture was then filtered, the filter cake was washed with ethanol, collected, and vacuum dried (50 °C) to obtain 80.7 g of compound K. (This contains byproducts; the next step involves feeding the compound in 100% molar yield.)

[0197] LCMS m / z = 290.0 [M+H] +

[0198] Step 11: (5-Bromo-7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)tert-butyl carbamate (L)

[0199] tert-butyl((5-bromo-7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate(L)

[0200] 80.7 g of compound K (total from the previous step) was added to a 1 L reactor, along with 556 ml of N,N-dimethylformamide (10 V), 29.26 g of triethylamine (1.5 eq), and 50.49 g of di-tert-butyl dicarbonate (1.2 eq). The reaction was carried out at 20 ± 5 °C for 16 h. After the reaction was complete, the temperature was lowered to an internal temperature of 5 ± 5 °C and stirred for 2 h. The mixture was then filtered, and the filter cake was added to 278 ml (5 V) of tetrahydrofuran. The mixture was kept at 5 ± 5 °C and stirred for 2 h. After filtration, the filter cake was collected and vacuum dried (50 °C) to obtain 33.84 g of compound L, with a yield of 45.2%.

[0201] 1 H NMR (400MHz, DMSO) δ12.66(s,1H),8.14(dd,2H),7.40(s,1H),4.38(d,2H),1.40(s,9H).

[0202] LCMS m / z = 390.0 [M+H] +

[0203] Step 12: (7-chloro-4-oxo-5-vinyl-3,4-dihydrophthalic acid-1-yl)methyl)tert-butyl carbamate (M)

[0204] tert-butyl((7-chloro-4-oxo-5-vinyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate(M)

[0205] Add 2.5 L of dioxane and 0.5 L of water to a 5 L reactor, start stirring, add 100 g of compound L, 43.12 g of potassium trifluoro(vinyl)borate (1.25 eq), and 106.98 g of anhydrous potassium carbonate (3 eq). Purge nitrogen under the liquid surface. After about 1 hour, add 1.16 g of palladium acetate (0.02 eq) and 4.31 g of 1,1'-bis(diisopropylphosphine)ferrocene (0.04 eq). Heat to 75–85 °C and react for 4 hours. After the reaction is complete, cool under nitrogen protection. After cooling to room temperature, add 1 L of purified water dropwise to crystallize. Stir for 0.5 hours, cool to 5 ± 5 °C, maintain the temperature and stir for 1 hour, filter, and dry the filter cake under vacuum at 55 °C to obtain 79.96 g of compound, with a yield of 92.7%.

[0206] 1 H NMR (400MHz, DMSO) δ12.57(s,1H),8.13(d,1H),7.97(d,2H),7.40(s,1H),5.84(d,1H),5.46

[0207] (d, 1H), 4.40(d, 2H), 1.40(s, 9H).

[0208] LCMS m / z = 366.1 [M+H] +

[0209] Step 13: (4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5-vinyl-3,4-dihydrophthalic acid-1-yl)methyl)tert-butyl carbamate (N)

[0210] tert-butyl((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-vinyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate(N)

[0211] Add 30L of dioxane to a 100L reactor, start stirring, and add 2.940kg of compound M, 2.723kg of pinacol diborate, and 2.631kg of potassium acetate. After purging nitrogen gas below the liquid surface for 1 hour, add 0.081kg of tris(dibenzylacetone)dipalladium and 0.086kg of 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl. React at 90±5℃ under nitrogen protection for about 2 hours. After the reaction was complete, the reaction solution was cooled to 35±5℃, and 45L of purified water was added to induce crystallization. The temperature was controlled at 25±5℃, and the mixture was filtered. The filter cake was washed twice with 10L of purified water. The resulting filter cake was then slurried with 15L of 2-methyltetrahydrofuran at 5±5℃ for 1 hour. After filtration, the filter cake was washed with 4L of 2-methyltetrahydrofuran. The filter cake was then vacuum dried at 55℃ for 18 hours. The material was collected to obtain intermediate N, with a weight of 3.140 kg and a yield of 82.26%.

[0212] 1 H NMR (400MHz, DMSO) δ12.52(s,1H),8.32–7.78(m,3H),7.29(s,1H),5.65(d,1H),5.39(d,1H),4.45(d,2H),1.42(s,9H),1.33(s,12H).

[0213] LCMS m / z = 428.2 [M+H] +

[0214] Step 14: (7-(5-(3-chloro-6-cyano-2-fluoro-5-(1-methylcyclopropoxy)phenyl)-1-methyl-1H-pyrazole-4-yl)-4-oxo-5-vinyl-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate (P)

[0215] tert-butyl((7-(5-(3-chloro-6-cyano-2-fluoro-5-(1-methylcyclopropoxy)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-5-vinyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate(P)

[0216] Reaction: 43L of 2-methyltetrahydrofuran and 17.0L of purified water were added to a 100L reactor. 3.001kg of compound N, 2.889kg of compound O, and 4.301kg of potassium phosphate were added with stirring. Nitrogen gas was introduced below the liquid surface for about 1 hour. Then, 0.078kg of [1,1'-bis(dicyclohexylphosphine)ferrocene]palladium(II) dichloride was added under nitrogen protection, and nitrogen gas was continued to be introduced below the liquid surface for about 0.5 hours. The temperature was raised to 55±5℃ and maintained for about 3 hours.

[0217] Post-processing: After the reaction was completed, the temperature was lowered to 30℃, filtered, and separated. The organic phase was washed with 15L of 12% sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure at 55℃±5℃. When the residue was about 15L, 5L of methanol was added and distilled twice. Then, 15L of methanol and 0.153kg of tributylphosphine were added. The mixture was stirred at 50±5℃ for 1 hour, then cooled to 0±5℃, filtered, and the filter cake was washed with 3L of methanol. The filter cake was then vacuum dried at 50±5℃ for about 16 hours. The material was collected to obtain intermediate P, with a weight of 3.412kg and a yield of 84.3%.

[0218] 1 H NMR(400MHz,DMSO)δ12.44(s,1H),8.32(s,1H),8.10(dd,1H),7.86(d,2H),7.44(s,1H),7.32 (t,1H),5.24(dd,2H),4.27(d,2H),3.81(s,3H),1.58(s,3H),1.38(s,9H),1.24–0.65(m,4H).

[0219] LCMS m / z = 605.2[M+H] +

[0220] Step 15: (R)-2-(4-(4-(aminomethyl)-1-oxo-8-vinyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile (tert-butyloxycarbonyl)-D-phenylalanine salt (R) 0 )

[0221] (R)-2-(4-(4-(aminomethyl)-1-oxo-8-vinyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile(tert-butoxycarbonyl)-D-phenylalanine(R) 0 )

[0222] Reaction: Add 30L of acetonitrile to a 100L reactor, start stirring, and add 2.102kg of compound P and 1.221kg of benzenesulfonic acid monohydrate; after the addition is complete, heat to 55±5℃ and maintain the temperature for about 3 hours.

[0223] Filtration: After the reaction is complete, cool to 5±5℃ and centrifuge, then wash the filter cake twice with 4.2L of acetonitrile.

[0224] Free reaction: Add 9.45L tetrahydrofuran and 3.15L water to a 100L reactor, then add the centrifuged filter cake and stir to dissolve. Add 30.45L water and 1.05L concentrated ammonia to a 50L reactor and cool to 10-15℃. Add the dissolved solution dropwise. After addition, cool to 5±5℃ and stir for about 15 hours. Filter. Add the filter cake to 10.5L purified water and slurry for about 1 hour. Filter again. Wash the filter cake twice with 4.2L purified water to obtain the wet S-racemate of compound, weighing 3.528kg (theoretical water content 1.776kg).

[0225] Separation: 2.3 L of anhydrous ethanol and 115 mL of purified water were added to a 5 L reactor. 230.0 g of the free S-racemate (obtained by drying the aforementioned wet sample) was added, and 133 g of Boc-D phenylalanine was added with stirring. The temperature was controlled at 20 ± 5 °C, and stirring was continued for 16 h. A solid precipitated, which was filtered. The filter cake was washed with 100 mL of anhydrous ethanol. The resulting wet sample was added to 0.76 L of anhydrous ethanol and 77 mL of purified water, and the mixture was stirred for 16 h. After filtration, the filter cake was rinsed with 100 mL of anhydrous ethanol. The filter cake was then dried at 45 °C for 16 h to obtain 87.6 g of compound R. 0 The yield was 25.0%, the purity was 99.2%, and the chiral purity was 98.1%. After concentrating the filtrate, it was separated twice more using the same method to obtain two more batches of R. 0 Product, combined 3 batches R 0 The overall yield of the product was 59.2%.

[0226] 1H NMR (400MHz, DMSO) δ12.48(s,1H),8.41(s,1H),8.12(dd,1H),7.86(d,1H),7.76(d,1H),7.53(d,J=1.4Hz,1H),7.33–7.03(m,5H),6.6 3(d,1H),5.36–5.19(m,2H),4.10–3.89(m,3H),3.80(s,3H),3.03(dd,1H),2.85(dd,1H),1.59(s,3H),1.29(d,9H),1.11–0.86(m,4H).

[0227] LCMS m / z = 505.1 [M-265+H] +

[0228] Step 16: (R)-2-(4-(4-(aminomethyl)-1-oxo-8-vinyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazole-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile(S)

[0229] (R)-2-(4-(4-(aminomethyl)-1-oxo-8-vinyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropoxy)benzonitrile(S)

[0230] Dissociation: In a 50L reactor, add 24L of purified water and 2.145kg of potassium carbonate, stir until dissolved, then add 2.389kg of compound R. 0 Add 10 L of ethyl acetate, stir to dissolve for 30 min, allow to stand and separate, collect the organic phase, extract the aqueous phase twice more with 10 L of ethyl acetate, separate the liquids, combine the three organic phases, and wash successively with 12 L of potassium carbonate aqueous solution and 12 L of sodium chloride aqueous solution. Add 2.501 kg of anhydrous sodium sulfate to the organic phase, stir and dry, filter, and concentrate the filtrate under reduced pressure below 40 °C; after concentrating the filtrates for about 5 h, about 5 L of concentrate remains, add 5 L of n-hexane and distill, a large amount of solid precipitates, distill for 4 h and then stop, to obtain the wet product, dry the wet product under reduced pressure at 45 °C for about 23 h, to obtain compound S 1.601 kg, yield 100%.

[0231] 1H NMR(400MHz,DMSO)δ12.33(s,1H),8.38(s,1H),8.14(dd,1H),7.85(d,1H),7.71(d,1H) ,7.63(d,1H),5.45–5.24(m,2H),3.80(s,3H),3.76(d,2H),1.59(s,3H),0.97(dt,4H).

[0232] LCMS m / z = 505.1 [M+H] +

[0233] Example 2: Preparation of compound O

[0234] 4-Chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(1-methylcyclopropoxy)benzonitrile (compound O)

[0235] 4-chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(1-methylcyclopropoxy)benzonitrile

[0236] Step 1: 4-Chloro-5-fluoro-2-(1-methylcyclopropoxy)benzonitrile (O-3)

[0237] 4-chloro-5-fluoro-2-(1-methylcyclopropoxy)benzonitrile

[0238] Compound O-1 (1750 g, 1.0 eq), cesium carbonate (2.25 kg, 2.0 eq), N,N-dimethylformamide (8.75 L, 5 V) were added to a 20 L reactor, followed by 1-methylcyclopropanol (1.1 eq). The mixture was heated to 55–60 °C and reacted for approximately 16 hours.

[0239] After the reaction was complete, the reaction solution was cooled to room temperature and added to 30 L of water. The aqueous phase was extracted with 30 L of methyl tert-butyl ether, separated, and the organic phase was washed twice with water and once with saturated brine. The organic phase was concentrated, and the crude product was distilled twice with n-hexane. 4 L of n-hexane was added, and the mixture was stirred for about 2 hours. The mixture was filtered, the filter cake was washed with n-hexane, and dried at 50 °C to give 1584 g of off-white solid, with a yield of 69.9%.

[0240] 1 H NMR (400MHz, DMSO) δ8.01(d,1H),7.54(d,1H),1.54(s,3H),1.00(t,2H),0.87(t,2H).

[0241] LCMS m / z = 226.1 [M+H] +

[0242] Step 2: 4-Chloro-3-fluoro-2-iodo-6-(1-methylcyclopropoxy)benzonitrile (O-4)

[0243] 4-chloro-3-fluoro-2-iodo-6-(1-methylcyclopropoxy)benzonitrile

[0244] Under N2 protection, compound O-3 (520 g, 1.0 eq) and tetrahydrofuran (7.8 L, 15 V) were added to a 30 L reactor and the temperature was lowered to -70 to -60 °C. While maintaining the temperature at -70 to -60 °C, lithium diisopropylamino (1.84 L, 1.6 eq) was added dropwise. After the addition was complete, stirring was continued for about 1 hour. While maintaining the temperature at -70 to -60 °C, an iodine / tetrahydrofuran solution (1.17 kg / 4.7 L, 2.0 eq) was added dropwise. After the addition was complete, stirring was continued for about 1 hour.

[0245] After the reaction was complete, a 10% ammonium chloride solution was added to the reaction mixture, and the mixture was stirred for 30 min. Then, 10 L of methyl tert-butyl ether was added for extraction. The mixture was separated, and the organic phase was washed twice with a 20% Na₂SO₃ aqueous solution. The organic phase was collected, concentrated, and the methyl tert-butyl ether was distilled off. The crude product was distilled once with n-hexane, and then slurried with 8 L of n-hexane and stirred overnight. The mixture was filtered, the filter cake was washed with n-hexane, and the solid was collected and dried at 50 °C to obtain a brown solid. The yield was 85.5%.

[0246] 1 H NMR (400MHz, CDCl3) δ7.34(d,1H),1.60(s,3H),1.00(t,2H),0.83(t,2H).

[0247] LCMS m / z = 352.1 [M+H] +

[0248] Step 3: 4-Chloro-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-6-(1-methylcyclopropoxy)benzonitrile (O-6)

[0249] 4-chloro-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-6-(1-methylcyclopropoxy)benzonitrile

[0250] Under nitrogen protection, compound O-4 (950g, 2.56mol, 1.0eq), compound O-5 (562g, 3.07mol, 1.2eq), potassium fluoride (392.5g, 6.4mol, 2.5eq), dioxane (5.0L), and water (1.0L) were added to a 20L reactor. The reactor was purged with nitrogen three times. Then, the catalyst bis(di-tert-butyl-4-dimethylaminophenylphosphine)palladium chloride (28.8g, 0.015eq) was added. The mixture was stirred for 10–15 min under nitrogen protection and then heated to 60–70℃ and stirred for approximately 18 hours.

[0251] After the reaction was complete, the reaction system was cooled and concentrated to remove most of the dioxane. The residue was dissolved in 10 L of dichloromethane / 5 L of water, separated, and the organic phase was washed twice with water. The organic phase was collected, concentrated and evaporated to dryness at 40 °C, and 1.0 L of anhydrous ethanol was added once. The residue was slurried with ethanol / water = 3 / 4 (1.4 L), stirred for 5 hours, filtered, and the filter cake was washed with ethanol / water = 3 / 4 (140 mL). The mixture was dried under vacuum, and the solid was collected and dried under vacuum at 50 °C to obtain a brown powder with a yield of 84%.

[0252] LCMS m / z = 306.2[M+H] +

[0253] Step 4: 4-Chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(1-methylcyclopropoxy)benzonitrile (O)

[0254] Compound O-6 (690 g, 2.26 mol, 1.0 eq), acetonitrile (4.9 L, 7 V), and N-iodosuccinimide (609 g, 2.7 mol, 1.2 eq) were added to a 10 L reactor, and the mixture was purged with nitrogen three times. Trifluoroacetic acid (87 mL, 1.13 mol, 0.5 eq) was added, and the mixture was stirred for 30 min. The temperature was raised to 65–75 °C, and the reaction was allowed to proceed for approximately 2–6 h.

[0255] After the reaction was complete, the reaction solution was cooled to 20-30℃, and 10L of Na2SO3 (281g, 2.23mol) solution was added with stirring. A brown solid precipitated out. The mixture was stirred for about 1 hour, filtered, and the filter cake was washed twice with water. The filter cake and 5L of acetonitrile were added to the reaction flask, heated to 65-70℃ and stirred for 30 minutes, then cooled and stirred at 20-30℃ for 2 hours. The mixture was filtered, and dried under vacuum at 50℃ to obtain an off-white solid with a yield of 80%.

[0256] 1 H NMR (400MHz, DMSO) δ8.03–7.54(m,2H),3.78(s,3H),1.60(s,3H),1.14–0.96(m,2H),0.93(d,2H).

[0257] LCMS m / z=432.0[M+H] + .

Claims

1. A method for preparing a compound P', comprising the following reaction: wherein PG is a protecting group, selected from Boc, Cbz, Pht, Fmoc, and Tfa.

2. A method of preparing a compound R 0 comprising the reaction: wherein PG is a protecting group, selected from Boc, Cbz, Pht, Fmoc, and Tfa.

3. A process for the preparation of compound S comprising the reaction: ###0002### S 4. A method for preparing compound H', comprising the following reaction: wherein R and R' are leaving groups.

5. A method of preparing compound G' comprising the reaction: ###00002### G' ###00003### G wherein R and R' are leaving groups.

6. A process for the preparation of compound F' comprising the reaction: wherein R and R' are leaving groups.

7. A process for the preparation of compound J' comprising the reaction: ###00006### J' ###00007### J wherein X is a halogen, and R and R' are leaving groups.

8. A process for the preparation of compound K' comprising the steps of: wherein R and R' are leaving groups.

9. A method for preparing a compound M', comprising the following reaction: wherein R and R' are leaving groups, and PG is a protecting group, selected from Boc, Cbz, Pht, Fmoc, and Tfa.

10. A method for preparing a compound N', comprising the following reaction: wherein R is a leaving group, and PG is a protecting group, selected from Boc, Cbz, Pht, Fmoc, and Tfa.

11. A process for the preparation of compound O comprising the reaction: ###00014### O ###00015### O 12. A method for preparing compound O-6, comprising the following reaction:

13. A process for the preparation of compound O-4 comprising the reaction: ###00019### O-4 ###00020### O-3 O-4 14. A process for the preparation of compound O-3 comprising the reaction: ###00019### O-3 ###00020### O-2 O-3 15. Compound E, F, G, H, I, J, K, L, M, N, O-3, O-4, or a salt thereof:

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