Preparation method for BRAF inhibitor

Abstract

The present invention provides a preparation method for a BRAF inhibitor (formula (A). The method involves mild reaction conditions, simple operations, high reaction yield, high product purity and convenient post-treatment, and thus is suitable for industrial production.

Description

A preparation method of BRAF inhibitor Technical Field

[0001] The present invention relates to a method for preparing a pharmaceutical compound, in particular to a method for preparing a BRAF inhibitor, and belongs to the technical field of pharmaceutical chemistry. Background Art

[0002] Kinases are enzymes that catalyze the transfer of a phosphate group from a high-energy, phosphate-donating molecule to a specific substrate. This process, called phosphorylation, involves the substrate acquiring the phosphate group and the high-energy ATP molecule donating the phosphate group. Kinases are classified into the following broad categories based on the substrates they target: protein kinases, lipid kinases, and carbohydrate kinases. Kinases are found in a wide variety of species, from bacteria to fungi to worms to mammals. Over 500 different kinases have been identified in humans.

[0003] MAP kinases (MAPKs) are a family of serine / threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all thought to participate in mitogenic stimulation of the MAPK pathway. Activation of this pathway at the receptor level triggers a signaling cascade whereby the Ras GTPase exchanges GDP for GTP. Next, Ras activates Raf kinase (also known as MAPKKK), which in turn activates MEK (MAPKK).

[0004] BRAF protein is a member of the RAF family of serine / threonine kinases that participates in the Ras RafMEK extracellular signal-regulated kinase (ERK) pathway or the mitogen-activated protein kinase (MAPK) / ERK signaling pathway cascade that affects cell division and differentiation. BRAF gene mutations can lead to uncontrolled growth and subsequent tumor formation. BRAF is mutated and / or overactivated in common human cancers, such as melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, and ovarian cancer and its metastatic cancers, and primary brain tumors. Although some BRAF inhibitors produce excellent extracranial responses, cancer may still develop brain metastases during or subsequently with BRAF inhibitor therapy. An estimated 20% of subjects with cancer will develop brain metastases, with the majority of brain metastases occurring in those subjects with melanoma, colorectal cancer, lung cancer, and renal cell carcinoma. Brain metastases remain a substantial contributor to overall cancer mortality in subjects with advanced cancer, and despite multimodality treatment and advances in systemic therapy, which includes combinations of surgery, radiotherapy, chemotherapy, immunotherapy, and / or targeted therapies, the prognosis remains poor.

[0005] In addition, BRAF has been identified as a potential target for the treatment of primary brain tumors. The prevalence of the BRAF V600E mutation in primary brain tumors has been reported by Schindler et al. in their analysis of 1,320 central nervous system (CNS) tumors and Behling et al. in their analysis of 969 CNS tumors in pediatric and adult populations. These studies, combined with other studies, have reported the presence of the BRAF V600E mutation in various cancers, including papillary craniopharyngioma, pleomorphic xanthomatous astrocytoma (PXA), ganglioglioma, astroblastoma, and others.

[0006] The blood-brain barrier (BBB) ​​is a highly selective physical transport and metabolic barrier that separates the CNS from the blood. The BBB prevents certain drugs from entering brain tissue and is a limiting factor for many peripherally administered agents to be delivered to the CNS. Many drugs commonly used to treat cancer cannot cross the blood-brain barrier. This means that these drugs cannot penetrate the brain and therefore cannot effectively kill cancer cells in the brain. Current treatments for subjects with brain tumors include surgical resection, radiotherapy, and / or chemotherapy using agents such as temozolomide and / or bevacizumab. However, surgical treatment of brain cancer is not always possible, for example, the tumor may not be accessible, or the subject may not be able to withstand neurosurgical trauma. In addition, known radiotherapy and treatment with cytotoxic agents have undesirable side effects. For example, there is increasing evidence that the use of temozolomide itself can induce mutations and worsen prognosis in a large proportion of subjects, and the bevacizumab label has a black box warning for gastrointestinal perforation, surgical and wound healing complications, and bleeding. Kinase inhibitors are used to treat many peripheral cancers. However, due to their structural properties, many kinase inhibitors such as BRAF inhibitors (e.g., vemurafenib and dabrafenib) are substrates of active transporters such as P-glycoprotein (P gp) or breast cancer resistance protein (BCRP). For example, dabrafenib was reported to have an MDR1 efflux ratio of 11.4, a BCRP efflux ratio of 21.0, and a total brain to plasma ratio of 0.023; whereas vemurafenib was reported to have an MDR1 efflux ratio of 83, a BCRP efflux ratio of 495, and a total brain to plasma ratio of 0.004.

[0007] Given that both P-gp and BCRP are expressed in the endothelial cells lining the blood and brain capillaries, the activity of both P-gp and BCRP in the BBB plays a key role in preventing most kinase inhibitors from distributing to the brain parenchyma. Therefore, kinase inhibitors are generally not suitable for the treatment of tumors or cancers in the brain (which is protected by the BBB). Therefore, there remains a need for treatment of tumors with BRAF mutations.

[0008] Additionally, there remains an unmet need for the treatment of CNS tumors, including those with BRAF mutations.

[0009] WO2024017294 discloses a BRAF inhibitor and its use, which involves a compound of the following formula (A):

[0010] The preparation route is disclosed as follows:

[0011] In the above preparation method, the reaction temperature of the second step is relatively high; there is a problem of position selectivity in the third step; the yield of the fourth step is low and purification by silica gel column is required, which has low efficiency, low yield and high cost, making it unsuitable for industrial scale-up production. Summary of the Invention

[0012] The present invention provides a method for preparing a compound of formula (A), which comprises the following reaction:

[0013] The reaction is a metal coupling reaction carried out in a solvent system in the presence of a palladium catalyst, a ligand and an alkaline reagent.

[0014] In some embodiments, the catalyst comprises a palladium catalyst selected from one or more of (Pd(OAc)2, [Pd(C3H5)Cl]2, Pd(TFA)2, Pd(MeCN)2Cl2, Pd2(dba)3, [Pd(cinnamyl)Cl]2), preferably [PdCl(C3H5)]2, Pd2(dba)3, more preferably [PdCl(C3H5)]2;

[0015] In some embodiments, the ligand is selected from one or more of dppf, dtbpf, Catacxium PtB, DPEPhos, AmgenPhos, Ad2nBuP, BI-DIME, XantPhos, dippf, rac-BI-DIME, tBuXPhos, (R)-BINAP, RuPhos, CPhos, and TrixiePhos, preferably tBuXPhos, RuPhos, CPhos, and TrixiePhos, and more preferably tBuXPhos.

[0016] In some embodiments, the palladium catalyst / phosphine ligand is selected from [PdCl(C3H5)]2 / tBuXPhos.

[0017] In some embodiments, the molar ratio of the feed materials of the reaction formula (C1): formula (B): [PdCl(C3H5)]2: tBuXPhos is 1.0: (1.0-2.0): (0.1%-2%): (0.1%-8%), or is 1.0: (1.0-1.5): (0.3%-1%): (1.0%-6%), or is 1.0: (1.0-1.2): (0.3%-1.0%): (1.0%-4.0%), or is 1.0: (1.0-1.10): (0.3%-1.0%): (1.0%-4.0%).

[0018] The alkaline agent is selected from one or more of sodium hydroxide, potassium carbonate, potassium tert-butoxide, potassium tert-amylate, sodium carbonate, cesium carbonate, cesium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide; preferably one or more of cesium carbonate, potassium carbonate, sodium carbonate and potassium phosphate; more preferably potassium carbonate.

[0019] In some embodiments, the reaction solvent used in the reaction is selected from one or more of polar aprotic solvents or non-polar solvents; or the reaction solvent is selected from one or more of toluene, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, acetonitrile, ethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, N,N-dimethylformamide, N-methylpyrrolidone, acetone, butanone, methyl isobutyl ketone, and 2-pentanone; or the reaction solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, cyclopentyl methyl ether, toluene, and tert-amyl alcohol; or the reaction solvent is selected from cyclopentyl methyl ether and toluene; or the reaction solvent is selected from toluene.

[0020] In some embodiments, the reaction temperature is 0-90°C, preferably 50-90°C, more preferably 60-80°C.

[0021] The present invention also provides a method for preparing a compound of formula (C1), which comprises the following reaction:

[0022] The reaction is carried out in a solvent system in the presence of a base.

[0023] In some embodiments, the alkaline agent is selected from one or more of sodium hydroxide, potassium carbonate, potassium tert-butoxide, potassium tert-amylate, sodium carbonate, cesium carbonate, cesium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide; preferably one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate; more preferably potassium carbonate.

[0024] In some embodiments, the reaction solvent used in the reaction is selected from one or more of polar aprotic solvents or non-polar solvents; or the reaction solvent is selected from one or more of toluene, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, acetonitrile, ethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, N,N-dimethylformamide, N-methylpyrrolidone, acetone, butanone, methyl isobutyl ketone, and 2-pentanone; or the reaction solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, toluene, tert-amyl alcohol, isopropanol, tert-butanol, and ethanol; or the reaction solvent is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, and N,N-dimethylacetamide; or the reaction solvent is selected from N,N-dimethylacetamide.

[0025] In some embodiments, the molar ratio of the feed materials of the reaction formula (D1): formula (D2): potassium carbonate is 1.0:(1.0~2.0):(1.0~4.0), or 1.0:(1.0~1.5):(1.0~3.0), or 1.0:(1.0~1.1):(1.0~2.0), or 1.0:(1.0~1.05):(1.0~1.8).

[0026] In some embodiments, the reaction temperature is 0-100°C, preferably 40-90°C, more preferably 50-80°C.

[0027] In some embodiments, the reaction quenching reagent is selected from aqueous solutions of acetic acid, phosphoric acid, sulfuric acid, and hydrochloric acid, preferably an aqueous solution of acetic acid.

[0028] The present invention also provides a method for preparing a compound of formula (D1), comprising the following reaction:

[0029] In some embodiments, the compound (E1) reacts with a reagent (E2) under acidic conditions to obtain a compound (D1).

[0030] In some embodiments, the reagent (E2) is selected from one or more of trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, triisopropyl orthoformate, and tributyl orthoformate; preferably one or more of triethyl orthoformate, trimethyl orthoformate, and triisopropyl orthoformate; more preferably triethyl orthoformate.

[0031] In some embodiments, the acidic reagent is selected from one or more of trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, toluenesulfonic acid, hydrochloric acid, and methanesulfonic acid; preferably one or more of trifluoroacetic acid, acetic acid, and p-toluenesulfonic acid; more preferably trifluoroacetic acid.

[0032] In some embodiments, the reaction temperature is 50-120°C, preferably 70-110°C, more preferably 80-100°C.

[0033] The present invention also provides a method for preparing a compound of formula (E1), comprising the following reaction:

[0034] In some embodiments, the reaction solvent used in the reaction is selected from one or more of polar aprotic solvents or non-polar solvents; or the reaction solvent is selected from one or more of toluene, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, acetonitrile, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyl tert-butyl ether, N,N-dimethylformamide, N-methylpyrrolidone, acetone, butanone, methyl isobutyl ketone, and 2-pentanone; or the reaction solvent is selected from one or more of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, and cyclopentyl methyl ether; or the reaction solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether; or the reaction solvent is selected from tetrahydrofuran.

[0035] In some embodiments, the reaction temperature is -50 to 20°C, preferably -30 to 0°C, and more preferably -20 to -10°C.

[0036] In some embodiments, the molar ratio of the feeds of the reaction (G1): (F1) is 1.0: (1.0-10.0), or 1.0: (2.0-8.0): (1.0-3.0), or 1.0: (2.0-5.0), or 1.0: (3.0-5.0).

[0037] In some embodiments, it further comprises the following polishing steps:

[0038] The solvent used in the refining step is selected from one or more polar aprotic solvents or non-polar solvents; or selected from one or more of toluene, methanol, ethanol, 95% ethanol, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, acetonitrile, ethyl ether, tetrahydrofuran, n-propanol, isopropanol, n-butanol, isobutanol, n-propanol, acetone, butanone, methyl isobutyl ketone, 2-pentanone, and water; or selected from one or more of isopropanol, toluene, water, ethanol, methyl tert-butyl ether, and methyl isobutyl ketone; or selected from one or more of isopropanol, toluene, and water; or selected from one or more of methyl isobutyl ketone and water; or selected from one or more of methyl isobutyl ketone and water.

[0039] In some embodiments, the dissolution temperature in the refining step is 0°C to 100°C, preferably 50°C to 100°C, and more preferably 80°C to 100°C.

[0040] In some embodiments, the crystallization temperature in the purification step is 0°C to 40°C, preferably 0°C to 30°C, and more preferably 0°C to 20°C.

[0041] In some embodiments, the solvent used in the refining step is selected from a methyl isobutyl ketone-water mixed solution, and the volume ratio of methyl isobutyl ketone:water in the mixed solution is 100:1-100:50, or 100:1-100:20, or 100:1-100:10, or 100:1-100:5.

[0042] The present invention also provides a method for preparing a compound of formula (D), comprising the following steps:

[0043] wherein R2 and R3 are each independently selected from an alkane, an aromatic hydrocarbon or a halogen, preferably a halogen, more preferably F, Cl or Br, and most preferably F;

[0044] In some embodiments, the compound of formula (J) is reacted to obtain the intermediate compound of formula (H), wherein the reaction is carried out in the presence of a Vilsmeier reagent, wherein the Vilsmeier reagent is a compound containing The reagent; the reaction solvent used is selected from at least one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and trichloroethane, preferably at least one of dichloromethane and chloroform; the reaction temperature is 0 to 60°C, preferably 25±5°C;

[0045] In some embodiments, the compound of formula (J) is reacted to obtain the intermediate compound of formula (H), and the reaction is carried out in the presence of DMF / oxalyl chloride, and the reaction solvent used is selected from at least one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and trichloroethane, preferably at least one of dichloromethane and chloroform; the reaction temperature is 0-60°C, preferably 25±5°C; optionally, DMF and oxalyl chloride are reacted at 5-20°C before adding the compound of formula (J) to react;

[0046] In some embodiments, the intermediate compound of formula (H) is reacted to obtain the compound of formula (D), and the reaction is carried out in the presence of a base, wherein the base is selected from at least one of N,N-diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, and triethylenediamine, preferably at least one of N,N-diisopropylethylamine and triethylamine;

[0047] In some embodiments, the intermediate compound of formula (H) is reacted to obtain a compound of formula (D), and the reaction solvent used in the reaction is selected from at least one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and trichloroethane, preferably at least one of dichloromethane and chloroform;

[0048] In some embodiments, the intermediate compound of formula (H) is reacted to obtain the compound of formula (D), and the reaction temperature is 0-60°C, preferably 5-25°C.

[0049] The present invention also provides a method for preparing a compound of formula (B1), comprising the following steps:

[0050] wherein HX is an organic acid or an inorganic acid selected from HOOC-COOH, HCl, HBr, HI, L-tartaric acid, benzoic acid or p-toluenesulfonic acid, preferably HOOC-COOH; PG is a protecting group selected from Boc, Ac or Cbz, preferably Boc, Cbz, most preferably Boc; n is selected from 0.5, 1, 1.5 or 2, preferably 0.5 or 1;

[0051] Optionally, in some embodiments, the compound of formula (K) reacts with the compound of formula (L) to obtain the compound of formula (M), and the reaction is carried out in the presence of a base, wherein the base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate, preferably one or more of triethylamine and N,N-diisopropylethylamine; the reaction solvent used in the reaction is selected from acetonitrile, toluene, methanol, ethanol, 95% ethanol, dichloromethane, 1,2-dichloroethane, ethyl acetate, methyl tert-butyl ether, diethyl ether, tetrahydrofuran, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, n-propanol, acetone, butanone, methyl isobutyl ketone, 2-pentanone, One or more of water, preferably acetonitrile; the reaction temperature of the reaction is 0-80°C, preferably 10-50°C, more preferably 30-35°C; optionally, in some embodiments, the compound of formula (M) is reacted to obtain a compound of formula (B1), and the reaction is carried out in the presence of an acid, the acid is selected from one or more of trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, and sulfuric acid, preferably one or more of trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, and sulfuric acid; the reaction solvent used in the reaction is selected from one or more of dichloromethane, acetonitrile, isopropanol, ethanol, and tetrahydrofuran, preferably one or more of dichloromethane and acetonitrile; the reaction temperature of the reaction is 0-40°C, preferably 20-25°C.

[0052] The present invention also provides a method for preparing a compound by combining the above-mentioned steps in sequence, for example:

[0053] A method for preparing a compound of formula (A), comprising the steps of (D1) → (C1) → (A);

[0054] A method for preparing a compound of formula (A), comprising the steps of (E1) → (D1) → (C1) → (A);

[0055] A method for preparing a compound of formula (A), comprising the steps of (G1) → (E1) → (D1) → (C1) → (A);

[0056] A method for preparing a compound of formula (A), comprising the steps of (J) → (H) → (D1) → (C1) → (A);

[0057] A method for preparing a compound of formula (A), comprising the steps of (J) → (H) → (D1) → (C1) → (A);

[0058] A method for preparing a compound of formula (C1), comprising the steps of (E1) → (D1) → (C1);

[0059] A method for preparing a compound of formula (C1), comprising the steps of (G1) → (E1) → (D1) → (C1);

[0060] A method for preparing a compound of formula (C1), comprising the steps of (J) → (H) → (D1) → (C1); a method for preparing a compound of formula (D1), comprising the steps of (G1) → (E1) → (D1);

[0061] The preparation method of the compound of formula (D1) comprises the steps of (J)→(H)→(D1).

[0062] In addition, the present invention also provides a compound of formula (C1), (M-1) or a salt thereof:

[0063] Definitions of abbreviations and key terms in this invention:

[0064] Technical effects of the present invention:

[0065] 1. The process route for synthesizing formula (A) of the present invention is novel, with mild reaction conditions in each step, simple operation, high yield, high product purity, convenient post-processing, and is suitable for industrial production.

[0066] 2. The process of the present invention has readily available raw materials and simple steps. The entire synthesis process does not use silica gel column chromatography or other preparative chromatography methods, has low cost, good intermediate stability, high purity, and high yield, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0067] The present invention is further described in detail below with reference to the embodiments, but the present invention is not limited thereto. Any equivalent replacements in the art made according to the disclosure of the present invention shall fall within the scope of protection of the present invention.

[0068] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0069] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0070] HPLC analysis was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SC-A18 100×4.6 mm, 3.5 μM).

[0071] Example 1: Preparation of A:

[0072] N-(2-cyano-3-((3-(2,2-difluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-2-azaspiro[3.3]heptane-2-sulfonamide

[0073] N-(2-cyano-3-((3-(2,2-difluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-2-azaspiro[3.3]heptane-2-sulfonamide

[0074] Step 1: Prepare E1

[0075] 2-amino-N-(2,2-difluoroethyl)-5-hydroxybenzamide

[0076] At room temperature, THF (40 L) and G1 (4.0 kg) were added to the reactor. The temperature was lowered to -25°C, and difluoroethylamine (7.2 kg, 3.86 eq) was added. The temperature was raised to -15°C. The reaction was continued at -15°C for 14 h. After the reaction was completed, water (30 L) and MTBE (20 L) were added to the reactor. The liquid phase was separated, and the organic phase was collected. The aqueous phase was extracted with MTBE (20 L). The organic phases were combined and washed with saturated brine (20 L x 2). The organic phase was concentrated under reduced pressure until almost no liquid flowed out. Then, n-heptane (8 L, 2 V) was added and concentrated to dryness. Ethyl acetate (6 L) was added and stirred for 30 min. Then, n-heptane (48 L) was added and stirred for 2 h. The mixture was filtered and dried to obtain E1 with a yield of 91% and a purity of 95.8%.

[0077] LC-MS: m / z = 217.1 [M+H] +

[0078] 1 H NMR(400MHz,d6-dmso)δ8.62(s,1H),8.48(t,J=11.6Hz,1H),6.93(d,J=16Hz,,2H),6.75-6.71(d d,J=16.0Hz,1H),6.61-6.58(d,J=8.0Hz,1H),6.25-5.90(m,1H),5.70(s,1H),3.65-3.42(m,2H).

[0079] Step 2: Prepare D1

[0080] 3-(2,2-difluoroethyl)-6-hydroxyquinazolin-4(3H)-one

[0081] Compound E1 (8.5 kg, 1.0 eq) was added to a 100 L reactor, followed by triethyl orthoformate (42.5 L) and trifluoroacetic acid (224.2 g, 0.05 eq). The temperature was raised to 90°C and the reaction was allowed to proceed for 12 h. The reaction was then cooled to 50°C, and n-heptane (51 L) was added. The reaction was then cooled to 25°C and stirred at 25°C for 1 h. The reaction mixture was filtered, and the filter cake was washed with n-hexane (8.5 L). D1 was obtained after drying with a yield of 91% and a purity of 97.4%.

[0082] LC-MS: m / z = 227.1 [M+H] +

[0083] 1H NMR(400MHz,)δ10.26(s,,1H),8.25(s,1H),7.65-7.63(d,J=8.0Hz,1H),7.57-7.56( d,J=4.0Hz,1H),7.39-7.36(d,J=12.0Hz,1H),6.62-6.36(m,1H),4.61-4.52(m,2H).

[0084] Step 3: Prepare C1

[0085] 6-bromo-2-((3-(2,2-difluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-3-fluorobenzonitrile

[0086] 9.671 kg of N,N-dimethylacetamide was added to the reactor, stirring was started, and 2.001 kg of D1, 1.966 kg of D2 (1.02 eq), and 2.071 kg of potassium carbonate (1.7 liters) were added. The temperature was raised to 50-55°C and the reaction was allowed to proceed for 8 hours. After completion of the reaction, an aqueous acetic acid solution (4.578 kg of acetic acid + 16.559 kg of water) was added to the reactor, the temperature was lowered, crystallization was carried out, and the product was filtered and dried to obtain C1 with a yield of 98.32% and a purity of 99.7%.

[0087] LC-MS: m / z = 424.0 [M+H] +

[0088] 1 H NMR(400MHz,d6-dmso)δ8.40-8.35(s,1H),7.92-7.74(m,4H),7.60-7.56(d,J=1 6.0Hz,1H),6.75-6.71(dd,J=12.0Hz,1H),6.55-6.25(m,1H),4.60-4.40(m,,1H)

[0089] Step 4: Prepare A

[0090] N-(2-cyano-3-((3-(2,2-difluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-2-azaspiro[3.3]heptane-2-sulfonamide

[0091] N-(2-cyano-3-((3-(2,2-difluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-2-azaspiro[3.3]heptane-2-sulfonamide

[0092] To a reactor, add 46.98 kg of toluene, 1.800 kg of Cl, 0.822 kg of B1 (1.1 eq), and 1.759 kg of potassium carbonate (3 eq). Add 15.2 g of allylpalladium(II) chloride dimer (II) dimer, and 72.1 g of 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, and replace the atmosphere with nitrogen. Raise the temperature to 70°C and start timing. Upon completion of the reaction, add aqueous acetic acid (5.41 kg of acetic acid + 15.31 kg of purified water). Cool the mixture to allow crystallization to obtain a filter cake. Add the filter cake to 14.30 kg of methyl isobutyl ketone, followed by 1.800 kg of acetic acid and 15.800 kg of purified water. Raise the temperature to dissolve the mixture. Separate the mixture, add 0.09 kg of activated carbon to the organic phase, and stir for 1 hour. The mixture was filtered, 0.360 kg of tributylphosphine was added to the filtrate, the temperature was lowered for crystallization, suction filtered, and dried to obtain A with a yield of 72% and a purity of 99.7%.

[0093] Step 5: Preparation of refined product A

[0094] N-(2-cyano-3-((3-(2,2-difluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-2-azaspiro[3.3]heptane-2-sulfonamide

[0095] N-(2-cyano-3-((3-(2,2-difluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-2-azaspiro[3.3]heptane-2-sulfonamide

[0096] Add 3.00 kg of crude A, 28.30 kg of methyl isobutyl ketone, and 2.101 kg of water to a reactor, start stirring, and heat to dissolve. Lower the internal temperature to 65°C, add 15 g (0.5%) seed crystals, cool, crystallize, and dry to obtain refined A. Yield: 88%, purity: 99.95%.

[0097] LC-MS: m / z = 520.12 [M+H] +

[0098] 1H NMR(400MHz,d6-dmso)δ10.39(s,1H),8.35(s,1H),7.91-7.43(m,5H),6.52-6.23(t,J= 4.8Hz,1H),4.53-4.52(m,2H),3.85(s,4H),2.12-2.08(t,J=8Hz,4H)1.78-1.70(m,2H).

[0099] Example 2: Preparation of D1

[0100] 3-(2,2-Difluoroethyl)-6-hydroxyquinazolin-4(3H)-one

[0101] 3-(2,2-difluoroethyl)-6-hydroxyquinazolin-4(3H)-one

[0102] Reaction: Under nitrogen, add 250.00g DCM and 10.50g DMF to a reactor, start stirring, cool to 5±5°C, add 18.23g oxalyl chloride dropwise so that the internal temperature does not exceed 20°C, and after completion of the addition, raise the temperature to 25±5°C and react for 0.5h. Add 10.00g of the compound of formula (J) and maintain the temperature at 25±5°C for 4h. Cool to 5±5°C and add 7.94g difluoroethylamine dropwise to the reactor, controlling the addition rate to keep the internal temperature below 25°C. After completion of the addition, add 42.20g DIPEA dropwise, controlling the addition rate to keep the internal temperature below 25°C, and after completion of the addition, maintain the temperature at 25±5°C and react overnight.

[0103] Post-treatment: 30.00 g of ethanol was added dropwise to quench the reaction, followed by addition of ethanol and water, cooling to allow crystallization, filtration, and drying to obtain 13.0 g of the compound of formula (D1). The yield was approximately 88.3%, and the HPLC purity was approximately 99.1%.

[0104] Example 3: Preparation of D1

[0105] Reaction: Under nitrogen, add 250.00 g of DCM, 10.00 g of the compound of formula (J), and 18.40 g of Vilsmeier reagent to a reactor. After addition, maintain the temperature at 25 ± 5°C and react for 4 h. Cool to 5 ± 5°C and add 7.94 g of difluoroethylamine dropwise, maintaining the internal temperature below 25°C. After addition, add 168.00 g of DIPEA dropwise, maintaining the internal temperature below 25°C. After addition, maintain the temperature at 25 ± 5°C and react for 16 h.

[0106] Post-treatment: 30.00 g of ethanol was added dropwise to quench the reaction, and then ethanol and water were added. The temperature was lowered for crystallization, filtered, and dried to obtain 12.90 g of the compound of formula (D1). The yield was about 87% and the HLPC purity was 98.8%.

[0107] Example 4: Preparation of B1

[0108] Step 1: Preparation of M-1

[0109] 9.1 kg (1 W) of the compound of formula (K-1) (oxalate) was added to 8 W of acetonitrile, and 2.48 W of triethylamine was added under stirring. The mixture was stirred for 0.5 h, and 2.5 W of the compound of formula (L-1) (hydrochloride) was added and reacted at 30-35 ° C. After the reaction, the acetonitrile was removed by rotary evaporation at 45 ° C. The mixture was cooled to room temperature, and 8 times the amount (8 W) of dichloromethane was added to the mixture, and the mixture was slurried and filtered. The mixture was then spin-dried. 0.3 W of ethyl acetate was added and stirred for 10 min. 1.2 W of petroleum ether was added for crystallization. The mixture was cooled to 0-10 ° C. and filtered to obtain a light yellow to white solid compound of formula (M-1). The mixture was dried at 40-45 ° C. The yield was about 55%, and the HLPC purity was 99%.

[0110] Step 2: Prepare B1

[0111] Add 8 times (8W) of dichloromethane to the reactor, add 1 times (1W) of the compound of formula (M-1), stir to dissolve, cool to 0-10°C, add 3 times (3W) of trifluoroacetic acid, and heat to 20-25°C for reaction; after the reaction is completed, spin dry, refine and filter with 2 times (2W) of dichloromethane, and dry at 30-35°C to obtain the compound of formula (B1), with a yield of about 75% and an HLPC purity of 99.5%.

[0112] Example 5: Preparation of C1

[0113] 1) Investigation of solvent system for C1 preparation

[0114] The first screening aimed to screen the effects of different solvents on the reaction: fixed D1 (5.0 g), E1 was 1.05 eq, 1.7 eq Cs2CO3, 10 V / M different organic solvents, and investigated the effects of different solvents on the reaction conversion rate at 50 °C.

[0115] Investigation of solvent system for C1 preparation

[0116] Conclusion: Different solvents had little effect on the reaction, and impurity levels were comparable. DMAc was safer for scale-up and was the preferred solvent.

[0117] 2) Investigation of C1 preparation reaction base

[0118] In the second screening, we investigated the effects of different bases on the conversion rate of reaction raw material D1 and related substances. The research results are shown in the table below.

[0119] Investigation of C1 Alkali Preparation System

[0120] Conclusion: From the above table, it can be seen that potassium carbonate, sodium carbonate and cesium carbonate have no significant effect on the reaction; after comparing the experimental data, potassium carbonate is preferred as the base for the reaction.

[0121] 3) Investigation of reaction temperature for C1 preparation

[0122] The third screening was aimed at examining the effects of different reaction temperatures on the conversion rate of the reaction raw material D1 and related substances. The research results are shown in the table below.

[0123] Investigation of reaction temperature for C1 preparation

[0124] Conclusion: From the above table, we can see that the higher the temperature, the better the reaction conversion and the less D1 residue. The reactions at 60-65℃ and 70-75℃ are equivalent. After comparing the experimental data, the optimal reaction temperature is 60-70℃.

[0125] 4) Investigation of post-processing methods for C1 preparation

[0126] The fourth screening aimed to investigate the effects of different post-treatments on the related substances of the reaction raw material D1 during the preparation of C1 reaction. The research results are shown in the table below.

[0127] Investigation of post-processing methods for C1 preparation

[0128] Conclusions: 1. The intermediate is unstable under alkaline conditions, and pure water treatment produces an impurity with an RRT of 1.02. 2. Post-treatment with aqueous acetic acid and aqueous hydrochloric acid has no significant effect on the relevant substances, while aqueous hydrochloric acid produces more severe gas production. Furthermore, the finished product requires further research on chloride ions. In summary, aqueous acetic acid is the preferred post-treatment reagent.

[0129] Example 6: Preparation of Compound A

[0130] 1) Preparation of Catalytic System A:

[0131] In Preparation A, we investigated the effects of different catalytic systems on the conversion of C1 and related substances. We used a fixed system of 1.0 eq C1, 1.1 eq B1, 3.0 eq Cs2CO3, 2.0 mol% [Pd(C3H5)Cl]2, and 8.0 mol% ligand (Pd:ligand = 1:2) at 15 V / M solvent. We investigated the effects of different ligands, various organic solvents, and reaction temperature at 90°C for 16 h on the conversion. The results are shown in the table below.

[0132] Investigation of the catalytic system for the preparation of compound A

[0133] Conclusion: 1. Toluene and CPME are better reaction solvents, with toluene being preferred; 2. tBu X-Phos is the preferred ligand.

[0134] 2) Preparation of Catalytic System A:

[0135] Fixed 1.0eq C1, 1.1eq B1, 3.0eq base, 2.0mol% catalyst, tBu X-Phos (Pd: ligand = 1:2) 15V / M toluene; investigate the effects of different catalysts on the reaction conversion rate and related substances under different base systems and reaction at 90℃ for 16h.

[0136] Investigation of the catalytic system for the preparation of compound A

[0137] Conclusion: 1. The preferred catalysts are [PdCl(C3H5)]2 and Pd2(dba)3, and [PdCl(C3H5)]2 is preferred; 2. Potassium carbonate can replace cesium carbonate, and the reaction conversion and purity are higher when potassium carbonate is used.

[0138] 3) Investigation of the catalytic system for preparing crude product A:

[0139] Fixed 1.0eq C1, 1.1eq B1, 3.0eq potassium carbonate, [Pd(C3H5)Cl]2, tBu X-Phos (Pd:ligand = 1:2), 15V / M toluene; investigated the effects of different catalyst equivalents and different temperatures for 16h on the reaction conversion rate and related substances.

[0140] Investigation of the catalytic system for the preparation of compound A

[0141] Conclusions: 1. Reaction conversion is positively correlated with temperature and catalyst equivalent. At 60°C, increasing the catalyst equivalent favorably promotes conversion. 2. At 1.0 mol% catalyst, good results were achieved at 60°C, 70°C, and 80°C, with 70°C being the preferred reaction temperature. 3. The reaction solution exhibited good stability, with the presence of high levels of related substances observed after 16 h at 80°C. 4. The reaction system was viscous, posing a risk of catalyst encapsulation. The preferred catalyst content was 1.0 mol%, and the preferred ligand content was 4.0 mol%.

[0142] 4) Investigation of solvent dosage for preparing compound A:

[0143] The reaction is heterogeneous, and the product precipitates as a salt, resulting in a viscous reaction system. The effects of varying solvent amounts on reaction conversion and related substances were investigated using a fixed mixture of 1.0 eq C1, 1.1 eq B1, 3.0 eq potassium carbonate, 1.0 mol% [Pd(C3H5)Cl]2, and 4 mol% tBu X-Phos (Pd:ligand = 1:2).

[0144] Investigation of solvent dosage for preparation of compound A

[0145] Conclusion: The concentration of raw material C1 was ≤5.0% at both 20 V / M and 30 V / M solvents. Compound A precipitated as a potassium salt in toluene, and the reaction system was viscous. To prevent the risk of encapsulation during scale-up, a 30 V / M solvent concentration was preferred.

[0146] 5) Preparation of Compound A Reaction Stability Investigation:

[0147] In the reaction of preparing compound A, we investigated the reaction stability. The research results are shown in the table below.

[0148] Investigation on the stability of the preparation reaction of compound A

[0149] Conclusion: The reaction solution has good stability and no significant changes in related substances can be observed when the reaction time is extended to 23 h.

[0150] 6) Preparation of Compound A: Investigation of Potassium Carbonate Particle Size

[0151] In the reaction of preparing compound A, we investigated the effect of potassium carbonate particle size on the C1 conversion rate and related substances of compound A. The research results are shown in the table below.

[0152] Investigation of the particle size of potassium carbonate in preparation A

[0153] Conclusion: The smaller the particle size, the better the reaction conversion. In scale-up production, 300-mesh potassium carbonate is preferred for the reaction.

[0154] 7) Investigation of purification methods for preparing compound A:

[0155] In the refining and purification of compound A, we investigated the effects of different purification systems on the yield of A. The research results are shown in the table below.

[0156] Investigation of the purification system for preparation of compound A

[0157] Conclusion: The reaction yield is higher when using MIBK+6% water, and this solvent system is preferred for refining and purification.

Claims

1. A method for preparing a compound of formula (A), comprising the following reaction:

2. A method for preparing a compound of formula (C1), comprising the following reaction:

3. A method for preparing a compound of formula (D1), comprising the following reaction: in, In formula (E2), R1 is selected from: -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CO(CH2)3CH3; or formula (E2) is selected from one or more of trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, triisopropyl orthoformate, and tributyl orthoformate; preferably one or more of triethyl orthoformate, trimethyl orthoformate, and triisopropyl orthoformate; more preferably triethyl orthoformate.

4. The preparation method according to claim 3, wherein the reaction is carried out in the presence of an acidic reagent, wherein the acidic reagent is selected from one or more of trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, toluenesulfonic acid, hydrochloric acid, and methanesulfonic acid; preferably one or more of trifluoroacetic acid, acetic acid, and p-toluenesulfonic acid; more preferably trifluoroacetic acid.

5. A method for preparing a compound of formula (E1), comprising the following reaction:

6. A method for preparing a compound of formula (D), comprising the following steps: in, R2 and R3 are each independently selected from an alkane, an aromatic hydrocarbon or a halogen, preferably a halogen, more preferably F, Cl or Br, most preferably F; Wherein, the compound of formula (J) is reacted in the presence of Vilsmeier reagent or DMF / oxalyl chloride to obtain the compound of formula (H); The Vilsmeier reagent contains of reagents.

7. A method for preparing a compound of formula (B1), comprising the following steps: in, HX is an organic acid selected from HOOC-COOH, HCl, HBr, HI, L-tartaric acid, benzoic acid or p-toluenesulfonic acid, preferably HOOC-COOH; PG is a protecting group selected from Boc, Ac or Cbz, preferably Boc or Cbz, most preferably Boc; n is selected from 0.5, 1, 1.5 or 2, preferably 0.5 or 1.

8. A compound of formula (C1), (M-1) or a salt thereof:

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