Preparation method of PARP1 inhibitor

Abstract

The invention relates to a preparation method of a PARP1 inhibitor AZD-5305, which is an improvement and optimization of an existing process. According to the method, 5-bromo-2-methyl-3-nitropyridine a is taken as a raw material, according to the characteristics of reactants and intermediate products, the reaction route is changed, the reaction conditions are further optimized, the raw material cost is reduced, the feeding and post-treatment difficulty can be reduced, the pollution to the environment is reduced, and the defects of long route (ten steps), high raw material price, low yield, low cost and the like in the prior art are overcome. The operation is complex; and the atom economy is poor. Meanwhile, the target product can be prepared by using the easily available and cheap starting raw materials, the conditions of the Wittig reaction are optimized, the use amount of the phosphine reagent is reduced, and harsh conditions such as sodium hydrogen, lithium aluminum hydride and hydrogen reduction are avoided, so that the reaction risk is reduced, and the operation is easy; by changing the conditions of the reduction reaction, two steps in the original step are shortened into one step, and the operation is simple and easy to implement. In a word, the synthesis method disclosed by the invention is mild in reaction condition, simple and convenient in operation method, suitable for small-amount preparation in a laboratory, and also suitable for industrial large-scale production.

Description

Field of the Invention

[0001] The invention relates to a method for preparing a PARP1 inhibitor and belongs to the technical field of organic synthesis. Background of the Invention

[0002] AZD-5305, CAS No. 2589531-76-8, has the following structure:

[0003]

[0004] AZD-5305 is a potent, selective and orally active second-generation PARP (highly selective PARP1) inhibitor with significant PARP1-DNA capture activity, no PARP2 activity, and no binding activity to other members of the PARP family. It has excellent adjuvant pharmacology and physicochemical properties, and has high oral bioavailability in preclinical species. In vitro, AZD-5305 selectively inhibits the growth of cell lines defective in the DNA repair pathway, with an IC50 of 3nM in wild-type A549 lung cancer cells, while there is no or minimal growth inhibition in other cells (IC50>10μM). The difference observed between the effects on DNA repair-deficient and proficient cell lines is unprecedented in PARP inhibitors, indicating that AZD-5305 shows great potential to improve the therapeutic index in the clinic. AZD-5305 monotherapy showed effective activity in animal tumor xenograft models and human tumor xenograft models. Compared with olaparib 100mg / kg QD, AZD-5305 at a dose of ≥0.1mg / kg QD in xenograft and PDX models resulted in deeper tumor regression and significantly prolonged regression time after drug withdrawal. At the same time, AZD-5305 also showed good efficacy when used in combination with chemotherapy.

[0005] Patent application WO2022074617 discloses the synthesis of AZD-5305. According to the disclosed technical scheme (the synthetic route is shown below), AZD-5305 is prepared by ten steps of reaction, which is lengthy and has a yield of only 11.8%. The initial raw material 5-nitro-6-methylnicotinate is expensive; the first and second steps require column chromatography; the second step Wittig reaction involves butyl lithium, sodium hydrogen dangerous reagents, and requires ultra-low temperature reaction at minus 78°C; the third step requires hydrogen / palladium carbon reduction, which is dangerous and uses heavy metal reagents; the fifth step uses lithium aluminum tetrahydride, and the reaction releases hydrogen, which is very dangerous; the yield of the eighth step is only 59%. In short, it has poor atomic economy, complicated operation, and is not easy to scale up industrially. Therefore, designing and implementing a synthesis method that is suitable for industrial production, simple to operate, and has a high yield has become the focus of research and development for those skilled in the art.

[0006]

[0007] AZD-5305 synthesis route disclosed in WO2022074617 Summary of the invention

[0008] The purpose of the present invention is to provide a method for preparing a PARP1 selective inhibitor to solve the problems mentioned in the above background technology. Specifically, the purpose of the present invention is to provide a method for preparing AZD-5305 represented by formula (I).

[0009] In order to solve the above technical problems, the first aspect of the present invention provides a method for preparing the compound AZD-5305 represented by formula (I), characterized in that it comprises the following steps:

[0010]

[0011]

[0012] The synthetic route of AZD-5305 of the present invention

[0013] Step 1: Similar to the Batcho–Leimgruber indole synthesis reaction; 5-bromo-2-methyl-3-nitropyridine a reacts with formamide acetal in an organic solvent under heating conditions to obtain an intermediate trans-β-dialkylamino-2-nitropyridine ethylene b; wherein the formamide acetal is preferably DMF-DMA;

[0014] Step 2: In the presence of sodium periodate, the C=C double bond of intermediate b is oxidatively broken to form aldehyde c; that is, intermediate b reacts with an oxidant in a solvent under heating conditions to obtain intermediate c; wherein the oxidant is preferably sodium periodate;

[0015] Step 3: intermediate c is subjected to Wittig reaction to obtain compound d; that is, intermediate c is reacted with a phosphine reagent in an organic solvent in the presence of an alkaline reagent to obtain intermediate d; wherein the alkaline reagent is preferably potassium hexamethyldisilazide and potassium tert-butoxide; the phosphine reagent is preferably triethyl 2-phosphonobutyrate and ethyl O,O'-bis(2,2,2-trifluoroethyl)phosphobutyrate;

[0016] Step 4: Reduction and ring closure of intermediate d to obtain compound e in one step; that is, intermediate d is added with an acid and a reducing agent in a solvent, and subjected to a reduction reaction under heating conditions to obtain intermediate e; wherein the acid is preferably hydrochloric acid and acetic acid, and the reducing agent is preferably zinc powder and iron powder;

[0017] Step 5: intermediate e is subjected to Suzuki-Miyaura reaction to obtain compound f; that is, intermediate e is reacted in a solvent under alkaline reagent conditions in the presence of potassium (4-tert-butyloxycarbonylpiperazine-1-yl)methyltrifluoroborate, a ligand and a palladium catalyst to obtain intermediate f; wherein the alkaline reagent is preferably cesium carbonate; the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium; the ligand is preferably 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl;

[0018] Step 6: intermediate f is de-Bocated to obtain compound g; that is, intermediate f is reacted with dioxane hydrochloride solution in an organic solvent to obtain intermediate g;

[0019] Step 7: Intermediate g reacts with compound i by nucleophilic substitution to obtain compound I; that is, intermediate g reacts with intermediate i in an organic solvent under alkaline reagent conditions to obtain compound AZD-5305 represented by formula (I); wherein the alkaline reagent is preferably lithium hydroxide, sodium hydroxide or cesium carbonate;

[0020] Wherein: X is selected from 0, 1, 2, 3 or 4.

[0021] A preferred embodiment of the present invention is a method for preparing a compound represented by formula (I), characterized in that the first step comprises the following steps:

[0022] 5-bromo-2-methyl-3-nitropyridine a is added to DMF-DMA in an organic solvent, and reacted under heating conditions. After the reaction is completed, it is cooled to room temperature, quenched, extracted, dried, filtered, and concentrated to obtain intermediate b; wherein:

[0023] The organic solvent is selected from N,N-dimethylformamide or dioxane; preferably N,N-dimethylformamide;

[0024] The reaction temperature is 60-120°C; preferably 90-110°C;

[0025] The molar ratio of 5-bromo-2-methyl-3-nitropyridine a and DMF-DMA is 1:1-1:3; preferably 1:1.5-1:2.

[0026] A preferred embodiment of the present invention is a method for preparing a compound represented by formula (I), characterized in that the second step comprises the following steps:

[0027] The intermediate b is reacted with sodium periodate in a solvent under heating conditions, cooled to room temperature, quenched, extracted, dried, filtered, concentrated, and separated and purified by column chromatography to obtain the intermediate c; wherein:

[0028] The solvent is selected from dioxane / water, THF / water; preferably a mixed solvent of THF / water (V / V=3:2);

[0029] The reaction temperature is 40-120°C; preferably 50-60°C;

[0030] The molar ratio of intermediate b to sodium periodate is 1:1-1:6, preferably 1:3.

[0031] A preferred embodiment of the present invention is a method for preparing a compound represented by formula (I), characterized in that the third step comprises the following steps:

[0032] Intermediate c reacts with triethyl 2-phosphonobutyrate in an organic solvent in the presence of potassium tert-butoxide to obtain intermediate d;

[0033] The organic solvent is selected from dioxane, THF or dichloromethane; preferably THF;

[0034] The reaction temperature is -78-100°C; preferably -78-10°C;

[0035] The molar ratio of intermediate c to triethyl 2-phosphonobutyrate is 1:1-1:2, preferably 1:1.2.

[0036] Compared with the second step in the synthesis route disclosed in WO2022074617, the steps of the present invention optimize the use of the base, replace sodium hydrogen with potassium tert-butoxide, avoid the use of dangerous reagents that produce hydrogen, and reduce the use of half the phosphine reagent.

[0037] A preferred embodiment of the present invention is a method for preparing a compound represented by formula (I), characterized in that in the fourth step:

[0038] The intermediate d is added with an acid and a reducing agent in a solvent and subjected to a reduction reaction under heating conditions to obtain the intermediate e;

[0039] The organic solvent is selected from ethanol, methanol, water or a mixed solvent; preferably ethanol: water = 10:1;

[0040] The reaction temperature is 0-80°C; preferably 40-50°C;

[0041] The molar ratio of the intermediate d to the iron powder is 1:1 to 1:20, preferably 1:10.

[0042] Compared with the third step in the synthesis route disclosed in WO2022074617, the steps of the present invention optimize the reaction steps, directly reduce the two-step reaction of palladium carbon hydrogenation and DDQ oxidation to one step of iron powder reduction, and avoid dangerous reactions and the use of heavy metals.

[0043] A preferred embodiment of the present invention is a method for preparing a compound represented by formula (I), characterized in that the fifth step comprises the following steps:

[0044] The intermediate e is reacted in a solvent under cesium carbonate conditions in the presence of potassium (4-tert-butyloxycarbonylpiperazine-1-yl)methyltrifluoroborate, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and a palladium catalyst tris(dibenzylideneacetone)dipalladium to obtain the intermediate f;

[0045] The organic solvent is selected from tetrahydrofuran, methanol, dioxane, N,N-dimethylformamide; preferably dioxane;

[0046] The reaction temperature is 25-120°C; preferably 80-100°C;

[0047] The molar ratio of intermediate e to potassium (4-tert-butyloxycarbonylpiperazine-1-yl)methyltrifluoroborate is 1; 1-1:3; preferably 1:1-1:1.5.

[0048] The molar ratio of intermediate e to tris(dibenzylideneacetone)dipalladium is 1:0.001-1:0.10, preferably 1:0.03.

[0049] The molar ratio of the intermediate e to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl is 1:0.001-1:0.20, preferably 1:0.06.

[0050] The intermediate e is mixed with potassium (4-tert-butyloxycarbonylpiperazine-1-yl)methyltrifluoroborate and an organic solvent to carry out a coupling reaction to obtain compound f. The reaction yield is high.

[0051] A preferred embodiment of the present invention is a method for preparing a compound represented by formula (I), characterized in that in the sixth step:

[0052] Intermediate f is subjected to a deprotection reaction in an organic solvent to obtain intermediate g;

[0053] The organic solvent is selected from dichloromethane, ethyl acetate, and dioxane; preferably dichloromethane;

[0054] The reaction temperature is 0-80°C; preferably 20-40°C;

[0055] The molar ratio of the intermediate f to the dioxane hydrochloride solution is 1:1-1:20; preferably 1:6-1:10.

[0056] A preferred embodiment of the present invention is a method for preparing a compound represented by formula (I), characterized in that in the seventh step:

[0057] Intermediate g and intermediate i undergo nucleophilic substitution reaction in an organic solvent under alkaline reagent conditions to obtain compound AZD-5305 (I);

[0058] The organic solvent is selected from N-methylpyrrolidone, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol; preferably N-methylpyrrolidone;

[0059] The reaction temperature is 50-150°C; preferably 90-120°C;

[0060] The molar ratio of intermediate g to intermediate i is 1:1-1:10; preferably 1:1-1:2.

[0061] The second aspect of the present invention provides a method for preparing intermediate i, the preparation method comprising the following steps:

[0062] Substitution reaction gives intermediate compound i.

[0063] A preferred embodiment of the present invention is a method for preparing an intermediate i, characterized in that it is the intermediate compound of the seventh step of claim 1, comprising the following steps:

[0064] Step a: 5-fluoro-2-pyridinecarboxylic acid h reacts with thionyl chloride and N,N-dimethylformamide in an organic solvent to obtain intermediate x;

[0065] Step b: Intermediate x reacts with methylamine methanol solution and triethylamine in an organic solvent to obtain intermediate i.

[0066]

[0067] A preferred embodiment of the present invention is a method for preparing intermediate i, characterized in that in the step a,

[0068] The organic solvent is selected from dichloromethane, chloroform, and tetrahydrofuran; preferably dichloromethane;

[0069] The reaction temperature is 0-80°C; preferably 40-60°C;

[0070] A preferred embodiment of the present invention is a method for preparing intermediate i, characterized in that in the step b,

[0071] The organic solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran; preferably dichloromethane;

[0072] The reaction temperature is -20-60°C; preferably 0-10°C. Beneficial effects of the present invention

[0073] Compared with the prior art, the beneficial effects of the present invention include:

[0074] The present invention provides a method for preparing a PARP1 selective inhibitor, which overcomes the shortcomings of the prior art such as long route, low yield, complex operation, environmental unfriendliness and poor atom economy, uses cheap and readily available raw materials, and can obtain the target product through seven steps of reaction.

[0075] The present invention can effectively shorten the reaction steps and reduce the difficulty of the reaction, effectively improve the reaction yield, and solve the technical problem of expensive raw materials by specially selecting the raw materials, reaction steps and reaction sequence.

[0076] The invention uses readily available and inexpensive starting materials to obtain the target product, optimizes the conditions of the Wittig reaction, reduces the amount of phosphine reagent used, avoids the use of harsh conditions such as sodium hydrogen, lithium aluminum tetrahydride, and hydrogen reduction, thereby reducing the risk of the reaction and making it easy to operate; by changing the conditions of the reduction reaction, the two steps in the original step are shortened to a one-step reaction, and the operation is simple and easy. The invention effectively overcomes the difficulties of synthesizing the target compound in the prior art, improves the reaction yield, and is not only suitable for small-scale laboratory preparation, but also suitable for industrial large-scale production. DETAILED DESCRIPTION

[0077] The content of the present invention can be more easily understood by referring to the following detailed description of the preferred implementation method of the present invention and the included embodiments. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs, and when there is a conflict, the definition of this specification shall prevail.

[0078] As used herein, the term "prepared with" is synonymous with "comprising". As used herein, the terms "comprising", "including", "having", "containing" or any other form of variation thereof, are intended to cover an exclusive inclusion. For example, elements inherent to the composition, process, method, article or device that comprises the listed elements.

[0079] When an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or a range limited by a series of upper preferred values ​​and lower preferred values, this should be understood to specifically disclose all ranges formed by any pairing of any upper range limit or preferred value with any lower range limit or preferred value, regardless of whether the range is disclosed separately. When a numerical range is described in this article, unless otherwise stated, the range is intended to include its end values ​​and all integers and fractions within the range.

[0080] Singular forms include plural references unless the context clearly indicates otherwise. "Optional" or "either" means that the subsequently described event or incident may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0081] Approximate terms in the specification and claims are used to modify quantities, indicating that the present invention is not limited to the specific quantity, but also includes acceptable and modified parts close to the quantity without causing changes in the relevant basic functions. Accordingly, a numerical value modified by "about", "approximately", etc. means that the present invention is not limited to the exact numerical value. In some examples, the approximate terms may correspond to the accuracy of the instrument for measuring the numerical value. In the specification and claims of this application, range limitations can be combined and / or interchanged, and if not otherwise stated, these ranges include all subranges contained therein.

[0082] In addition, the indefinite articles "a" and "an" before the elements or components of the present invention do not limit the quantity requirements (i.e. the number of occurrences) of the elements or components. Therefore, "a" or "an" should be interpreted as including one or at least one, and the elements or components in the singular form also include the plural form, unless the number obviously refers to the singular form. DETAILED DESCRIPTION

[0083] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually carried out under normal conditions.

[0084] The room temperature described in the examples refers to 10-20°C.

[0085] Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and used directly without further treatment.

[0086] The reaction was terminated as judged by TLC analysis and / or by LCMS analysis, by the consumption of the starting material.

[0087] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) has a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products is 0.4 mm to 0.5 mm. Use UV light (254 nm) and / or iodine on silica gel for visualization, and / or heat with TLC dyes such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution or ceric sulfate solution.

[0088] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention.

[0089] 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0090] The mass spectrum is obtained by LC / MS, and the ionization method can be ESI or APCI.

[0091] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0092] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Aldrich Chemical Company, Acros Organics, BiDe Pharmaceutical Technology Co., Ltd. and Aladdin Biochemical Technology Co., Ltd.

[0093] "CD3OD" means deuterated methanol.

[0094] "CDCl3" means deuterated chloroform.

[0095] "DMSO-d6" means deuterated dimethyl sulfoxide.

[0096] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.

[0097] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0098] The compound is purified by silica gel column chromatography and thin layer chromatography, wherein the eluent or developing solvent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, can also be added for adjustment.

[0099] The abbreviations used in the present invention have the conventional meanings in the art, such as:

[0100] "TLC" means thin layer chromatography.

[0101] "DMF-DMA" means N,N-dimethylformamide dimethyl acetal.

[0102] "THF" means tetrahydrofuran.

[0103] "EA" means ethyl acetate.

[0104] "PE" stands for petroleum ether.

[0105] "DCM" means dichloromethane.

[0106] "MeOH" means methanol.

[0107] “DDQ” 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).

[0108] Example 1 Preparation of the compound of formula (I)

[0109] first step

[0110] Preparation of intermediate b

[0111] (E)-2-(5-bromo-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine

[0112] Compound 5-bromo-2-methyl-3-nitropyridine a (500g, 2.30mol, 1eq) was added to a 5L reaction bottle, and N,N-dimethylformamide (2.5L, 5v / m) and DMF-DMA (500ml, 3.76mol, 1.64eq) were added in sequence. The reaction was carried out at 100°C for 5 hours, and TLC showed that the raw material disappeared. After cooling to room temperature, 2.5L of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (1L×3), separated, and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate b (600g, 2.21mol) as a black solid with a yield of 96%. It was used directly in the next step without purification.

[0113] 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.34 (s, 1H), 8.10-8.07 (d, 1H), 6.18-6.15 (d, 1H), 3.05 (brs, 6H).

[0114] Step 2 Preparation of Intermediate C

[0115] 5-bromo-3-nitropicolinaldehyde

[0116] The crude intermediate b (600 g, 2.2 mol, 1 eq) was diluted with 1.2 L of tetrahydrofuran / water (V / V=3:2), heated to an internal temperature of 50°C, sodium periodate (1400 g, 6.48 mol, 3 eq) was dissolved in 1 L of water and slowly added dropwise, the temperature was controlled at 50-60°C, the reaction was carried out for 3 hours, and the reaction was monitored by TLC. After cooling to room temperature, 1 L of water was added for quenching, and the reaction was extracted with ethyl acetate (1.5 L×3), the liquids were separated, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and purified by column chromatography (EA:PE=1:5-1:3). Intermediate c (384 g, 1.66 mol) was obtained as a light yellow solid with a yield of 75%.

[0117] 1 H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 9.04 (s, 1H), 8.38 (s, 1H).

[0118] Step 3 Preparation of Intermediate d

[0119] ethyl (E)-2-((5-bromo-3-nitropyridin-2-yl)methylene)butanoate

[0120] Dissolve intermediate c (384g, 1.66mol, 1eq) in tetrahydrofuran (2L, 5v / m), add triethyl 2-phosphonobutyrate (500g, 1.98mol, 1.2eq), and replace with argon. Cool to 0°C in an ice-salt bath, slowly drop potassium tert-butoxide (1M THF solution) (1.4L, 1eq), and naturally rise to room temperature after the drop is complete. React for 1 hour. Slowly add the reaction solution to a saturated aqueous ammonium chloride solution (2L), extract with ethyl acetate (1L×3), and concentrate. Purify by column chromatography (EA:PE=1:5-1:3). Obtain intermediate d (390g, 1.19mol), a light yellow oil, with a yield of 85% (calculated based on the effective purity of compound c).

[0121] 1 H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.47 (s, 1H), 7.00 (s, 1H), 4.17-4.15 (q, 2H), 2.54-2.52 (q, 2H), 1.34-1.22 (m, 6H).

[0122] Step 4 Preparation of Intermediate e

[0123] 7-bromo-3-ethyl-1,5-naphthyridin-2(1H)-one

[0124] Dissolve intermediate d (340g, 1.03mol, 1eq) in 6.8L ethanol / 680ml water, add acetic acid (1.36L, 4v / m). Slowly add iron powder (570g, 10.2mol, 10eq), ensuring that the temperature is ≤50℃ during the addition process. After adding the iron powder, heat to 50℃ and react for 3 hours. TLC shows that the reaction is over. Add diatomaceous earth to filter, rinse the filter cake with ethanol (1L), concentrate the ethanol, filter the solid, and rinse the filter cake with water (1L×3). Add ethyl acetate (1L) to the filter cake for pulping and filter to obtain intermediate e (139g, 0.55mol), light gray powder, with a yield of 55%.

[0125] 1 H NMR (400 MHz, DMSO) δ 11.97 (s, 1H), 8.53 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 2.54-2.52 (q, 2H), 1.20-1.16 (t, 3H).

[0126] Step 5 Preparation of Intermediate f

[0127] tert-butyl 4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1-carboxylate

[0128] Into a 5L reaction bottle, intermediate e (136.6g, 0.54mol, 1eq), potassium (4-tert-butyloxycarbonylpiperazin-1-yl)methyltrifluoroborate (214.5g, 0.70mol, 1.3eq), 1,4-dioxane (2L) / water (665ml), cesium carbonate (527g, 1.62mol, 3eq), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (15.5g, 0.06eq) and tris(dibenzylideneacetone)dipalladium (14.8, 0.03eq) were added in sequence. The gas was replaced with argon three times and reacted in an oil bath at 85°C for 3-5 hours (a large amount of gas was generated in the initial stage, so pay attention to degassing). The reaction of compound e was completed after monitoring by TLC. The reaction solution was concentrated to remove 1,4-dioxane, and water (2 L) was added to the residue, extracted with DCM / MeOH (10:1) (1 L × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was slurried with EA (1.5 L), filtered, rinsed with ethyl acetate (1 L), rinsed with PE (1 L), and dried to obtain intermediate f (183.8 g, 0.50 mol) as a white solid with a yield of 92%.

[0129] 1 H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 7.82(s, 1H),7.73 (s, 1H), 3.67(s, 2H), 3.45-3.31(br, 4H), 2.67-2.66(q, 2H), 2.47-2.44(br, 4H), 1.45 (s, 9H), 1.29-1.26 (t, 3H).

[0130] Step 6 Preparation of Intermediate G

[0131] 3-ethyl-7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-onedihydrochloride

[0132] Dissolve intermediate f (183.8 g, 0.50 mol) in DCM (2 L), add hydrochloric acid / dioxane solution (4 M, 1 L) dropwise, stir at room temperature for 12 hours after addition, and the raw material disappears when detected by TLC. Concentrate the solvent under reduced pressure, add ethyl acetate (2 L) to the residue for pulping, filter, rinse with ethyl acetate (1 L), and dry in vacuo to obtain intermediate g (205.7 g) as a light yellow-green solid with a yield of 100%. X is selected from 0, 1, 2, 3 or 4.

[0133] 1H NMR (400 MHz, DMSO) δ 12.29 (s, 1H), 9.87(brs, 1H),8.74 (s, 1H),7.95 (s, 1H), 7.83 (s, 1H), 5.63(brs, 4H),4.57 (s, 2H), 3.45(brs, 4H),2.55-2.50(q, 2H), 1.20-1.17 (t, 3H).

[0134] Step 7 Preparation of Compound (I)

[0135] Dissolve intermediate g (150.4 g, 0.44 mol, 1 eq) and compound i (91 g, 0.59 mol, 1.35 eq) in N-methylpyrrolidone (970 ml, 6.5 v / m), add lithium hydroxide (52.4 g, 2.19 mol, 5 eq), replace with argon three times, and react in an oil bath at 100 ° C for 16-20 hours. The reaction solution was poured into water (5V), extracted with DCM / MeOH (8:1) 4L×1.2L×2 to obtain 122g; the mother liquor was passed through a vacuum column: PE / EA=3:1 to EA to DCM / MeOH (8:1), and the crude product was slurried with EA (100ml) overnight, filtered, rinsed with EA, rinsed with PE, and vacuum dried (40°C) to obtain compound AZD-5305(I) (130g, 0.32mol, purity 99.50%) as a white solid with a yield of 89.4%.

[0136] MS m / z (ESI):407[M+1]

[0137] 1 H NMR (400 MHz, DMSO) δ 11.87 (s, 1H), 8.42 (s, 2H), 8.27 (s, 1H), 7.84 (d, 1H), 7.82 (s, 1H), 7.63 (s, 1H), 7.40-7.38 (d, 1H), 3.65 (s, 2H), 3.34 (brs, 4H), 2.77 (s, 3H), 2.55-2.50 (brs, 6H), 1.20-1.17 (t, 3H).

[0138] Preparation of intermediate i

[0139] 5-fluoro-N-methylpicolinamide

[0140] Suspend 5-fluoro-2-pyridinecarboxylic acid h (100g, 0.71mol, 1eq) in 500ml DCM, add thionyl chloride (422g, 3.55mol, 5eq) and N,N-dimethylformamide (1ml), react at 50℃ for 0.5 hours, react at 60℃ for 3 hours, the solution becomes clear, and the raw material disappears after TLC monitoring; concentrate DCM and thionyl chloride, and remove the residue with dichloromethane (500ml each time) to obtain the acid chloride, which is used directly. Add methylamine methanol solution and triethylamine to DCM (1L), protect with argon, cool to 0℃ with ice salt bath, and dropwise add the above acid chloride (diluted with 250ml dichloromethane). After addition, naturally warm to room temperature and stir for 20 hours. Wash the reaction solution with water (1L), extract the aqueous layer with ethyl acetate (500ml), combine the organic layers, dry with anhydrous sodium sulfate, and column chromatography (PE / EA=4:1 to 3:1 to 1:1). Intermediate i (91.1 g, 0.59 mol) was obtained as an off-white solid with a yield of 83.6%.

[0141] 1 H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.26-8.23(m, 1H), 7.86 (brs,1H), 7.55-7.51 (m, 1H), 3.04 (s, 3H).

Claims

1. A method for preparing the compound AZD-5305 represented by formula (I), characterized in that: The method includes: The first step: 5-bromo-2-methyl-3-nitropyridine a reacts with formamide acetal in an organic solvent under heating conditions to obtain an intermediate b; wherein the formamide acetal is preferably DMF-DMA; Step 2: intermediate b reacts with an oxidant in a solvent under heating conditions to obtain intermediate c; wherein the oxidant is preferably sodium periodate; Step 3: intermediate c reacts with a phosphine reagent in an organic solvent in the presence of an alkaline reagent to obtain intermediate d; wherein the alkaline reagent is preferably potassium hexamethyldisilazide and potassium tert-butoxide; the phosphine reagent is preferably triethyl 2-phosphonobutyrate and ethyl O,O'-bis(2,2,2-trifluoroethyl)phosphobutyrate; Step 4: Add an acid and a reducing agent to the intermediate d in a solvent, and carry out a reduction reaction under heating conditions to obtain an intermediate e; wherein the acid is preferably hydrochloric acid and acetic acid, and the reducing agent is preferably zinc powder and iron powder; Step 5: The intermediate e is reacted in a solvent under alkaline reagent conditions in the presence of potassium (4-tert-butyloxycarbonylpiperazine-1-yl)methyltrifluoroborate, a ligand and a palladium catalyst to obtain the intermediate f; wherein the alkaline reagent is preferably cesium carbonate; the palladium catalyst is preferably tris(dibenzylideneacetone)dipalladium; the ligand is preferably 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; Step 6: Intermediate f reacts with dioxane hydrochloride solution in an organic solvent to obtain intermediate g; Step 7: Intermediate g and intermediate i are subjected to nucleophilic substitution reaction in an organic solvent under alkaline reagent conditions to obtain compound AZD-5305 (I); wherein the alkaline reagent is preferably lithium hydroxide, sodium hydroxide and cesium carbonate; Wherein: X is selected from 0, 1, 2, 3 or 4.

2. The preparation method according to claim 1, characterized in that The first step includes the following steps: 5-bromo-2-methyl-3-nitropyridine a is added to DMF-DMA in an organic solvent, and reacted under heating conditions. After the reaction is completed, it is cooled to room temperature, quenched, extracted, dried, filtered, and concentrated to obtain intermediate b; wherein: The organic solvent is selected from N,N-dimethylformamide and dioxane; preferably N,N-dimethylformamide; The reaction temperature is 60-120°C; preferably 90-110°C; The molar ratio of 5-bromo-2-methyl-3-nitropyridine a and DMF-DMA is 1:1-1:3; preferably 1:1.5-1:

2.

3. The preparation method according to claim 1, characterized in that: The second step includes the following steps: Intermediate b is reacted with sodium periodate in a solvent under heating conditions, cooled to room temperature, quenched, extracted, dried, filtered, concentrated, and separated and purified by column chromatography to obtain intermediate c; wherein: The solvent is selected from dioxane / water, THF / water; preferably a mixed solvent of THF / water (V / V=3:2); The reaction temperature is 40-120°C; preferably 50-60°C; The molar ratio of intermediate b to sodium periodate is 1:1-1:6, preferably 1:

3.

4. The preparation method according to claim 1, characterized in that: The third step includes the following steps: Intermediate c reacts with triethyl 2-phosphonobutyrate in an organic solvent in the presence of potassium tert-butoxide to obtain intermediate d; The organic solvent is selected from dioxane, THF, and dichloromethane; preferably THF; The reaction temperature is -78-100°C; preferably -78-10°C; The molar ratio of intermediate c to triethyl 2-phosphonobutyrate is 1:1-1:2, preferably 1:1.

2.

5. The preparation method according to claim 1, characterized in that: In the fourth step: Intermediate d is added to a solvent with an acid and a reducing agent, and subjected to a reduction reaction under heating conditions to obtain intermediate e. The organic solvent is selected from ethanol, methanol, water or a mixed solvent; preferably ethanol: water = 10:1; The reaction temperature is 0-80°C; preferably 40-50°C; The molar ratio of the intermediate d to the iron powder is 1:1 to 1:20, preferably 1:

10.

6. The preparation method according to claim 1, characterized in that: The fifth step includes the following steps: The intermediate e is reacted in a solvent under cesium carbonate conditions in the presence of potassium (4-tert-butyloxycarbonylpiperazine-1-yl)methyltrifluoroborate, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and a palladium catalyst tris(dibenzylideneacetone)dipalladium to obtain the intermediate f; The organic solvent is selected from tetrahydrofuran, methanol, dioxane, N,N-dimethylformamide; preferably dioxane; The reaction temperature is 25-120°C; preferably 80-100°C; The molar ratio of intermediate e to potassium (4-tert-butyloxycarbonylpiperazine-1-yl)methyltrifluoroborate is 1; 1-1:3; preferably 1:1-1:1.

5. The molar ratio of intermediate e to tris(dibenzylideneacetone)dipalladium is 1:0.001-1:0.10; preferably 1:0.03; The molar ratio of intermediate e to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl is 1:0.001-1:0.20; preferably 1:0.06; The intermediate e is mixed with potassium (4-tert-butoxycarbonylpiperazine-1-yl)methyltrifluoroborate and an organic solvent to carry out a coupling reaction to obtain a compound f.

7. The preparation method according to claim 1, characterized in that: In the sixth step: Intermediate f is deprotected in an organic solvent to obtain intermediate g. The organic solvent is selected from dichloromethane, ethyl acetate, and dioxane; preferably dichloromethane; The reaction temperature is 0-80°C; preferably 20-40°C; The molar ratio of the intermediate f to the dioxane hydrochloride solution is 1:1-1:20, preferably 1:6-1:

10.

8. The preparation method according to claim 1, characterized in that: In the seventh step: Intermediate g and intermediate i undergo nucleophilic substitution reaction in an organic solvent under alkaline reagent conditions to obtain compound AZD-5305 (I); The organic solvent is selected from N-methylpyrrolidone, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol; preferably N-methylpyrrolidone; The reaction temperature is 50-150°C; preferably 90-120°C; The molar ratio of intermediate g to intermediate i is 1:1-1:10; preferably 1:1-1:

2.

9. A method for preparing an intermediate i, characterized in that: It is the intermediate compound of the seventh step of claim 1, comprising the following steps: Step a: 5-fluoro-2-pyridinecarboxylic acid h reacts with thionyl chloride and N,N-dimethylformamide in an organic solvent to obtain intermediate x; Step b: Intermediate x reacts with methylamine methanol solution and triethylamine in an organic solvent to obtain intermediate i.

10. The preparation method according to claim 9, characterized in that: In the step a, The organic solvent is selected from dichloromethane, chloroform, and tetrahydrofuran; preferably dichloromethane; The reaction temperature is 0-80°C; preferably 40-60°C.

11. The preparation method according to claim 9, characterized in that: In the step b, The organic solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran; preferably dichloromethane; The reaction temperature is -20-60°C; preferably 0-10°C.

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