A process for the preparation of a parp1 inhibitor intermediate

Abstract

The application provides a preparation method of a PARP1 inhibitor intermediate, which comprises the following steps: after 6-hydroxy nicotinic acid is reacted with nitric acid, an intermediate shown in formula I is prepared through halogenation reaction, esterification reaction, hydrolysis reaction and the like. The method has low synthesis cost and high product yield, provides a new advantageous process route for synthesis of the PARP1 inhibitor, and has industrialized popularization and application prospects.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for preparing a PARP1 inhibitor intermediate. Background Technology

[0002] PARP1 inhibitors are medical agents that can affect the way cancer cells replicate. Current research shows that PARP inhibitors can enhance the effectiveness of breast cancer drugs and can also treat various hereditary cancers such as ovarian cancer, prostate cancer, and pancreatic cancer. Therefore, researchers have been continuously studying novel PARP1 inhibitors to enhance efficacy and reduce toxicity.

[0003] Chinese patent application CN114144413A discloses a novel PARP1 inhibitor with the following structure:

[0004]

[0005] This study demonstrated that the inhibitor possesses excellent PARP1 inhibitory activity, and Formula I-1 is the key starting material for synthesizing the aforementioned PARP1 inhibitor:

[0006]

[0007] However, the aforementioned key starting materials are difficult to obtain and have high market prices. How to reduce the preparation cost and adapt to industrial production has become a key challenge in the synthesis of PARP1 inhibitors.

[0008] Chinese patent application CN114605320A discloses the following synthetic route for the above-mentioned starting materials, but the synthetic materials used are still difficult to obtain and expensive.

[0009]

[0010] Therefore, it is of great significance to further explore preparation schemes for PARP1 synthesis raw materials that are low in cost and suitable for large-scale production. Summary of the Invention

[0011] The purpose of this invention is to provide a method for preparing a PARP1 inhibitor intermediate.

[0012] This invention provides a method for preparing a PARP1 inhibitor intermediate, comprising the following steps:

[0013] (1) 6-hydroxynicotinic acid as shown in Formula IV was reacted with fuming nitric acid in concentrated acid to prepare 2-hydroxy-3-nitropyridine-5-carboxylic acid as shown in Formula III;

[0014] (2) The 2-hydroxy-3-nitropyridine-5-carboxylic acid shown in Formula III reacts with a halogenating agent in an organic solvent, and then C is added. 1～4 The alkyl alcohol reaction yields methyl 6-halo-5-nitronicotinate as shown in Formula II;

[0015] (3) Methyl 6-halo-5-nitronicotinic acid as shown in Formula II reacts with malonate diester in an organic solvent under alkaline conditions, and then reacts with acid to obtain the PARP1 inhibitor intermediate shown in Formula I.

[0016] The reaction formula is as follows:

[0017]

[0018] Where R is C 1～4 Alkyl group, where X is a halogen.

[0019] Furthermore, the concentrated acid mentioned in step (1) is concentrated sulfuric acid;

[0020] And / or the halogenating agent in step (2) is a chlorinating agent or a brominating agent, wherein the chlorinating agent includes thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, and oxalyl chloride, and the brominating agent includes phosphorus tribromide and phosphorus oxybromide; the organic solvent is a mixture of toluene and N,N-dimethylformamide; the C 1～4 Alkyl alcohols are methanol, ethanol, propanol, n-butanol, tert-butanol, or isobutanol;

[0021] And / or the malonate diester in step (3) is dimethyl malonate or diethyl malonate; the base is sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide; the organic solvent is N-methylpyrrolidone, N,N-dimethylformamide, dimethylacetamide, toluene or tetrahydrofuran; the acid is sulfuric acid or hydrochloric acid.

[0022] Furthermore, the halogenating agent in step (2) is thionyl chloride, and the C 1～4 Alkyl alcohol is methanol;

[0023] And / or the base mentioned in step (3) is sodium hydride, and the organic solvent is N-methylpyrrolidone.

[0024] Further, the mass-to-volume ratio of 6-hydroxynicotinic acid to fuming nitric acid and concentrated acid in step (1) is (40-60) g:(40-60) mL:(40-60) mL;

[0025] And / or the molar ratio of 2-hydroxy-3-nitropyridine-5-carboxylic acid to the halogenating agent in step (2) is 1:(2-4); the molar ratio of 2-hydroxy-3-nitropyridine-5-carboxylic acid to C 1～4 The mass ratio of alkyl alcohols is (40-60):(70-90);

[0026] And / or the molar ratio of methyl 6-halo-5-nitronicotinic acid, dicofol and base in step (3) is 1:(1-5):(1-5); the mass ratio of methyl 6-halo-5-nitronicotinic acid and acid is (40-50):(60-250).

[0027] Furthermore, the mass-to-volume ratio of 6-hydroxynicotinic acid to fuming nitric acid and concentrated acid in step (1) is 50g:50mL:50mL;

[0028] And / or the molar ratio of 2-hydroxy-3-nitropyridine-5-carboxylic acid to the halogenating agent in step (2) is 1:3, wherein the 2-hydroxy-3-nitropyridine-5-carboxylic acid and C 1～4 The mass ratio of alkyl alcohols is 50:80;

[0029] And / or the molar ratio of methyl 6-halo-5-nitronicotinic acid, dicofol and base in step (3) is 1:2:2.2, and the mass ratio of methyl 6-halo-5-nitronicotinic acid to acid is 45:(63-234).

[0030] Further, the reaction conditions described in step (1) are 70-90℃ for 8-16 hours;

[0031] And / or the reaction conditions of 2-hydroxy-3-nitropyridine-5-carboxylic acid with the halogenating agent in step (2) are: first reacting at 75-85°C for 1-3 hours, then reacting at 90-110°C for 8-16 hours; the addition of C 1～4 The alkyl alcohol reaction is carried out under inert gas protection, with C added below 20°C. 1～4 Alkyl alcohol, then react at 20–30°C for 4–6 hours;

[0032] And / or the reaction conditions of methyl 6-halo-5-nitronicotinate and diester of malonate in step (3) are 40-60℃ for 3-5 hours under alkaline conditions; the reaction conditions of adding acid are 90-110℃ for 8-16 hours.

[0033] Furthermore, the reaction conditions described in step (1) are 80°C for 8–16 h;

[0034] And / or the reaction conditions of the 2-hydroxy-3-nitropyridine-5-carboxylic acid with the halogenating agent in step (2) are: first react at 80°C for 2 hours, then react at 100°C for 8–16 hours; the addition of C 1～4 The alkyl alcohol reaction is carried out under inert gas protection, with C added below 20°C. 1～4 Alkyl alcohol, then react at 20–30°C for 5 hours;

[0035] And / or the reaction conditions of methyl 6-halo-5-nitronicotinic acid and diester in step (3) under alkaline conditions are 50°C for 4 hours; the reaction conditions of adding acid are 100°C for 8 to 16 hours.

[0036] Furthermore, the structure of the above-mentioned PARP1 inhibitor is shown in Formula V:

[0037]

[0038] Where R1 is C 1～4 Alkyl or C 1～4 fluoroalkyl, where R2 is hydrogen, halogen, or C. 1～4 Alkyl or C 1～4 fluoroalkyl, where R3 is hydrogen or C 1～4 alkyl.

[0039] Furthermore, the above preparation method also includes the step of esterifying the intermediate shown in Formula I with ethanol in the presence of a catalyst to prepare intermediate I-1; preferably, the catalyst is thionyl chloride;

[0040] The reaction formula is as follows:

[0041]

[0042] Furthermore, the molar ratio of the intermediate and the catalyst shown in Formula I above is 1:(1 to 5), preferably 1:1.2;

[0043] The mass-to-volume ratio of the intermediate shown in Formula I to ethanol is (110-120) g:(1100-1200) mL, preferably 115 g:1150 mL;

[0044] The esterification reaction conditions are: heating under reflux for 8–16 hours.

[0045] The beneficial effects of this invention are: the starting material cost of the method for preparing key intermediates of PARP1 inhibitors is low, the reaction yield is high, it is suitable for industrial-scale production, and it has broad application prospects.

[0046] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0047] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0048] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0049] Example 1: Synthesis of the intermediate of the present invention

[0050]

[0051] Step 1:

[0052] 6-hydroxynicotinic acid (50 g, 359.43 mmol, 1 eq) was added to 50 mL of concentrated sulfuric acid, heated to 80 °C, and 50 mL of fuming nitric acid was added dropwise. After the addition was complete, the reaction was kept at this temperature overnight under HPLC control. After the reaction, the temperature was lowered to 0 °C, 50 mL of water was added dropwise, and the mixture was kept at this temperature and stirred for half an hour. The mixture was then filtered, and the filter cake was washed with 50 mL of ethanol and dried to obtain 53 g of 2-hydroxy-3-nitropyridine-5-carboxylic acid, with a yield of 80%.

[0053] Step 2:

[0054] 4-Hydroxy-3-nitrobenzoic acid and 2-hydroxy-3-nitropyridine-5-carboxylic acid (50 g, 0.27 mol, 1 eq) were dissolved in 500 mL of toluene. 5 mL of LDM was added, followed by thionyl chloride (96.9 g, 0.81 mol, 3 eq). After the addition was complete, the mixture was heated to 80 °C and reacted for 2 hours, then heated to 100 °C and reacted overnight. After the reactants had reacted completely, the temperature was lowered to approximately 5 °C and controlled below 20 °C. Methanol (80 g, 1.6 W) was added dropwise under nitrogen protection. After the addition was complete, the mixture was reacted at room temperature for 5 hours. After the reaction was complete, the temperature was controlled below 10 °C. The reaction mixture was added in portions to water (200 mL) and ethyl acetate (100 mL), and stirred for half an hour. The mixture was separated, and the aqueous phase was extracted once again with ethyl acetate (100 mL). The combined organic phases were washed once with tap water (100 mL) and once with saturated brine (100 mL). The mixture was concentrated to a large solid volume, and petroleum ether was added to slurry to obtain 47 g of solid. 6-Chloro-5-nitronicotinic acid methyl ester, yield 80%;

[0055] Step 3:

[0056] Add NaH (18.3g, 0.457mol, 60% purity, 2.2eq) (1.0-5.0eq, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, etc. can also be used) to 360mL of NMP (DMF, DMAC, toluene, THF, etc. can also be used). Slowly add diethyl malonate (66.56g, 0.415mol, 2eq) (1.0-5.0eq). After the addition is complete, stir for half an hour. Dissolve methyl 6-chloro-5-nitronicotinic acid (45g, 0.207mol, 1eq) in 90mL of NMP and slowly add it dropwise to the reaction solution. After the addition is complete, raise the temperature to 50℃ and react for 4 hours. When the reaction is basically complete, add 390g of 60% pure NMP. H2SO4 was heated to 100℃ and reacted overnight. After the intermediate reaction was complete, the mixture was cooled, 1350 mL of water was added, and 900 mL of ethyl acetate was added and stirred. The mixture was filtered through a diatomaceous earth filter, separated, and the aqueous phase was extracted again with 900 mL of ethyl acetate. The organic phases were combined, washed with 600 mL of water and 600 mL of saturated brine, and concentrated to a large amount of solid. Petroleum ether was added and the mixture was stirred, filtered, and dried to obtain 28.4 g of 6-methyl-5-nitropyridine-3-carboxylic acid, with a yield of 75%.

[0057] Example 2: Synthesis of the intermediate of the present invention

[0058]

[0059] Step 1:

[0060] 6-hydroxynicotinic acid (50 g, 359.43 mmol, 1 eq) was added to 50 mL of concentrated sulfuric acid, heated to 80 °C, and 50 mL of fuming nitric acid was added dropwise. After the addition was complete, the reaction was kept at this temperature overnight under HPLC control. After the reaction, the temperature was lowered to 0 °C, 50 mL of water was added dropwise, and the mixture was kept at this temperature and stirred for half an hour. The mixture was then filtered, and the filter cake was washed with 50 mL of ethanol and dried to obtain 53 g of 2-hydroxy-3-nitropyridine-5-carboxylic acid, with a yield of 80%.

[0061] Step 2:

[0062] 4-Hydroxy-3-nitrobenzoic acid and 2-hydroxy-3-nitropyridine-5-carboxylic acid (50 g, 0.27 mol, 1 eq) were dissolved in 500 mL of toluene. 5 mL of LDM was added, followed by thionyl chloride (96.9 g, 0.81 mol, 3 eq). After the addition was complete, the mixture was heated to 80 °C and reacted for 2 hours, then heated to 100 °C and reacted overnight. After the reactants had reacted completely, the temperature was lowered to approximately 5 °C and controlled below 20 °C. Methanol (80 g, 1.6 W) was added dropwise under nitrogen protection. After the addition was complete, the mixture was reacted at room temperature for 5 hours. After the reaction was complete, the temperature was controlled below 10 °C. The reaction mixture was added in portions to water (200 mL) and ethyl acetate (100 mL), and stirred for half an hour. The mixture was separated, and the aqueous phase was extracted once again with ethyl acetate (100 mL). The combined organic phases were washed once with tap water (100 mL) and once with saturated brine (100 mL). The mixture was concentrated to a large solid volume, and petroleum ether was added to slurry to obtain 47 g of solid. 6-Chloro-5-nitronicotinic acid methyl ester, yield 80%;

[0063] Step 3:

[0064] Sodium tert-butoxide (43.83 g, 0.457 mol, 2.2 eq) (1.0–5.0 eq) was added to 270 mL of THF. Diethyl malonate (66.56 g, 0.415 mol, 2 eq) (1.0–5.0 eq) was slowly added. After the addition was complete, the mixture was stirred for half an hour. Methyl 6-chloro-5-nitronicotinic acid (45 g, 0.207 mol, 1 eq) was dissolved in 180 mL of THF and slowly added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 50 °C and the reaction was carried out for 4 hours. After the reaction was basically complete, the THF was concentrated and 290 mL of 6 mol / L sodium hydroxide solution was added. The HCl solution was heated to 100°C and reacted overnight. After the intermediate reaction was complete, the mixture was cooled, 1350 mL of water was added, and 900 mL of ethyl acetate was added and stirred. The mixture was filtered through a diatomaceous earth filter, and the aqueous phase was extracted again with 900 mL of ethyl acetate. The organic phases were combined, washed with 600 mL of water and 600 mL of saturated brine, and concentrated to a large amount of solid. Petroleum ether was added and the mixture was stirred, filtered, and dried to obtain 30.3 g of 6-methyl-5-nitropyridine-3-carboxylic acid, with a yield of 80%.

[0065] Example 3: Esterification of the intermediate of the present invention

[0066]

[0067] Step 4:

[0068] 115 g of 6-methyl-5-nitropyridine-3-carboxylic acid (0.631 mol, 1 eq) was added to 1150 mL of ethanol. Thionyl chloride (90.14 g, 757.69 mmol, 1.2 eq) (1.0–5.0 eq) was added dropwise at room temperature. After the addition was complete, the mixture was refluxed overnight. Once the reactants had mostly reacted, the reaction solution was concentrated to dryness. 2 L of ethyl acetate was added to dissolve the solution, followed by 500 mL of saturated sodium bicarbonate solution. The mixture was stirred for 10 minutes, separated, and the organic phase was washed with 500 mL of saturated sodium bicarbonate solution for another 10 minutes. The organic phase was then separated, washed with 500 mL of saturated brine, and the filtrate was concentrated to dryness. 150 mL of petroleum ether was added, and the mixture was cooled to 0 °C and slurried. The mixture was filtered and dried to obtain 103.8 g of a yellow solid, with a yield of 85%.

[0069] After obtaining the compound shown in Formula I-1, the PARP1 inhibitor with the structure shown in Formula V can be further prepared according to the method disclosed in Chinese Patent Application Publication No. CN114144413A.

[0070]

[0071] In summary, the method of the present invention can produce starting materials for PARP1 inhibitors using inexpensive and readily available raw materials, with low cost and high yield, and has value for widespread application.

Claims

1. A process for the preparation of a PARP1 inhibitor intermediate I-1 characterized in that, Comprise the following steps: (1) 6-hydroxy nicotinic acid represented by formula IV is reacted with fuming nitric acid in concentrated sulfuric acid to prepare 2-hydroxy-3-nitro pyridine-5-carboxylic acid represented by formula III; (2) 2-hydroxy-3-nitro pyridine-5-carboxylic acid represented by formula III is reacted with thionyl chloride in an organic solvent, then methanol is added to react, to prepare 6-halo-5-nitro nicotinic acid methyl ester represented by formula II; (3) 6-halo-5-nitro nicotinic acid methyl ester represented by formula II is reacted with malonic acid diester under the action of a base in an organic solvent, then acid is added to react, to prepare the intermediate represented by formula I; (4) the intermediate represented by formula I is esterified with ethanol under the action of thionyl chloride to prepare PARP1 inhibitor intermediate I-1; The reaction formula is as follows: ； wherein R is C 1~4 alkyl, X is halogen; The mass-volume ratio of 6-hydroxy nicotinic acid, fuming nitric acid and concentrated sulfuric acid in step (1) is 50 g : 50 mL : 50 mL; the reaction condition in step (1) is 80℃ for 8-16h; The molar ratio of 2-hydroxy-3-nitro pyridine-5-carboxylic acid and thionyl chloride in step (2) is 1 : 3; the mass ratio of 2-hydroxy-3-nitro pyridine-5-carboxylic acid and methanol is 50 : 80; the reaction condition of 2-hydroxy-3-nitro pyridine-5-carboxylic acid and thionyl chloride in step (2) is first 80℃ for 2h, then 100℃ for 8-16h; the condition of adding methanol to react is that methanol is added under inert gas protection condition below 20℃, then reacted at 20-30℃ for 5h; The molar ratio of 6-halo-5-nitro nicotinic acid methyl ester, malonic acid diester and base in step (3) is 1 : 2 : 2.2, and the mass ratio of 6-halo-5-nitro nicotinic acid methyl ester and acid is 45 : (63-234); The base in step (3) is sodium tert-butoxide; the organic solvent is tetrahydrofuran; the reaction condition of 6-halo-5-nitro nicotinic acid methyl ester and malonic acid diester under the action of a base in step (3) is 50℃ for 4h; the reaction condition of adding acid is 100℃ for 8-16h; the malonic acid diester in step (3) is diethyl malonate; and the acid is hydrochloric acid; The molar ratio of the intermediate represented by formula I and thionyl chloride is 1 : 1.2; The mass-volume ratio of the intermediate represented by formula I and ethanol is 115 g : 1150 mL; The esterification reaction condition is heating reflux reaction for 8-16h.

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