6-nitro-7-bromo-8-fluoro-quinazoline intermediate and synthesis method thereof

Abstract

The invention provides a novel, simple and practical 6-nitro-7-bromo-8-fluoro-quinazoline intermediate (compound I) and a preparation method thereof. The method has the advantages of short reaction steps and simple operation, and is suitable for large-scale production. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a 6-nitro-7-bromo-8-fluoro-quinazoline derivative and a synthesis method thereof, and belongs to the field of organic synthesis. Background Art

[0002] The 6-nitro-quinazoline nucleus is an important heterocyclic compound. It has attracted the attention of researchers due to its wide range of biological activities, especially its application in the field of anti-tumor drugs. In the development of anti-tumor drugs, quinazoline compounds show potential therapeutic effects because they can inhibit the proliferation of tumor cells. In particular, the application of the 6-nitro-quinazoline nucleus is particularly important in the study of KRAS inhibitors. By substituting and modifying different sites of the 6-nitro-quinazoline nucleus, anti-tumor drugs with different biological activities can be designed.

[0003] The full name of the KRAS gene is Kirsten rat sarcoma viral oncogene homolog, which means "Kirsten rat sarcoma viral oncogene homolog" in Chinese. It belongs to the RAS gene family and is an important "switch" in the intracellular signal transduction pathway, located on the inner side of the cell membrane. The KRAS protein is a small GTPase that switches between inactive and activated states in the cell to regulate cell growth and proliferation. When KRAS binds to guanine nucleoside diphosphate (GDP), it is in an inactive state; when it binds to guanine nucleoside triphosphate (GTP), it is in an activated state and can activate downstream signaling pathways. KRAS gene mutations can cause the protein to be continuously activated, thereby promoting the occurrence and development of tumors. KRAS is a common oncogene, and its mutations are closely related to the occurrence and development of many tumors. The development of KRAS inhibitors is one of the hot topics in the field of tumor treatment.

[0004] In patent WO2023138583, the application of 6-nitro-quinazoline nucleus in KRAS inhibitors is disclosed, and a variety of 6-nitroquinazoline derivatives with anti-tumor activity are designed and synthesized. In the patent, the following formula ( Figure 1) is used to prepare intermediate 4, and then substitution at different sites is performed to synthesize 6-nitro-quinazoline derivatives with tumor activity. The inventors found that intermediate 4 and its synthesis route have the following problems: 1) Intermediate 4 is relatively unstable, sensitive to water, and easily hydrolyzed and deteriorated; 2) The activity of Cl at the 2- and 4-positions in the structure of intermediate 4 is not much different, which affects the next step of obtaining a highly selective single-site reaction product; 3) In the reaction route, intermediate 4 is obtained by high-temperature (200°C) cyclization in the first step, nitration in the second step, and chlorination in the third step; 4) Impurities 1 (IMP-1) and impurities 2 (IMP-2) will inevitably be produced during the chlorination reaction in step 3, and intermediate 4 cannot be purified by conventional means.

[0005]

[0006] In summary, intermediate 4 has problems such as unstable storage, poor reaction site selectivity, high equipment requirements for the synthesis route, uncontrollable impurities, and difficulty in purification, making it unsuitable for large-scale production. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a novel, simple and practical 6-nitro-7-bromo-8-fluoro-quinazoline intermediate (Compound I) and a preparation method thereof.

[0008]

[0009] To solve the above technical problems, the technical solution adopted by the present invention can be used as follows: Figure 2 )express:

[0010]

[0011]

[0012] Wherein, X is Cl or Br.

[0013] Compound III can be prepared according to the method of "Compound IV" in Example 1 published in CN112341351. 1) Step 1, Compound III reacts with a halogenating agent to generate an active acyl halide intermediate III-1.

[0014] Specifically, the halogenating agent is selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, thionyl bromide, oxalyl bromide, phosphorus oxybromide, preferably thionyl chloride or oxalyl chloride; the molar ratio of the halogenating agent to compound III is 1 to 2:1; the reaction solvent is one or more of dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene or xylene, preferably one or two of dichloromethane or toluene; the reaction temperature is 0 to 70°C; further, a catalytic amount of N,N-dimethylformamide (DMF) can be added during the reaction; the molar ratio of the catalyst DMF to compound III is 0 to 0.1:1.

[0015] After the reaction is completed, the reaction solution is concentrated to obtain the intermediate III-1 which is directly used in the next reaction.

[0016] 2) Step 2: Compound III-1 is condensed with 2-methylisothiourea sulfuric acid in a suitable solvent and under suitable alkaline conditions to generate compound II.

[0017] Specifically, the appropriate solvent is one or more of ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and N-methylpyrrolidone, preferably one or two of ethylene glycol dimethyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran; the appropriate base is an aqueous solution of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate, preferably an aqueous solution of one or two of sodium hydroxide, potassium hydroxide or sodium carbonate, potassium carbonate; the molar ratio of the base to compound III-1 is 1 to 4:1; the reaction temperature is 0 to 35°C, preferably 0 to 10°C. After the reaction is completed, the post-treatment method is filtering, washing with water, and drying to obtain intermediate II. 3) Step 3, compound II is cyclized in an appropriate solvent at a certain reaction temperature to obtain compound I.

[0018] Specifically, the appropriate solvent is one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone, N,N-diethylformamide, N,N-diethylacetamide, pyridine, 1,4-dioxane, preferably one or two of N,N-dimethylformamide, N,N-dimethylacetamide or 1,4-dioxane; the reaction temperature is 20-150°C, preferably 80-120°C. After the reaction is completed, the post-treatment method is to cool the reaction solution to room temperature, add water, precipitate, filter, wash with water, and dry to obtain the target I.

[0019] The main advantage of the present invention is that the present invention discloses a novel 6-nitro-7-bromo-8-fluoro-quinazoline derivative, which has a novel structure and multiple active sites, and can more conveniently carry out derivatization modification at different sites. At the same time, the stability is high and the storage is convenient. At the same time, the present invention also discloses a synthesis method of the 6-nitro-7-bromo-8-fluoro-quinazoline derivative, which has short reaction steps, simple operation, and is suitable for scaled-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 : Test Example 1 Compound I was placed at high temperature and high humidity for 0 days 1 H-NMR graph

[0021] Figure 2 : Test Example 1 Compound I was placed at high temperature for 30 days 1 H-NMR graph

[0022] Figure 3 : Test Example 1 Compound I was placed in high humidity for 30 days 1 H-NMR graph DETAILED DESCRIPTION

[0023] Without further detailed description, those skilled in the art can make the best use of the present invention with the help of the above description. 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 operations or steps in the following examples that do not specify specific conditions are usually carried out according to the conventional conditions in the art.

[0024] Unless otherwise specified, the raw materials or reagents used in the examples are all commercially available. Unless otherwise specified, the reagents and solvents are used directly without purification or special treatment, and all solvents are from commercial suppliers. The room temperature is 5-35°C.

[0025] Compound III can be prepared according to the method of "Compound IV" in Example 1 published in CN112341351. NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer. The measurement solvent is indicated in the spectrum analysis.

[0026] MS was determined using Agilent 1200-G1956A / 1200-6110A / 1200-6140A / 1260-6125B / Prime-6125B / 1260-6120 LC / MS, SHIMADZU 20A-2010 / 20A-2020 LC / MS, and Waters ACQ-QDA LC / MS.

[0027] HPLC analysis was performed using a SHIMADZU 20A high performance liquid chromatograph.

[0028] Example 1: (4-bromo-2,3-difluoro-5-nitrophenyl)carbamide thiomethyl ester

[0029]

[0030] Step 1: 4-Bromo-2,3-difluoro-5-nitrobenzoyl chloride

[0031] Add 4-bromo-2,3-difluorobenzoic acid (Compound III, 10.0 g, 35.4 mmol) to 100 ml of DCM, add DMF (0.258 g, 3.54 mmol), and stir evenly. Slowly add thionyl chloride (5.47 g, 46.02 mmol) at room temperature, and after the addition, heat to reflux for 1-2 hours. After the reaction is completed, concentrate, add a small amount of toluene and continue to concentrate to near dryness to obtain yellow-brown semi-solid 4-bromo-2,3-difluoro-5-nitrobenzoyl chloride (10.2 g, yield 96%), which is directly used for subsequent reactions.

[0032] Step 2: (4-bromo-2,3-difluoro-5-nitrophenyl)carbamide thiomethyl ester

[0033] Add 4-bromo-2,3-difluoro-5-nitrobenzoyl chloride (5.0g, 16.6mmol) to 2-methyltetrahydrofuran (20ml) and stir evenly, then cool to 0-10°C. Add 2-methylisothiourea sulfuric acid (7.14g, 41.5mmol) to 100ml sodium carbonate solution (5.28g, 49.8mmol), stir at 0-10°C for 10-30 minutes. Add the above 2-methyltetrahydrofuran solution dropwise to the alkaline aqueous solution at 0-10°C and stir for 1-2 hours. Filter, wash the filter cake with 100ml water, and dry to obtain the product 4-bromo-2,3-difluoro-5-nitrophenyl)carbamide thiomethyl ester (5.5g, yield 93.5%). LCMS (m / z): 355.9 (M+H).

[0034] Compound II can also be obtained by the following method (Example 2-4):

[0035] Example 2

[0036] Step 1: The same method as in Example 1, Step 1 was used, but 100 ml of toluene was used instead of 100 ml of DCM, and the reaction was carried out at 50-70° C. for 1-2 hours. Yield: 9.8 g (92% of theoretical value).

[0037] Step 2: The same method as in Example 1, Step 2 was used, but 20 ml of ethylene glycol dimethyl ether was used instead of 20 ml of 2-methyltetrahydrofuran. The reaction mixture was reacted at 0-10°C for 1-2 hours. Yield: 5.6 g (95% of theoretical value).

[0038] Example 3

[0039] Step 1, adopt the same method as Example 1, Step 1, but use oxalyl chloride (3.0 g, 23.6 mmol) instead of thionyl chloride (5.47 g, 46.02 mmol), and react at 30-40° C. for 1-2 hours. Yield: 9.3 g (87.5% of theoretical value).

[0040] Step 2: The same method as in Example 1, Step 2 was used, but 70 ml of 1M potassium hydroxide was used instead of 100 ml of sodium carbonate aqueous solution. Yield: 4.9 g (83% of theoretical value).

[0041] Example 4

[0042]

[0043] Step 1: 4-Bromo-2,3-difluoro-5-nitrobenzoyl bromide

[0044] 4-Bromo-2,3-difluorobenzoic acid (Compound III, 10.0 g, 35.4 mmol) was added to 100 ml of DCM, and sulfoxide bromide (9.6, 46.02 mmol) was slowly added at room temperature. After the addition was completed, the mixture was reacted at room temperature for 1-2 hours. After the reaction was completed, the mixture was concentrated, and a small amount of toluene was added to continue concentrating to near dryness to obtain a yellow-brown semi-solid 4-bromo-2,3-difluoro-5-nitrobenzoyl bromide (9.6, yield 78.6%), which was directly used for subsequent reactions.

[0045] Step 2: The same method as in Example 1, Step 2 was used, except that 4-bromo-2,3-difluoro-5-nitrobenzoyl bromide (5.0 g, 16.6 mmol) was used instead of 4-bromo-2,3-difluoro-5-nitrobenzoyl chloride (5.7 g, 16.6 mmol). Yield: 4.8 g (81.6% of theoretical value).

[0046] Example 5: 7-Bromo-8-fluoro-2-(methylthio)-6-nitroquinazolin-4-ol

[0047]

[0048] Dissolve (4-bromo-2,3-difluoro-5-nitrophenyl)carbamide thiomethyl ester (5.0 g, 14.1 mmol) in 50 ml of 1,4-dioxane, heat to 80-100 ° C, and stir to react for 3-5 hours. Cool down and add 100 ml of ice water. Filter, wash the filter cake with 100 ml of water, and dry to obtain a yellow solid 7-bromo-8-fluoro-2-(methylthio)-6-nitroquinazolin-4-ol (4.1 g, yield 85.9%). LCMS (m / z): 335.9 (M+H).

[0049] 1 H-NMR (d6-DMSO, 400Hz): δppm 2.62 (s, 3H), 8.41 (d, J = 1.7Hz, 1H), 13.28 (s, 1H).

[0050] Compound I can also be obtained by the following method (Examples 7-8):

[0051] Example 6: The same method as Example 5 was used, but pyridine (50 ml) was used instead of 1,4-dioxane (50 ml) and the reaction was stirred at 20-40° C. for 3-5 hours. Yield: 3.7 g (77.5% of theoretical value).

[0052] Example 7: The same method as Example 5 was used, but DMF (50 ml) was used instead of 1,4-dioxane (50 ml), and the reaction was stirred at 100-120° C. for 3-5 hours. Yield: 4.3 g (91.2% of theoretical value).

[0053] Test Example 1: Preliminary stability study of compound I

[0054] The obtained compound I was placed in a high temperature and high humidity environment for 30 days for HPLC and 1 H-NMR detection.

[0055] The test conditions are:

[0056] High temperature conditions: temperature 60℃

[0057] High humidity conditions: humidity 75% (saturated sodium chloride solution) temperature 25°C

[0058] The results showed that compound I was placed under high temperature and high humidity test conditions for 30 days, and the HPLC purity and 1 H-NMR (such as Figure 1-3 ) did not undergo any change, proving to be stable under this condition.

[0059] Test Example 2: 1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0060]

[0061] Step 1: Add compound I (3.33 g, 10 mmol) and DIPEA (3.88 g, 30 mmol) to DMF (30 mL), stir to dissolve, and continue to add 3-methylpiperidin-3-ol hydrochloride (0.20 g, 12 mmol) and BOP (8.84 g, 20 mmol). The resulting mixture was heated to 50-80 ° C and reacted for more than 4 hours. After the reaction was completed, it was cooled to room temperature and water (400 mL) was added to quench the reaction. Filter, wash the filter cake twice with water (200 mL), collect the filter cake and dry it to obtain 4.1 g of brown solid 1-(7-bromo-8-fluoro-2-(methylthio)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol, with a yield of 95%. LCMS (m / z): 431.0 (M+H).

[0062] Step 2: Under nitrogen environment, 1-(7-bromo-8-fluoro-2-(methylthio)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (2.15 g, 5 mmol) and (((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.9 g, 6.5 mmol) were added to a mixed solution of toluene (40 mL) and water (10 mL). Cesium carbonate (6.5 g, 20 mmol) was added at room temperature, and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium (II) (0.33 g, 1 mmol) was added under nitrogen protection, and the temperature was raised to reflux (100°C) for more than 12 hours. After the reaction was completed, the temperature was lowered to room temperature, water (100 mL) was added and stirred evenly, and then extracted with 150 mL of ethyl acetate three times, and the ethyl acetate layers were combined and collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated to near dryness under reduced pressure. The concentrated residue was heated and dissolved with DMF (10 mL), and water (100 mL) was added. After the precipitate was precipitated, it was filtered, and the filter cake was washed with 50 mL of water. The filter cake was collected and dried to obtain 1.8 g of yellow solid 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(methylthio)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol, with a yield of 54%. LCMS (m / z): 677.3 (M+H).

[0063] Step 3: Add 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (0.7 g, 10 mmol) to DCM (100 mL), add m-CPBA (4.3 g, 25 mmol), and stir at room temperature for about 2-3 hours. After the reaction, sodium sulfite aqueous solution (80 mL) was added, stirred for 1-2 hours, separated, the organic phase was washed with sodium bicarbonate aqueous solution (100 mL), separated, the aqueous phase was extracted with DCM (50 mL*3), the organic phases were combined and washed with saturated sodium chloride aqueous solution (50 mL), filtered, the filtrate was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 6 g of yellow-brown solid 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(methylsulfonyl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol, with a yield of 84%. LCMS (m / z): 709.2 (M+H).

[0064] Step 4: Under nitrogen protection, sodium tert-butoxide (52.5 mg, 0.55 mmol) was added to dry tetrahydrofuran (5 mL), and (tetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (78 mg, 0.55 mmol) was added, and the mixture was stirred at room temperature for half an hour for standby use. 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (0.35 g, 0.5 mmol) was added to dry tetrahydrofuran (10 mL) to dissolve, and then added to the above sodium alcoholate solution, and stirred for reaction for more than two hours. After the reaction was completed, 15 mL of water was added for dilution, and then the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined and washed with a saturated sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.3 g of a brown solid with a yield of 80%. LCMS (m / z): 771.0 (M+H).

[0065] Step 5: Add 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.2 g, 0.26 mmol) to DMF (3 mL) at room temperature and stir to dissolve. Add cesium fluoride (0.16 g, 1.0 mmol) and stir at room temperature for more than 2 hours. After the reaction, water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.14 g of a brown compound 1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol, with a yield of 90%. LCMS (m / z): 614.1 (M+H). HNMR(400MHz,CD3OD)δppm8.88(s,1H),8.15-8.06(m,2H),7.61(t,J=7.7Hz,1H),7.48-7.40(m,2H),4.56(br d,J=13.6Hz,1lH),4.39-4.23(m,3H),3.70-3.51(m,2H),3.45-3.39(m,1H),3.27-3 .17(m,2H),2.90-2.79(m,2H),2.20-2.09(m,2H),2.06-1.76(m,1OH),1.30(s,3H).

Claims

1. A compound of formula I and a method for preparing the same.

2. As claimed in claim 1, the synthetic route of the compound of formula I is: in, X is Cl or Br. The synthesis method comprises the following steps: Step 1: Compound III reacts with a halogenating agent to generate an active acyl halide intermediate III-1. Step 2: Compound III-1 is condensed with 2-methylisothiourea sulfuric acid in a suitable solvent and under suitable alkaline conditions to generate compound II. Step 3: Compound II is cyclized in a suitable solvent at a certain reaction temperature to obtain compound I.

3. The preparation method according to claim 2, characterized in that : Step 1, the halogenating agent is selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, thionyl bromide, oxalyl bromide, phosphorus oxybromide, preferably thionyl chloride or oxalyl chloride; the feeding molar ratio of the halogenating agent to compound III is 1-2:1; the reaction solvent is one or more of dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene or xylene, preferably one or two of dichloromethane or toluene; the reaction temperature is 0-70°C; further, a catalytic amount of N,N-dimethylformamide (DMF) can be added during the reaction; the feeding molar ratio of the catalyst DMF to compound III is 0-0.1:

1.

4. The preparation method according to claim 2, characterized in that: Step 2, the appropriate solvent is one or more of ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, preferably one or two of ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran; the appropriate base is an aqueous solution of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, preferably an aqueous solution of one or two of sodium hydroxide, potassium hydroxide or sodium carbonate, potassium carbonate; the molar ratio of the base to compound III-1 is 1 to 4:1; the reaction temperature is 0 to 35°C, preferably 0 to 10°C. After the reaction is completed, the post-treatment method is filtering, washing with water, and drying to obtain intermediate II.

5. The preparation method according to claim 2, characterized in that: Step 3, the appropriate solvent is one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone, N,N-diethylformamide, N,N-diethylacetamide, pyridine, 1,4-dioxane, preferably one or two of N,N-dimethylformamide, N,N-dimethylacetamide or 1,4-dioxane; the reaction temperature is 20-150°C, preferably 80-120°C. After the reaction is completed, the post-treatment method is to cool the reaction solution to room temperature, add water, precipitate, filter, wash with water, and dry to obtain the target I.

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