Synthesis process of KRAS inhibitor type antitumor drug MRTX849

Abstract

The invention relates to a synthesis process of a KRAS inhibitor type antitumor drug MRTX849, which comprises the following steps: by taking a benzyl-protected compound 2 as an initial raw material, firstly carrying out amidation reaction, introducing a piperidine ring into a main chain structure, carrying out cyclization reaction to obtain a compound 6, then directly introducing a nitrogen methyl tetrahydropyrrole ring through Mitsunobu reaction, then removing benzyl protection, introducing a naphthalene ring through SNAr reaction, and finally obtaining the KRAS inhibitor type antitumor drug MRTX849. According to the process disclosed by the invention, the reaction is further reduced to seven steps, a coupling reaction catalyzed by palladium is reduced to one step, an oxidation reaction with relatively high risk is avoided, the overall yield is improved, the process is stable, the operation is simple, the post-treatment is easy, and the process has more advantages on industrial enlarged production.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a synthesis process of a KRAS inhibitor-type anti-tumor drug MRTX849. Background Art

[0002] GaN RAS (rat sarcoma) gene is an important oncogene, whose mutations are present in about 30% of human tumors. KRAS (Kirsten rat sarcoma viral oncogene homolog) is one of the three subtypes of RAS and is more prone to mutations than the other two RAS subtypes. The activating mutation rates in pancreatic cancer and colorectal cancer are as high as 90% and 50%, respectively. MRTX849 is a highly selective covalent inhibitor of KRASG12C developed by Mirati Therapeutics that can stably bind to KRASG12C in an inactive state. Studies have shown that MRTX849 exhibits good anti-tumor efficacy within a dose range.

[0003] There are two existing synthetic routes for the synthesis of MRTX849:

[0004] (1) Synthesis Route I:

[0005] Synthesis Route I uses a benzyl-protected compound as the starting material and undergoes 11 steps to obtain the final product. The synthesis route is as follows:

[0006] This route has a long reaction process, low yields, and is a linear synthesis with low efficiency. It also involves multiple palladium-catalyzed coupling reactions, resulting in high costs and the use of environmentally hazardous reagents such as phosphorus oxychloride and sodium hydride. Therefore, Route I is not suitable for scale-up industrial production.

[0007] (2) Synthesis Route II:

[0008] Synthesis Route II reduces the reaction steps to 9 steps. The synthesis route is as follows:

[0009] However, this strategy remains a linear synthesis strategy with low efficiency and yield. Route II still involves multiple steps using palladium-containing reagents as catalysts, resulting in high production costs. It also utilizes oxidation reactions that are difficult to control and are relatively dangerous, so this route still has room for improvement. Summary of the Invention

[0010] The purpose of the present invention is to overcome the problems existing in the prior art and provide a synthesis process for the KRAS inhibitor anti-tumor drug MRTX849, which reduces the reaction steps to 7 and reduces the palladium-catalyzed coupling reaction to 1 step, avoiding the more dangerous oxidation reaction, improving the overall yield, and having more advantages for industrial scale-up production.

[0011] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0012] A process for synthesizing the KRAS inhibitor anti-tumor drug MRTX849, comprising:

[0013] Using benzyl protected compound 2 as the starting material: First, the piperidine ring is introduced into the main chain structure through an amidation reaction, and compound 6 is obtained after a cyclization reaction: Then, the nitrogen methyl tetrahydropyrrole ring was directly introduced through the Mit sunobu reaction, and then the benzyl protection was removed. The naphthalene ring was introduced through the SNAr reaction, and finally the Boc protecting group was removed. Compound 1 was obtained through acylation reaction: The overall synthetic route is as follows:

[0014]

[0015] Furthermore, the process specifically comprises the following steps:

[0016] Step S1: Synthesis of Compound 4: (2S)-tert-butyl-4-(1-benzyl-3-oxypiperidinyl-4-carbonyl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0017] Methyltetrahydrofuran, compound 2: 1-benzyl-3-oxopiperidine-4-carboxylic acid, carbonyldiimidazole CDI, and N,N-diisopropylethylamine DIPEA were added to a three-necked flask and stirred at room temperature for a period of time under nitrogen protection. Compound 3: (S) tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate was then added and the reaction continued for a period of time. Water was added to the reaction solution at room temperature and stirred for a period of time. The layers were separated and the organic phase was washed with saturated sodium chloride solution. The organic phase was concentrated to obtain a brown solid crude product, which was recrystallized from a 1 / 1 ethyl acetate / n-heptane solution to obtain a white solid.

[0018] Step S2: Synthesis of Compound 6: (S)-tert-butyl-4-(7-benzyl-2-hydroxy-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0019] Compound 4, compound 5: urea, and boron trifluoride etherate were added to a sealed reactor in sequence, and the mixture was heated to 105°C in an external bath and stirred. After the reaction was complete, the mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was washed with saturated sodium chloride solution. The organic phase was concentrated and cooled to 0-5°C to precipitate a large amount of yellow solid. The mixture was stirred for a period of time, filtered, washed with ethyl acetate, and dried to obtain compound 6.

[0020] Step S3: Synthesis of Compound 8: (S)-tert-butyl-4-(7-benzyl-2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0021] Compound 6, triphenylphosphine, tetrahydrofuran (THF), and compound 7: (S)-(1-methylpyrrolidin-2-yl)methanol were added to a round-bottom flask, and the temperature was lowered to 0°C. Diethyl azodicarboxylate (DEAD) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred to complete the reaction. Water and ethyl acetate were added, and the reaction was stirred for a period of time. The organic layer was separated and washed with a saturated sodium chloride solution. Zinc chloride was added, and the mixture was stirred for a period of time. The organic layer was filtered to remove the generated triphenylphosphine. The filtrate was dried over anhydrous Na2SO4 and concentrated to obtain a crude white solid. The crude product was recrystallized from ethanol and dried to obtain a white solid.

[0022] Step S4: Synthesis of Compound 9: (S)-tert-butyl-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0023] Ethanol and compound 8 were added to the hydrogenation reaction kettle in sequence, stirred and dissolved, palladium carbon was added, and the reaction kettle was replaced with hydrogen several times. The hydrogen was pressurized, the temperature was increased, and the reaction was stirred until the reaction was complete. Microcrystalline cellulose was added and filtered to remove the palladium carbon. The filtrate was concentrated under reduced pressure and cooled to 0°C to crystallize to obtain a white solid;

[0024] Step S5: Compound 11: Synthesis of (S)-tert-butyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0025] To a round-bottom flask, add N,N-dimethylformamide (DMF), compound 9, compound 10: 1-bromo-8-chloronaphthalene, and cesium carbonate in sequence, stir and heat, react for a period of time, cool to room temperature, filter to remove insoluble cesium carbonate, then add water and isopropyl acetate (IPAC) to the filtrate and stir for a period of time, then let stand to separate the layers. The organic phase is then washed with water several times, concentrated, and n-heptane is slowly added dropwise with stirring. Solid precipitates, which is filtered and dried to obtain a white solid.

[0026] Step S6: Synthesis of Compound 12: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropyrrolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl)carboxylate:

[0027] Acetonitrile and compound 11 were added to a round-bottom flask in sequence, stirred and heated to dissolve. Hydrochloric acid solution was slowly added dropwise to the reaction flask and stirred for a period of time. Solids gradually precipitated. The reaction solution was concentrated, cooled to 0°C, and stirred for a period of time. The hydrochloride of compound 12 was obtained by filtration and dried to obtain a white solid.

[0028] Step S7: Synthesis of Compound 1: 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrrolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0029] Tetrahydrofuran (THF), compound 12, and N,N-diisopropylethylamine (DIPEA) were added to a round-bottom flask in sequence and stirred at room temperature for a period of time. Compound 13: acryloyl chloride was slowly added dropwise to the reaction flask and stirred for a period of time. Water and isopropyl acetate (IPAC) were added to the reaction solution, and the mixture was allowed to stand for phase separation after stirring. The organic phase was washed with water several times and concentrated to obtain a crude yellow solid. The product was crystallized from a 5 / 1 acetonitrile / water mixture to obtain a white solid, which was then dried to obtain a white solid.

[0030] Furthermore, in step S2, Lewis acid is used for acid catalysis during the ring-closure reaction to synthesize compound 6.

[0031] Furthermore, in step S2, the acid catalyst is boron trifluoride, the equivalent weight is 1.2, and the reaction temperature is 100°C.

[0032] Furthermore, in step S3, the synthesis of compound 8 is carried out by Mitsunobu reaction, preferably triphenylphosphine and diethyl azodicarboxylate DEAD are used as the reaction conditions for this step, and preferably tetrahydrofuran THF is used as the solvent for this step.

[0033] Furthermore, in step S5, the synthesis of compound 11 is an aromatic nucleophilic substitution reaction SNAr, using N,N-dimethylformamide DMF as a solvent to increase the solubility of the raw materials and inorganic base in the reaction system, and using cesium carbonate as an inorganic base to improve the conversion rate of the reaction.

[0034] The beneficial effects of the present invention are:

[0035] The present invention designs and synthesizes the KRAS inhibitor antitumor drug MRTX849. The target compound MRTX849 is obtained through seven steps of reaction, including an amidation reaction. The palladium-catalyzed coupling reaction is reduced to one step, avoiding the more dangerous oxidation reaction. The overall yield is improved, the process is stable, the operation is simple, the post-processing is easy, and it is easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The figure is a synthetic route of MRTX849 of the process of the present invention.

[0037] Explanation of the numbers in the figure: 1. Smart meter body, 2. Partition, 3. Power chamber, 4. Side chamber, 5. Power adapter, 6. Back panel, 7. Port group, 8. Insulation sleeve, 9. Wire. DETAILED DESCRIPTION

[0038] The present invention will be described in detail below with reference to the accompanying drawings and in combination with embodiments.

[0039] A process for synthesizing the KRAS inhibitor anti-tumor drug MRTX849, comprising:

[0040] Using benzyl protected compound 2 as the starting material: First, the piperidine ring is introduced into the main chain structure through an amidation reaction, and compound 6 is obtained after a cyclization reaction: Then, the nitrogen methyl tetrahydropyrrole ring was directly introduced through the Mit sunobu reaction, and then the benzyl protection was removed. The naphthalene ring was introduced through the SNAr reaction, and finally the Boc protecting group was removed. Compound 1 was obtained through acylation reaction: The overall synthetic route is as follows:

[0041]

[0042] First, prepare the instruments and reagents:

[0043] Reagents: 1-benzyl-3-oxopiperidine-4-carboxylic acid, methyltetrahydrofuran, carbonyldiimidazole, N,N-diisopropylethylamine, ethyl acetate, n-heptane, urea, boron trifluoride etherate, triphenylphosphine, etc.

[0044] Instruments: Agilent 1200 LC-MS mass spectrometer (Agilent, USA), Bruker AV-400 nuclear magnetic resonance instrument (Bruker, Switzerland);

[0045] The process specifically includes the following steps:

[0046] Step S1: Synthesis of Compound 4: (2S)-tert-butyl-4-(1-benzyl-3-oxypiperidinyl-4-carbonyl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0047] In a 500 mL three-necked flask, 250 mL of methyltetrahydrofuran, 23.3 g (0.1 mol) of 1-benzyl-3-oxopiperidine-4-carboxylic acid (Compound 2), 21.08 g (0.13 mol) of carbonyldiimidazole (CDI), and 25.8 g (0.2 mol) of N,N-diisopropylethylamine (DIPEA) were added and stirred at room temperature for 1 h under nitrogen protection. Then, 27.0 g (0.12 mol) of (S)-tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate (Compound 3) was added and the reaction was continued for 5 h. 200 mL of water was added to the reaction solution at room temperature and stirred for 10 min. The layers were separated and the organic phase was washed with 100 mL of saturated sodium chloride solution. The organic phase was concentrated to obtain a brown solid crude product, which was recrystallized from a 1 / 1 ethyl acetate / n-heptane solution to obtain 40.7 g of a white solid with a yield of 92.5%; LC-MS (m / z): 441.34 [M+H] + ;

[0048] Step S2: Synthesis of Compound 6: (S)-tert-butyl-4-(7-benzyl-2-hydroxy-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0049] To a 500 mL sealed reactor, 35.2 g (0.08 mol) of compound 4, 6.0 g (0.1 mol) of urea (compound 5), and 14.2 g (0.1 mol) of boron trifluoride etherate were added in sequence. The mixture was heated to 105°C in an external bath and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature, 500 ml of ethyl acetate and 500 mL of water were added, and the organic layer was washed with 200 ml of saturated sodium chloride solution. The organic phase was concentrated to 150 g and cooled to 0-5°C. A large amount of yellow solid precipitated, which was stirred for 30 min, filtered, washed with ethyl acetate, and dried to obtain 32.4 g of compound 6, with a yield of 87.3%; LC-MS (m / z): 465.34 [M+H] + ;

[0050] Step S3: Synthesis of Compound 8: (S)-tert-butyl-4-(7-benzyl-2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0051] In a 500 mL round-bottom flask, 23.2 g (0.05 mol) of compound 6, 13.1 g (0.05 mol) of triphenylphosphine, 200 mL of THF, and 6.9 g (0.06 mol) of (S)-(1-methylpyrrolidin-2-yl)methanol (compound 7) were added, and the temperature was lowered to 0°C. 10.4 g (0.06 mol) of diethyl azodicarboxylate (DEAD) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred for 3 h until the reaction was complete. 200 ml of water and 200 mL of ethyl acetate were added, and the mixture was stirred for 10 min. The organic layer was separated and washed with 100 ml of saturated sodium chloride solution. 20.4 g (0.15 mol) of zinc chloride was added, and the mixture was stirred for 2 h. The resulting triphenylphosphine was removed by filtration. The filtrate was dried over anhydrous Na2SO4 and concentrated to obtain a crude white solid, which was recrystallized from 95% ethanol and dried at 60°C to obtain 25.0 g of a white solid with a yield of 89.0%; LC-MS (m / z): 562.23 [M+H] + ;

[0052] Step S4: Synthesis of Compound 9: (S)-tert-butyl-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:

[0053] To a 500mL hydrogenation reactor, 200mL of ethanol and 22.5g (0.04mol) of compound 8 were added in sequence, stirred and dissolved, 5g of 5% palladium carbon was added, the reactor was replaced with hydrogen three times, the hydrogen pressure was increased to 2atm, the temperature was raised to 40°C, and the reaction was stirred for 5h to complete. Microcrystalline cellulose was added and filtered to remove palladium carbon. The filtrate was concentrated under reduced pressure to 100g and cooled to 0°C to crystallize to obtain 17.8g of a white solid with a yield of 94.7%; 1HNMR (CDCl 3,400MHZ), δ:1.46(s,9H);1.63-1.86(m,3H);2.05-2.14(m,1H);2.22-2.34(m,1H).2.45(s,3H);2. 55-2.86(m,5H); 2.89-3.03(m,2H); 3.05-3.31(m,4H); 3.86-4.17(m,6H); 4.38(m,1H); 4.59(m,1H);

[0054] Step S5: Compound 11: Synthesis of (S)-tert-butyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0055] To a 250 mL round-bottom flask were added 75 mL of DMF, 14.1 g (0.03 mol) of compound 9, 8.7 g (0.036 mol) of 1-bromo-8-chloronaphthalene (compound 10), and 14.7 g (0.045 mol) of cesium carbonate. The mixture was stirred and heated to 90 ° C. for 5 h. The mixture was cooled to room temperature and the insoluble cesium carbonate was removed by filtration. 150 mL of water and 150 mL of isopropyl acetate (IPAC) were added to the filtrate and stirred for 5 minutes. The mixture was allowed to stand for stratification. The organic phase was washed twice with 50 mL of water. The organic phase was concentrated to about 50 mL. 100 mL of n-heptane was slowly added dropwise with stirring. A solid precipitated and was filtered and dried at 60 ° C. to obtain 17.3 g of a white solid with a yield of 91.2%; 1HNMR (CDCl3, 400 MHz) ), δ:1.46(s,9H);2.11-2.22(m,1H);2.21-2.38(m,2H).2.50-2.57(m,1H);2 .61-2.78(m,2H); 2.78-3.40(m,10H); 3.50-3.64(m,2H); 3.74-4.09(m,4H); 4 .21-4.45(m,2H);4.54-4.64(m,2H);4.94-5.25(m,1H);7.19-7.24(m,1H);7. 29-7.41(m,2H);7.49-7.53(m,1H);7.58-7.66(m,1H);7.76(d,J=8.0Hz,1H);

[0056] Step S6: Synthesis of Compound 12: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropyrrolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl)carboxylate:

[0057] To a 250 mL round-bottom flask, 150 mL of acetonitrile and 15.8 g (0.025 mol) of compound 11 were added in sequence, and the mixture was stirred and heated to 50 ° C for dissolution. 14.5 g (0.125 mol) of 31% hydrochloric acid solution was slowly added dropwise to the reaction flask and stirred for 3 h. Solids gradually precipitated. The reaction solution was concentrated to 75 mL, cooled to 0 ° C, and stirred for 2 h. The hydrochloride of compound 12 was obtained by filtration and dried at 50 ° C to obtain 13.5 g of a white solid with a yield of 95.2%; 1HNMR (CDCl3, 400 MHZ), δ: 1.65-1.76 (m, 3H); 2.05-2.12 (m, 1H); 2.21-2.38 (m, 1H). 2.48 (d, J =2.8Hz,3H);2.46-2.58(m,3H);2.68(m,1H);2.80-3.01(m,2H);3.01-3. 21(m,5H);3.18-3.39(m,1H);3.48-3.61(m,1H);3.71-3.91(m,2H);3.91 -4.07(m,1H);4.12-4.19(m,1H);4.32-4.50(m,2H);7.19-7.25(m,1H);7 .29-7.40(m,2H); 7.49-7.54(m,1H); 7.62(m,1H); 7.75(d,J=8.0Hz,1H);

[0058] Step S7: Synthesis of Compound 1: 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrrolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile:

[0059] To a 250 mL round-bottom flask, 100 mL of tetrahydrofuran, 11.3 g (0.02 mol) of compound 12, and 5.17 g (0.04 mol) of DIPEA were added in sequence and stirred at room temperature for 30 minutes. 2.2 g (0.024 mol) of acryloyl chloride (compound 13) was slowly added dropwise to the reaction flask and stirred for 3 hours. 100 mL of water and 100 mL of isopropyl acetate (IPAC) were added to the reaction solution. After stirring, the mixture was allowed to stand for phase separation. The organic phase was washed twice with 50 mL of water. The organic phase was concentrated to obtain a yellow solid crude product, which was crystallized from a 5 / 1 mixture of acetonitrile and water to obtain a white solid. The product was dried at 50 ° C to obtain 10.2 g of white Solid, yield 87.2%; δ: 1.68-1.86 (m, 3H); 2.03-2.12 (m, 1H); 2.21-2.28 (m, 1H). 2.48 (d, J = 2.0 Hz, 3H); 2.49-2.74 (m, 3H); 2.77-2.92 (m, 1H); 2.99-3.25 (m, 5H); 3.31-3.50 (m, 1H); 3.55-3.61 (m, 1H); 3.71-3.91 (m, 2H); 3.96-4.29 (m, 3H); 4.32-4.50 (m, 2H); 4.55-5.11

[0060] (m,1H);5.80(m,1H);6.30-6.46(m,1H);6.50-6.73(m,1H);7.19-7.26(m,1H ); 7.27-7.40 (m, 2H); 7.48-7.56 (m, 1H); 7.63 (m, 1H); 7.74 (d, J = 8.0Hz, 1H).

[0061] Optimization of synthesis conditions of compound 6

[0062] The ring-closure reaction for the synthesis of compound 6 can be catalyzed by either acid or base. Therefore, we screened the types and equivalents of acids and bases to identify optimal reaction conditions. While the target product was obtained using either acid or base, the conversion rate was very low with weak acids, and strong acids resulted in significant loss of the Boc protecting group. Lewis acids, however, were effective in catalyzing the reaction. Screening for alkaline catalysts yielded no promising results.

[0063] Table 1 Screening of acidic catalysts for the synthesis of compound 6

[0064]

[0065] Table 2 Screening of basic catalysts for the synthesis of compound 6

[0066]

[0067] According to the above table, boron trifluoride was selected as the catalyst for this reaction after screening, and then the catalyst equivalent number and reaction temperature were further screened.

[0068] Table 3 Screening of catalyst equivalents and reaction temperature for the synthesis of compound 6

[0069]

[0070]

[0071] According to the above table, the boron trifluoride equivalent of 1.2 and the reaction temperature of 100°C were finally selected as the optimal reaction conditions.

[0072] Optimization of synthesis conditions of compound 8

[0073] The synthesis of compound 8 is a Mit-sunobu reaction. The present invention screened the commonly used reagents for this reaction to find the optimal reaction conditions.

[0074] Table 4 Synthesis conditions of compound 8

[0075]

[0076] According to the above table, the present invention finally selected triphenylphosphine and DEAD as the optimal reaction conditions for this step of reaction.

[0077] The present invention also optimizes and screens the reaction solvent for this step of the reaction.

[0078] Table 5 Synthesis conditions of compound 8

[0079]

[0080] According to the above table, THF, ether and dichloromethane can all achieve a conversion rate greater than 98%. However, considering the safety of industrial production and environmental friendliness, the present invention ultimately selected THF as the solvent for this step of the reaction.

[0081] Optimization of synthesis conditions of compound 11

[0082] The synthesis of compound 11 is a SNAr reaction, and the present invention screens the base and solvent in this reaction.

[0083] Table 6 Synthesis conditions of compound 11

[0084]

[0085] According to the above table, from the perspective of the reaction process, DMF as a solvent can increase the solubility of the raw materials and inorganic base in the reaction system, and cesium carbonate as an inorganic base can improve the conversion rate of the reaction.

[0086] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A synthesis process of KRAS inhibitor anti-tumor drug MRTX849, characterized in that: The process includes: Starting from benzyl protected compound 2: First, the piperidine ring is introduced into the main chain structure through an amidation reaction, and compound 6 is obtained after a cyclization reaction: Then, the nitrogen methyl tetrahydropyrrole ring was directly introduced through the Mit sunobu reaction, and then the benzyl protection was removed. The naphthalene ring was introduced through the SNAr reaction, and finally the Boc protecting group was removed. Compound 1 was obtained through acylation reaction: The overall synthetic route is as follows:

2. The synthesis process of the KRAS inhibitor anti-tumor drug MRTX849 according to claim 1, characterized in that: The process specifically includes the following steps: Step S1: Synthesis of Compound 4: (2S)-tert-butyl-4-(1-benzyl-3-oxypiperidinyl-4-carbonyl)-2-(cyanomethyl)piperazine-1-carboxylate: Methyltetrahydrofuran, compound 2: 1-benzyl-3-oxopiperidine-4-carboxylic acid, carbonyldiimidazole CDI, and N,N-diisopropylethylamine DIPEA were added to a three-necked flask and stirred at room temperature for a period of time under nitrogen protection. Compound 3: (S) tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate was then added and the reaction continued for a period of time. Water was added to the reaction solution at room temperature and stirred for a period of time. The layers were separated and the organic phase was washed with saturated sodium chloride solution. The organic phase was concentrated to obtain a brown solid crude product, which was recrystallized from a 1 / 1 ethyl acetate / n-heptane solution to obtain a white solid. Step S2: Synthesis of Compound 6: (S)-tert-butyl-4-(7-benzyl-2-hydroxy-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Compound 4, compound 5: urea, and boron trifluoride etherate were added to a sealed reactor in sequence, and the mixture was heated to 105°C in an external bath and stirred. After the reaction was complete, the mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was washed with saturated sodium chloride solution. The organic phase was concentrated and cooled to 0-5°C to precipitate a large amount of yellow solid. The mixture was stirred for a period of time, filtered, washed with ethyl acetate, and dried to obtain compound 6. Step S3: Synthesis of Compound 8: (S)-tert-butyl-4-(7-benzyl-2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Compound 6, triphenylphosphine, tetrahydrofuran (THF), and compound 7: (S)-(1-methylpyrrolidin-2-yl)methanol were added to a round-bottom flask, and the temperature was lowered to 0°C. Diethyl azodicarboxylate (DEAD) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred to complete the reaction. Water and ethyl acetate were added, and the reaction was stirred for a period of time. The organic layer was separated and washed with a saturated sodium chloride solution. Zinc chloride was added, and the mixture was stirred for a period of time. The organic layer was filtered to remove the generated triphenylphosphine. The filtrate was dried over anhydrous Na2SO4 and concentrated to obtain a crude white solid. The crude product was recrystallized from ethanol and dried to obtain a white solid. Step S4: Synthesis of Compound 9: (S)-tert-butyl-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate: Ethanol and compound 8 were added to the hydrogenation reaction kettle in sequence, stirred and dissolved, palladium carbon was added, and the reaction kettle was replaced with hydrogen several times. The hydrogen was pressurized, the temperature was increased, and the reaction was stirred until the reaction was complete. Microcrystalline cellulose was added and filtered to remove the palladium carbon. The filtrate was concentrated under reduced pressure and cooled to 0°C to crystallize to obtain a white solid; Step S5: Compound 11: Synthesis of (S)-tert-butyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropiperido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate: To a round-bottom flask, add N,N-dimethylformamide (DMF), compound 9, compound 10: 1-bromo-8-chloronaphthalene, and cesium carbonate in sequence, stir and heat, react for a period of time, cool to room temperature, filter to remove insoluble cesium carbonate, then add water and isopropyl acetate (IPAC) to the filtrate and stir for a period of time, then let stand to separate the layers. The organic phase is then washed with water several times, concentrated, and n-heptane is slowly added dropwise with stirring. Solid precipitates, which is filtered and dried to obtain a white solid. Step S6: Synthesis of Compound 12: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrol-2-yl)methoxy)-5,6,7,8-tetrahydropyrrolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl)carboxylate: Acetonitrile and compound 11 were added to a round-bottom flask in sequence, stirred and heated to dissolve. Hydrochloric acid solution was slowly added dropwise to the reaction flask and stirred for a period of time. Solids gradually precipitated. The reaction solution was concentrated, cooled to 0°C, and stirred for a period of time. The hydrochloride of compound 12 was obtained by filtration and dried to obtain a white solid. Step S7: Synthesis of Compound 1: 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrrolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile: Tetrahydrofuran (THF), compound 12, and N,N-diisopropylethylamine (DIPEA) were added to a round-bottom flask in sequence and stirred at room temperature for a period of time. Compound 13: acryloyl chloride was slowly added dropwise to the reaction flask and stirred for a period of time. Water and isopropyl acetate (IPAC) were added to the reaction solution, and the mixture was allowed to stand for phase separation after stirring. The organic phase was washed with water several times and concentrated to obtain a crude yellow solid. The product was crystallized from a 5 / 1 acetonitrile / water mixture to obtain a white solid, which was then dried to obtain a white solid.

3. The synthesis process of the KRAS inhibitor anti-tumor drug MRTX849 according to claim 2, characterized in that: In step S2, Lewis acid is used for acid catalysis during the ring-closure reaction to synthesize compound 6.

4. The synthesis process of the KRAS inhibitor anti-tumor drug MRTX849 according to claim 3, characterized in that: In step S2, the acid catalyst is boron trifluoride, the equivalent weight is 1.2, and the reaction temperature is 100°C.

5. The synthesis process of the KRAS inhibitor anti-tumor drug MRTX849 according to claim 2, characterized in that: In step S3, the synthesis of compound 8 is carried out by Mitsunobu reaction, preferably triphenylphosphine and diethyl azodicarboxylate DEAD are used as the reaction conditions for this step, and preferably tetrahydrofuran THF is used as the solvent for this step.

6. The synthesis process of the KRAS inhibitor anti-tumor drug MRTX849 according to claim 2, characterized in that: In step S5, the synthesis of compound 11 is an aromatic nucleophilic substitution reaction SNAr, using N,N-dimethylformamide DMF as a solvent to increase the solubility of the raw materials and inorganic base in the reaction system, and using cesium carbonate as an inorganic base to improve the conversion rate of the reaction.

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