Preparation method of pyridopyrimidinone compound
The preparation process of pyridopyrimidinone compounds is simplified through the ring-forming reaction promoted by palladium catalyst and ligand, and the problems of long synthetic routes and expensive reagents in the prior art are solved, and efficient and safe preparation of compounds is achieved, which is suitable for industrial production. .
Patent Information
- Application Number
- CN202310795111.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-06-30
- Publication Date
- 2024-12-31
AI Technical Summary
The existing preparation methods for pyridinopyrimidinone compounds have problems such as long synthetic routes, expensive reagents, complex operations, serious pollution and low product purity, making them difficult to be suitable for industrial production.
Using palladium catalysts and ligands (such as Pd(OAc)2 and Xantphos or Pd(OAc)2 and BINAP) to ring-in reaction with Compound 1 in solvent, using cyanate and base, control the reaction conditions for efficient preparation Compound 2.
It simplifies the preparation process, improves the reaction yield, reduces costs, improves the purity and safety of the product, and is suitable for industrial production.
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Figure CN119219623A_ABST
Abstract
Description
Technical Field
[0001] The invention provides a method for preparing a pyridopyrimidone compound. Background Art
[0002] The target compound 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione is an important intermediate for the synthesis of KRas G12C inhibitors and KRas G12D inhibitors and has broad application prospects.
[0003] Patents WO2020146613 A1, WO222194191A1, WO222015375A1, and WO2022031678A1 report methods for preparing target compounds. Compound 1 reacts with CO in an organic solvent under the action of a catalyst to obtain compound 3. Compound 3 reacts with trichloroacetyl isocyanate to obtain compound 4. Compound 5 reacts with NH3 / MeOH to obtain the target compound. The target compound is obtained through three-step reactions. The specific synthesis route is as follows:
[0004]
[0005] Currently, the synthesis of the target compound requires three steps of reaction, and the final product is a crude product. This synthesis route has many defects, such as a long synthesis route, expensive reagents and catalysts, complicated operation, large amount of three wastes, serious pollution, low product purity, and is not suitable for industrial production. Summary of the invention
[0006] The technical problem to be solved by the present invention is that the existing preparation method has the defects of long synthesis route and expensive reagents, and provides a preparation method of pyridopyrimidone compound. The preparation method is simple, has high yield, mild reaction conditions, good safety, avoids the use of expensive reagents, reduces the overall material and research and development costs, and is suitable for industrial production.
[0007] The present invention provides a preparation method of a compound 2, which comprises the following steps: in a solvent, under the action of a palladium catalyst and a ligand, compound 1, CO and cyanate undergo a cyclization reaction as shown below to form compound 2; the cyanate is sodium cyanate or potassium cyanate; the palladium catalyst and the ligand are any of the following combinations: a combination of Pd(OAc)2 and Xantphos, a combination of Pd(OAc)2 and BINAP, and a combination of Pd(cod)Cl2 and BINAP; X1 in the compound 1 is I, Br or OTf; X2 in the compound 1 and the compound 2 is C or N, R1 is H, F or CF3, and R2 is Cl or Br;
[0008]
[0009] In some embodiments, X1 is I, Br or OTf, X2 is N, R1 is H, and R2 is Cl.
[0010] In some embodiments, the compound 1 is
[0011] In some embodiments, the cyanate salt is potassium cyanate.
[0012] In some embodiments, the palladium catalyst and ligand are a combination of Pd(OAc)2 and Xantphos.
[0013] In some embodiments, the solvent is an ether solvent (e.g., 1,4-dioxane) and / or an amide solvent (e.g., N,N-dimethylformamide), preferably an ether solvent. The volume mass ratio of the solvent to the compound 1 is preferably 3-10 ml / g, for example, 5 ml / g.
[0014] In some embodiments, the cyclization reaction is carried out in the presence of a base, and the base is an organic base or an inorganic base;
[0015] The organic base is preferably selected from one or more of triethylamine, diisopropylethylamine, trimethylamine, tri-n-butylamine, N,N-dimethyllaurylamine, diisopropylamine, N,N-dimethylaniline, dimethylbenzylamine, triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2,2,2]octane, 4-dimethylaminopyridine (DMAP), pyridine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-trimethylpyridine, imidazole, pyrimidine, pyridazine, N-methylmorpholine, tetramethylethylenediamine and tetramethylguanidine (TMG), such as triethylamine;
[0016] The inorganic base is preferably selected from one or more of carbonates (such as sodium carbonate, potassium carbonate or cesium carbonate), bicarbonates (such as sodium bicarbonate or potassium bicarbonate) and hydroxides (such as sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide), preferably carbonates, more preferably sodium carbonate.
[0017] The molar ratio of the base to the compound 1 is preferably (1:1)-(10:1), for example 2.5:1.
[0018] In some embodiments, the molar ratio of the cyanate to the compound 1 is (1:1)-(5:1), for example, 1.5:1.
[0019] In some embodiments, the molar ratio of the palladium catalyst to the compound 1 is (0.0025:1)-(0.5:1), for example 0.05:1.
[0020] In some embodiments, the molar ratio of the ligand to the compound 1 is (0.0025:1)-(0.5:1), for example 0.05:1.
[0021] In some embodiments, the system of the cyclization reaction is first replaced with an inert gas (such as argon) and then replaced with CO; preferably, the system of the cyclization reaction is first replaced with an inert gas three times and then replaced twice with CO. After the CO replacement, the pressure of the system of the cyclization reaction is preferably (0.2-10) MPa, for example 1.0 MPa.
[0022] In some embodiments, the reaction temperature of the cyclization reaction is 10-120°C, such as 70°C.
[0023] In some embodiments, the reaction time of the cyclization reaction is 1-24 hours, such as 6 hours.
[0024] In some embodiments, the cyclization reaction includes the following post-treatment steps: acidification (e.g., acidification with 10% hydrochloric acid to pH 7.5), heating (e.g., heating to 50°C), cooling (e.g., cooling to 20°C), filtration, washing (e.g., rinsing with water) and drying.
[0025] The present invention also provides a method for preparing MRTX1133, and the structural formula of MRTX1133 is as follows:
[0026]
[0027] It includes the following steps:
[0028] (1) Prepared by the preparation method of the above compound 2
[0029] (2) MRTX1133 was further prepared.
[0030] In some embodiments, in the above step (2), MRTX1133 is prepared by the method reported in reference J.Med.Chem.2022,65,4,3123-3133; for example, MRTX1133 is prepared by the method shown below:
[0031]
[0032] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.
[0033] The reagents and raw materials used in the present invention are commercially available.
[0034] The positive progressive effects of the present invention are: the preparation method of the present invention is simple, the reaction yield is high, the reaction conditions are mild, the safety is good, the use of expensive reagents is avoided, the overall material and research and development costs are reduced, and it is suitable for industrial production. DETAILED DESCRIPTION
[0035] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.
[0036]
[0037] Example 1
[0038] Compound 1 (50.0 g, 183.5 mmol, 1.0 eq), KOCN (22.3 g, 274.9 mmol, 1.5 eq), Pd(OAc)2 (1.5 g, 9.2 mmol, 0.05 eq), and Xantphos (5.3 g, 9.2 mmol, 0.05 eq) were dissolved in 1,4-dioxane (250 ml, 5 V); the gas was replaced with argon 3 times and CO 2 times, the pressure was maintained at 1.0 MPa, and the mixture was heated to 70°C for 6 h. Water was added, and 10% HCl was added dropwise to adjust the pH to 7.5; the mixture was heated to 50°C and then cooled to 20°C, filtered, the filter cake was rinsed with water, and then dried to obtain 22.6 g of the product with a yield of 57%. MS (ESI): m / z calcd for C7H4ClFN3O2 + ,[M+H] + :216.0,found:216.0. 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),11.75(s,1H),8.60(s,1H). 1 H NMR (400MHz, MeOD) δ8.68 (s, 1H). 19 F NMR(376MHz,DMSO-d6)δ-137.04. 13C NMR (100 MHz, DMSO-d6) δ160.9, 149.8, 144.1 (d, J = 6.4 Hz), 141.6 (d, J = 258 Hz), 140.45 (d, J = 15.3 Hz), 137.35 (d, J = 12.5 Hz), 113.3. HPLC purity is 98.2%, (HPLC test conditions: chromatographic column: Agilent_ZORBAX Eclipse Plus C18_100x4.6mm_3.5μm, flow rate: 1.5ml / min, time: 0-13min, gradient elution, mobile phase is H2O:CH3CN (v / v) = 95:5-10:90; UV detection wavelength: 220nm).
[0039] Example 2
[0040] Compound 1 (50.0 g, 183.5 mmol, 1.0 eq), KOCN (22.3 g, 274.9 mmol, 1.5 eq); Pd(cod)Cl2 (2.6 g, 9.2 mmol, 0.05 eq), BINAP (5.7 g, 9.2 mmol, 0.05 eq) were dissolved in 1,4-dioxane (250 ml, 5 V); argon was replaced 3 times, CO was replaced 2 times, the pressure was maintained at 1.0 MPa, and the reaction was heated to 70°C for 6 hours. Water was added, and 10% HCl was added dropwise to adjust the pH to 7.5; after heating to 50 degrees, the temperature was lowered to 20 degrees, and the filter cake was filtered with suction, and then dried to obtain 18.9 g of the product, with a yield of 48% and a HPLC purity of 98.3%.
[0041] Example 3
[0042] Compound 1 (50.0 g, 183.5 mmol, 1.0 eq), KOCN (22.3 g, 274.9 mmol, 1.5 eq); Pd(OAc)2 (1.5 g, 9.2 mmol, 0.05 eq), BINAP (5.7 g, 9.2 mmol, 0.05 eq) were dissolved in 1,4-dioxane (250 ml, 5 V); the gas was replaced by argon 3 times, replaced by CO 2 times, the pressure was maintained at 1.0 MPa, and the reaction was heated to 70°C for 6 h. Water was added, and 10% HCl was added dropwise to adjust the pH to 7.5; the mixture was heated to 50°C and then cooled to 20°C, filtered, the filter cake was rinsed with water, and then dried to obtain 20.5 g of the product, with a yield of 52% and a HPLC purity of 98.2%.
[0043] Example 4
[0044] Compound 1 (50.0 g, 183.5 mmol, 1.0 eq), KOCN (22.3 g, 274.9 mmol, 1.5 eq); Pd(OAc)2 (1.5 g, 9.2 mmol, 0.05 eq), Xantphos (5.3 g, 9.2 mmol, 0.05 eq) and sodium carbonate (46.4 g, 458.8 mmol, 2.5 eq) were dissolved in 1,4-dioxane (250 ml, 5 V); the gas was replaced by argon 3 times and CO 2 times, the pressure was maintained at 1.0 MPa, and the reaction was heated to 70°C for 6 h. Water was added, and 10% HCl was added dropwise to adjust the pH to 7.5; the mixture was heated to 50°C and then cooled to 20°C, filtered, the filter cake was rinsed with water, and then dried to obtain 25.6 g of the product, with a yield of 65% and a HPLC purity of 98.5%.
[0045] Example 5
[0046] Compound 1 (50.0 g, 183.5 mmol, 1.0 eq), KOCN (22.3 g, 274.9 mmol, 1.5 eq); Pd(OAc)2 (1.5 g, 9.2 mmol, 0.05 eq), Xantphos (5.3 g, 9.2 mmol, 0.05 eq) and triethylamine (46.4 g, 458.8 mmol, 2.5 eq) were dissolved in 1,4-dioxane (250 ml, 5 V); the gas was replaced by argon 3 times and CO 2 times, the pressure was maintained at 1.0 MPa, and the reaction was heated to 70°C for 6 h. Water was added, and 10% HCl was added dropwise to adjust the pH to 7.5; the mixture was heated to 50°C and then cooled to 20°C, filtered, the filter cake was rinsed with water, and then dried to obtain 29.9 g of the product, with a yield of 76% and a HPLC purity of 98.8%.
[0047] MRTX1133 was prepared by the method reported in J.Med.Chem.2022,65,4,3123-3133
[0048] Comparative Example 1
[0049] Compound 1 (50.0 g, 183.5 mmol, 1.0 eq), KOCN (22.3 g, 274.9 mmol, 1.5 eq); Pd(cod)Cl2 (2.6 g, 9.2 mmol, 0.05 eq), Xantphos (5.3 g, 9.2 mmol, 0.05 eq) were dissolved in 1,4-dioxane (250 ml, 5 V); argon was replaced 3 times, CO was replaced 2 times, the pressure was maintained at 1.0 MPa, and the reaction was heated to 70°C for 6 h. Water was added, and 10% HCl was added dropwise to adjust the pH to 7.5; after heating to 50 degrees, the temperature was lowered to 20 degrees, and the filter cake was filtered with suction, and then dried to obtain 12.6 g of the product, with a yield of 32% and a HPLC purity of 97.9%.
[0050] Comparative Example 2
[0051] Compound 1 (50.0 g, 183.5 mmol, 1.0 eq), KOCN (22.3 g, 274.9 mmol, 1.5 eq); Pd(cod)Cl2 (2.6 g, 9.2 mmol, 0.05 eq), dppp (3.8 g, 9.2 mmol, 0.05 eq) were dissolved in 1,4-dioxane (250 ml, 5 V); argon was replaced 3 times, CO was replaced 2 times, the pressure was maintained at 1.0 MPa, and the reaction was heated to 70°C for 6 hours. Water was added, and 10% HCl was added dropwise to adjust the pH to 7.5; after heating to 50 degrees, the temperature was lowered to 20 degrees, and the filter cake was filtered with suction, and then dried to obtain 11.2 g of the product, with a yield of 28% and a HPLC purity of 97.6%.
[0052] Comparative Example 3
[0053] Compound 1 (50.0 g, 183.5 mmol, 1.0 eq), KOCN (22.3 g, 274.9 mmol, 1.5 eq); Pd(cod)Cl2 (2.6 g, 9.2 mmol, 0.05 eq), dppb (3.9 g, 9.2 mmol, 0.05 eq) were dissolved in 1,4-dioxane (250 ml, 5 V); argon was replaced 3 times, CO was replaced 2 times, the pressure was maintained at 1.0 MPa, and the reaction was heated to 70°C for 6 hours. Water was added, and 10% HCl was added dropwise to adjust the pH to 7.5; after heating to 50 degrees, the temperature was lowered to 20 degrees, and the filter cake was filtered with suction, and then dried to obtain 15.7 g of the product, with a yield of 40% and a HPLC purity of 98.2%.
[0054] Comparative Example 4
[0055] Compound 1 (50.0 g, 183.5 mmol, 1.0 eq), KOCN (22.3 g, 274.9 mmol, 1.5 eq); Pd(cod)Cl2 (2.6 g, 9.2 mmol, 0.05 eq), tBu3P (1.86 g, 9.2 mmol, 0.05 eq) were dissolved in 1,4-dioxane (250 ml, 5 V); argon was replaced 3 times, CO was replaced 2 times, the pressure was maintained at 1.0 MPa, and the reaction was heated to 70°C for 6 hours. Water was added, and 10% HCl was added dropwise to adjust the pH to 7.5; after heating to 50 degrees, the temperature was lowered to 20 degrees, and the filter cake was filtered with suction, and then dried to obtain 11.2 g of the product, with a yield of 19% and a HPLC purity of 97.5%.
Claims
1. A method for preparing compound 2, comprising the following steps: in a solvent, under the action of a palladium catalyst and a ligand, compound 1 undergoes a cyclization reaction as shown below with CO and cyanate to form compound 2; the cyanate is sodium cyanate or potassium cyanate; the palladium catalyst and the ligand are any of the following combinations: a combination of Pd(OAc)2 and Xantphos, a combination of Pd(OAc)2 and BINAP, a combination of Pd(cod)Cl2 and BINAP; X1 in compound 1 is I, Br or OTf; X2 in compound 1 and compound 2 is C or N, R1 is H, F or CF3, and R2 is Cl or Br; 2. The preparation method according to claim 1, characterized in that It meets one or more of the following conditions: (1) X1 is I, Br or OTf, X2 is N, R1 is H, and R2 is Cl; (2) The cyanate is potassium cyanate; and (3) the palladium catalyst and the ligand are a combination of Pd(OAc)2 and Xantphos.
3. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The compound 1 is (2) The solvent is an ether solvent and / or an amide solvent; preferably an ether solvent; and (3) the cyclization reaction is carried out in the presence of a base; the base is an inorganic base or an organic base.
4. The preparation method according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The ether solvent is 1,4-dioxane; (2) The amide solvent is N,N-dimethylformamide; (3) the organic base is selected from one or more of triethylamine, diisopropylethylamine, trimethylamine, tri-n-butylamine, N,N-dimethyllaurylamine, diisopropylamine, N,N-dimethylaniline, dimethylbenzylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, 4-dimethylaminopyridine, pyridine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-trimethylpyridine, imidazole, pyrimidine, pyridazine, N-methylmorpholine, tetramethylethylenediamine and tetramethylguanidine; and (4) the inorganic base is selected from one or more of carbonates, bicarbonates and hydroxides; preferably carbonates.
5. The preparation method according to claim 4, characterized in that: It meets one or more of the following conditions: (1) The organic base is triethylamine; (2) The carbonate is sodium carbonate, potassium carbonate or cesium carbonate; preferably sodium carbonate; (3) The bicarbonate is sodium bicarbonate or potassium bicarbonate; and (4) the hydroxide is sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide.
6. The preparation method according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The volume mass ratio of the solvent to the compound 1 is 3-10 ml / g; preferably 5 ml / g; (2) The molar ratio of the base to the compound 1 is (1:1)-(10:1); preferably 2.5:1; (3) The molar ratio of the cyanate to the compound 1 is (1:1)-(5:1); preferably 1.5:1; (4) The molar ratio of the palladium catalyst to the compound 1 is (0.0025:1)-(0.5:1); preferably 0.05:1; and (5) the molar ratio of the ligand to the compound 1 is (0.0025:1)-(0.5:1); preferably 0.05:
1.
7. The preparation method according to claim 1, characterized in that: The system of the cyclization reaction is first replaced with an inert gas and then replaced with CO; preferably, the system of the cyclization reaction is first replaced with an inert gas three times and then replaced with CO twice.
8. The preparation method according to claim 7, characterized in that: It meets one or more of the following conditions: (1) After the CO substitution, the pressure of the system for the cyclization reaction is (0.2-10) MPa; preferably 1.0 MPa; (2) The reaction temperature of the cyclization reaction is 10-120°C, preferably 70°C; (3) The reaction time of the cyclization reaction is 1-24 hours, preferably 6 hours; and (4) the inert gas is argon.
9. A method for preparing MRTX1133, wherein the structural formula of MRTX1133 is as follows: It includes the following steps: (1) prepared by the preparation method according to any one of claims 1 to 8 (2) MRTX1133 was further prepared.
10. The preparation method according to claim 9, characterized in that: In step (2), MRTX1133 was prepared by the following method: