Preparation method of N-demethylated ribociclib
Through carboxyamine condensation, coupling and deBoc reaction, the problem of insufficient synthesis route of N-demethylbenini succinic acid in rebaccinic acid is solved, and high-efficiency and low-cost N-demethylbenini is achieved. Bosini is prepared, which improves the purity of the product and provides an important basis for the Ribosini succinic acid impurity reference product.
Patent Information
- Application Number
- CN202411254289.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-09
- Publication Date
- 2024-12-13
AI Technical Summary
Among the existing synthesis routes of ribosinib succinate, the synthesis route of N-demethylribosinib caused by the use of a small amount of methylamine in the raw material dimethylamine is relatively small, which is a technical problem that needs to be solved urgently.
Through three-step reactions of carboxyamine condensation, coupling and deBoc, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid and methylamine hydrochloride, metal Reagents and acid conditions to synthesize N-demethylribosinib.
It has achieved cheap and easy-to-get raw materials, simple steps, high yield, low overall cost, and improved product purity. It can be used as a reference for rebosini succinate impurity, which is of great significance to the research of product impurities.
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Figure CN119119054A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of N-desmethylribociclib. Background Art
[0002] Ribociclib succinate was developed by Novartis Pharmaceuticals Ltd. It is a cyclin-dependent kinases 4 / 6 (CDK4 / 6) inhibitor that has demonstrated significant efficacy in tumor treatment. In the clinical treatment of breast cancer, the combination of ribociclib succinate and endocrine therapy drugs significantly prolonged the progression-free survival of patients and improved their quality of life. It effectively blocks the proliferation signaling pathway of tumor cells, thereby inhibiting the growth and spread of tumors. It also performs well in terms of safety and tolerability.
[0003] The chemical name of Ribociclib succinate is 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate. Its structure is as follows:
[0004]
[0005] 7-Cyclopentyl-N-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide is a key impurity in ribociclib, commonly known as N-desmethylribociclib, and its structure is as follows:
[0006]
[0007] Since a small amount of methylamine is used in the raw material dimethylamine, this impurity is introduced into the final product. The synthesis route of this impurity is currently rarely disclosed, which is a technical problem that needs to be solved urgently. Summary of the invention
[0008] In view of the deficiencies in the prior art, the present invention provides a method for preparing N-desmethylribociclib, and the synthetic route is as follows:
[0009]
[0010] The following steps are involved:
[0011] Step 1: Compound (1) 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid is added to an organic solvent A, and a condensing agent B is added, and the mixture is stirred to generate an intermediate state, and methylamine hydrochloride and triethylamine are added to generate an acid-amine condensation reaction to generate compound (2) 2-chloro-7-cyclopentyl-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;
[0012] Step 2: under nitrogen protection, metal reagent solution D is added dropwise to a tetrahydrofuran solution of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. After the addition is completed and the temperature is kept for reaction, compound (2) 2-chloro-7-cyclopentyl-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide is added, and the temperature is raised to react to generate compound (3) (tert-butyl 6-((7-cyclopentyl-6-(N-methylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate;
[0013] Step 3: Compound (3) (tert-butyl 6-((7-cyclopentyl-6-(N-methylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate is deBocated in solvent G under acid E conditions. After concentrating and recovering the solvent, the pH value is adjusted and filtered to obtain compound (4), namely N-desmethylribociclib.
[0014] Furthermore, in step 1, the organic solvent A is N,N-dimethylacetamide (DMAc) or N,N-dimethylformamide (DMF).
[0015] Furthermore, in step 1, the condensing agent B can be selected from N,N'-carbonyldiimidazole (CDI) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).
[0016] Furthermore, in step 1, the volume ratio of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid to the organic solvent A is 1:2 to 1:10.
[0017] Furthermore, in step 1, the molar ratio of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid to the condensing agent B is 1:1.1 to 1:2, preferably 1:1.2 to 1:1.5.
[0018] Furthermore, in step 1, the molar ratio of compound (1) to methylamine hydrochloride is 1:1.5 to 1:2.
[0019] Furthermore, in step 1, the reaction temperature is -10 to 20°C, preferably 0 to 10°C.
[0020] Further, in step 2, solvent C is tetrahydrofuran or methyltetrahydrofuran.
[0021] Further, in step 2, the metal reagent D is any one of isopropylmagnesium chloride tetrahydrofuran solution, cyclohexylmagnesium chloride tetrahydrofuran solution, and bistrimethylsilylamide lithium n-hexane solution.
[0022] Furthermore, in step 2, the molar ratio of compound (2) to metal reagent D is 1:2 to 1:6.
[0023] Furthermore, in step 2, the molar ratio of compound (2) to tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate is 1:1 to 1:1.2.
[0024] Furthermore, in step 2, the reaction temperature is raised to 20-60°C.
[0025] Further, in step 3, the acid E is hydrochloric acid or trifluoroacetic acid.
[0026] Furthermore, in step 3, the organic solvent F is any one of tetrahydrofuran, methanol, and dioxane.
[0027] Furthermore, in step 3, the molar ratio of compound (3) to acid E is 1:2 to 1:3.
[0028] Furthermore, in step 3, the reaction temperature is 20-60°C.
[0029] The invention uses 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid as a raw material and undergoes three-step reactions of carboxyamine condensation, coupling, and Boc removal to synthesize (6-((7-cyclopentyl-6-(N-methylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester. Compared with the prior art, the invention has the following beneficial effects:
[0030] 1. The raw materials of the present invention are cheap and easily available, the steps are simple, the yield is high, and the overall cost is low.
[0031] 2. The product of the present invention has high purity and can be used as an impurity reference substance for ribociclib succinate, which is of great significance for the impurity research of the product. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Figure 1 The compound (2) prepared in Example 1 1 HMNR spectrum;
[0033] Figure 2 The compound (4) prepared in Example 1 1 HMNR spectrum. DETAILED DESCRIPTION
[0034] The exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although exemplary embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided in order to enable a more thorough understanding of the present invention and to be able to fully convey the scope of the present invention to those skilled in the art. It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with the embodiments.
[0035] Example 1
[0036] Step 1: Preparation of compound (2)
[0037] Dissolve 50g of compound (1) in 250ml of DMF, cool to -10℃, add 43g of CDI under nitrogen protection, react for 2 hours, and judge from TLC plate that compound (2) disappears, add 19.1g of methylamine hydrochloride, add 28g of triethylamine dropwise at controlled temperature, keep warm for 2 hours, judge from TLC plate that intermediate state reaction is complete, add water to quench, extract with methyl tert-butyl ether, dry and concentrate to obtain solid, yield 87%.
[0038] The prepared compound (2) 1 The HMNR spectrum is shown in Figure 1 As shown, 1 HNMR (400MHz, DMSO-d6, δppm): 1.65 (m, 2H), 2.01 (m, 4H), 2.28 (m, 2H), 2.80 (d, 3H), 5.48 (m, 1H), 7.05 (s, 1H), 8.79 (s, 1H), 9.05 (s, 1H).
[0039] Step 2: Preparation of compound (3)
[0040] 28 g of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate was added to 150 mL of tetrahydrofuran, and the atmosphere was replaced with nitrogen. The temperature was controlled at 5-15°C, and 100 mL of 2M isopropylmagnesium chloride tetrahydrofuran solution was added dropwise. The mixture was kept warm for 1 hour. 28 g of compound (2) was added, and the temperature was raised to 60°C. The mixture was kept warm for 2 hours. Acetic acid was added to the reaction mixture to quench the reaction. The mixture was cooled to room temperature, filtered, rinsed with a small amount of acetone, and dried to constant weight.
[0041] Step 3: Preparation of compound (4)
[0042] 10g of compound (3) was added to 50ml of tetrahydrofuran, and 3.2ml of concentrated hydrochloric acid was added. The reaction was stirred at 20℃. The reaction was judged to be complete by thin layer plate. Part of the solvent was concentrated, and the pH was adjusted to 8-9 with 10% sodium hydroxide aqueous solution. The mixture was filtered and dried to constant weight. 10g of the crude product was added to 80g of methanol and heated under reflux for 2 hours. The mixture was cooled to room temperature and filtered. A small amount of methanol was used for elution and the mixture was dried to constant weight. The total yield of the two steps was 85%.
[0043] The prepared compound (4) 1 The HMNR spectrum is shown in Figure 2 As shown, 1 HNMR (400MHz, DMSO-d6, δppm): 1.64 (m, 2H), 1.99 (m, 4H), 2.50 (m, 2H), 2.78 (d, 3H), 3.22 (d, 4H), 3.35 (d, 4H), 5.55 (m, 1H), 6.92 (s, 1H), 7.51 (m, 1H), 8.07 (d, 1H), 8.20 (d, 1H), 8.58 (d, 1H), 8.84 (s, 1H), 9.05 (br, 1H), 9.52 (s, 1H).
[0044] Example 2
[0045] Step 1: Preparation of compound (2)
[0046] Dissolve 50g of compound (1) in 250ml of DMAc, cool to 10°C, add 60g of CDI under nitrogen protection, react for 2 hours, and judge that compound (2) disappears on thin layer plate. Add 20g of methylamine hydrochloride, and add 30g of triethylamine dropwise at controlled temperature. Keep warm for 2 hours. Judge that intermediate state reaction is complete on thin layer plate. Add water to quench, extract with methyl tert-butyl ether, dry and concentrate to obtain solid. Yield: 92%.
[0047] Step 2: Preparation of compound (3)
[0048] 36 g of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate was added to 300 mL of methyltetrahydrofuran, and the temperature was controlled at 5-15°C. 300 mL of 1 M cyclohexylmagnesium chloride tetrahydrofuran solution was added dropwise. The mixture was kept warm for 1-2 hours. 30 g of compound (2) was added, and the temperature was raised to 40°C. The mixture was kept warm for 2 hours. Acetic acid was added to the reaction mixture to quench the reaction. The mixture was cooled to room temperature, filtered, rinsed with a small amount of acetone, and dried to constant weight.
[0049] Step 3: Preparation of compound (4)
[0050] 5 g of compound (3) was added to 30 g of methanol, and 2.7 g of trifluoroacetic acid was added. The mixture was stirred at 40°C for reaction. The reaction was completed as judged by thin layer plate. The pH was adjusted to 8-9 with 10% aqueous sodium hydroxide solution, filtered, and dried to constant weight. 5 g of crude product was added to 30 g of methanol and heated under reflux for 2 hours, cooled to 5-10°C, filtered, and dried to constant weight. The total yield of the two steps was 83%.
[0051] Example 3
[0052] Step 1: Preparation of compound (2)
[0053] Dissolve 50 g of compound (1) in 250 ml of DMF, cool to 20°C, add 54 g of EDCI under nitrogen protection, react for 2 hours, and judge from the thin layer plate that compound (2) disappears. Add 25.4 g of methylamine hydrochloride, and add 28 g of triethylamine dropwise at the same temperature. Keep warm for 2 hours. Judge from the thin layer plate that the intermediate state reaction is complete, add water to quench, extract with methyl tert-butyl ether, and dry and concentrate to obtain a solid with a yield of 87%.
[0054] Step 2: Preparation of compound (3)
[0055] 15 g of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate was added to 150 mL of tetrahydrofuran, and the atmosphere was replaced with nitrogen. The temperature was controlled at 5-15°C, and 280 mL of 1 M lithium bistrimethylsilylamide n-hexane solution was added dropwise. The mixture was kept warm for 1 hour. 13 g of compound (2) was added, and the temperature was raised to 20°C. The mixture was kept warm for 2 hours. Acetic acid was added to the reaction mixture to quench the reaction. The mixture was cooled to room temperature, filtered, rinsed with a small amount of acetone, and dried to constant weight.
[0056] Step 3: Preparation of compound (4)
[0057] 10g of compound (3) was added to 50g of dioxane, and 4.8ml of concentrated hydrochloric acid was added. The mixture was stirred at 60℃ for reaction. The reaction was judged to be complete by thin layer plate. The pH was adjusted to 8-9 with 10% aqueous sodium hydroxide solution, and the mixture was filtered and dried to constant weight. 10g of the crude product was added to 80g of methanol and heated under reflux for 1 hour, cooled to room temperature, filtered, and dried to constant weight. The total yield of the two steps was 82%.
[0058] The present invention has been described in detail above through embodiments, but the contents described are only exemplary embodiments of the present invention and cannot be considered to limit the scope of implementation of the present invention. The protection scope of the present invention is defined by the claims. Anyone who utilizes the technical solution described in the present invention, or a technician in the field, inspired by the technical solution of the present invention, designs a similar technical solution within the essence and protection scope of the present invention to achieve the above technical effects, or makes equal changes and improvements to the scope of application, etc., shall still fall within the scope of protection covered by the patent of the present invention.
Claims
1. A method for preparing N-desmethylribociclib, characterized in that: The synthetic route is as follows: The following steps are involved: Step 1: Compound (1) is added with organic solvent A and condensing agent B, and stirred to generate an intermediate state, and methylamine hydrochloride and triethylamine are added to generate compound (2) by acid-amine condensation reaction; Step 2: under nitrogen protection, add metal reagent solution D dropwise to a tetrahydrofuran solution of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. After the addition is complete and the mixture is heated to react, compound (2) is added and the mixture is heated to react to generate compound (3). Step 3: Compound (3) is subjected to Boc removal in solvent G under acid E conditions, and after concentration and recovery of the solvent, the pH value is adjusted and filtered to obtain compound (4).
2. The method for preparing N-desmethylribociclib according to claim 1, characterized in that: In step 1, the organic solvent A is N,N-dimethylacetamide or N,N-dimethylformamide; the condensation agent B is N,N'-carbonyldiimidazole or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
3. The method for preparing N-desmethylribociclib according to claim 1, characterized in that: In step 1, the volume ratio of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid to organic solvent A is 1:2 to 1:10; the molar ratio of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid to condensation agent B is 1:1.1 to 1:2; and the molar ratio of compound (1) to methylamine hydrochloride is 1:1.5 to 1:
2.
4. The method for preparing N-desmethylribociclib according to claim 1, characterized in that: In step 1, the reaction temperature is -10 to 20°C.
5. The method for preparing N-desmethylribociclib according to claim 1, characterized in that: In step 2, the solvent C is tetrahydrofuran or methyltetrahydrofuran; the metal reagent D is any one of isopropylmagnesium chloride tetrahydrofuran solution, cyclohexylmagnesium chloride tetrahydrofuran solution, and bistrimethylsilylamide lithium n-hexane solution.
6. The method for preparing N-desmethylribociclib according to claim 1, characterized in that: In step 2, the reaction temperature is raised to 20-60°C.
7. The method for preparing N-desmethylribociclib according to claim 1, characterized in that: In step 2, the molar ratio of compound (2) to metal reagent D is 1:2 to 1:6; the molar ratio of compound (2) to tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate is 1:1 to 1:1.
2.
8. The method for preparing N-desmethylribociclib according to claim 1, characterized in that: In step 3, the acid E is hydrochloric acid or trifluoroacetic acid; the organic solvent F is any one of tetrahydrofuran, methanol and dioxane.
9. The method for preparing N-desmethylribociclib according to claim 1, characterized in that: In step 3, the reaction temperature is 20-60°C.
10. The method for preparing N-desmethylribociclib according to claim 1, characterized in that: In step 3, the molar ratio of compound (3) to acid E is 1:2 to 1:3.