Preparation method of ribociclib intermediate

Abstract

The invention discloses a ribociclib intermediate preparation method, which comprises: adding a compound (I) into DMSO or DMF, dropwise adding DIEA or triethylamine, and carrying out a ring closing reaction under the action of a catalyst cuprous chloride or cuprous bromide to generate a compound (II); adding the compound (II) into a reaction solvent, controlling the temperature at 70-110 DEG C, adding an oxidant manganese dioxide, carrying out a heat preservation reaction until the raw material disappears, filtering a solid, adding potassium carbonate into a mother solution, controlling the temperature at 0-20 DEG C, dropwise adding hydrogen peroxide, continuously oxidizing until an intermediate disappears, adding water to carry out a quenching reaction, extracting impurities by using an organic solvent, adjusting the pH value of a water phase, separating out the solid, and filtering to obtain a compound (III), one or more of toluene; and finally, the compound (III) generates an intermediate state in a solvent E through a condensing agent CDI or EDCI, after methanol is dropwise added for reaction, water is added for quenching and filtering to obtain a compound (IV), and the solvent E is any one of DMF, tetrahydrofuran and methyl tetrahydrofuran. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing a ribociclib intermediate. Background Art

[0002] Ribociclib succinate was developed by Novartis Pharmaceuticals Ltd. in Switzerland. As an inhibitor of cyclin-dependent kinase 4 / 6 (CDK4 / 6), ribociclib succinate inhibits tumor growth and spread in the clinical treatment of breast cancer, and has excellent 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, and its structure is as follows:

[0004]

[0005] The intermediate 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester has the following structure:

[0006]

[0007] There are few reports on the synthesis of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester. In patent CN111100128A, 2,4,6-trihydroxypyrimidine is used as a raw material and phosphorus oxychloride is used to generate 2,4,6-trichloropyrimidine-3-carboxaldehyde, and then condensation, ring closure, and dechlorination steps are performed to synthesize chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester. This process uses phosphorus oxychloride and precious metal palladium, resulting in high process costs and is environmentally unfriendly. Summary of the invention

[0008] In view of the deficiencies of the prior art, the present invention provides a method for preparing ribociclib intermediate 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester, and the synthetic route is as follows:

[0009]

[0010] The following steps are involved:

[0011] Step 1: Compound (I) 3-[2-chloro-4-(cyclopentylamino)-5-pyrimidinyl]-2-propyn-1-ol is added to solvent C and base B is added dropwise, and a ring-closing reaction occurs under the action of catalyst A to generate compound (II) 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-methanol, wherein catalyst A is cuprous chloride or oxadiazine bromide, base B is N,N-diisopropylethylamine (DIEA) or triethylamine, and solvent C is N,N-dimethylaniline (DMSO) or N,N-dimethylformamide (DMF);

[0012] Step 2: Compound (II) 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-methanol is added to the reaction solvent, the temperature is controlled at 70-110°C, manganese dioxide as an oxidant is added, the reaction is kept warm until the raw material disappears, the solid is filtered, potassium carbonate is added to the mother liquor, the temperature is continued to be controlled at 0-20°C, hydrogen peroxide is added dropwise to continue oxidation until the intermediate disappears, water is added to quench the reaction, impurities are extracted with an organic solvent, the pH is adjusted with an aqueous phase, the precipitated solid is filtered to obtain compound (III) 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid, wherein the reaction solvent is one or both of DMF and toluene;

[0013] Step 3: Compound (III) 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid is reacted with a condensing agent D in a solvent E to generate an intermediate state. After methanol is added dropwise to complete the reaction, water is added to quench the reaction and filtered to obtain compound (IV) 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester, wherein the condensing agent D is N,N'-carbonyldiimidazole (CDI) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and the solvent E is any one of DMF, tetrahydrofuran, and methyltetrahydrofuran.

[0014] Furthermore, in step 1, the molar ratio of compound (I) to catalyst A is 1:0.1 to 1:0.5.

[0015] Furthermore, in step 1, the molar ratio of compound (I) to base B is 1:0.5 to 1:1, preferably 1:0.5 to 1:0.7.

[0016] Furthermore, in step 1, the reaction temperature is 50-80°C.

[0017] Furthermore, in step 1, the volume ratio of compound (I) to solvent C is 1:3 to 1:10, preferably 1:5 to 1:8.

[0018] Furthermore, in step 2, the molar ratio of compound (II) to oxidant manganese dioxide is 1:3 to 1:5.

[0019] Furthermore, in step 2, the molar ratio of compound (II) to the oxidant hydrogen peroxide is 1:1 to 1:1.5.

[0020] Furthermore, in step 3, the reaction temperature is 0 to 30°C.

[0021] Furthermore, in step 3, the molar ratio of compound (III) to condensing agent D is 1:1 to 1:2.

[0022] Furthermore, in step 3, the mass ratio of compound (III) to methanol is 1:0.5 to 1:2.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The process is relatively simple, the reaction temperature is between 0 and 100°C, which is suitable for process scale-up. The reaction does not use precious metals, so the cost is relatively low.

[0025] 2. The product process is controllable, and the intermediate obtained has high purity, which can reach 99.7%, meeting the production requirements of Riboxil intermediates. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The compound (IV) prepared in Example 1 1 HMNR spectrum;

[0027] Figure 2 This is the HPLC spectrum of compound (IV) prepared in Example 1. DETAILED DESCRIPTION

[0028] 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.

[0029] Example 1

[0030] Step 1: Preparation of compound (II)

[0031] Dissolve 100 g of compound (I) in 300 ml of DMSO, add 5.7 g of cuprous bromide and 20 g of triethylamine under nitrogen protection, raise the temperature to 50°C and keep the reaction until completion, cool to room temperature, add 200 g of ammonia water to remove copper, continue to add 3 kg of water for crystallization, and filter to obtain a brown solid with a yield of 98%.

[0032] Step 2: Preparation of compound (III)

[0033] 22g of compound (II) was added to 110ml of toluene solvent, and 23g of manganese dioxide was added at room temperature. The mixture was heated to 70-80°C, and the reaction was carried out until the raw material disappeared. The mixture was cooled to 30-40°C, and the insoluble matter was filtered out. The residue was slurried with toluene and then filtered. The mother liquors were combined, and 30g of potassium carbonate was added. The mixture was cooled to 0-10°C, and 12g of hydrogen peroxide was added dropwise. After the addition was completed, the mixture was kept warm and the reaction was continued until the intermediate state was completely reacted. An ice-water solution was added to quench the reaction, and the liquids were separated. The pH value of the aqueous phase was adjusted to 1-2 with hydrochloric acid, and the solid was filtered and dried to obtain an off-white solid with a yield of 82%.

[0034] Step 3: Preparation of compound (IV)

[0035] 20 g of compound (III) was added to 80 ml of tetrahydrofuran, and 12.2 g of CDI was added under nitrogen protection. The mixture was stirred at 0°C for 2 hours, 10 g of methanol was added dropwise, and stirring was continued for 0.5 hours. The reaction was completed as judged by TLC plate. 200 mL of water was added to the reaction solution, and the product was precipitated. It was filtered and dried to constant weight. The yield was 96%.

[0036] like Figure 1 As shown, the prepared compound (IV) 1 HNMR (400MHz, DMSO-d6, δppm): 1.66 (m, 2H), 2.02 (m, 4H), 2.27 (m, 2H), 3.90 (s, 3H), 5.68 (m, 1H), 7.73 (s, 1H), 9.11 (s, 1H).

[0037] like Figure 2 As shown, the liquid phase spectrum of compound (IV) has a purity of 99.7% and a maximum impurity of 0.24%. The purity is relatively high and meets the requirements of intermediates.

[0038] Example 2

[0039] Step 1: Preparation of compound (II)

[0040] Dissolve 100 g of compound (I) in 400 ml of DMSO. Under nitrogen protection, add 28.6 g of cuprous bromide and 26 g of triethylamine. Heat to 70°C and keep warm until the reaction is complete. Cool to room temperature, add 200 g of ammonia water to remove copper, add 3 kg of water to crystallize, and filter to obtain a brown solid with a yield of 99%.

[0041] Step 2: Preparation of compound (III)

[0042] Add 26 g of compound (II) to 150 ml of DMF solvent, add 45 g of manganese dioxide at room temperature, heat to 100-110°C, react until the raw material disappears, cool to 30-40°C, filter out insoluble matter, rinse the filter residue with DMF, combine the mother liquors, add 32 g of potassium carbonate, cool to 10-20°C, start to drop 12 g of hydrogen peroxide, keep warm and continue to react until the intermediate state reaction is complete, add ice-water solution to quench the reaction, extract impurities with toluene, adjust the pH of the aqueous phase to 1-2 with hydrochloric acid, filter and dry to obtain an off-white solid with a yield of 80%.

[0043] Step 3: Preparation of compound (IV)

[0044] 20 g of compound (III) was added to 80 ml of methyltetrahydrofuran, and 24 g of CDI was added under nitrogen. The mixture was stirred at 15°C for 2 hours. 15 g of methanol was added dropwise and stirring was continued for 0.5 hour. The reaction was completed as judged by TLC plate. 200 mL of water was added to the reaction solution. The product was precipitated, filtered and dried to constant weight. The yield was 95%.

[0045] Example 3

[0046] Step 1: Preparation of compound (II)

[0047] 100 g of compound (I) was dissolved in 1000 ml of DMF. Under nitrogen protection, 16 g of cuprous chloride and 30 g of DIEA were added. The temperature was raised to 80°C and the reaction was carried out until completion. The temperature was lowered to room temperature. 200 g of aqueous ammonia was added to remove copper. 3 kg of water was added for crystallization. A brown solid was obtained by suction filtration. The yield was 98%.

[0048] Step 2: Preparation of compound (III)

[0049] Add 38g of compound (II) to 240ml of a mixed solvent of DMF and toluene (DMF / toluene volume ratio of 5:1), add 50g of manganese dioxide at room temperature, heat to 80-110°C, react until the raw material disappears, cool to 50°C, filter out insoluble matter, rinse the filter residue with DMF, combine the mother liquors, add 32g of potassium carbonate, cool to 5-15°C, start to drop 25.6g of hydrogen peroxide, keep warm and continue to react until the intermediate state reaction is complete, add ice-water solution to quench the reaction, separate the liquids to remove toluene, adjust the pH of the aqueous phase to 1-2 with hydrochloric acid, filter and dry to obtain an off-white solid with a yield of 85%.

[0050] Step 3: Preparation of compound (IV)

[0051] 20 g of compound (III) was added to 80 ml of DMF, and 23 g of EDCI was added under nitrogen. The mixture was stirred at 30°C for 2 hours, and 40 g of methanol was added dropwise. The mixture was stirred for 0.5 hours. The reaction was completed as determined by TLC plate. 200 mL of water was added to the reaction solution. The product was precipitated, filtered, and dried to constant weight. The yield was 94%.

[0052] 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 a ribociclib intermediate, characterized in that: The synthetic route is as follows: The following steps are involved: Step 1: Compound (I) is added to solvent C and base B is added dropwise, and a ring-closing reaction occurs under the action of catalyst A to generate compound (II), wherein catalyst A is cuprous chloride or cuprous bromide, base B is N,N-diisopropylethylamine or triethylamine, and solvent C is N,N-dimethylaniline or N,N-dimethylformamide; Step 2: Compound (II) is added to the reaction solvent, the temperature is controlled at 70-110°C, manganese dioxide as an oxidant is added, the reaction is kept warm until the raw material disappears, the solid is filtered, potassium carbonate is added to the mother liquor, hydrogen peroxide is added dropwise at a temperature of 0-20°C, and oxidation is continued until the intermediate disappears, water is added to quench the reaction, impurities are extracted with an organic solvent, the pH is adjusted with water, the precipitated solid is filtered to obtain compound (III), wherein the reaction solvent is one or both of N,N-dimethylformamide and toluene; Step 3: Compound (III) is reacted with a condensing agent D in a solvent E to generate an intermediate state. After methanol is added dropwise to complete the reaction, water is added to quench the reaction and the mixture is filtered to obtain compound (IV), wherein the condensing agent D is N,N'-carbonyldiimidazole or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the solvent E is any one of N,N-dimethylformamide, tetrahydrofuran, and methyltetrahydrofuran.

2. The method for preparing a ribociclib intermediate according to claim 1, characterized in that: In step 1, the molar ratio of compound (I) to catalyst A is 1:0.1 to 1:0.

5.

3. The method for preparing a ribociclib intermediate according to claim 1, characterized in that: In step 1, the molar ratio of compound (I) to base B is 1:0.5 to 1:

1.

4. The method for preparing a ribociclib intermediate according to claim 1, characterized in that: In step 1, the reaction temperature is 50-80°C.

5. The method for preparing a ribociclib intermediate according to claim 1, characterized in that: In step 1, the volume ratio of compound (I) to solvent C is 1:3 to 1:

10.

6. The method for preparing a ribociclib intermediate according to claim 1, characterized in that: In step 2, the molar ratio of compound (II) to oxidant manganese dioxide is 1:3 to 1:

5.

7. The method for preparing a ribociclib intermediate according to claim 1, characterized in that: In step 2, the molar ratio of compound (II) to oxidant hydrogen peroxide is 1:1 to 1:1.

5.

8. The method for preparing a ribociclib intermediate according to claim 1, characterized in that: In step 3, the reaction temperature is 0-30°C.

9. The method for preparing a ribociclib intermediate according to claim 1, characterized in that: In step 3, the molar ratio of compound (III) to condensing agent D is 1:1 to 1:

2.

10. The method for preparing a ribociclib intermediate according to claim 1, characterized in that: In step 3, the mass ratio of compound (III) to methanol is 1:0.5 to 1:2.

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