Preparation method of pipericil intermediate

Abstract

The invention belongs to the technical field of raw medicine synthesis, and discloses a preparation method of a pipericil intermediate. The preparation method of the pipericil intermediate comprises the following steps: mixing 5-bromo-2-nitropyridine, N-Boc-piperazine, an inorganic base and a solvent, and reacting to obtain a first product; and mixing the first product, a sodium sulfide solution and a solvent, and carrying out a reduction reaction to obtain the pipericil intermediate. In the first step of the preparation method, inorganic base potassium carbonate / sodium carbonate is used for replacing organic base triethylamine, so that the pollution is reduced, the yield is increased, and the cost is reduced. In the second step, a reducing agent sodium sulfide is used for replacing palladium carbon / raney nickel for catalytic hydrogenation, so that the safety of the process is improved, and the cost is reduced.

Description

Technical Field

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

[0002] Palbociclib, with the chemical name of 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]-pyrido[2,3-d]pyrimidin-7(8H)-one, was developed by Pfizer Pharmaceuticals Co., Ltd. and approved by the U.S. FDA in February 2015 under the trade name IBRANCE. The drug is an experimental, oral, targeted CDK4 / 6 inhibitor that can selectively inhibit cyclin-dependent kinases 4 and 6 (CDK4 / 6), restore cell cycle control, and block tumor cell proliferation. Palbociclib is the world's first marketed CDK4 / 6 kinase inhibitor, used to treat advanced / metastatic breast cancer in postmenopausal women.

[0003] Compound 1 is an important intermediate for the preparation of palbociclib (see the following route).

[0004]

[0005] Using compound 1 in the above process as a raw material, palbociclib is obtained through four steps of reaction: substitution reaction, coupling reaction, hydrolysis and neutralization reaction.

[0006] At present, the preparation of compound 1 is mainly prepared by substitution reaction using ethanol as solvent and triethylamine as base. Then it is reduced by hydrogenation with palladium carbon / Raney nickel; the synthetic route is as follows:

[0007]

[0008] The above process uses organic base triethylamine and palladium carbon / Raney nickel catalytic hydrogenation, which has high preparation cost and pollutes the environment. Therefore, it is of great significance to provide a palbociclib intermediate that reduces environmental pollution and production cost. Summary of the invention

[0009] The purpose of the present invention is to provide a method for preparing a palbociclib intermediate, so as to solve the problems of high cost and dangerous process in the prior art.

[0010] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0011] The present invention provides a method for preparing a palbociclib intermediate, comprising the following steps:

[0012] (1) mixing 5-bromo-2-nitropyridine, N-Boc-piperazine, an inorganic base and a solvent, and reacting to obtain a first product;

[0013] (2) mixing the first product, sodium sulfide solution and solvent, and performing a reduction reaction to obtain a palbociclib intermediate.

[0014] Preferably, the usage ratio of 5-bromo-2-nitropyridine, N-Boc-piperazine, inorganic base and solvent in step (1) is 90-120 g: 120-140 g: 75-105 g: 300-500 mL.

[0015] Preferably, the inorganic base in step (1) comprises at least one of sodium carbonate or potassium carbonate.

[0016] Preferably, the solvent in step (1) comprises water.

[0017] Preferably, the mixing process in step (1) comprises:

[0018] The inorganic base and the solvent are mixed and dispersed, and after dispersion, 5-bromo-2-nitropyridine and N-Boc-piperazine are added;

[0019] The dispersion time is 15 to 30 minutes.

[0020] Preferably, the reaction temperature in step (1) is 80-100° C., the reaction time is 10-15 h, and the reaction atmosphere is nitrogen.

[0021] Preferably, after the reaction in step (1) is completed, post-treatment is also included;

[0022] The post-treatment includes: cooling the product obtained after the reaction to 20-30° C., then filtering, washing the filter cake obtained after filtration with water, adding n-heptane and water to the washed filter cake for slurrying, filtering again, washing and drying the filter cake to obtain the first product.

[0023] Preferably, in step (2), the dosage ratio of the first product, the sodium sulfide solution and the solvent is 90-120 g: 240-300 g: 300-500 mL.

[0024] Preferably, the dosage ratio of sodium sulfide nonahydrate to water in the sodium sulfide solution is 120-160 g:120-150 mL.

[0025] Preferably, the solvent in step (2) comprises water.

[0026] Preferably, the mixing process in step (2) comprises:

[0027] The first product and the solvent are mixed, heated to a reduction reaction temperature, and then a sodium sulfide solution is added dropwise.

[0028] Preferably, the temperature of the reduction reaction in step (2) is 60-65° C.; and the time of the reduction reaction is 2-4 hours.

[0029] Preferably, after the reduction reaction in step (2) is completed, post-treatment is also included;

[0030] The post-treatment comprises: concentrating the obtained product after the reduction reaction is completed, then adding toluene for extraction, then decolorizing with activated carbon, filtering, concentrating the filtered filtrate, cooling and crystallizing, and filtering to obtain the palbociclib intermediate.

[0031] It can be seen from the above technical solution that compared with the prior art, the present invention has the following beneficial effects:

[0032] The invention provides a preparation method of a palbociclib intermediate, wherein in the first step, inorganic base potassium carbonate / sodium carbonate is used instead of organic base triethylamine, thereby reducing pollution, improving yield and reducing cost. In the second step, reducing agent sodium sulfide is used instead of palladium carbon / Raney nickel for catalytic hydrogenation, thereby improving process safety and reducing cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required to be used in the description of the embodiments or the prior art are briefly introduced below.

[0034] Figure 1 It is the HPLC spectrum of palbociclib intermediate 1 in Example 1. DETAILED DESCRIPTION

[0035] The present invention provides a method for preparing a palbociclib intermediate, comprising the following steps:

[0036] (1) mixing 5-bromo-2-nitropyridine, N-Boc-piperazine, an inorganic base and a solvent, and reacting to obtain a first product;

[0037] (2) mixing the first product, sodium sulfide solution and solvent, and performing a reduction reaction to obtain a palbociclib intermediate.

[0038] In the present invention, the structural formula of the palbociclib intermediate is shown in Formula 1 below:

[0039]

[0040] The process route of the palbociclib intermediate in the present invention is as follows:

[0041]

[0042] Among them, compound 3 is 5-bromo-2-nitropyridine, compound 4 is N-Boc-piperazine, compound 2 is the first product, and compound 1 is a palbociclib intermediate.

[0043] In the present invention, the amount ratio of 5-bromo-2-nitropyridine, N-Boc-piperazine, inorganic base and solvent in step (1) is preferably 90-120g:120-140g:75-105g:300-500mL, more preferably 95-110g:125-130g:95-100g:300-450mL, more preferably 100-105g:125-128g:100-102g:300-400mL.

[0044] In the present invention, the inorganic base in step (1) preferably includes at least one of sodium carbonate or potassium carbonate.

[0045] In the present invention, the solvent in step (1) preferably comprises water.

[0046] In the present invention, the mixing process in step (1) comprises:

[0047] The inorganic base and the solvent are mixed and dispersed, and after dispersion, 5-bromo-2-nitropyridine and N-Boc-piperazine are added;

[0048] The dispersion time is preferably 15 to 30 min, more preferably 18 to 25 min, and even more preferably 20 to 23 min.

[0049] In the present invention, the reaction temperature in step (1) is preferably 80-100°C, more preferably 85-95°C, more preferably 88-90°C; the reaction time is preferably 10-15h, more preferably 11-14h, more preferably 12-13h; the reaction atmosphere is preferably nitrogen.

[0050] In the present invention, after the reaction in step (1) is completed, post-treatment is also included;

[0051] The post-treatment comprises: cooling the product obtained after the reaction to 20-30° C., filtering, washing the filter cake obtained after filtering with water, adding n-heptane and water to the washed filter cake for pulping, filtering again, washing and drying the filter cake to obtain the first product;

[0052] The beating temperature is preferably 50-60°C, more preferably 52-58°C, and more preferably 53-55°C; the beating time is preferably 0.5-3h, more preferably 0.75-2.5h, and more preferably 1-2h;

[0053] After beating, the temperature is lowered to 20-30°C, preferably to 22-29°C, and more preferably to 25-26°C.

[0054] The drying temperature is preferably 50-60°C, more preferably 52-57°C, and more preferably 54-55°C;

[0055] The drying method is preferably vacuum drying.

[0056] In the present invention, the usage ratio of the first product, sodium sulfide solution and solvent in step (2) is preferably 90-120 g: 240-300 g: 300-500 mL, more preferably 95-115 g: 250-280 g: 300-450 mL, and more preferably 100-110 g: 260-270 g: 350-400 mL.

[0057] In the present invention, the usage ratio of sodium sulfide to water in the sodium sulfide solution is preferably 120-160 g:120-150 mL, more preferably 130-158 g:130-145 mL, and more preferably 140-150 g:135-140 mL.

[0058] In the present invention, the sodium sulfide in step (2) is preferably sodium sulfide nonahydrate.

[0059] In the present invention, the solvent in step (2) preferably includes water.

[0060] In the present invention, the mixing process in step (2) comprises:

[0061] The first product and the solvent are mixed, heated to a reduction reaction temperature, and then a sodium sulfide solution is added dropwise.

[0062] In the present invention, the temperature of the reduction reaction in step (2) is preferably 60-65°C; more preferably 61-64°C, more preferably 62-63°C; the time of the reduction reaction is preferably 2-4h, more preferably 2.5-3.5h, more preferably 3-3.25h.

[0063] In the present invention, after the reduction reaction in step (2) is completed, post-treatment is also included;

[0064] The post-treatment comprises: concentrating the obtained product after the reduction reaction is completed, then adding toluene for extraction, then sequentially performing activated carbon decolorization and filtering, concentrating the filtered filtrate, cooling and crystallizing, and filtering to obtain the palbociclib intermediate;

[0065] The activated carbon decolorization and filtration further comprises cooling the obtained filtrate to -5 to 0°C and stirring for 1 hour, preferably cooling to -4 to -1°C, and more preferably -3 to -2°C.

[0066] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0067] Example 1

[0068] 1) Under nitrogen protection, 101.98 g of potassium carbonate was added to 300 mL of water and stirred for 20 minutes; 100 g of 5-bromo-2-nitropyridine and 137.60 g of N-Boc-piperazine were added, and the temperature was raised to 90° C. for reaction for 12 h; after the reaction was completed, the temperature was lowered to 20° C., filtered, and the filter cake was washed twice with water; the filter cake was added to 300 mL of n-heptane and 300 g of water, heated to 55° C. for stirring and beating for 1 h, then cooled to 20° C., filtered, and the filter cake was washed twice, and then vacuum dried at 50° C. to obtain 125 g of the first product 2, with a weight yield of 125%.

[0069] 2) 100 g of the first product 2 was put into 300 mL of methanol, the temperature was raised to 60 ° C, and a mixed solution of 156 g of sodium sulfide nonahydrate and 150 mL of water was added dropwise. After the addition was completed, the reaction was continued for 2 hours; after the reaction was completed, the obtained product was concentrated, and then 500 mL of toluene was added for extraction twice, and then the organic phase was decolorized with 10 g of egret activated carbon, filtered, and the filtrate was concentrated to 300 mL, cooled to -5 ° C, stirred for 1 hour, filtered, and dried to obtain 62.5 g of palbociclib intermediate 1, with a weight yield of 62.5%.

[0070] The HPLC spectrum of the above prepared palbociclib intermediate 1 is as follows Figure 1 As shown. Figure 1 It can be seen that the purity of intermediate 1 meets the requirements for preparing palbociclib.

[0071] Example 2

[0072] 1) Under nitrogen protection, 78.32g potassium carbonate was added to 300mL water and stirred for 20 minutes. 100g 5-bromo-2-nitropyridine and 137.60g N-Boc-piperazine were added, and the temperature was raised to 95°C for reaction for 12h; after the reaction, the temperature was lowered to 20°C, filtered, and the filter cake was washed with water twice; the filter cake was added to 300mL n-heptane and 300g water, heated to 55°C for stirring and beating for 1h, then cooled to 20°C, filtered, and the obtained filter cake was washed twice, and then vacuum dried at 50°C to obtain 136g of the first product 2, with a weight yield of 136%.

[0073] 2) 100 g of the first product 2 was put into 300 mL of methanol, the temperature was raised to 60 ° C, and a mixed solution of 156 g of sodium sulfide nonahydrate and 150 mL of water was added dropwise. After the addition was completed, the reaction was continued for 2 hours; after the reaction was completed, the obtained product was concentrated, and then 500 mL of toluene was added for extraction twice, and then the organic phase was decolorized with 10 g of egret activated carbon, filtered, and the filtrate was concentrated to 300 mL, cooled to -5 ° C, stirred for 1 hour, filtered, and dried to obtain 63 g of palbociclib intermediate 1, with a weight yield of 63%.

[0074] The embodiment of the present invention provides a new process for preparing palbociclib intermediate 1. The process avoids the disadvantage of using triethylamine as an acid-binding agent to prepare intermediate 2 as reported in the original research literature, directly uses an inorganic base as an acid-binding agent, successfully prepares intermediate 2, saves working hours, reduces pollution, improves yield, and reduces costs. In the process of preparing product 1 from intermediate 2, sodium sulfide is used as a reducing agent, which improves process safety and reduces costs compared to the method of using palladium carbon or Raney nickel hydrogenation reduction in most processes.

[0075] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a palbociclib intermediate, characterized in that: The following steps are involved: (1) mixing 5-bromo-2-nitropyridine, N-Boc-piperazine, an inorganic base and a solvent, and reacting to obtain a first product; (2) mixing the first product, sodium sulfide solution and solvent, and performing a reduction reaction to obtain a palbociclib intermediate.

2. The method for preparing a palbociclib intermediate according to claim 1, characterized in that: The usage ratio of 5-bromo-2-nitropyridine, N-Boc-piperazine, inorganic base and solvent in step (1) is 90-120 g: 120-140 g: 75-105 g: 300-500 mL.

3. The method for preparing a palbociclib intermediate according to claim 1, characterized in that: The inorganic base in step (1) comprises at least one of sodium carbonate or potassium carbonate; And / or, the solvent in step (1) includes water.

4. The method for preparing a palbociclib intermediate according to claim 1, characterized in that: The mixing process in step (1) comprises: The inorganic base and the solvent are mixed and dispersed, and after dispersion, 5-bromo-2-nitropyridine and N-Boc-piperazine are added; The dispersion time is 15 to 30 minutes.

5. The method for preparing a palbociclib intermediate according to claim 1, characterized in that: The reaction temperature in step (1) is 80-100° C., the reaction time is 10-15 h, and the reaction atmosphere is nitrogen.

6. The method for preparing a palbociclib intermediate according to claim 1, characterized in that: After the reaction in step (1) is completed, post-treatment is also included; The post-treatment includes: cooling the product obtained after the reaction to 20-30° C., then filtering, washing the filter cake obtained after filtration with water, adding n-heptane and water to the washed filter cake for slurrying, filtering again, washing and drying the filter cake to obtain the first product.

7. The method for preparing a palbociclib intermediate according to claim 1, characterized in that: In step (2), the ratio of the first product, the sodium sulfide solution and the solvent is 90-120 g: 240-300 g: 300-500 mL; And / or, the ratio of sodium sulfide to water in the sodium sulfide solution is 120-160 g: 120-150 mL; And / or, the solvent in step (2) includes water.

8. The method for preparing a palbociclib intermediate according to claim 1, characterized in that: The mixing process in step (2) includes: The first product and the solvent are mixed, heated to a reduction reaction temperature, and then the sodium sulfide solution is added dropwise.

9. The method for preparing a palbociclib intermediate according to claim 1, characterized in that: The temperature of the reduction reaction in step (2) is 60-65° C.; the time of the reduction reaction is 2-4 hours.

10. The method for preparing a palbociclib intermediate according to claim 1, characterized in that: After the reduction reaction in step (2) is completed, post-treatment is also included; The post-treatment includes: concentrating the obtained product after the reduction reaction is completed, then adding toluene for extraction, and then sequentially performing activated carbon decolorization and filtering, concentrating the filtered filtrate, cooling and crystallizing, and filtering to obtain the palbociclib intermediate 1.

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