Preparation method of key intermediate of anti-breast cancer drug palbociclib

Abstract

The invention discloses a preparation method of an anti-breast cancer drug palbociclib key intermediate, and belongs to the field of medical technology synthesis. The preparation method comprises the following steps: reacting a compound VIII with N, O-dimethyl hydroxylamine in the presence of an organic solvent, alkali and a condensing agent to prepare a compound VII, and then carrying out nucleophilic substitution reaction, methylation reaction, Wittig-Horner reaction, bromination and oxidation reaction to prepare an intermediate compound I. The whole reaction route is shortened, the use of flammable and explosive organic metal reagents is avoided, the operability is strong, the method is green and environment-friendly, the total yield and purity of the product are improved, and the method is suitable for industrial mass production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology synthesis, and particularly relates to a preparation method of a key intermediate of the anti-breast cancer drug Palbociclib. Background Art

[0002] Palbociclib was developed by Pfizer in the United States and is an oral small molecule inhibitor of cyclin-dependent kinases (CDK4 / CDK6). It is used in combination with letrozole for the first-line treatment of postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who have not received prior systemic treatment to control advanced disease. Subsequently, in February 2016, the indication was approved to be expanded, and it is used in combination with fulvestrant for the second-line treatment of hormone receptor-positive (HR+), HER2- advanced or metastatic breast cancer with disease progression after endocrine therapy. It was approved by the FDA for marketing on February 3, 2015, and approved by the European Medicines Agency on November 9, 2016. It is marketed in the United States and Europe by Pfizer under the trade name Ibrance and was launched in China on July 2018.

[0003] The Chinese chemical name of Palbociclib is: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one, and its structural formula is:

[0004]

[0005] There are many synthetic routes for Palbociclib, but the main industrial production routes are the following three:

[0006] 1. The original research synthetic route 1 of Palbociclib was reported in patents WO2003062236, WO2010039997 and the literature J.Med.Chem.2005,48,2371-2387:

[0007]

[0008] Synthetic route 1 obtains the key intermediate I through substitution, reduction, oxidation, methylation, oxidation, Wittig-Horner reaction, and NBS bromination oxidation, and then obtains Palbociclib through N-alkylation reaction, and then through Stille coupling and hydrolysis reaction. This route has a long process, multiple oxidation-reduction reactions, cumbersome operations, high reagent hazards, and difficult impurity separation, which greatly limits industrial production.

[0009] 2. Pfizer has improved the synthesis method of palbociclib in patents WO2008032157 and WO2014128588. The specific synthesis route is shown in Route 2:

[0010]

[0011] The synthesis route 2 obtains the key intermediate II through ammoniation reaction, Heck coupling, ring closing, and bromination, and then obtains palbociclib through N-alkylation reaction, and then through Heck coupling and hydrolysis reaction. This route shortens the steps, but the coupling reaction is applied twice, requiring precious metal palladium and expensive ligands, increasing the cost. At the same time, the chlorine and bromine in the key intermediate II have similar activities, poor selectivity, and are prone to generate impurities, reducing the product quality and yield, which is not conducive to industrial production.

[0012] 3. Chinese patent CN104610254 reports a new synthesis route for synthesizing palbociclib using 2,4-dichloro-5-cyanopyrimidine as the raw material, as follows Route 3:

[0013]

[0014] The synthesis route 3 obtains the key intermediate III through the addition of methylmagnesium bromide, carbonyl protection, N-alkylation reaction, and deprotection reaction, and then reacts with diketene and closes the ring. Then palbociclib is obtained through protection, ammoniation, and deprotection reactions. The key to this route is the synthesis of intermediate III, which avoids the use of precious metal palladium-catalyzed coupling in Routes 1 and 2, reducing the cost. However, it uses toxic diketene and uses protecting groups multiple times, increasing the operation steps and difficulty, and generating more three wastes, restricting its green and environmental protection industrial production requirements.

[0015] Through the above synthesis routes of palbociclib, it is found that the original research company and related patent technology routes mainly start from constructing the pyrido[2,3-d]pyrimidin-7-one intermediate for fragment synthesis. Among them, the halogen atoms of the pyrido[2,3-d]pyrimidin-7-one intermediate II in Route 2 have similar activities and poor selectivity, and the pyrido[2,3-d]pyrimidin-7-one intermediate III in Route 3 requires the use of protecting groups and increases the reaction steps. Therefore, the synthesis of the pyrido[2,3-d]pyrimidin-7-one intermediate I in Route 1 is the key to preparing palbociclib.

[0016] The Chinese chemical name of the key intermediate I of palbociclib: 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one, the English chemical name: 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one, and its chemical structural formula is as follows:

[0017]

[0018] The existing synthetic route 1 of palbociclib key intermediate Ⅰ has harsh operating conditions, lengthy steps, and great environmental hazards. The research on the synthetic process is not yet mature. Therefore, it is of great significance to develop a production process with mild conditions, high process yield, simple and environmentally friendly operation, and suitable for industrialization. Summary of the Invention

[0019] In view of the deficiencies of the prior art, the present invention provides a method for preparing a key intermediate of a new anti-breast cancer drug palbociclib. This method avoids the problems of using flammable, explosive, and organometallic reducing agents and highly toxic metal oxidants, shortens the reaction steps, reduces costs, and is greener, safer, and more suitable for industrial production.

[0020] During the research process, the inventors found that in the preparation process of palbociclib intermediate, the method of using Weinreb amide (Compound Ⅵ) to prepare Compound Ⅴ avoids the cumbersome processes of reduction, oxidation, addition, and re-oxidation in the original technology, has mild conditions and simple operation, and at the same time avoids the residue of heavy metals in the product. Therefore, the present invention is proposed.

[0021] The present invention provides a method for preparing a key intermediate of an anti-breast cancer drug palbociclib, and the synthetic route is as follows:

[0022]

[0023] It includes the following steps:

[0024] 1) After mixing Compound Ⅷ with an organic solvent and a base, a condensing agent is added for activation, and then N,O-dimethylhydroxylamine is added to obtain Compound Ⅶ;

[0025] 2) Compound Ⅶ is dissolved in an organic solvent, and undergoes a nucleophilic substitution reaction with cyclopentylamine under the action of a base to obtain Compound Ⅵ;

[0026] 3) Compound Ⅵ is dissolved in an organic solvent, and under nitrogen protection, a methylmagnesium bromide solution is added dropwise to undergo a methylation reaction to obtain Compound Ⅴ;

[0027] 4) After dissolving triethyl phosphonoacetate, a base is added and the reaction is carried out at low temperature. Then, the solution of Compound Ⅴ is added dropwise to the reaction system. After a Wittig-Horner reaction, ring closure is carried out by heating to obtain Compound Ⅳ;

[0028] 5) Compound Ⅳ is dissolved in an organic solvent, and reacts with NBS under acid catalysis to obtain Compound Ⅰ in one step through bromination and oxidation.

[0029] According to the method of the present invention, the reaction process conditions in each step are as follows:

[0030] Preferably, the organic solvent in step 1) is dichloromethane, tetrahydrofuran or toluene; the base is triethylamine, diisopropylethylamine or pyridine; the condensing agent is CDI, DCC or DMAP; the reaction temperature is 10-30 °C; the molar ratio of compound VIII, base, condensing agent, and N,O-dimethylhydroxylamine is 1:2-3:1-2:1-2.

[0031] Preferably, the organic solvent in step 2) is dichloromethane, acetonitrile or ethanol; the base is triethylamine, diisopropylethylamine or N-methylmorpholine; the reaction temperature is 15-30 °C; the molar ratio of compound VII, base, and cyclopentylamine is 1:1-2:1-1.5.

[0032] Preferably, the organic solvent in step 3) is tetrahydrofuran, toluene or ethylene glycol dimethyl ether; the reaction temperature is 0-10 °C; the reaction time is 1-2 h; the molar ratio of compound VI and methylmagnesium bromide is 1:1.5-3.

[0033] Preferably, the organic solvent in step 4) is tetrahydrofuran, toluene or ethylene glycol dimethyl ether; after dropping at 0-10 °C, the temperature is raised to reflux for reaction; the base is sodium hydride, sodium tert-butoxide or sodium ethoxide; the molar ratio of compound V, base, and triethyl phosphonoacetate is 1:1.5-3:1.5-3.

[0034] Preferably, the organic solvent in step 5) is tetrahydrofuran, acetonitrile or dioxane; the reaction temperature is 10-30 °C for reaction; the acid is acetic acid, p-toluenesulfonic acid or oxalic acid; the molar ratio of compound V, acid, NBS, and water is 1:0.05-0.2:2-3:1-2.

[0035] The technical features and beneficial effects of the present invention are as follows:

[0036] a) The method for preparing ketone using Weinreb amide in the present invention shortens the route, avoids the use of flammable and explosive organometallic reagents, reduces the danger, and does not use metal oxidants, reducing environmental pollution.

[0037] b) The raw materials used in the present invention are cheap and easily available, the overall reaction route is short, the cost is reduced, the operability is strong, it is green and environmentally friendly, the total yield and purity of the product are improved, and it is suitable for industrial production. Specific embodiments:

[0038] To make the purpose, technical solutions and advantages of the implementation of the present invention clearer, the specific embodiments of the present invention will be clearly and completely described below, so as to further understand the present invention, but the present invention is not limited thereto.

[0039] Example 1: Preparation of compound VII

[0040]

[0041] Compound VIII (50 g, 244.3 mmol), N,N - diisopropylethylamine (63.1 g, 488.6 mmol) and 150 mL of dichloromethane were stirred and dissolved at room temperature. CDI (79.2 g, 488.6 mmol) was added, and the mixture was stirred at room temperature for 15 min. N,O - dimethylhydroxylamine (14.9 g, 244.3 mmol) was added, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until completion. The mixture was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain 59.9 g of yellow oil VII, with a yield of 99%.

[0042] 1 1H - NMR (600 MHz, CDCl3) δ: 9.39 (s, 1H), 3.58 (s, 3H), 3.44 (s, 3H), 2.40 (s, 3H); ESI - MS m / z: [M + H] + Theoretical value 248.03, measured value 248.03.

[0043] Example 2: Preparation of Compound VII

[0044] Compound VIII (50 g, 244.3 mmol), triethylamine (74.16 g, 732.9 mmol) and 150 mL of tetrahydrofuran were stirred and dissolved at room temperature. DCC (50.4 g, 244.3 mmol) was added, and the mixture was stirred at room temperature for 30 min. N,O - dimethylhydroxylamine (29.8 g, 488.6 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC until completion. The mixture was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain 58.7 g of yellow oil VII, with a yield of 97%.

[0045] Example 3: Preparation of Compound VI

[0046]

[0047] Compound VII (49.5 g, 200 mmol) and triethylamine (40.5 g, 400 mmol) were dissolved in 150 ml of dichloromethane. Cyclopentylamine (17 g, 200 mmol) was slowly added dropwise to the above reaction system at room temperature, and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC until completion. n - Hexane (200 ml) was slowly added thereto, and the mixture was stirred in an ice bath for 2 h and then filtered. The white solid VI (58.1 g) was obtained by vacuum drying, with a yield of 98% and a purity of 99.4%.

[0048] 1H-NMR(600MHz,CDCl3)δ:8.92(s,1H),4.38 - 4.43(m,1H),3.58(s,3H),3.44(s,3H),2.54(s,3H),1.92 - 1.96(m,2H),1.66 - 1.76(m,4H),1.49 - 1.54(m,2H),1.43(s,1H); ESI-MS m / z: [M + H] + Theoretical value 297.14, measured value 297.15.

[0049] Example 4: Preparation of Compound VI

[0050] Dissolve Compound VII (49.5 g, 200 mmol) and N,N - diisopropylethylamine (25.8 g, 200 mmol) in 150 ml of ethanol. Slowly add cyclopentylamine (25.5 g, 300 mmol) dropwise to the above reaction system at room temperature. Stir at room temperature for 2 h. Monitor the completion of the reaction by TLC. Slowly add water (200 ml) to it. After stirring in an ice bath for 2 h, filter and vacuum dry to obtain 57.2 g of white solid VI, with a yield of 96.5% and a purity of 99.3%.

[0051] Example 5: Preparation of Compound V

[0052]

[0053] Under nitrogen protection, dissolve Compound VI (53.3 g, 180 mmol) in 150 mL of anhydrous tetrahydrofuran. Cool to 0 °C in an ice - water bath. Slowly add a tetrahydrofuran solution of methylmagnesium bromide (90 ml, 3.0 mol / L). Control the temperature at 0 - 10 °C during the addition and react for 1.5 h. Monitor the reaction by TLC. After the reaction is completed, slowly add saturated ammonium chloride solution to quench the reaction. After concentrating under reduced pressure to remove tetrahydrofuran, add 150 mL of ethyl acetate and wash with saturated aqueous sodium bicarbonate until neutral, then wash once with saturated aqueous sodium chloride. Dry the organic phase with anhydrous sodium sulfate and rotary evaporate under reduced pressure to obtain 39.8 g of white solid V, with a yield of 88% and a purity of 98.9%.

[0054] 1 H-NMR(600MHz,CDCl3)δ:9.07(s,1H),4.40 - 4.46(m,1H),2.56(s,3H),2.54(s,3H),1.96 - 2.02(m,2H),1.64 - 1.78(m,4H),1.51 - 1.58(m,2H),0.61(s,1H); ESI-MS m / z: [M + H] + Theoretical value 252.12, measured value 252.12.

[0055] Example 6: Preparation of Compound V

[0056] Under nitrogen protection, compound VI (53.3 g, 180 mmol) was dissolved in 150 mL of anhydrous toluene, cooled to 0 °C in an ice-water bath, and a tetrahydrofuran solution of methylmagnesium bromide (180 ml, 3.0 mol / L) was slowly added dropwise, with the temperature controlled at 0 - 10 °C during the addition. The reaction was carried out for 2 h, and the reaction was monitored by TLC. After the reaction was completed, saturated ammonium chloride solution was slowly added to quench the reaction. The layers were separated, and the organic phase was washed with saturated aqueous sodium bicarbonate until neutral, then washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 40.7 g of white solid V, with a yield of 90% and a purity of 98.9%.

[0057] Example 7: Preparation of Compound IV

[0058]

[0059] Under nitrogen protection, sodium hydride (5.04 g, 210 mmol) was dispersed in 120 mL of anhydrous tetrahydrofuran, and the temperature of the system was cooled to 0 °C. Triethyl phosphonoacetate (94.2 g, 420 mmol) was slowly added dropwise. Compound V (35.2 g, 140 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran and slowly added dropwise to the reaction system. After completion, the temperature was raised to 70 °C and refluxed for 8 h. After the reaction was monitored by TLC and completed, 50 ml of water was added dropwise to quench the reaction. It was cooled to room temperature, filtered by suction, and the filter cake was washed with n-hexane and water and dried in vacuo to obtain 35.85 g of white solid IV, with a yield of 93% and a purity of 99.6%.

[0060] 1 HNMR (600 MHz, CDCl3) δ: 8.76 (s, 1H), 6.51 (s, 1H), 4.53 - 4.59 (m, 1H), 2.54 (s, 3H), 2.43 (s, 3H), 2.32 - 2.39 (m, 2H), 1.87 - 1.95 (m, 2H), 1.79 - 1.85 (m, 2H), 1.53 - 1.61 (m, 2H); ESI-MS m / z: [M + H] + Theoretical value 276.12, measured value 276.12.

[0061] Example 8: Preparation of Compound IV

[0062] Under nitrogen protection, sodium ethoxide (28.6 g, 420 mmol) was dispersed in 120 mL of anhydrous ethylene glycol dimethyl ether, and the temperature of the system was cooled to 0 °C. Triethyl phosphonoacetate (47.1 g, 210 mmol) was slowly added dropwise. Compound V (35.2 g, 140 mmol) was dissolved in 100 mL of anhydrous ethylene glycol dimethyl ether and slowly added dropwise to the reaction system. After completion, the temperature was raised to 85 °C and refluxed for 10 h. After monitoring the reaction by TLC and completion, 50 mL of water was added dropwise to quench the reaction. After cooling to room temperature, filtration was carried out, and the filter cake was washed with methyl tert-butyl ether and water and dried in vacuo to obtain 36.32 g of white solid IV with a yield of 94.2% and a purity of 99.7%.

[0063] Example 9: Preparation of Compound I

[0064]

[0065] Compound IV (32.8 g, 119 mmol), NBS (63.5 g, 357 mmol) and 150 mL of acetonitrile were successively added to the reaction system. After stirring evenly, glacial acetic acid (1.43 g, 23.8 mmol) and water (4.3 mL, 238 mmol) were added dropwise at room temperature. The reaction was carried out at room temperature for 2 h. After monitoring the reaction by TLC and completion, the reaction solution was poured into 450 mL of water and stirred for another 0.5 h. Filtration was carried out, and the filter cake was recrystallized with 150 mL of ethanol and dried in vacuo at 50 °C to obtain 37.9 g of white solid I with a yield of 86% and a purity of 99.9%.

[0066] 1 HNMR (600 MHz, CDCl3) δ: 9.02 (s, 1H), 4.82 - 4.87 (m, 1H), 2.97 (s, 3H), 2.48 (s, 3H), 2.17 - 2.24 (m, 2H), 1.89 - 1.97 (m, 4H), 1.56 - 1.64 (m, 2H); 13 CNMR (150 MHz, CDC13) δ: 174.44, 157.94, 149.81, 149.12, 132.68, 120.99, 109.30, 60.78, 38.93, 33.50, 26.20, 15.68; ESI-MS m / z: [M + H] + Theoretical value 370.0219, measured value 370.0222.

[0067] Example 10: Preparation of Compound I

[0068] Compound Ⅳ (32.8 g, 119 mmol), NBS (42.4 g, 238 mmol) and 200 mL of dioxane were successively added to the reaction system. After stirring evenly, p-toluenesulfonic acid (1.02 g, 5.95 mmol) and water (2.1 ml, 119 mmol) were added dropwise at room temperature. The reaction was carried out at room temperature for 1.5 h. The completion of the reaction was monitored by TLC. The reaction solution was poured into 450 mL of water, and stirring was continued for 0.5 h. The mixture was filtered by suction. The filter cake was recrystallized with 150 ml of ethanol and then dried in vacuo at 50 °C to obtain 37.0 g of white solid Ⅰ, with a yield of 84% and a purity of 99.9%.

[0069] The above-described embodiments are only preferred embodiments of the present invention and do not impose any limitations on the present invention. Any simple modifications, changes, and equivalent transformations made to the above embodiments without creative labor based on the technical essence of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. A preparation method of a key intermediate of the anti-breast cancer drug palbociclib, characterized in that, The preparation steps are as follows: 1) Compound VIII reacts with N,O-dimethylhydroxylamine under the conditions of an organic solvent, a base, and a condensing agent to prepare compound VII; 2) Compound VII is dissolved in an organic solvent and undergoes a nucleophilic substitution reaction with cyclopentylamine under the action of a base to obtain compound VI; 3) Compound VI is dissolved in an organic solvent, and a methylation reaction occurs by dropping a solution of methylmagnesium bromide under nitrogen protection to obtain compound V; 4) After triethyl phosphonoacetate is dissolved, a base is added and the reaction is carried out at low temperature. Then, the solution of compound V is dropped into the reaction system. After a Wittig-Horner reaction, ring closure is achieved by heating to obtain compound IV; 5) Compound IV is dissolved in an organic solvent and reacts with NBS under acid catalysis to obtain compound I in one step through bromination and oxidation; The synthetic route is as follows:

2. The method according to claim 1, wherein In step 1), the organic solvent is dichloromethane, tetrahydrofuran, or toluene; the base is triethylamine, diisopropylethylamine, or pyridine; the condensing agent is CDI, DCC, or DMAP; the reaction temperature is 10 - 30°C; and the molar ratio of compound VIII, base, condensing agent, and N,O-dimethylhydroxylamine is 1:2 - 3:1 - 2:1 - 2.

3. The method according to claim 1, characterized in that In step 2), the organic solvent is dichloromethane, acetonitrile, or ethanol; the base is triethylamine, diisopropylethylamine, or N-methylmorpholine; the reaction temperature is 15 - 30°C; and the molar ratio of compound VII, base, and cyclopentylamine is 1:1 - 2:1 - 1.

5.

4. The method according to claim 1, wherein In step 3), the organic solvent is tetrahydrofuran, toluene, or ethylene glycol dimethyl ether.

5. The method according to claim 1, characterized in that In step 4), the reaction temperature is 0 - 10°C and the reaction time is 1 - 2 h.

6. The method according to claim 1, characterized in that, In step 4), the molar ratio of compound VI to methylmagnesium bromide is 1:1.5 - 3.

7. The method according to claim 1, characterized in that In step 4), the organic solvent is tetrahydrofuran, toluene, or ethylene glycol dimethyl ether. After dropping at 0 - 10°C, the temperature is raised to reflux for reaction; the base is sodium hydride, sodium tert-butoxide, or sodium ethoxide; and the molar ratio of compound V, base, and triethyl phosphonoacetate is 1:1.5 - 3:1.5 - 3.

8. The method according to claim 1, characterized in that, In step 5), the organic solvent is tetrahydrofuran, acetonitrile, or dioxane; the reaction temperature is 10 - 30°C; the acid is acetic acid, p-toluenesulfonic acid, or oxalic acid; and the molar ratio of compound V, acid, NBS, and water is 1:0.05 - 0.2:2 - 3:1 - 2.

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