LU508058B1 - Method for preparing abemaciclib and intermediate thereof - Google Patents

Abstract

The present invention provides a method for preparing abemaciclib and intermediate thereof. The present invention relates to an intermediate of abemaciclib which is 3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) prop -2-en-1-one (V) and also provides a method for preparing the intermediate. Abemaciclib (I) can be prepared from intermediate V and N-(5-((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) guanidine (VI) by cyclization. The preparation method has the advantages of easy availability of raw materials, low cost, less side reactions, safety and environmental protection.

Description

DESCRIPTION

METHOD FOR PREPARING ABEMACICLIB AND INTERMEDIATE THEREOF

TECHNICAL FIELD

The present invention relates to a method for preparing abemaciclib intermediate, falling within the field of pharmaceutical and chemical industry.

BACKGROUND

Abemaciclib is an oral cyclin-dependent kinase CDK4/6 inhibitor developed by Lilly with primary indications for hormone receptor positive (HR+) and HER2 negative (HER2-) breast cancer. The other English name of abemaciclib is bemaciclib, and free base CAS

No: 1231929-97-7, with the chemical name = N-[5-[(4-ethyl-1-piperazinyl) methyl]-2-pyridyl]-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]-2-pyri midinamine, and the structural formula thereof is represented by formula |. Abemaciclib is approved for marketing in US food and drug administration (FDA) in 2017 and in China in 2020. Clinical research results show that abemaciclib is the first and only CDK4/6 inhibitor that can prolong progression-free survival (PFS) mainly in China patients. The marketing of the drug can benefit many domestic patients.

LE LU508058

In its original compound patent US20100160340, lilly reported a synthetic method for the synthesis of abemaciclib starting from 4-bromo-2, 6-difluoroaniline. The reaction scheme is as follows:

Br Se ge By N F + ~ . N y 01 SERUNEE ESS ENS ut YT STN Bed, FORCE i ES. SERIE § | i SIRES à 3 } OS N ar

ONE MARS Ta N Sa Plyy BOR

INT SES

+ = $ N A >

N ea cs PA i an i $

Fe N° + ® N Ne 2 ut = Ne

Hpi > ON A À Xa À = ¢ § Ne Naw Hi

A we Mgt ope 2" SN Sp Sp Ne Rigger, i a

Ÿ AF PETE REET dd Pasta. Kalten, AS

Y Ay ARS TRIG SRA Sag sd RRP, ANERNSS, WA pue sn... mn. LY J ‘ Sep

The above reaction scheme has several disadvantages: the first step is the use of homogeneous palladium catalyst in the last three-step chemical reaction, which is difficult to recover and costly. The legal limit of palladium residue in API is below 10ppm, and the quality control is also difficult. Secondly, the use of phosphorus oxychloride will lead to greater environmental processing pressure; finally, the boronate intermediate undergoes a competing reaction of two chlorines upon Suzuki coupling with 2, 4-dichloro-5-fluoropyrimidine and impurities are difficult to control.

Yet another method reported in the known literature fortilide reported in the known literature is to utilize the pyrimidine ring in the cyclization reaction framework product of guanidines.

_ LU508058

The PCT patent WO2016110224 first discloses a process for the synthesis of abemaciclib by cyclization of guanidines according to the following scheme: © 3 § $ © # A Tr i pe ag Se a Ne pt ne 5 sa : 3 Nig 5

The reaction scheme suffers from similar disadvantages: the reaction uses three fluorine-containing raw materials, 2, 6-difluoroaniline, fluoroacetonitrile and triflic acid, which not only has high cost, but also causes a lot of fluorine-containing waste which is difficult to handle. The use of phosphorus trichloride also results in difficult environmental processing. Sodium hydride has a potential safety hazard in production. Triflic acid is also relatively corrosive to equipment.

Chinese patent CN110218189 reports another method for the synthesis of abecitil by cyclization of guanidine compounds, and the reaction scheme is as follows: x ; . on ge Ne a Ne

NEN Ÿ UN % % PE 3 TI Se i SRS , HR Det ¥ Sgt wed

Q N

& ; x amas > > RS EE NE i 3 $ a | PTS ES PS x SN N ; $ x SSSR ta” Sy EN Ate

ES § | 8 ES { à Sons

Na WE ag : ‘ ce ” ! 3 $ SESE 3

The reaction route has obvious advantages in raw material cost and discards the raw materials such as phosphorus oxychloride, phosphorus trichloride and sodium hydride which have great environmental protection and safety pressure. However, the starting material fluoromethyl magnesium bromide is not commercially available, and no synthetic method can be found in the Scifinder database.

The synthesis of fluoromethyl magnesium bromide will directly affect the success or failure of the whole synthetic process.

SUMMARY

The present invention provides a novel method for preparing abemaciclib and intermediate thereof, the preparation method has cheap and easily available raw materials, and the process is relatively green and environment-friendly, and the palladium residue meets the requirements of drug supervision.

A method for preparing abemaciclib intermediate includes the following steps: (1) reacting |-isopropyl-2-methyl-4-fluoro-IH-benzo [d] imidazole -6-carbonitrile (Il) with a Grignard reagent to obtain compound lll; x.

Ni. > né “EASA à . ;

PSS EME A i i ; Fr 1 \ vo

NE SR ad (2)the compound Ill undergoing a condensation reaction with N,

N-dimethylformamide acetal to obtain a compound IV; and 0D ss Fray = My Le = Ny pes N ST OS Dr Ries =

As sf Sata (3) the compound IV undergoing fluorination reaction under the action of a

Selectfluor to obtain the abemaciclib intermediate V:

X NÉ Selig, Ÿ AN

Pow S

In the present invention, the use of fluoromethyl magnesium bromide, which is difficult to obtain and difficult to synthesize, is effectively avoided, and methyl magnesium chloride, which is readily available on the market, is used instead, followed by fluorination with an industrial fluorinating agent-selective fluorine.

Since fluorine is easily selected for free radical fluorination of active hydrogen such as methyl hydrogen of the starting compound IV (literature reference: angew. Chem. Int.

Ed. 2014, 53, 1-5 and Org. Bio mol. Chem. 2015, 13, 2890-2894), so their side reactions are effectively suppressed by the addition of a radical scavenger to give the directed fluorinated product V. The process does not involve other raw materials with considerable safety and environmental concerns.

In step (1), the Grignard reagent is methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide

In step (2), the N, N-dimethylformamide acetal is N, N-dimethylformamide dimethyl acetal (DMF-DMA) or N, N-dimethylformamide diethyl acetal (DMF-DEA). The reaction solvent in step (2) is toluene, xylene, N, N-dimethylformamide, dimethylsulfoxide or acetonitrile.

In step (3), the selective Selectfluor is 1-chloromethyl-4-fluoro-1, 4-diazoniabicyclo [2.2.2] octane ditetrafluoroborate or 1-fluoro-4-methyl-1, 4-diazabicyclo [2.2.2] octane tetrafluoroborate (Selectfluorll). The reaction is performed under basic conditions, and the base is sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate or an organic amine such as triethylamine and 4-dimethylaminopyridine (DMAP). Preferably, the base is sodium acetate. The reaction requires the addition of a radical scavenger such as 2, 2, 6, 6-tetramethylpiperidinooxy (TEMPO) or a phenolic compound. Preferably, the phenolic compound is 2,6-di-tert-butyl-p-cresol (BHT).

The reaction solvent is dichloromethane, acetone, tetrahydrofuran, acetonitrile or an alcohol solvent, and preferably, the alcohol solvent comprises methanol, and the ethanol is isopropanol.

The present invention also provides a process for the preparation of abemaciclib comprising the following steps: (A) obtaining abemaciclib intermediate V according to the above method; and (B) obtaining the novel anti-tumor drug abemaciclib | by cyclization of an abemaciclib intermediate V and a guanidine intermediate VI under the action of a base.

NN “x a Se _ SD CNT = ye

À À be ; ose, ets” sh Aon À,

The guanidine intermediate VI is a free base or a salt thereof such as nitrate, hydrochloride. The base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium methoxide or an organic amine such as triethylamine, 1, 8-diazabicycloundec-7-ene (DBU). Preferably, the base is sodium methoxide.

Compared with the prior art, the present method avoids the use of a variety of expensive fluorine-containing raw materials and palladium-based catalysts, the process raw materials are readily available, the cost is low, competitive side reactions are less, and the process is relatively green, low-carbon, safe and environmentally friendly. The fluorine atom on the pyrimidine ring is derived from a relatively inexpensive, readily available industrial feedstock-selected fluorine reagent. The process discards the phosphorus oxychloride, phosphorus trichloride and sodium hydride which have great environmental safety problems.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a high-resolution mass spectrum of obtained abemaciclib of the present invention.

DETAILED DESCRIPTION

Specific examples of the present invention are illustrated with reference to the following embodiments. The examples are intended to illustrate the present invention and are not intended to limit the present invention in any way.

The synthesis method of the raw material 1-isopropyl-2-methyl-4-fluoro-1H-benzo[d]imidazo-6-formonitrile(ll) is referred to the

Chinese patent CN110218189.

Example 1 synthesis of compound Ill:

Ses 9 Le

ETS EN

FX g i 1-Isopropyl-2-methyl-4-fluoro-1H-benzo [d] imidazole-6-carbonitrile Il (21.73 g, 0.1 mol) was weighed into a reaction flask, and tetrahydrofuran (60 mL) was added for stirring and dissolution. After cooling to 0-5°C in an ice-water bath, methylmagnesium chloride tetrahydrofuran solution (3 M, 34 mL) was added dropwise, and the mixture was allowed to warm to room temperature for 1 hour. 10% ammonium chloride solution (60 mL) was added to quench the reaction. Dichloromethane (80 mL) was added to stir for then the layers were separated, the organic layer was washed with water twice, dried with anhydrous sodium sulfate, suction filtered, washed with dichloromethane, and rotovaped to obtain intermediate Ill (21.37 g) in 91% yield.

Example 2 synthesis of compound Ill:

EN Se on Fo 1-Isopropyl-2-4-fluoro-methyl-1H-benzo [d] imidazole-6-carbonitrile Il (21.73 g, 0.1 mol) was weighed into a reaction flask, and tetrahydrofuran (60 mL) was added for stirring and dissolution. After cooling to 0-5°C in an ice-water bath, methylmagnesium bromide 2-methyl tetrahydrofuran solution (3 M, 34 mL) was added dropwise, and the mixture was allowed to warm to room temperature for 1 hour. 10% ammonium chloride solution (60 mL) was added to quench the reaction, methyl tert-butyl ether (100 mL) was added to stir for 15 min, then the layers were separated, the organic layer was washed with water twice, dried with anhydrous sodium sulfate, suction filtered, washed with dichloromethane, and rotovaped to obtain intermediate Ill (21.63 g) in 92% yield.

Example 3 synthesis of compound Ill: a. Sa

Fou § 3 1-Isopropyl-2-methyl-4-fluoro-1H-benzo [d] imidazole-6-carbonitrile Il (21.73 g, 0.1 mol) was weighed into a reaction flask, and tetrahydrofuran (60 mL) was added for stirring and dissolution. After cooling to 0-5°C in an ice-water bath, methyl magnesium iodide tetrahydrofuran solution (1 M, 100 mL) was added dropwise, and the mixture was allowed to warm to room temperature for 1 hour. 10% ammonium chloride solution (60 mL) was added to quench the reaction, dichloromethane (100 mL) was added to stir for min, then the layers were separated, the organic layer was washed with water twice, dried with anhydrous sodium sulfate, suction filtered, washed with dichloromethane and rotovaped to give intermediate Ill (20.46 g) in 87% yield.

Example 4 synthesis of compound IV:

Md EE

Compound Ill (23.43 g, 0.1 mol) and N, N-dimethylformamide dimethyl acetal (17.87 g, 0.15 mol) were weighed into a reaction bottle, toluene (60 mL) was added to stir and dissolve for 5 min, and the temperature was raised for 10 h. The reaction was concentrated under reduced pressure to give intermediate Ill (28.94 g) in 100% yield.

Example 5 synthesis of compound IV: 3 RE # IN

Compound Ill (23.43 g, 0.1 mol) and N, N-dimethylformamide diethyl acetal (22.08 g, 0.15 mol) were weighed into a reaction bottle, N, N-dimethylformamide (60 mL) was added to stir and dissolve for 5 min, and the temperature was raised for 10 h. The reaction was concentrated under reduced pressure to give intermediate Ill (31.74 g) in 100% yield.

Example 6 synthesis of compound V:

Se Sd

Fo FV

Compound IV (28.94 g, 0.1 mol), 1-chloromethyl-4-fluoro-1, 4-diazoniabicyclo [2.2.2] octane bistetrafluoroborate (35.43 g, 0.1 mol), sodium acetate (8.2 g, 0.1 mol) and 2, 6-di-tert-butyl-p-cresol (66.11 g, 0.3 mol) were weighed into a reaction flask.

Tetrahydrofuran (200 mL) was added and the reaction was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was spin-dried, dichloromethane

(160 mL) and water (160 mL) were added and stirred for 15 min, and then the layers were separated.

The organic layer was washed with ice-cold 5% sodium hydroxide solution twice, dried over anhydrous sodium sulfate, washed with dichloromethane and spin-dried to obtain intermediate Ill (25.87 g) in a yield of 84%.

Example 7 synthesis of compound V: “ee Nu er Nues ' AN Selene, | oP voy Fy

Compound IV (28.94 g, 0.1 mol), I-chloromethyl-4-fluoro-I, 4-diazoniabicyclo [2.2.2] octane bistetrafluoroborate (35.43 g, 0.1 mol), 4-dimethylamino pyridine (12.22 g, 0.1 mol) and 2, 2, 6, 6-tetramethy! piperidine oxide (3.13 g, 0.02 mol) were weighed into a reaction flask. Methanol (200 mL) was added and the reaction was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was spin-dried, dichloromethane (160 mL) and water (160 mL) were added, stirred for 15 min, and then the layers were separated. The organic layer was washed twice with ice-cold 5% sodium hydroxide solution, dried over anhydrous sodium sulfate, suction filtered, washed with dichloromethane, and spin-dried to obtain intermediate Ill (20.68 g) in 67% yield.

Example 8 synthesis of compound V:

Se ga Senet Se

NS À Sekten. | N

Fo Fy

Compound IV (28.94 g, 0.1 mol), 1-chloromethyl-4-fluoro-1, 4-diazoniabicyclo [2.2.2] octane bistetrafluoroborate (35.43 g, 0.1 mol), potassium carbonate (13.82 g, 0.1 mol) and 2, 6-di-tert-butyl-p-cresol (6.61 g, 0.03 mol) were weighed into a reaction flask.

Acetone (200 mL) was added and the reaction was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was spin-dried, dichloromethane (160 mL) and water (160 mL) were added and stirred for 15 min, then the layers were separated, and the organic layer was washed twice with ice-cold 5% sodium hydroxide solution, dried with anhydrous sodium sulfate, suction filtered, washed with dichloromethane, and spin-dried to obtain intermediate II! (23.64 g) in a yield of 77%.

Example 9 synthesis of compound V: x “Nay gr Sy ee

YN KENNEN | NA

Sata Std ; M ! y ’

Compound IV (28.94g, 0.1 mol), 1-fluoro-4-methyl-1, 4-diazabicyclo [2.2.2] octane tetrafluoroborate (31.98 g, 0.1 mol), sodium acetate (82 g, 0.1 mol) and 2, 6-di-tert-butyl-p-cresol (22.04 g, 0.1 mol) were weighed into a reaction flask.

Dichloromethane (200 mL) was added and the reaction was stirred at room temperature for 5 hours. After the completion of the reaction, water (160 mL) was added and stirred for 15 minutes. The layers were separated and the organic layer was washed twice with ice -5% sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered by suction, washed with dichloromethane and rotovaped to give intermediate Ill (24.1 g) in 78% yield.

Example 10 synthesis of abemaciclib (1):

Fou 3 È

Compound V (30.73 g, 0.1 mol), compound VI nitrate (32.54 g, 0.1 mol) and 27% sodium methoxide methanol solution (20 g, 0.1 mol) were weighed into a reaction flask,

N, N-dimethylformamide (130 mL) was added to slowly raise the temperature to about 100°C for reaction, the low boiling point was evaporated at the same time, and the solvent was evaporated under reduced pressure after 5 hours of reaction.

White product | (44.13 g, HPLC purity 98.0%) was obtained by recrystallization with 95% ethanol (165 mL) in 87% yield, HRMS:calcd for C 27 H 33 F2 N8 [M +H] + 507.2791 found 507.2788.

Claims (10)

1. A method for preparing abemaciclib intermediate, comprising the following steps: (1) reacting l-isopropyl-2-methyl-4-fluoro-IH-benzo [d] imidazole-6-carbonitrile (Il) with a Grignard reagent to obtain compound III; > “Ny age ARMS ESS Sp Lo # Po Fo pm (2)the compound Ill undergoing a condensation reaction with N, N-dimethylformamide acetal to obtain a compound IV; and 2 Le Pats, = A a of DMF acetal 2 A ta of So 1 La ju RR RN [ia Ÿ T Fa ee f Sa => wu (3) the compound IV undergoing fluorination reaction under the action of a Selectfluor to obtain the abemaciclib intermediate V: Ro IEA * Bo Jt + i NN “Ny Ne N Ny No > 3 x { Redgate à à A i} ¢ R or SR, Sssaise, R og ba Sg N de “WN Ê FV

2. The method for preparing abemaciclib intermediate according to claim 1, wherein in step (1), the Grignard reagent is methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.

3. The method for preparing abemaciclib intermediate according to claim 1, wherein in step (2), the N, N-dimethylformamide acetal is N, N-dimethylformamide dimethyl acetal (DMF-DMA) or N, N-dimethylformamide diethyl acetal (DMF-DEA).

4. The method for preparing abemaciclib intermediate according to claim 1, wherein the reaction solvent in step (2) is toluene, xylene, N, N-dimethylformamide, dimethylsulfoxide or acetonitrile.

5. The method for preparing abemaciclib intermediate according to claim 1, wherein in step (3), the selective Selectfluor is 1-chloromethyl-4-fluoro-1, 4-diazoniabicyclo [2.2.2] octane ditetrafluoroborate or 1-fluoro-4-methyl-1, 4-diazabicyclo [2.2.2] octane tetrafluoroborate (Selectfluorll).

6. The method for preparing abemaciclib intermediate according to claim 1, wherein in step (3), the reaction is performed under basic condition, and the base used is sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate or organic amine compound.

7. The method for preparing abemaciclib intermediate according to claim 1, wherein in step (3), a radical scavenger is added, and the radical scavenger used is 2, 2, 6, 6-tetramethylpiperidinooxy (TEMPO) or a phenolic compound.

8. The method for preparing abemaciclib intermediate according to claim 1, wherein the reaction solvent in step (3) is dichloromethane, acetone, tetrahydrofuran, acetonitrile or an alcohol solvent.

9. A method for preparing abemaciclib intermediate, comprising the following steps: (A) obtaining abemaciclib intermediate V according to the method according to any one of claims 1-8; and (B) obtaining the novel anti-tumor drug abemaciclib | by cyclization of an abemaciclib intermediate V and a guanidine intermediate VI under the action of a base;

_ LU508058 gg Te Va ar Nap Net Se i Fo COX we pe En 8 ? Ang ) Be A

10. The method for preparing abemaciclib intermediate 9, wherein in step (B), the guanidine intermediate VI is a free base or a salt thereof; and the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium methoxide or an organic amine compound.