CN107522701A - A kind of synthetic method for the BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia - Google Patents

A kind of synthetic method for the BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia Download PDF

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CN107522701A
CN107522701A CN201710778626.9A CN201710778626A CN107522701A CN 107522701 A CN107522701 A CN 107522701A CN 201710778626 A CN201710778626 A CN 201710778626A CN 107522701 A CN107522701 A CN 107522701A
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pyrazine
bases
imidazo
phenyl
reaction
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CN107522701B (en
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莫国宁
查晓明
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SUZHOU FUSHILAI PHARMACEUTICAL Co Ltd
China Pharmaceutical University
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SUZHOU FUSHILAI PHARMACEUTICAL Co Ltd
China Pharmaceutical University
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

A kind of synthetic method for the BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia, step：Prepare (S) 2 (8 aminooimidazoles simultaneously the base of [1,5 a] pyrazine 3) 1 pyrrolidinecarboxylic acid benzyl ester；Prepare (S) 2 (base of 8 t-butoxycarbonyl amino imidazos [1,5 a] pyrazine 3) 1 pyrrolidinecarboxylic acid benzyl ester；Prepare (S) 2 (base of the bromine imidazo of 8 t-butoxycarbonyl amino 1 [1,5 a] pyrazine 3) 1 pyrrolidinecarboxylic acid benzyl ester；Prepare (S) 2 { base of 8 t-butoxycarbonyl amino 1 [4 (2 pyridine radicals carbamyl) phenyl] imidazo [1,5 a] pyrazine 3 } 1 pyrrolidinecarboxylic acid benzyl ester；Prepare (S) 2 { base of 8 t-butoxycarbonyl amino 1 [4 (2 pyridine radicals carbamyl) phenyl] imidazo [1,5 a] pyrazine 3 } pyrrolidines；Prepare (S) 2 { base of 8 t-butoxycarbonyl amino 1 [4 (2 pyridine radicals carbamyl) phenyl] imidazo [1,5 a] pyrazine 3 } 1 (2 butine acyl group) pyrrolidines；Prepare Acalabrutinib.High income；Simple flow；It is green.

Description

A kind of BTK inhibitor Acalabrutinib's for treating chronic lymphocytic leukemia Synthetic method
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, and in particular to a kind of chronic lymphocytic leukemia for the treatment of BTK inhibitor Acalabrutinib synthetic method.
Background technology
Second generation bruton's EGFR-TK (BTK) inhibitor Acalabrutinib is Astrazeneca AB's research and development PTS, for treating chronic lymphocytic leukemia.Entitled (the S) -2- of its chemistry { 8- amino -1- [4- (2- pyridine radicals ammonia Formoxyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines, its chemical structural formula is：
Acalabrutinib has obtained European Bureau of Drugs Supervision and has authorized Orphan drug qualification, and continuous three Orphan drugs of harvest adapt to Disease, respectively for chronic lymphocytic leukemia (CLL)/small lymphocyte lymthoma (SLL), lymphoma mantle cell (MCL) and Lymphoma lymphoplasmacytic.The medicine is played a role by permanent bond BTK, and BTK is one of a kind of Special Proteins Point, and this Special Proteins can from CLL cell surfaces by signal transmit nucleus in gene, so as to promote cancer cell to survive And growth, by blocking BTK, medicine Acalabrutinib cans suppress the growth signals of CLL cells, until promoting cancer thin Born of the same parents are dead.Peak value is sold up to 5,000,000,000 dollars after Acalabrutinib estimation listings, will be new as the one of Astrazeneca AB Heavy pound medicine.
The patent US20140155406A1 of Yuan Yan companies, WO2016024227Al disclose one kind and prepared Acalabrutinib synthetic route, it is as follows：
Due to-the NH on pyrazine ring2To react reactive group, continuous several steps are reacted, multiple by unavoidably causing Competitive side reaction, more impurity is introduced, intermediate down and the quality of final products and purifying process are caused not Profit influences, and causes complex operation cumbersome, is unfavorable for amplification production and Industry Promotion.In order to seek more efficient easily to prepare Acalabrutinib, it is therefore necessary to explore that technological process is short, simple to operate, cost is cheap and safety and environmental protection and use suitable The Acalabrutinib of industrialized production synthetic method.
The content of the invention
For the deficiencies in the prior art and defect, it is an object of the invention to provide one kind to treat chronic lymphocytic The BTK inhibitor Acalabrutinib of leukaemia synthetic method, this method process route is reasonable, operation is succinct, reagent is easy to get It is high with total recovery and be satisfied industrial amplification production requirement and excellent green safe environment protecting can be embodied.
The purpose of the present invention is such to what is reached, a kind of BTK inhibitor for treating chronic lymphocytic leukemia Acalabrutinib synthetic method, comprises the following steps：
(1) (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters are prepared：By (S) -2- (8- chlorine imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester is pressurizeed with ammoniacal liquor in 1-METHYLPYRROLIDONE Aminating reaction, obtain (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters；
(2) (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyls are prepared Ester：Will be by (S) -2- that step (1) obtains (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester and two Dimethyl dicarbonate butyl ester carries out amidation process in a solvent, obtains (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrroles Piperazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters；
(3) (S) -2- (8- t-butoxycarbonyl amino -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidines first is prepared Acid benzyl ester：Will be by (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrroles that step (2) obtain Alkane benzyl formate carries out bromination reaction in a solvent with bromide reagent, obtains (S) -2- (8- t-butoxycarbonyl amino -1- bromine imidazoles And [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters；
(4) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } -1- pyrrolidinecarboxylic acid benzyl esters：Will be by (S) -2- (8- t-butoxycarbonyl amino -1- bromines that step (3) obtain Imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester and 4- (2- pyridine radicals carbamyl) phenyl boric acid be in palladium chtalyst Catalyzed coupling reaction is carried out in the system that agent, inorganic salts, organic solvent and water form, obtains (S) -2- { 8- tertbutyloxycarbonyl ammonia Base -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- pyrrolidinecarboxylic acid benzyl esters；
(5) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } pyrrolidines：Will be by (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals that step (4) obtain Carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } the progress catalytic hydrogenation deaminizating protection of -1- pyrrolidinecarboxylic acids benzyl ester Reaction, obtains (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } pyrrolidines；
(6) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines：(S) -2- { 8- t-butoxycarbonyl aminos -1- will be obtained by step (5) [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } pyrrolidines and 2- butine acyl chlorides be in acid binding agent alkali Amidation process is carried out with the system of solvent composition, obtains (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals ammonia Formoxyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines；
(7) Acalabrutinib is prepared：Will be by (S) -2- { 8- t-butoxycarbonyl amino -1- [4- that step (6) obtain (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines put into by three In the system that fluoroacetic acid and solvent are formed, deprotection reaction, the BTK inhibitor for the chronic lymphocytic leukemia that obtains medical treatment are carried out Acalabrutinib。
In the specific embodiment of the present invention, the mass percent concentration of the ammoniacal liquor described in step (1) is 28%； The mol ratio of both described (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester and ammoniacal liquor For 1.0: (5.5~6.5).
In another specific embodiment of the present invention, the solvent described in step (2) is dichloromethane, the chloroethenes of 1,2- bis- Alkane, chloroform, toluene, methyl tertiary butyl ether(MTBE), acetonitrile or 1,4- dioxane；(8- aminooimidazoles are simultaneously [1,5-a] by described (S) -2- Pyrazine -3- bases) mol ratio of -1- pyrrolidinecarboxylic acids benzyl ester and di-tert-butyl dicarbonate is 1.0: 1.0~1.2.
In another specific embodiment of the present invention, the bromide reagent described in step (3) is sub- for N- bromos succinyl Amine or bromine water；Described solvent is tetrahydrofuran, dichloromethane, 1,2- dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N, N- Dimethyl acetamide, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Wherein, described (S) -2- (8- t-butoxycarbonyl amino imidazoles And [1,5-a] pyrazine -3- bases) mol ratio of -1- pyrrolidinecarboxylic acids benzyl ester and bromide reagent is 1.0: 1.05~1.18.
In another specific embodiment of the present invention, the palladium catalyst described in step (4) is [1,1'- double (diphenyl Phosphino-) ferrocene] palladium chloride, four (triphenyl phosphorus) palladiums or two (triphenylphosphine) palladium chlorides；Described inorganic salts are carbonic acid Potassium, sodium carbonate, potassium phosphate, lithium chloride, sodium bromide, KBr, potassium acetate, KI or potassium chloride；Described organic solvent is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, chloroform, second Nitrile, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Wherein, described (S) -2- (8- t-butoxycarbonyl amino -1- bromines imidazo [1, 5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester, 4- (2- pyridine radicals carbamyl) phenyl boric acid, palladium catalyst, inorganic salts four The mol ratio of person is 1.0: 1.1~1.3: 0.025~0.075: 1.15~2.25.
In the also specific embodiment of the present invention, the catalytic hydrogenation deaminizating protection reaction described in step (5) Temperature be 30~60 DEG C, the reaction time is 6~12h.
There is a specific embodiment in the present invention, the acid binding agent alkali described in step (6) is N, N- diisopropyls Ethamine, triethylamine, diethylamine, trimethylamine, pyridine, piperidines, DMAP, 2,6- lutidines, aniline, N, N- bis- Toluidines, N, N- diethylanilines, tri-isopropyl amine, tri-n-butylamine, TMG, N-methylmorpholine or N-ethylmorpholine；It is described Solvent for tetrahydrofuran, dichloromethane, 1,2- dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide, Methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Wherein, (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyls Base) phenyl] imidazo [1,5-a] pyrazine -3- bases } pyrrolidines, 2- butine acyl chlorides, the mol ratio between acid binding agent alkali be 1.0: 1.0~1.5: 1.1~1.8.
In a still more specific embodiment of the invention, the solvent described in step (7) is methanol, ethanol, dichloromethane Alkane, ethyl acetate, tetrahydrofuran, isopropanol or dioxane；Wherein, (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyrroles Piperidinyl carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases -1- (2- butine acyl group) pyrrolidines, between trifluoroacetic acid Mol ratio is 1.0: 1.1~1.5.
The present invention's and then in a specific embodiment, the pressure of the aminating reaction described in step (1) is 0.2- 0.3MPa, reaction temperature are 70~90 DEG C, and the reaction time is 4~8h；The temperature of amidation process described in step (2) be 10~ 35 DEG C, the reaction time is 1~6h；The temperature of bromination reaction described in step (3) is 20~35 DEG C, and the reaction time is 2~6h；Step Suddenly the temperature of the catalyzed coupling reaction described in (4) is 80-110 DEG C, reaction time 12-24h；Amidatioon described in step (6) The temperature of reaction is 40~60 DEG C, and the reaction time is 4~12h；The temperature of deprotection reaction described in step (7) is 50~80 DEG C, the reaction time is 4~10h.
Technical scheme provided by the invention has following technique effect：First, only make after being completed due to the reaction of each step normal The post processing and purifying of rule property are less, controllable without column chromatography, impurity, can directly carry out next step reaction, therefore Operation is simplified, while each step can obtain higher yield；Second, the process route initiation material and used of the present invention Reagent is easy to get, and the technical scheme of synthetic reaction is reasonable, great simplification of flowsheet, can largely produce to meet bulk drug Use demand, suitable for industrialized production；Third, due to being reacted in preparation process without using hypertoxic harmful reagent, each unit Pollutant will not be produced, thus green safe effect can be embodied.
Embodiment
It will be detailed below the BTK inhibitor Acalabrutinib of the treatment chronic lymphocytic leukemia described in detail conjunction It is into route：
Embodiment 1
(1) (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters are prepared：
(S) -2- (8- chlorine imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester (10g, 28mmol) is dissolved in N- Methyl pyrrolidone (80mL), add mass percent concentration 28% ammoniacal liquor (168mmol), reactant mixture be placed in it is closed not Become rusty in steel reactor the stirring reaction 6h under 85 DEG C, the pressure of 2.5 atmospheric pressure, after completion of the reaction, is cooled to 40 DEG C and releasers It is pressure, is slowly added to water (50mL), is cooled to 10 DEG C, crystallization 3h, filtering, recrystallisation from isopropanol, obtains (S) -2- (8- amino miaows Azoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters, off-white powder (8.5g), yield 90%, the reaction of this step Formula is as follows：
(2) (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyls are prepared Ester：
(S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester (8g, 24mmol) is dissolved in Dichloromethane (100mL), addition di-tert-butyl dicarbonate (5.7g, 26mmol), reactant mixture stirring reaction 3h at 25 DEG C, After completion of the reaction, post-treated and purifying, obtains (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- Pyrrolidinecarboxylic acid benzyl ester, off-white powder (10g), yield 96%, the reaction equation of this step are as follows：
(3) (S) -2- (8- t-butoxycarbonyl amino -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidines first is prepared Acid benzyl ester：
(S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester (10g, Tetrahydrofuran (80mL) 23mmol) is dissolved in, is slowly added to N- bromo-succinimides (4.5g, 25mmol), reactant mixture 25 DEG C stirring reaction 4h.Reaction finishes, and is slowly added to water (80mL), is cooled to -10 DEG C of crystallization 3h, filtering, recrystallisation from isopropanol, obtains (S) -2- (8- t-butoxycarbonyl aminos -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters, off-white color are solid Body (11.1g), yield 94.5%, the reaction equation of this step are as follows：
(4) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } -1- pyrrolidinecarboxylic acid benzyl esters：
(S) -2- (8- t-butoxycarbonyl amino -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters (11g, 21mmol), 4- (2- pyridine radicals carbamyl) phenyl boric acid (5.7g, 23.4mmol), [double (diphenylphosphinos) two of 1,1'- Luxuriant iron] palladium chloride (0.78g, 1.1mmol), potassium carbonate (4.0g, 29mmol), N,N-dimethylformamide (120mL) and water (50mL) is added in reaction bulb, and reactant mixture is heated to 90 DEG C of stirring reaction 20h, and reaction solution is down to room temperature, and concentrated by rotary evaporation is extremely Do, add ethyl acetate extraction, salt washing, magnesium sulfate is dried, and to doing, ethyl acetate and n-hexane mixed solvent enter concentrated by rotary evaporation Row recrystallization, obtains (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazos [1,5-a] Pyrazine -3- bases } -1- pyrrolidinecarboxylic acid benzyl esters, off-white powder (10.3g), yield 76.5%, the reaction equation of this step is as follows：
(5) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } pyrrolidines：
(S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } -1- pyrrolidinecarboxylic acids benzyl ester (10g, 15.8mmol) is dissolved in methanol (80mL), and palladium charcoal (0.5g) is added, is passed through hydrogen The lower 35 DEG C of reactions 8h of normal pressure.Filter and catalyst is removed by diatomite, filtrate concentrated by rotary evaporation obtains (S) -2- { tertiary fourths of 8- to doing Oxygen carbonyl amino -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } pyrrolidines, white solid Powder (7.6g), yield 96%, the reaction equation of this step are as follows：
(6) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines：
(S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } pyrrolidines (7g, 14mmol) is dissolved in tetrahydrofuran (75mL), stirs, add 2- butine acyl chlorides (1.7g, 16.6mmol), DIPEA (2.7g, 21mmol), 50 DEG C of stirring reaction 8h of reactant mixture, reaction solution rotation is added dropwise Steaming is concentrated to dryness, and is added watery hydrochloric acid and is adjusted to neutrality, adds ethyl acetate extraction, and magnesium sulfate is dried, concentrated by rotary evaporation to dry, methanol Recrystallization, obtains (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } -1- (2- butine acyl group) pyrrolidines, off-white powder (7g), yield 88%, the reaction equation of this step is as follows：
(7) Acalabrutinib is prepared：
(S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } -1- (2- butine acyl group) pyrrolidines (7g, 12.4mmol) and methanol (70mL) is dissolved in, add trifluoroacetic acid (1.55g, 13.6mmol), for 65 DEG C of stirring reaction 6h to reacting complete, reaction solution is added drop-wise to the water (150mL) of stirring, is cooled to 0 DEG C crystallization 3h, filtering, the BTK inhibitor Acalabrutinib for the chronic lymphocytic leukemia that obtains medical treatment, white solid (5.3g), yield 92%, the reaction equation of this step are as follows：
Embodiment 2：
(1) (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters are prepared：
(S) -2- (8- chlorine imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester (15g, 42mmol) is dissolved in N- Methyl pyrrolidone (75mL), add mass percent concentration 28% ammoniacal liquor (273mmol), reactant mixture be placed in it is closed not Become rusty in steel reactor the stirring reaction 8h under 70 DEG C, the pressure of 3 atmospheric pressure, after completion of the reaction, is cooled to 40 DEG C and delivery systmes Pressure, water (50mL) is slowly added to, is cooled to 10 DEG C, crystallization 3h, filtering, recrystallisation from isopropanol, obtains (S) -2- (8- aminooimidazoles And [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters, off-white powder (12.9g), yield 91%, the reaction of this step Formula is the same as embodiment 1.
(2) (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyls are prepared Ester：
(S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester (12g, 35.6mmol) is molten In chloroform (80mL), di-tert-butyl dicarbonate (7.8g, 35.6mmol) is added, reactant mixture stirring reaction 1h at 35 DEG C, After completion of the reaction, post-treated and purifying, obtains (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- Pyrrolidinecarboxylic acid benzyl ester, off-white powder (14.8g), yield 95%, the reaction equation of this step is the same as embodiment 1.
(3) (S) -2- (8- t-butoxycarbonyl amino -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidines first is prepared Acid benzyl ester：
(S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester (14g, 1,2- dichloroethanes (90mL) 32mmol) is dissolved in, is slowly added to bromine water (6g, 37.8mmol), 20 DEG C of stirrings of reactant mixture are anti- Answer 6h.Reaction finishes, and is slowly added to water (15mL), is cooled to -5 DEG C of crystallization 4h, filtering, recrystallisation from isopropanol, obtains (S) -2- (8- T-butoxycarbonyl amino -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters, off-white powder (15.8g), yield 95.5%, the reaction equation of this step is the same as embodiment 1.
(4) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } -1- pyrrolidinecarboxylic acid benzyl esters：
(S) -2- (8- t-butoxycarbonyl amino -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters (15g, 29mmol), 4- (2- pyridine radicals carbamyl) phenyl boric acid (8.4g, 34.7mmol), four (triphenyl phosphorus) palladiums (0.84g, 0.73mmol), sodium carbonate (6.9g, 65mmol), tetrahydrofuran (100mL) and water (40mL) are added in reaction bulb, reaction mixing Thing is heated to 80 DEG C of stirring reaction 24h, and reaction solution is down to room temperature, and concentrated by rotary evaporation adds ethyl acetate extraction to doing, and salt is washed, Magnesium sulfate is dried, and to doing, ethyl acetate and n-hexane mixed solvent are recrystallized concentrated by rotary evaporation, obtain (S) -2- { tertiary fourth oxygen of 8- Carbonylamino -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- pyrrolidinecarboxylic acid benzyls Ester, off-white powder (14.4g), yield 78%, the reaction equation of this step is the same as embodiment 1.
(5) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } pyrrolidines：
(S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } -1- pyrrolidinecarboxylic acids benzyl ester (14g, 22mmol) is dissolved in isopropanol (85mL), and Raney's nickel (0.5g) is added, is passed through hydrogen The lower 60 DEG C of reactions 12h of gas normal pressure.Filter and catalyst is removed by diatomite, filtrate concentrated by rotary evaporation obtains (S) -2- { uncles 8- to doing Butoxy carbonyl amino -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } pyrrolidines, white is admittedly Body powder (10.4g), yield 94%, the reaction equation of this step is the same as embodiment 1.
(6) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines：
(S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } pyrrolidines (10g, 20mmol) is dissolved in DMF (80mL), stirs, add 2- butine acyl chlorides (3.1g, 30mmol), triethylamine (2.2g, 22mmol), 60 DEG C of stirring reaction 4h of reactant mixture, reaction solution concentrated by rotary evaporation is added dropwise To doing, add watery hydrochloric acid and adjust to neutrality, add ethyl acetate extraction, magnesium sulfate is dried, and concentrated by rotary evaporation to doing, tie again by methanol Crystalline substance, obtain (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- Base } -1- (2- butine acyl group) pyrrolidines, off-white powder (10.2g), yield 90.2%, the same embodiment of reaction equation of this step 1。
(7) Acalabrutinib is prepared：
(S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } -1- (2- butine acyl group) pyrrolidines (10g, 17.7mmol) and ethanol (100mL) is dissolved in, add trifluoroacetic acid (2.6g, 23mmol), for 50 DEG C of stirring reaction 10h to reacting complete, reaction solution is added drop-wise to the water (70mL) of stirring, is cooled to 0 DEG C Crystallization 3h, filtering, the BTK inhibitor Acalabrutinib for the chronic lymphocytic leukemia that obtains medical treatment, white solid (7.5g), yield 91%, the reaction equation of this step is the same as embodiment 1.
Embodiment 3：
(1) (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters are prepared：
(S) -2- (8- chlorine imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester (4.5g, 12.6mmol) is molten In 1-METHYLPYRROLIDONE (70mL), the ammoniacal liquor (69.4mmol) of mass percent concentration 28% is added, reactant mixture is placed in In closed stainless steel cauldron under 90 DEG C, the pressure of 2 atmospheric pressure stirring reaction 4h, after completion of the reaction, be cooled to 35 DEG C and release System pressure is put, is slowly added to water (50mL), 10 DEG C, crystallization 3h is cooled to, filtering, recrystallisation from isopropanol, obtains (S) -2- (8- ammonia Base imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters, off-white powder (3.9g), yield 92%, this step Reaction equation is the same as embodiment 1.
(2) (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyls are prepared Ester：
(S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester (3.5g, 10.4mmol) Isosorbide-5-Nitrae-dioxane (50mL) is dissolved in, adds di-tert-butyl dicarbonate (2.7g, 12.4mmol), reactant mixture stirs at 10 DEG C Reaction 6h is mixed, after completion of the reaction, post-treated and purifying, obtains (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrroles Piperazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters, off-white powder (4.3g), yield 95%, the reaction equation of this step is the same as embodiment 1.
(3) (S) -2- (8- t-butoxycarbonyl amino -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidines first is prepared Acid benzyl ester：
(S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester (4g, Toluene (50mL) 9.6mmol) is dissolved in, is slowly added to N- bromo-succinimides (1.8g, 10.1mmol), 35 DEG C of reactant mixture Stirring reaction 2h.Reaction finishes, and is slowly added to water (25mL), is cooled to -10 DEG C of crystallization 3h, filtering, recrystallisation from isopropanol, obtains (S) -2- (8- t-butoxycarbonyl aminos -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters, off-white color are solid Body (4.7g), yield 94%, the reaction equation of this step is the same as embodiment 1.
(4) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } -1- pyrrolidinecarboxylic acid benzyl esters：
(S) -2- (8- t-butoxycarbonyl amino -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters (4g, 7.7mmol), 4- (2- pyridine radicals carbamyl) phenyl boric acid (2.4g, 10mmol), two (triphenylphosphine) palladium chlorides (0.41g, 0.58mmol), potassium phosphate (1.9g, 8.9mmol), methyl tertiary butyl ether(MTBE) (100mL) and water (40mL) add reaction bulb In, reactant mixture is heated to 100 DEG C of stirring reaction 12h, and reaction solution is down to room temperature, concentrated by rotary evaporation to dry, addition ethyl acetate Extraction, salt washing, magnesium sulfate are dried, and to dry, ethyl acetate and n-hexane mixed solvent are recrystallized concentrated by rotary evaporation, obtain (S)- 2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- pyrroles Alkane benzyl formate is coughed up, off-white powder (3.9g), yield 79%, the reaction equation of this step is the same as embodiment 1.
(5) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } pyrrolidines：
(S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } -1- pyrrolidinecarboxylic acids benzyl ester (3.5g, 5.5mmol) is dissolved in ethanol (50mL), and palladium charcoal (0.2g) is added, is passed through hydrogen The lower 45 DEG C of reactions 6h of normal pressure.Filter and catalyst is removed by diatomite, filtrate concentrated by rotary evaporation obtains (S) -2- { tertiary fourths of 8- to doing Oxygen carbonyl amino -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } pyrrolidines, white solid Powder (2.6g), yield 95%, the reaction equation of this step is the same as embodiment 1.
(6) prepare (S) -2- 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1, 5-a] pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines：
(S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } pyrrolidines (2.5g, 5mmol) is dissolved in toluene (50mL), stirs, add 2- butine acyl chlorides (0.62g, 6mmol), drop Add N, N- dimethylanilines (1g, 8.5mmol), 40 DEG C of stirring reaction 12h of reactant mixture, reaction solution concentrated by rotary evaporation to dry, addition Watery hydrochloric acid is adjusted to neutrality, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation recrystallizing methanol, obtains (S) -2- to doing { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- (2- fourths Alkynes acyl group) pyrrolidines, off-white powder (2.5g), yield 88%, the reaction equation of this step is the same as embodiment 1.
(7) Acalabrutinib is prepared：
(S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } -1- (2- butine acyl group) pyrrolidines (2.5g, 4.4mmol) and dichloromethane (10mL) is dissolved in, add trifluoroacetic acid (0.76g, 6.6mmol), for 80 DEG C of stirring reaction 4h to reacting complete, reaction solution is added drop-wise to the water (25mL) of stirring, is cooled to 0 DEG C Crystallization 3h, filtering, the BTK inhibitor Acalabrutinib for the chronic lymphocytic leukemia that obtains medical treatment, white solid (1.8g), yield 89%, the reaction equation of this step is the same as embodiment 1.

Claims (9)

  1. A kind of 1. synthetic method for the BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia, it is characterised in that Comprise the following steps：
    （1）Prepare (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters：By (S) -2- (8- Chlorine imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester and ammoniacal liquor carries out pressurization ammonia in 1-METHYLPYRROLIDONE Change reaction, obtain (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters；
    （2）Prepare (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters：Will By step（1）Obtained (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester and two carbonic acid Di tert butyl carbonate carries out amidation process in a solvent, obtain (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine - 3- yls) -1- pyrrolidinecarboxylic acid benzyl esters；
    （3）Prepare (S) -2- (8- t-butoxycarbonyl amino -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyls Ester：Will be by step（2）Obtained (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- pyrrolidines first Acid benzyl ester carries out bromination reaction in a solvent with bromide reagent, obtains (S) -2- (8- t-butoxycarbonyl amino -1- bromine imidazos [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acid benzyl esters；
    （4）Prepare (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazos [1,5-a] Pyrazine -3- bases } -1- pyrrolidinecarboxylic acid benzyl esters：Will be by step（3）Obtained (S) -2- (8- t-butoxycarbonyl amino -1- bromine imidazoles And [1,5-a] pyrazine -3- bases) -1- pyrrolidinecarboxylic acids benzyl ester and 4- (2- pyridine radicals carbamyl) phenyl boric acid be in palladium catalyst, nothing Catalyzed coupling reaction is carried out in the system of machine salt, organic solvent and water composition, obtains (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- pyrrolidinecarboxylic acid benzyl esters；
    （5）Prepare (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazos [1,5-a] Pyrazine -3- bases } pyrrolidines：Will be by step（4）Obtained (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals ammonia first Acyl group) phenyl] imidazo [1,5-a] pyrazine -3- bases } the progress catalytic hydrogenation deaminizating protection reaction of -1- pyrrolidinecarboxylic acids benzyl ester, Obtain (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- Base } pyrrolidines；
    （6）Prepare (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazos [1,5-a] Pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines：Will be by step（5）Obtain (S) -2- { 8- t-butoxycarbonyl amino -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases pyrrolidines and 2- butine acyl chlorides in acid binding agent alkali and Amidation process is carried out in the system of solvent composition, obtains (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals ammonia first Acyl group) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines；
    （7）Prepare Acalabrutinib：Will be by step（6）Obtained (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyrroles Piperidinyl carbamyl) phenyl] imidazo [1,5-a] pyrazine -3- bases } -1- (2- butine acyl group) pyrrolidines put into by trifluoro second In the system that acid and solvent are formed, deprotection reaction, the BTK inhibitor for the chronic lymphocytic leukemia that obtains medical treatment are carried out Acalabrutinib。
  2. 2. a kind of BTK inhibitor Acalabrutinib's for treating chronic lymphocytic leukemia according to claim 1 Synthetic method, it is characterised in that step（1）The mass percent concentration of described ammoniacal liquor is 28%；Described (S) -2- (8- amino Imidazo [1,5-a] pyrazine -3- bases) mol ratio of both -1- pyrrolidinecarboxylic acids benzyl ester and ammoniacal liquor is 1.0:（5.5~6.5）.
  3. 3. a kind of BTK inhibitor Acalabrutinib's for treating chronic lymphocytic leukemia according to claim 1 Synthetic method, it is characterised in that step（2）Described solvent is dichloromethane, 1,2- dichloroethanes, chloroform, toluene, methyl- tert Butyl ether, acetonitrile or 1,4- dioxane；Described (S) -2- (8- aminooimidazoles simultaneously [1,5-a] pyrazine -3- bases) -1- pyrrolidines The mol ratio of benzyl formate and di-tert-butyl dicarbonate is 1.0: 1.0 ~ 1.2.
  4. 4. a kind of BTK inhibitor Acalabrutinib's for treating chronic lymphocytic leukemia according to claim 1 Synthetic method, it is characterised in that step（3）Described bromide reagent is N- bromo-succinimides or bromine water；Described solvent is Tetrahydrofuran, dichloromethane, 1,2- dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, DMAC N,N' dimethyl acetamide, methyl- tert fourth Base ether or 1,4- dioxane；Wherein, described (S) -2- (8- t-butoxycarbonyl aminos imidazo [1,5-a] pyrazine -3- bases) -1- Pyrrolidinecarboxylic acid benzyl ester and the mol ratio of bromide reagent are 1.0: 1.05 ~ 1.18.
  5. 5. a kind of BTK inhibitor Acalabrutinib's for treating chronic lymphocytic leukemia according to claim 1 Synthetic method, it is characterised in that step（4）Described palladium catalyst is [double (diphenylphosphino) ferrocene of 1,1'-] dichloride Palladium, four (triphenyl phosphorus) palladiums or two (triphenylphosphine) palladium chlorides；Described inorganic salts are potassium carbonate, sodium carbonate, potassium phosphate, chlorine Change lithium, sodium bromide, KBr, potassium acetate, KI or potassium chloride；Described organic solvent is N,N-dimethylformamide, N, N- dimethyl acetamides, tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, chloroform, acetonitrile, methyl tertiary butyl ether(MTBE) or 1, 4- dioxane；Wherein, described (S) -2- (8- t-butoxycarbonyl aminos -1- bromines imidazo [1,5-a] pyrazine -3- bases) -1- pyrroles Cough up the mol ratios of alkane benzyl formate, 4- (2- pyridine radicals carbamyl) phenyl boric acid, palladium catalyst, inorganic salts for 1.0: 1.1 ~ 1.3∶0.025~0.075∶1.15~2.25。
  6. 6. a kind of BTK inhibitor Acalabrutinib's for treating chronic lymphocytic leukemia according to claim 1 Synthetic method, it is characterised in that step（5）The temperature of described catalytic hydrogenation deaminizating protection reaction is 30 ~ 60 DEG C, during reaction Between be 6 ~ 12h.
  7. 7. a kind of BTK inhibitor Acalabrutinib's for treating chronic lymphocytic leukemia according to claim 1 Synthetic method, it is characterised in that step（6）Described acid binding agent alkali is N, N- diisopropylethylamine, triethylamine, diethylamine, front three Amine, pyridine, piperidines, DMAP, 2,6- lutidines, aniline, N, N- dimethylanilines, N, N- diethylanilines, Tri-isopropyl amine, tri-n-butylamine, TMG, N-methylmorpholine or N-ethylmorpholine；Described solvent is tetrahydrofuran, dichloromethane Alkane, 1,2- dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide, methyl tertiary butyl ether(MTBE) or 1,4- dioxies six Ring；Wherein, (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazo [1,5-a] pyrroles Piperazine -3- bases } pyrrolidines, 2- butine acyl chlorides, the mol ratio between acid binding agent alkali be 1.0: 1.0 ~ 1.5: 1.1 ~ 1.8.
  8. 8. a kind of BTK inhibitor Acalabrutinib's for treating chronic lymphocytic leukemia according to claim 1 Synthetic method, it is characterised in that step（7）Described solvent is methanol, ethanol, dichloromethane, ethyl acetate, tetrahydrofuran, different Propyl alcohol or dioxane；Wherein, (S) -2- { 8- t-butoxycarbonyl aminos -1- [4- (2- pyridine radicals carbamyl) phenyl] imidazoles And [1,5-a] pyrazine -3- bases -1- (2- butine acyl group) pyrrolidines, the mol ratio between trifluoroacetic acid be 1.0: 1.1 ~ 1.5.
  9. 9. a kind of BTK inhibitor Acalabrutinib's for treating chronic lymphocytic leukemia according to claim 1 Synthetic method, it is characterised in that step（1）The pressure of described aminating reaction is 0.2-0.3MPa, and reaction temperature is 70 ~ 90 DEG C, Reaction time is 4 ~ 8h；Step（2）The temperature of described amidation process is 10 ~ 35 DEG C, and the reaction time is 1 ~ 6h；Step（3） The temperature of described bromination reaction is 20 ~ 35 DEG C, and the reaction time is 2 ~ 6h；Step（4）The temperature of described catalyzed coupling reaction For 80-110 DEG C, reaction time 12-24h；Step（6）The temperature of described amidation process is 40 ~ 60 DEG C, and the reaction time is 4~12h；Step（7）The temperature of described deprotection reaction is 50 ~ 80 DEG C, and the reaction time is 4 ~ 10h.
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