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Acalabrutinib, ACP-196, Акалабрутиниб , أكالابروتينيب , 阿可替尼 ,

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ChemSpider 2D Image | acalabrutinib | C26H23N7O2

Acalabrutinib.png

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Acalabrutinib

  • Molecular FormulaC26H23N7O2
  • Average mass465.507 Da

AcalabrutinibrINN, ACP-196,

FDA 2017 APPROVED, Lymphoma, mantle cell, ACERTA PHARMA

Orphan Drug, breakthrough therapy designation,

CAS 1420477-60-6 [RN]

(S)-4-[8-Amino-3-[1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-(pyridin-2-yl)benzamide

(S)-4-(8-amino-3-n-but-2-vnoylpyrrolidin-2-vnimidazo[1 ,5-alpyrazin-1-yl)-N-(pyridin-2-yl)benzamide

4-{8-Amino-3-[(2S)-1-(2-butynoyl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide
Benzamide, 4-[8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinyl-
Calquence [Trade name]
UNII:I42748ELQW
Акалабрутиниб [Russian] [INN]
أكالابروتينيب [Arabic] [INN]
阿可替尼 [Chinese] [INN]
4-[8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinyl-benzamide
4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide
I42748ELQW
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Image result for Acalabrutinib
 Acalabrutinib, also known as ACP-196, is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, ACP-196 inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.
Image result for Acalabrutinib

Acalabrutinib (rINN,[1] ACP-196) is a novel experimental anti-cancer drug and a 2nd generation Bruton’s tyrosine kinase (BTK) inhibitor[2][3] developed by Acerta Pharma.[4] It is more potent and selective (fewer side-effects) than ibrutinib, the first-in-class BTK inhibitor.[2][3][5]

The compound was granted orphan drug designation for the treatment of chronic lymphocytic leukemia, Waldenström’s macroglobulinemia and mantle cell lymphoma in the U.S. and the E.U. in 2015 and 2016, respectively. In 2017, the product was granted breakthrough therapy designation in the U.S. for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

Acalabrutinib is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, acalabrutinib inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosinekinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.

Acalabrutinib is a Bruton’s Tyrosine Kinase (BTK) inhibitor developed at Acerta Pharma launched in 2017 in the U.S. for the oral treatment of adults with mantle cell lymphoma who have received at least one prior therapy.

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Image result for Acalabrutinib

To date, acalabrutinib has been used in trials studying the treatment of B-All, Myelofibrosis, Ovarian Cancer, Multiple Myeloma, and Hodgkin Lymphoma, among others. As of October 31, 2017 the FDA approved Astra Zeneca’s orally administered Calquence (acalabrutinib) medication as a Bruton Tyrosine Kinase (BTK) inhibitor indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have already received at least one prior therapy, marking the company’s first entry into the treatment of blood cancers. Also known as ACP-196, acalabrutinib is also considered a second generation BTK inhibitor because it was rationally designed to be more potent and selective than ibrutinib, theoretically expected to demonstrate fewer adverse effects owing to minimized bystander effects on targets other than BTK. Nevertheless, acalabrutinib was approved under the FDA’s accelerated approval pathway, which is based upon overall response rate and faciliates earlier approval of medicines that treat serious conditions or/and that fill an unmet medical need based on a surrogate endpoint. Continued approval for acalabrutinib’s currently accepted indication may subsequently be contingent upon ongoing verification and description of clinical benefit in confimatory trials. Furthermore, the FDA granted this medication Priority Review and Breakthrough Therapy designations. It also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. At this time, more than 35 clinical trials across 40 countries with more than 2500 patients are underway or have been completed with regards to further research into better understanding and expanding the therapeutic uses of acalabrutinib [L1009].
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Clinical and Regulatory Status

Pre-clinical

Relative to ibrutinib, acalabrutinib demonstrated higher selectivity and inhibition of the targeted activity of BTK, while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1.[3] In addition, in platelets treated with ibrutinib, thrombus formation was clearly inhibited while no impact to thrombus formation was identified relative to controls for those treated with acalabrutinib.[3] These findings strongly suggest an improved safety profile of acalabrutinib with minimized adverse effects relative to ibrutinib.[3]

As was conducted in the development of ibrutinib, pre-clinical studies of acalabrutinib included in vitro and in vivo pharmacodynamic evaluation in a canine lymphoma model.[6] A dose-dependent relationship resulting in cyto-toxicity and anti-proliferative effects was first demonstrated in a canine lymphoma cell line in vitro.[6] In vivo, the compound was found to be generally safe and well tolerated in the dosage range of 2.5–20 mg/kg every 12 or 24 hours, with clinical benefit observed in 30% of canine patients while observed adverse events consisted primarily of gastrointestinal effects such as anorexia, weight loss, vomiting, diarrhea and lethargy.[6]

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Clinical

The interim results of the still on-going first human phase 1/2 clinical trial (NCT02029443) with 61 patients for the treatment of relapsed chronic lymphocytic leukemia (CLL) are encouraging, with a 95% overall response rate demonstrating potential to become a best-in-class treatment for CLL.[2][7] Notably, a 100% response rate was achieved for those patients which were positive for the 17p13.1 gene deletion – a subgroup of patients that typically results in a poor response to therapy and expected outcomes.[3]

The most common adverse events were headache, diarrhea and weight gain.[3] Despite the appearance of a greater occurrence of transient headaches, the pre-clinical data suggests a preferred advantage of acalabrutinib over ibrutinib due to expected reduced adverse events of skin rash, severe diarrhea, and bleeding risk.[3] An additional clinical trial is currently in progress to directly compare the safety and efficacy performance of acalabrutinib to ibrutinib to better elucidate the differences in the therapeutic agents.[3]

While the primary indication is for CLL, as of late 2016, acalabrutinib is under evaluation for multiple indications in 20+ clinical trials (alone and in combination with other interventions) for various blood cancers, solid tumors, and rheumatoid arthritis.[7][8] Approximately 1,000 patients have been treated with acalabrutinib in clinical trials so far, including more than 600 on acalabrutinib alone and almost 400 on additional therapies in combination with acalabrutinib.[9]

Regulatory

As of February 2016, acalabrutinib had received orphan designation in the United States for CLL only,[10] and was similarly designated as an orphan medicinal product by the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) for treatment of three indications – chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and lymphoplasmacytic lymphoma (Waldenström’s macroglobulinaemia, MG).[11] If the drug is ultimately approved, this designation will result in a 10-year period of market exclusivity for the stated indications within Europe.[12]

Commercial Aspects

Acerta Pharma, the innovator responsible for the discovery and development of acalabrutinib, is a clinical stage biopharmaceutical company recently founded in 2012 in Oss, the Netherlands.[13] A combined $13 Million in Series A funding was secured March 14, 2013 from various investor sources including the venture capital firms of BioGeneration Ventures and OrbiMed Advisors, the Dutch State and Province of Brabant through the Brabant Development Agency, and the private US equity firm Frazier Healthcare.[14] Further undisclosed amounts of Series B funding was secured May 2015 from the mutual fund company T. Rowe Price.[15]

After the promising results for the treatment of CLL in initial clinical trials,[2] Astra Zeneca purchased a 55% stake in Acerta Pharma for $4 billion in December 2015, with an option to acquire the remaining 45% stake for an additional $3 billion, conditional on the first approval in both the US and Europe and the establishment of commercial opportunity.[16]

Intellectual Property

Several patents have been filed by Acerta Pharma through the World Intellectual Property Organization (WIPO) for the use of acalabrutinib (and structurally similar derivatives) either alone or in combination with additional therapeutic agents for the treatment of various hematological and solid tumor cancers as well as inflammatory and autoimmune diseases.[17][18][19][19][20][21][22][23][24][25][26][27]

Notably, patents filed through WIPO still need to be filed appropriately for each individual nation on the path to commercialization. For example, one related United States patent application is US2014155385, which was filed July 11, 2012 and approved June 5th, 2014 for the use of 6-5 membered fused pyridine ring compounds (including acalabrutnib and its structurally similar derivatives) in the treatment of BTK mediated disorders.[28]

SYNTHESIS

Inventors Tjeerd A. BarfChristiaan Gerardus Johannes Maria Jansde Adrianus Petrus Antonius MANArthur A. OubrieHans C.A. RaaijmakersJohannes Bernardus Maria RewinkelJan-Gerard SterrenburgJacobus C.H.M. Wijkmans
Applicant Msd Oss B.V.

WO 2013010868

Synthesis of acalabrutinib, using 3-chloropyrazine-2-carbonitrile as the starting material, is described. The method comprises reduction of the starting material, condensation with N-Cbz-L-proline, intramolecular cyclization, bromination, Suzuki coupling with (4-(2-pyridylcarbamoyl)phenyl)boronic acid and condensation with 2-butynoic acid. WO 2013010868

Reduction of 3-chloropyrazine-2-carbonitrile  with H2 over Raney-Ni in AcOH, followed by treatment with aqueous HCl in Et2O gives (3-chloro-2-pyrazinyl)methylamine hydrochloride , which upon condensation with N-Cbz-L-proline  in the presence of HATU and Et3N in CH2Cl2 affords amide .

Intramolecular cyclization of intermediate  by means of DMI and POCl3 in acetonitrile at 63 °C provides N-Cbz-8-chloro-3-[2(S)-pyrrolidinyl]imidazo[1,5-a]pyrazine , which is brominated with NBS in DMF to yield N-Cbz-1-bromo-8-chloro-3-[2(S)-pyrrolidinyl]imidazo[1,5-a]pyrazine .

Reaction of chloro compound  with NH3 in i-PrOH at 110 °C produces N-Cbz-1-bromo-3-[2(S)-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine , which upon Suzuki coupling with (4-(2-pyridylcarbamoyl)phenyl)boronic acid in the presence of PdCl2(dppf) and K2CO3 in dioxane at 140 °C under microwave irradiation furnishes diaryl derivative .

Removal of the benzyloxycarbonyl moiety in intermediate  using HBr in AcOH generates pyrrolidine derivative , which is condensed with 2-butynoic acid  in the presence of HATU and Et3N in CH2Cl2 to afford the target acalabrutinib 

PATENT

WO 2013010868

https://www.google.com/patents/WO2013010868A1?cl=en

scheme I

Figure imgf000026_0001

 scheme II

Figure imgf000027_0001

Intermediate 1

Figure imgf000032_0001

(S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-alpyrazin-3-vnpyrrolidine-1-carboxylate

(a) (3-Chloropyrazin-2-yl)methanamine. hydrochloride

To a solution of 3-chloropyrazine-2-carbonitrile (160 g, 1 .147 mol) in acetic acid (1.5 L) was added Raney Nickel (50% slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50°C and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl ether (1 .14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend. The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40°C. The product brown solid obtained was dissolved in methanol at 60°C. The mixture was filtered and partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40°C to give 153.5 g of (3-chloropyrazin-2- yl)methanamine. hydrochloride as a brown solid (74.4 %, content 77 %).

(b) (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate

To a solution of (3-chloropyrazin-2-yl)methanamine.HCI (9.57 g, 21.26 mmol, 40% wt) and Z-Pro-OH (5.3 g, 21 .26 mmol) in dichloromethane (250 mL) was added triethylamine (1 1.85 mL, 85 mmol) and the reaction mixture was cooled to 0°C. After 15 min stirring at 0°C, HATU (8.49 g, 22.33 mmol) was added. The mixture was stirred for 1 hour at 0°C and then overnight at room temperature. The mixture was washed with 0.1 M HCI-solution, 5% NaHC03, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 5 g of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (62.7%).

(c) (S)-Benzyl 2-(8-chloroimidazo[1 ,5-alpyrazin-3-yl)pyrrolidine-1-carboxylate

(S)-Benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (20.94 mmol, 7.85 g) was dissolved in acetonitrile (75 ml), 1 ,3-dimethyl-2-imidazolidinone (62.8 mmol, 6.9 ml, 7.17 g) was added and the reaction mixture was cooled to 0°C before POCI3 (84 mmol, 7.81 ml, 12.84 g) was added drop wise while the temperature remained around 5°C. The reaction mixture was refluxed at 60-65°C overnight. The reaction mixture was poured carefully in ammonium hydroxide 25% in water (250 ml)/crushed ice (500 ml) to give a yellow suspension (pH -8-9) which was stirred for 15 min until no ice was present in the suspension. Ethyl acetate was added, layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The organic layers were combined and washed with brine, dried over sodium sulfate, filtered and evaporated to give 7.5 g crude product. The crude product was purified using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 6.6 g of (S)-benzyl 2-(8- chloroimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (88%).

(d) (S)-Benzyl 2-(1-bromo-8-chloroimidazo[1 ,5-alpyrazin-3-yl)pyrrolidine-1-carboxylate

N-Bromosuccinimide (24.69 mmol, 4.4 g) was added to a stirred solution of (S)-benzyl 2-(8- chloroimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (24.94 mmol, 8.9 g) in DMF (145 mL). The reaction was stirred 3 h at rt. The mixture was poored (slowly) in a stirred mixture of water (145 mL), ethyl acetate (145 mL) and brine (145 mL). The mixture was then transferred into a separating funnel and extracted. The water layer was extracted with 2×145 mL ethyl acetate. The combined organic layers were washed with 3×300 mL water, 300 mL brine, dried over sodium sulfate, filtered and evaporated. The product was purified using silica gel chromatography (ethyl acetate/heptane = 3/1 v/v%) to give 8.95 g of (S)-benzyl 2-(1-bromo-8-chloroimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (82.3%).

(e) (S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-alpyrazin-3-yl)pyrrolidine-1-carboxylate

(S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (20.54 mmol, 8.95 g) was suspended in 2-propanol (1 13 ml) in a pressure vessel. 2-propanol (50 ml) was cooled to -78°C in a pre-weighed flask (with stopper and stirring bar) and ammonia gas (646 mmol, 1 1 g) was lead through for 15 minutes. The resulting solution was added to the suspension in the pressure vessel. The vessel was closed and stirred at room temperature and a slight increase in pressure was observed. Then the suspension was heated to 1 10 °C which resulted in an increased pressure to 4.5 bar. The clear solution was stirred at 1 10 °C, 4.5 bar overnight. After 18h the pressure remained 4 bar. The reaction mixture was concentrated in vacuum, the residue was suspended in ethyl acetate and subsequent washed with water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate and concentrated to give 7.35 g of (S)-benzyl 2-(8-amino-1-bromoimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1- carboxylate (86%).

Intermediate 2

Figure imgf000034_0001

(S)-4-(8-Amino-3-(pyrrolidin-2-v0im^

(a) (S)-Benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamov0

carboxylate

(S)-benzyl 2-(8-amino-1-bromoimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1 -carboxylate (0.237 mmol, 98.5 mg) and 4-(pyridin-2-yl-aminocarbonyl)benzeneboronic acid (0.260 mmol, 63.0 mg) were suspended in a mixture of 2N aqueous potassium carbonate solution (2.37 mmol, 1 .18 mL) and dioxane (2.96 mL). Nitrogen was bubbled through the mixture, followed by the addition of 1 , 1 ‘- bis(diphenylphosphino)ferrocene palladium (ii) chloride (0.059 mmol, 47.8 mg). The reaction mixture was heated for 20 minutes at 140°C in the microwave. Water was added to the reaction mixture, followed by an extraction with ethyl acetate (2x). The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. The product was purified using silicagel and dichloromethane/methanol = 9/1 v/v% as eluent to afford 97.1 mg of (S)-benzyl 2-(8-amino-1-(4-(pyridin- 2-ylcarbamoyl)phenyl)imidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1 -carboxylate (77%).

(b) (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5-alpyrazin-1-yl)-N-(pyridin-2-yl)benzamide

To (S)-benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1- carboxylate (0.146 mmol, 78 mg) was added a 33% hydrobromic acid/acetic acid solution (1 1.26 mmol, 2 ml) and the mixture was left at room temperature for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The aqueous phase was neutralized using 2N sodium hydroxide solution, and then extracted with dichloromethane. the organic layer was dried over magnesium sulfate, filtered and evaporated to give 34 mg of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5-a]pyrazin-1-yl)-N- (pyridin-2-yl)benzamide (58%).

Example 6

Figure imgf000038_0001

(S)-4-(8-amino-3-n-but-2-vnoylpyrrolidin-2-vnimidazo[1 ,5-alpyrazin-1-yl)-N-(pyridin-2-yl)benzamide

This compound was prepared, in an analogues manner as described in Example 2, from the compound described in intermediate 2b and 2-butynoic acid, to afford the title compound (10.5 mg, 18.0%). Data: LCMS (B) Rt : 2.08 min; m/z 466.1 (M+H)+.

PATENT

WO 2016024228

https://www.google.com/patents/WO2016024228A1?cl=en

PATENT

CN 107056786

Step SI:

[0029] The pressure in the reactor was added 3-chloro-2-carboxaldehyde l-yl P ratio of (II) (0.71g, 5mmol) and dioxane (20mL), under stirring ammonia gas (I. 7g, 0 . Imol), was added 4- (pyridin-2-yl – aminocarbonyl) phenylboronic acid (III) (2.42g, lOmmol), Ming dicarbonyl acetylacetonate (0.26g, lmmol), and water 4mL. The reactor was sealed, gradually warmed to 80~90 °, the reaction 16-18 hours, TLC detection, the reaction was complete. Concentrated under reduced pressure, the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and water successively, dried over anhydrous sodium sulfate. Concentrated to give brown oil, ethyl acetate and petroleum ether (volume ratio 1: 2) column chromatography to give an off-white solid 4- [amino (3-chloro-2-pyrazinyl) methyl] -N- (2-pyridyl) benzamide (IV) 1.38g, yield 81 · 2%; ESI-MS (m / z): 340 (m + H).

[0030] Step S2:

[0031] added in the reactor [1- (1-oxo-2-butyn-1-yl)] – L- proline (1.09g, 6mmol) and thionyl chloride (IOmL), was added dropwise 4mL of triethylamine and heated to 30 to 40 degrees, after the reaction for 2-4 hours under reduced pressure to remove excess thionyl chloride, the residue that is [I- (1- oxo-2-butyn-1-yl )] – L- proline acid chloride (V). The resulting [I- (1- oxo-2-butynyl -1_ yl)] _ L_ proline acid chloride (V) dissolved in 20mL dichloromethane burning, to a solution of 4- [amino (3-chloro -2-P ratio piperazinyl) methyl] -N- (2- pyridinyl) benzamide (IV) (1.35g, 4mmol) and triethylamine (0.6g, 6mmol) in dichloromethane (30mL) solution of in. Dropwise, warmed to 30-50 °, the reaction was stirred for 6 ~ 8 hours, TLC detection, the reaction was complete. Cooled to room temperature, washed with saturated sodium bicarbonate solution, brine and water, dried over anhydrous sodium sulfate. Concentrated to give a beige solid of 4- [1- (1-acyl-2-yne-2-yl) carboxamido (3-chloro-2-pyrazinyl) methyl] -N- (2- pyridinyl) benzamide (VI) 1.8g, yield 89.6% C3ESI-MS (m / z): 503 (m + H).

[0032] Step S3:

[0033] in a reaction flask was added 4- [I- (1- but-2-yn-acyl-2-yl) carboxamido (3-chloro-2-pyrazinyl) methyl] -N- ( 2-P ratio piperidinyl) benzamide (VI) (1 · 0g, 2mmol), phosphorus oxychloride (1 · 53g, IOmmol) and acetonitrile (25 mL), warmed to 80 ~ 100 ° with stirring, maintaining the temperature reaction 6 ~ 8 h, TLC the reaction was complete. Cooled to room temperature, the reaction solution was poured into 50mL concentration of 8% aqueous ammonia was added ethyl acetate, and the organic phase was separated, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine and water, dried over anhydrous over sodium sulfate. Concentrated and the resulting residue with ethyl acetate and petroleum ether (volume ratio 2: 1) column chromatography to give an off-white solid 4- [8-Chloro -3- [(2S) -I- (1- oxo-2 – butyn-1-yl) -2-pyrrolidinyl] imidazo [I, 5-a] pyrazin-1-yl] -N-2- pyridinyl benzamide (VII) 0.85g, yield 87.8 %; EI-MS m / z: 485 [m + H] + square

[0034] Step S4:

[0035] The pressure reactor was added to 4- [8-Chloro -3- [(2S) -I- (1- oxo-2-butyn-1-yl) -2-pyrrolidinyl] imidazo [ I, 5-a] pyrazin – Buji] -N-2- pyridinyl benzamide (VII) (0.48g, lmmol) and isopropanol (15 mL), cooled to 0 degrees, by controlling the dose into ammonia gas (0.51g, 30mmol), the reactor is closed, warmed up to room temperature for 1 hour, and then continuously increasing the reaction temperature to 110~120 °, maintained at the reaction temperature and pressure 20~24 h, TLC the reaction was complete. Cooled to room temperature, slowly vented, and concentrated under reduced pressure, the resulting residue was dissolved with ethyl acetate, water and saturated brine, dried over anhydrous sodium sulfate. Concentrated and the resulting residue with ethyl acetate and petroleum ether (volume ratio 2: 1) column chromatography to give an off-white solid Acre imatinib ⑴ 0.40g, yield 86 · 0%; 1Η bandit R (DMS0-d6) 1.63 (m, lH), 1.97 (s, 3H), 2.02 ~2.12 (m, lH), 2 · 28~2.35 (m, 2H); 3.36~3.85 (m, 2H), 5 · 47~5.49 (m , lH), 6 · 17~6.23 (m, 2H), 7.12~7.20 (m, 2H), 7 · 73~7.86 (m, 4H), 8 · 16~8.25 (m, 3H), 8 · 41 ( dd, lH), 10.86 (s, lH); EI-MS m / z: 466 [m + H] +.

[0036] 3-chloro starting material employed in the method above relates to the present invention yl pyrazin-2-carbaldehyde (II) and 4- (pyridin-2-yl – aminocarbonyl) phenylboronic acid (III), respectively, refer to methods for their preparation Document “Tetrahedron Letters, 47 (l), 31-34; 2006” international Patent W02013010868 and method for preparing the same compound. Raw [1- (1-oxo-2-butyn-1-yl)] – L- proline acid chloride (V), in one embodiment, the compound may be made [the I-(1-oxo-known -2-yn-1-yl)] – L- proline acylation.

PATENT

US 20170224688

PATENT

CN 107522701

 Example I

[0030] (1) Preparation of ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0031] (S) -2- (8- chloro-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (10g, 28mmol) was dissolved in N- methylpyrrolidone ( SOML), the mass concentration was added 28% aqueous ammonia (168mm〇l), the reaction mixture was placed in a sealed stainless steel autoclave at 85 ° C, stirring the reaction under a pressure of 2.5 atm 6h, after the completion of the reaction, was cooled to 40 ° C and delivery system pressure, slow addition of water (50 mL), cooled to 10 ° C, crystallization 3h, filtered, and recrystallized from isopropanol to give ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin – 3- yl) -1-pyrrolidine-carboxylate, an off-white solid (8.5 g of), yield 90%, reaction formula of this step is as follows:

Figure CN107522701AD00091

[0033] (2) Preparation of (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5_a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0034] (S) -2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (8g, 24mmol) was dissolved in dichloromethane (IOOmL) was added tert-butyl dicarbonate (5.7g, 26mmol), reaction mixture was stirred 3h at 25 ° C, after completion of the reaction, post-treatment and purification to give ⑸-2- (8- tert-butoxycarbonyl-amino-imidazole and [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (IoG), 96% yield, this step follows the reaction formula:

Figure CN107522701AD00092

[0036] (3) Preparation of (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0037] (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (IOg, 23mmol) was dissolved in tetrahydrofuran ( 80mL), was slowly added N- bromosuccinimide (4.5g, 25mmol), the reaction mixture was 25 ° C the reaction was stirred for 4h. The mixture was then slowly added water (80 mL), cooled to -10 ° C crystallization 3h, filtered, and recrystallized from isopropanol to give (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [ I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (I I. Ig), a yield of 94.5%, the reaction formula of this step is as follows:

Figure CN107522701AD00093

[0039] (4) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} 1-pyrrolidine-carboxylic acid benzyl ester:

[0040] (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (I Ig, 2lmmol ), 4- (2-pyridyl-carbamoyl) phenylboronic acid (5.7g, 23.4mmol), [1, Γ – bis (diphenylphosphino) ferrocene] dichloropalladium cesium (〇.78g, the I · lmmol), potassium carbonate (4.0g, 29mmol), N, N- dimethylformamide (120 mL) and water (50mL) added to the reaction flask, the reaction mixture was heated to 90 ° C the reaction was stirred for 20 h, the reaction solution was reduced at room temperature, was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give (S) -2- {8- tert butoxycarbonyl group -I- [4- (2-P of pyridine-ylcarbamoyl) phenyl] imidazole and sat Jie [I, 5_a] pyrazin-3-yl} -1-pyrrolidine-carboxylate, class as a white solid (10.3 g of), a yield of 76.5%, the reaction formula of this step is as follows:

Figure CN107522701AD00101

[0042] (5) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} pyrrolidine:

[0043] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1- [1-carboxylic acid than the burning section slightly ester (10g, 15.8mmol) was dissolved in methanol (80mL), was added cesium charcoal (0.5g), under a hydrogen pressure into 35 ° C the reaction 8h. Concentrated suction through Celite to remove the catalyst and the filtrate was rotary evaporated to dryness to afford ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [ I, 5-a] pyrazin-3-yl} pyrrolidine as a white solid powder (7.6 g of), 96% yield, this step follows the reaction formula:

Figure CN107522701AD00102

[0045] (6) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} -1- (2-butynoyl) pyrrolidine:

[0046] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } ratio slightly burning Jie (7g, 14mmol) was dissolved in tetrahydrofuran (75 mL), with stirring, was added 2-butyne chloride (I. 7g, 16.6mmol), was added dropwise N, N- diisopropylethylamine (2.7 g, 21 mmol), the reaction mixture was 50 ° C the reaction was stirred for 8h, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was added was adjusted to neutral, extracted with ethyl acetate was added, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give ⑸ -2_ {8-tert-butoxycarbonyl-amino -1- [4- (2-P of pyridine-ylcarbamoyl) phenyl] imidazole and sat Jie [I, 5_a] [! than 3-yl} -1 – (2_ butynoyl) pyrrolidine-white solid (7g), in 88% yield, this step follows the reaction formula:

Figure CN107522701AD00111

[0048] ⑺ prepared Acalabrutinib:

[0049] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1- (2-butynoyl) pyrrolidine (7g, 12.4mmol) and dissolved in methanol (70 mL), trifluoroacetic acid (1.55g, 13.6mmol), 65 ° C until the reaction was complete the reaction was stirred for 6h, the reaction was added dropwise to a stirred solution of water (150 mL), cooled to 0 ° C crystallization 3h, filtered to give the treatment of chronic lymphocytic leukemia BTK inhibitors Acalabrut inib, as a white solid (5.3 g of), 92% yield, this step is the following reaction formula:

Figure CN107522701AD00112

[0051] Example 2:

[0052] (1) Preparation of ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0053] (S) -2- (8- chloro-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (15g, 42mmol) was dissolved in N- methylpyrrolidone ( 75 mL), aqueous ammonia (273_〇1) was added mass percent concentration of 28%, the reaction mixture was placed in a sealed stainless steel autoclave at 70 ° C, stirring the reaction under a pressure of 3 atm 8h, after the completion of the reaction, was cooled to 40 ° C and releasing the pressure in the system, slow addition of water (50 mL), cooled to 10 ° C, crystallization 3h, filtered, and recrystallized from isopropanol to give ⑸-2- (8- amino-imidazo [I, 5-a] pyrazine 3-yl) pyrrolidine-carboxylic acid benzyl ester, off-white solid (12.9 g of), yield 91% ,, this step reaction scheme in Example 1.

[0054] (2) Preparation of (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5_a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0055] (S) -2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (12g, 35.6mmol) was dissolved in chloroform (80mL), was added tert-butyl dicarbonate (7.8g, 35.6mmol), the reaction mixture was stirred for lh the reaction at 35 ° C, after completion of the reaction, post-treatment and purification to give ⑸-2- (8- tert-butoxycarbonyl-amino-imidazole and [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (14.8 g of), in 95% yield, this step is the same reaction scheme as in Example 1.

[0056] (3) Preparation of (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0057] (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (Hg, 32mmol) was dissolved in 1, 1,2-dichloroethane (90mL), was slowly added bromine (6g, 37.8mmol), the reaction mixture was 20 ° C the reaction was stirred for 6h. After the reaction, water was slowly added (I5mL), cooled to -5 ° C crystallization 4h, filtered and recrystallized from isopropanol to give ⑸-2- (8- tert-butoxycarbonyl-amino-1-bromo-imidazo [1, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (15.8 g), yield 95.5%, the reaction of the present step is the same formula as in Example 1.

[0058] (4) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} 1-pyrrolidine-carboxylic acid benzyl ester:

[0059] (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (15g, 29mmol) , 4- (2-pyridyl-carbamoyl) phenylboronic acid (34 · 7mmol 8 · 4g,), tetrakis (triphenylphosphine) palladium (0 · 84g, 0.73mmol), sodium carbonate (6.9g, 65mmol), tetrahydrofuran (IOOmL) and water (40 mL) was added a reaction flask, the reaction mixture was heated to 80 ° C the reaction was stirred for 24h, the reaction was cooled to room temperature, and concentrated by rotary evaporation to dryness, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazole and [I, 5-a] pyrazin-3-yl} -1-pyrrolidine-carboxylate, an off-white solid (14.4g), 78% yield, this step is the same reaction scheme as in Example 1.

[0060] (5) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} pyrrolidine:

[0061] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-yl _3- it is slightly burned} -1-carboxylic acid ester section (14g, 22mmol) dissolved in isopropanol (85mL), was added Raney nickel (0.5g), under a hydrogen pressure into the reaction 60 ° C 12h. Concentrated suction through Celite to remove the catalyst and the filtrate was rotary evaporated to dryness to afford ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [ I, 5-a] pyrazin-3-yl} pyrrolidine as a white solid powder (10.4 g of), 94% yield, this step is the same reaction scheme as in Example 1.

[0062] (6) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} -1- (2-butynoyl) pyrrolidine:

[0063] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } pyrrolidine (10g, 20mmo 1) was dissolved in N, N- dimethylformamide (SOML), with stirring, was added 2-butyne chloride (3. lg, 30mmol), dropwise addition of triethylamine (2.2g, 22mmol ), the reaction mixture was 60 ° C the reaction was stirred for 4h, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was added was adjusted to neutral, extracted with ethyl acetate was added, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, and recrystallized from methanol to give ⑸- 2- {8-tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl} -l- (2- butynoyl) pyrrolidine-white solid (10.2 g of), a yield of 90.2%, the same reaction scheme of the present embodiment step 1〇

[0064] ⑺ prepared Acalabrutinib:

[0065] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1- (2-butynoyl) pyrrolidine (IOg, 17.7mmol) was dissolved in ethanol, and (IOOmL), trifluoroacetic acid (2.6g, 23mmol), 50 ° C with stirring until the reaction was complete IOh reaction, the reaction solution was added dropwise to a stirred solution of water (70 mL), cooled to 0 ° C crystallization 3h, filtered to give the treatment of chronic lymphocytic leukemia BTK inhibitors AcaIabrut inib, as a white solid (7.5 g of), yield 91%, reaction of this step formula same as in Example 1.

[0066] Example 3:

[0067] (1) Preparation of ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0068] (S) -2- (8- chloro-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (4.5g, 12.6mmol) was dissolved in N- methyl pyrrolidinone (70 mL), was added mass percent concentration of 28% aqueous ammonia (69.4 mmol), the reaction mixture was placed in the autoclave 90 ° C, the reaction was stirred under atmospheric pressure of 4h, after the completion of the reaction, it was cooled to 35 ° C a sealed stainless steel reactor and releasing the pressure in the system, slow addition of water (50 mL), cooled to 10 ° C, crystallization 3h, filtered, and recrystallized from isopropanol to give ⑸-2- (8- amino-imidazo [I, 5-a] pyrazine 3-yl) pyrrolidine-carboxylic acid benzyl ester, off-white solid (3.9 g of), 92% yield, this step is the same reaction scheme as in Example 1.

[0069] (2) Preparation of (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0070] (S) -2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester (3 · 5g, 10 · 4mmol) was dissolved in 1, 4- dioxane (50 mL), was added tert-butyl dicarbonate (2.7g, 12.4mmol), the reaction mixture was stirred at 10 ° C the reaction 6h, after the completion of the reaction, workup and purification, to give (S) 2- (8-tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (4.3 g of), in 95% yield, according to the present step reaction scheme in Example 1.

[0071] (3) Preparation of (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0072] (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [l, 5_a] pyrazin-3-yl) -1_ pyrrolidine-carboxylate (4g, 9.6mmol) was dissolved in toluene (50 mL ), was slowly added N- bromosuccinimide (I. 8g, 10. lmmol), the reaction mixture was 35 ° C the reaction was stirred for 2h. The mixture was then slowly added water (25 mL), cooled to -10 ° C crystallization 3h, filtered, and recrystallized from isopropanol to give (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [ I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (4.7 g), 94% yield, this step is the same reaction scheme as in Example 1.

[0073] (4) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} 1-pyrrolidine-carboxylic acid benzyl ester:

[0074] (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (4g, 7 · 7mmol), 4_ (2- piperidinyl than Jie carbamoyl) phenylboronic acid (2 · 4g, IOmmol), bis (triphenylphosphine) dichloride Leba (0.41g, 0.58mmol), potassium phosphate (I. 9g, 8.9mmol), methyl tert-butyl ether (IOOmL) and water (40 mL) was added a reaction flask, the reaction mixture was heated to 100 ° C the reaction was stirred for 12h, the reaction was cooled to room temperature, and concentrated by rotary evaporation to dryness, was added acetic acid extracted with ethyl, brine, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2 – pyridin-ylcarbamoyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl} -1-pyrrolidine-carboxylate, an off-white solid (3.9 g of), in 79% yield, this step the reaction scheme in Example 1.

[0075] (5) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5_a] pyrazin-3 -} pyrrolidine:

[0076] (S) -2- {8- tert-butoxycarbonyl group -I- [4- (2- carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1 Jie section than slightly burning acid ester (3.5g, 5.5mmol) was dissolved in ethanol (50mL), was added cesium charcoal (0.2g), under a hydrogen pressure into 45 ° C the reaction 6h. Concentrated suction through Celite to remove the catalyst and the filtrate was rotary evaporated to dryness to afford ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [ I, 5-a] pyrazin-3-yl} pyrrolidine as a white solid powder (2.6 g of), in 95% yield, this step is the same reaction scheme as in Example 1.

[0077] (6) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} -1- (2-butynoyl) pyrrolidine:

[0078] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } ratio slightly burning Jie (2.5g, 5mmol) was dissolved in toluene (50 mL), with stirring, was added 2-butyne chloride (0.62g, 6mmol), was added dropwise N, N- dimethylaniline (Ig, 8.5mmo 1), The reaction mixture was 40 ° C the reaction was stirred for 12h, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was added was adjusted to neutral, extracted with ethyl acetate was added, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, and recrystallized from methanol to give ⑸-2- {8-tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl} -1- (2-butyn acyl) pyrrolidine-white solid (2.5g), 88% yield, this step is the same reaction scheme as in Example 1.

[0079] ⑺ prepared Acalabrutinib:

[0080] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-yl _3_ } -1- (2-block group) ratio slightly burning Jie (2.5g, 4.4mmol) was dissolved in dichloromethane and burned (IOmL), two gas was added acetic acid (0.76g, 6.6mmol), 80 ° C The reaction was stirred 4h until the reaction was complete, the reaction was added dropwise to a stirred solution of water (25 mL), cooled to 0 ° C crystallization 3h, filtered to give the treatment of chronic lymphocytic leukemia BTK inhibitors AcaIabrut inib, as a white solid (1.8 g of), the yield of 89%, this step is the same reaction scheme as in Example 1.

PATENT

US 20170035881

References

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  26. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Jul 28, 2016), Compositions and methods for treatment of chronic lymphocytic leukemia and small lymphocytic leukemia using a btk inhibitor, retrieved 2016-11-19
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  28. Jump up^ Barf, Tjeerd A.; Jans, Christian Gerardus Johannes Maria; Man, Petrus Antonius De Adrianus; Oubrie, Arthur A.; Raaijmakers, Hans C. A.; Rewinkel, Johannes Bernardus Maria; Sterrenburg, Jan-Gerard; Wijkmans, Jacobus C. H. M. (5 June 2014), United States Patent Application: 0140155385 – 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS, retrieved 2016-11-19

ADDITIONAL INFORMATION

Acalabrutinib is a potent and selective BTK (Bruton’s tyrosine kinase) inhibitor. BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. BTK inhibitors targeting B cell receptor signaling and other survival mechanism showed great promise for the treatment of chronic lymphocytic leukemia (CLL)s holds great promise.

As of 2015 it is in late stage clinical trials for relapsed chronic lymphocytic leukemia. Interim results are encouraging : 95% overall response rate. It is also in another 20 clinical trials (alone and in combination) for various cancers.

REFERENCES

1: Maly J, Blachly JS. Chronic Lymphocytic Leukemia: Exploiting Vulnerabilities with Targeted Agents. Curr Hematol Malig Rep. 2016 Feb 11. [Epub ahead of print] PubMed PMID: 26893063.

2: Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. doi: 10.1056/NEJMoa1509981. Epub 2015 Dec 7. PubMed PMID: 26641137.

Patent ID

Patent Title

Submitted Date

Granted Date

US2017231995 BTK Inhibitors to Treat Solid Tumors Through Modulation of the Tumor Microenvironment
2015-08-11
US2017095471 Methods of Treating Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia Using a BTK Inhibitor
2015-01-21
Patent ID

Patent Title

Submitted Date

Granted Date

US2017231986 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor
2015-08-11
US2017035756 METHODS OF BLOCKING THE CXCR-4/SDF-1 SIGNALING PATHWAY WITH INHIBITORS OF BRUTON’S TYROSINE KINASE
2015-04-10
US2017266191 Therapeutic Combination of PI3K Inhibitor and a BTK Inhibitor
2014-12-05
US2016159810 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS
2016-02-09
2016-06-09
US2017143712 Methods of Treating Cancers, Immune and Autoimmune Diseases, and Inflammatory Diseases Based on BTK Occupancy and BTK Resynthesis Rate
2017-02-07
Patent ID

Patent Title

Submitted Date

Granted Date

US2017035881 Therapeutic Combinations of an IRAK4 Inhibitor and a BTK Inhibitor
2016-10-19
US2017071962 Therapeutic Combinations of a Proteasome Inhibitor and a BTK Inhibitor
2016-09-12
US9717745 PHARMACEUTICAL COMPOSITIONS AND THEIR USE FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASES
2016-06-15
US9758524 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS
2016-02-09
2016-06-02
US2017224819 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a CDK 4/6 Inhibitor
2015-08-11
Patent ID

Patent Title

Submitted Date

Granted Date

US2017029428 Solid Forms and Formulations of Imidazopyrazine Compound
2016-07-01
US2017239351 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, a PD-1 Inhibitor, and/or a PD-L1 Inhibitor
2015-08-11
US2017136014 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor and/or a JAK-2 Inhibitor
2015-06-17
US9290504 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS
2012-07-11
2014-06-05
US2017224688 Methods of Using BTK Inhibitors to Treat Dermatoses
2017-02-03
Acalabrutinib
Acalabrutinib.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C26H23N7O2
Molar mass 465.507 g/mol
3D model (JSmol)

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3 (FDA Orange Book Patent ID)
Patent 9290504
Expiration Jul 11, 2032
Applicant ASTRAZENECA
Drug Application N210259 (Prescription Drug: CALQUENCE. Ingredients: ACALABRUTINIB)
FDA Orange Book Patents: 2 of 3 (FDA Orange Book Patent ID)
Patent 9758524
Expiration Jul 11, 2032
Applicant ASTRAZENECA
Drug Application N210259 (Prescription Drug: CALQUENCE. Ingredients: ACALABRUTINIB)
FDA Orange Book Patents: 3 of 3 (FDA Orange Book Patent ID)
Patent 9796721
Expiration Jul 1, 2036
Applicant ASTRAZENECA
Drug Application N210259 (Prescription Drug: CALQUENCE. Ingredients: ACALABRUTINIB)

////////////AcalabrutinibrINNACP-196, fda 2017, Акалабрутиниб , أكالابروتينيب , 阿可替尼 , Orphan Drug, breakthrough therapy designation, Lymphoma, mantle cell, ACERTA PHARMA

CC#CC(=O)N1CCC[C@H]1c2nc(c3n2ccnc3N)c4ccc(cc4)C(=O)Nc5ccccn5

CC#CC(=O)N1CCCC1C2=NC(=C3N2C=CN=C3N)C4=CC=C(C=C4)C(=O)NC5=CC=CC=N5

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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