CN108250186A - The synthetic method of Acalabrutinib and its intermediate - Google Patents

The synthetic method of Acalabrutinib and its intermediate Download PDF

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CN108250186A
CN108250186A CN201810121426.0A CN201810121426A CN108250186A CN 108250186 A CN108250186 A CN 108250186A CN 201810121426 A CN201810121426 A CN 201810121426A CN 108250186 A CN108250186 A CN 108250186A
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formula
acalabrutinib
reaction
synthetic method
intermediate compound
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CN108250186B (en
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郑旭春
张平
张一平
付晨晨
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Ke Chao Bio Tech Ltd Hangzhou
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Ke Chao Bio Tech Ltd Hangzhou
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a kind of synthetic methods of Acalabrutinib, including obtaining Formula 2 as starting material direct polycondensation and cyclisation using L proline derivatives Formula 1 and 2 chlorine, 2 formoxyl acetonitrile, after bromo with cheap chloroethene methylal intermediate compound of formula 3 obtained by the reaction, then pass through hydrolysis, ring-closure reaction obtains key intermediate compound formula 6, then Suzuki couplings are carried out with borate intermediate Formula 8, it is deprotected into salt again and obtains Formula 10, it finally carries out being condensed to yield final products Acalabrutinib formulas 11 with tetrolic acid.The route is easy to operate, and not only total recovery is higher, and obtained product purity is also higher, is suitble to amplification production.

Description

The synthetic method of Acalabrutinib and its intermediate
Technical field
The invention belongs to field of medicine and chemical technology, be related to for treat malignant tumor medicine Acalabrutinib intermediates and The chemical synthesis process of bulk pharmaceutical chemicals.
Background technology
Acalabrutinib (ACP-196) is a kind of second generation Bu Ludun researched and developed by AstraZeneca (AstraZeneca) Family name's tyrosine kinase (BTK) inhibitor, for treating chronic lymphocytic leukemia, for inhibiting the existence and life of tumour cell With preferable effect, compared to the BTK inhibitor ibrutinib of the first generation, drug selectivity higher, side effect is lower. On October 31st, 2017, Acalabrutinib with ultrafast speed obtain FDA approval listing, granted indication for previously at least Received the lymphoma mantle cell patient of first-line treatment failure, the clinical trial of other indications at present also make good progress, great Market prospects.
Acalabrutinib chemistry is entitled：(S) -4- (8- amino -3- (1- (butyl- 2- alkynes acyl group) pyrrolidin-2-yl) miaows Azoles [1,5-a] piperidin-1-yl)-N- (pyridine -2- bases) benzamide, structural formula is as follows：
Patent WO2013010868A reports the synthetic method of Acalabrutinib, using the chloro- 3- cyanopyrazines of 2- as rise Beginning raw material will obtain 3- chloropyrazine -2- methylamines and is condensed, then pass through cyclization, bromo, ammonolysis with Cbz-L- proline after cyano reduction Etc. series reactions obtain key intermediate (S)-phenyl 2- (8- amino -1- bromines imidazoles [1,5-a] pyrazine -3- bases) pyrrolidines - Then 1- carboxylates are docked, last acidolysis remove-insurance with 4- (pyridine -2- bases) formyl phenalgin ylboronic acids by Suzuki couplings again Shield, amidation obtain final products, and synthetic route is as described below.
The chloro- 3- cyanopyrazines of starting material 2- are expensive in the route, and Material Cost is higher；Aminating reaction needs to use Autoclave, severe reaction conditions, reaction selectivity are poor；(S)-phenyl 2- (8- amino -1- bromines imidazoles [1,5-a] pyrazines -3- Base) pyrrolidines -1- carboxylates and 4- (pyridine -2- bases) formyl phenalgin ylboronic acids Suzuki coupling needs to urge using more noble metal Agent, route cost are higher；Follow-up strong acid deprotection reaction amido bond is also easily hydrolyzed, and reaction yield is relatively low；Finally and fourth The condensation reaction yield of acetylenic acid is very low, and route cost is higher.
The route linear step is long, and technics comparing is cumbersome, and amplification production line cost is higher.There is still a need for find technique road Line is simple, yield is higher, method synthesis Acalabrutinib of low cost, suitable for industrialized production.
Invention content
In view of the deficiencies of the prior art, the object of the present invention is to provide a kind of Acalabrutinib and its key intermediates Novel synthesis, this method process route is simple, it is of low cost, suitable for industrialized production.
One of the object of the invention provides a kind of Acalabrutinib intermediate compound of formula 3, and structural formula is as follows：
Wherein, Pg protecting groups are tertbutyloxycarbonyl (Boc) or benzyloxycarbonyl group (Cbz).
The invention further relates to the synthetic methods of Acalabrutinib intermediate compound of formula 3, include the following steps：
(1) the chloro- 2- formoxyls acetonitriles of Formula 1 and 2- carry out ring-closure reaction and obtain Formula 2；
(2) chemical formula 2 is obtained into intermediate compound of formula 3 by bromo-reaction；
Preferably, the ring-closure reaction selects alkali as potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, the tert-butyl alcohol Sodium, triethylamine, diisopropylethylamine etc.；The reaction dissolvent selected is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N- Methyl pyrrolidone, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans, 1,4- dioxane, toluene, dimethylbenzene or chlorobenzene etc..Instead It is 20~180 DEG C to answer temperature.
Preferably, the brominated reagent used in the bromo-reaction is selected from bromine, NBS, pyridinium tribromide or dibromo Glycolylurea etc.；Reaction dissolvent is selected from dichloromethane, chloroform, tetrahydrofuran, dioxane, acetonitrile, acetic acid, methanol, ethyl alcohol or isopropyl Alcohol etc.；Reaction temperature is -10~80 DEG C.
The second object of the present invention is to provide the synthetic method of Acalabrutinib, including Formula 10 and butine Acid carries out condensation reaction and obtains final products 11；
Preferably, the condensing agent of the condensation reaction is selected from EDCI/HOBT, HBTU, CDI or DCC etc.；Alkali is selected from two Wopropyl ethyl amine, triethylamine or N-methylmorpholine etc.；Reaction dissolvent is selected from N,N-dimethylformamide, N, N- dimethylacetamides Amine, N-Methyl pyrrolidone, dichloromethane, 1,2- dichloroethanes, toluene, acetonitrile or 1,4- dioxane etc.；Reaction temperature for- 15~35 DEG C.
The third object of the present invention provides the synthetic method of Acalabrutinib key intermediates 10, including walking as follows Suddenly：
(1) Formula 7 carries out condensation reaction with 2-aminopyridine and obtains Formula 8；
(2) Formula 6 and Formula 8 obtain compound 9 by Suzuki coupling reactions；
(3) Formula 9 is sloughed into protection and obtains intermediate formula 10；
Preferably, the condensation reaction selects condensing agent as EDCI/HOBT, HBTU, CDI or DCC etc.；Alkali is selected from two The organic bases such as wopropyl ethyl amine, triethylamine or N-methylmorpholine；Reaction dissolvent is selected from N,N-dimethylformamide, N, N- dimethyl Acetamide, N-Methyl pyrrolidone, dichloromethane, 1,2- dichloroethanes, toluene, acetonitrile or 1,4- dioxane etc.；Reaction temperature Spend is -15~35 DEG C.
Preferably, noble metal catalyst is selected to be selected from palladium, palladium bichloride or Pd (dppf) in the coupling reaction Cl2；Ligand is not selected or selects ligand such as triphenylphosphine, tricyclohexyl phosphine, tri-tert-butylphosphine or bis- (di-t-butyl) Phenylphosphines Wait ligands；Alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate；Reaction dissolvent is selected from DMAC N,N' dimethyl acetamide, N, N- bis- Methylformamide, tetrahydrofuran, 1,4- dioxane, 2- methyltetrahydrofurans or toluene etc.；Reaction temperature is 25~130 DEG C.
Preferably, in the step 3, when Pg is Boc protecting groups, simultaneously one pot of hydrolysis under hydrochloric acid effect of chemical formula 9 Method obtains 10 with hydrochloric acid into salt；Answer solvent be selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, 1,2- dichloromethane, 1,4- dioxane, toluene, ethyl acetate, isopropyl acetate etc.；Reaction temperature is -15~110 DEG C.
Preferably, in the step 3 when Pg is Cbz protecting groups, the first hydrogenation under palladium catalyst effect of chemical formula 9 is gone back Original, then with hydrochloric acid 10 are obtained into salt；Palladium catalyst is selected from palladium carbon or palladium dydroxide；Reaction dissolvent is selected from methanol, ethyl alcohol, isopropyl Alcohol, tetrahydrofuran, ethyl acetate, isopropyl acetate etc.；Reaction temperature is 0~65 DEG C.
The four of the object of the invention provide a kind of synthetic method of Acalabrutinib intermediate compound of formula 6, including such as Lower step：
(1) Formula 3 carries out condensation reaction with chloroacetaldehyde dimethylacetal and obtains intermediate compound of formula 5；
(2) Formula 5 is deprotected, annulation obtains intermediate compound of formula 6；
Wherein, Pg is tertbutyloxycarbonyl (Boc) or benzyloxycarbonyl group (Cbz).
Preferably, the condensation reaction selects alkali as potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, the tert-butyl alcohol Sodium, triethylamine, diisopropylethylamine etc.；Reaction dissolvent N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, tetrahydrochysene Furans, 2- methyltetrahydrofurans, 1,4- dioxane, toluene, dimethylbenzene, chlorobenzene or acetone etc..Reaction temperature is -10~180 ℃。
Preferably, used in the deprotection, annulation deprotection acid selected from hydrochloric acid, acetic acid, trifluoracetic acid or P-methyl benzenesulfonic acid etc.；The aminating agent of selection is ammonia, ammonium acetate or ammonium formate etc.；The reaction dissolvent selected is N, N- dimethyl methyls Amide, DMAC N,N' dimethyl acetamide, N-Methyl pyrrolidone, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans, 1,4- dioxies six Ring, toluene, dimethylbenzene or chlorobenzene etc..Reaction temperature is 20~180 DEG C.
The present invention about Acalabrutinib synthesis technology with L-PROLINE derivative compound formula 1 and the chloro- 2- first of 2- Acyl acetonitrile is starting material direct polycondensation and is cyclized and obtains Formula 2, anti-with cheap chloroethene methylal after bromo The intermediate compound of formula 3 that should be obtained, then by hydrolysis, ring-closure reaction obtain key intermediate compound formula 6, then with boron Acid esters intermediate compound of formula 8 carries out Suzuki couplings, then is deprotected into salt and obtains Formula 10, is finally carried out with tetrolic acid It is condensed to yield final products Acalabrutinib formulas 11.In addition, when to select Pg be Boc protecting groups, follow-up deprotection reaction can be with Avoid using palladium catalyzed hydrogenation, advantageously reduce the heavy-metal residual of final products, and be deprotected, salification process can also be It is completed in one kettle way, greatly improves route efficiency.These improvement all greatly improve route efficiency, and reduce technique Cost, and reduce the generation of by-product, conducive to final finished purity is improved.The route is easy to operate, not only total recovery compared with Height, obtained product purity is also higher, is suitble to amplification production.
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment is carried out lower based on the technical solution of the present invention Implement, give detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementation Example.
Embodiment 1
Addition compound 1a (21.33g, 100mmol) in three-necked flask, the chloro- 2- formoxyls acetonitriles of 2- (10.35, 100mmol) and acetonitrile (106mL), addition triethylamine (20.23g, 200mmol) are heated to back flow reaction mistake after stirring evenly Night.Reaction terminates rotation and removes part isopropyl alcohol, adds in water (213mL), a large amount of solids are precipitated, and filters, and crude product uses isopropanol and stone again Oily ether mixed solvent mashing, filtration drying obtain compound 2a (21.77g, 83%).MS (ESI) m/z=263.2 [M+H]+。
Embodiment 2
Addition compound 1b (24.73g, 100mmol) in three-necked flask, the chloro- 2- formoxyls acetonitriles of 2- (10.35, 100mmol) with DMAC (124mL), potassium carbonate (27.64g, 200mmol) is added in, 75~80 DEG C of reactions are heated to after stirring evenly Overnight.Reaction terminates to add in water (247mL), and a large amount of solids are precipitated, and filters, and crude product is beaten again with isopropanol and petroleum ether mixed solvent Slurry, filtration drying obtain compound 2b (23.11g, 78%).MS (ESI) m/z=297.1 [M+H]+。
Embodiment 3
Compound 2a (26.23g, 100mmol) and acetonitrile (131mL) are added in three-necked flask, is stirring evenly and then adding into NBS (19.58g, 110mmol), 25~30 DEG C are reacted 4~6 hours.Reaction terminates rotation and removes partial acetonitrile, adds in 5% sodium hydrogensulfite A large amount of solids are precipitated in solution (262mL), and filtering, crude product is beaten again with ethyl acetate and petroleum ether mixed solvent, and filtration drying obtains Compound 3a (29.68g, 87%).MS (ESI) m/z=341.0 [M+H]+1HNMR(400MHz,DMSO-d6)δ12.72(br, 1H),4.66-4.85(m,1H),3.18-3.40(m,2H),1.71-2.30(m,4H),1.14-1.45(m,9H)。
Embodiment 4
Compound 2b (29.63g, 100mmol), acetic acid (18.02g, 300mmol) and dichloromethane are added in three-necked flask (148mL) is cooled to 0~5 DEG C after stirring evenly, bromine (17.58g, 110mmol) is slowly added dropwise, 25~30 are warming up to after dripping off DEG C reaction 3~4 hours.Reaction terminates 10% sodium hydroxide solution of addition (262mL) and reaction is quenched, and liquid separation, water phase uses dichloro again Methane (148mL) extracts 1 time, merges organic phase and is washed with 5% sodium sulfite solution (148mL), saturated salt solution (148mL) is washed Wash, sodium sulphate drying, concentration remove partial solvent, add in petroleum ether mashing, filtration drying obtain compound 3b (30.77g, 82%).MS (ESI) m/z=375.2 [M+H]+1HNMR(400MHz,DMSO-d6)δ12.61(br,1H),7.25-7.40(m, 5H),4.76-5.25(m,3H),3.18-3.40(m,2H),1.71-2.30(m,4H).
Embodiment 5
Compound 3a (34.12g, 100mmol), potassium carbonate (27.64g, 200mmol) and N, N- bis- are added in three-necked flask Methylformamide (170mL) is slowly added dropwise after stirring evenly into chloroacetaldehyde dimethylacetal (14.95g, 120mmol), 25~30 DEG C Reaction is overnight.Reaction terminates to add in water (170mL), is extracted 2 times with ethyl acetate (170mL), merges organic phase, saturated salt solution (170mL) is washed, sodium sulphate drying, and concentration removing solvent obtains compound 4a crude products and directly casts single step reaction.MS(ESI)m/z =429.2 [M+H]+。
Embodiment 6
Compound 3b (37.52g, 100mmol), potassium carbonate (27.64g, 200mmol) and acetonitrile are added in three-necked flask (186mL) is slowly added dropwise after stirring evenly into chloroacetaldehyde dimethylacetal (14.95g, 120mmol), and 25~30 DEG C of reactions are overnight. Reaction terminates rotation and removes partial acetonitrile, adds in water (186mL), is extracted 2 times with ethyl acetate (186mL), merges organic phase, saturation food Brine (186mL) washs, sodium sulphate drying, and concentration removing solvent obtains compound 4b crude products and directly casts single step reaction.MS(ESI) M/z=463.1 [M+H]+。
Embodiment 7
Compound 4a (42.93g, 100mmol) and toluene (429mL) are added in three-necked flask, is slowly added after stirring evenly Enter acetic acid (18.02g, 300mmol), be heated to 75~80 DEG C and react 6~8 hours.Raw material adds in ammonium acetate after disappearing substantially (38.54g, 500mmol), heating reflux reaction 10~16 hours, reaction terminate to be cooled to room temperature, and it is molten to add in 5% sodium hydroxide Liquid (429mL), liquid separation, water phase again with toluene extract 1 time, merge organic phase, saturated salt solution (215mL) washing, and sodium sulphate is done Dry, concentration removes solvent, ethyl acetate petroleum ether mixed solvent recrystallization, filtering, dry compound 6a (27.14g, 2 steps 71%).MS (ESI) m/z=382.1 [M+H]+
Embodiment 8
Compound 4b (46.33g, 100mmol) and toluene (463mL) are added in three-necked flask, is slowly added after stirring evenly Enter trifluoracetic acid (18.02g, 300mmol), be heated to 75~80 DEG C and react 6~8 hours.Raw material is cooled to room temperature after disappearing substantially, 5% sodium hydroxide solution (463mL) washing is added in, saturated salt solution (231mL) washs 1 time, sodium sulphate drying, filtering, filtrate Ammonium acetate (38.54g, 500mmol), heating reflux reaction 10~16 hours are added in, reaction terminates to be cooled to room temperature, and adds in water (463mL), liquid separation after stirring, water phase again with toluene extract 1 time, merge organic phase, saturated salt solution (231mL) washing, sulfuric acid Sodium is dried, and concentration removes solvent, isopropanol petroleum ether mixed solvent recrystallization, filtering, dry compound 6b (31.64g, 2 steps 76%).MS (ESI) m/z=416.0 [M+H]+。
Embodiment 9
7 (24.81g, 100mmol) and n,N-Dimethylformamide (124mL) are added in three-necked flask, is stirred evenly rear cold To 0~5 DEG C, EDCI (23.00g, 120mmol) is added in, adds in 2-aminopyridine (11.29g, 110mmol), diisopropyl is added dropwise Ethamine (25.85g, 200mmol) reacts 6~8 hours for 25~30 DEG C after adding.Reaction terminates to add in water (248mL), uses acetic acid Ethyl ester (124mL) extracts 3 times, merges 10% sodium bicarbonate solution of organic phase (124mL) and washs 1 time, saturated common salt is washed 2 times (124mL), anhydrous sodium sulfate drying, is beaten after concentration with ethyl acetate petroleum ether mixed solvent, filtering, dry compound 8 (27.56g, 85%).MS (ESI) m/z=325.3 [M+H]+
Here EDCI can be replaced with HBTU, CDI or DCC.
Embodiment 10
Compound 6a (38.23g, 100mmol) is added in three-necked flask and compound 8 (34.04g, 105mmol) adds in N, Dinethylformamide (191mL) stirring and dissolving adds in cesium carbonate (48.87g, 150mmol), stirs evenly rear vacuum switching nitrogen Gas 3 times, nitrogen protection is lower to add in Pd (dppf) Cl2(1.46g, 2mmol) is heated to 100~110 DEG C and reacts 6-8 hours.Reaction End is cooled to room temperature and adds in water (382mL), ethyl acetate (191mL) stirring liquid separation, and water phase is extracted again with ethyl acetate (191mL) 1 time, merge organic phase saturated salt solution (191mL) and wash 2 times, sodium sulphate drying, concentration removes most of solvent, adds in petroleum ether (191mL), heating, cooling mashing, filtration drying obtain compound 9a (39.47g, yield 79%).MS (ESI) m/z=500.3 [M +H]+。
Here Pd (dppf) Cl2It can be replaced with palladium, palladium bichloride；Cesium carbonate can use potassium carbonate, sodium carbonate or potassium phosphate Instead of.
Embodiment 11
Compound 6b (41.63g, 100mmol) is added in three-necked flask and compound 8 (34.04g, 105mmol) adds in N, Dinethylformamide (191mL) stirring and dissolving adds in aqueous potassium phosphate solution (42.45g, 200mmol are dissolved in 208mL water), stirs Vacuum switching nitrogen 3 times after mixing uniformly, nitrogen protection is lower to add in Pd (dppf) Cl2(1.46g, 2mmol), is heated to 100~110 DEG C reaction 6-8 hours.Reaction terminates to be cooled to room temperature addition water (208mL), ethyl acetate (208mL) stirring liquid separation, and water phase is used again Ethyl acetate (208mL) extracts 1 time, merges organic phase saturated salt solution (208mL) and washes 2 times, and sodium sulphate drying, concentration removes big Partial solvent adds in petroleum ether (208mL), heating, and cooling is beaten, and filtration drying obtains compound 9b (44.29g, yield 83%). MS (ESI) m/z=534.2 [M+H]+
Embodiment 12
Compound 9a (49.96g, 100mmol) is added in three-necked flask, absolute ethyl alcohol (500mL) is stirring evenly and then adding into 34% ethanol solution hydrochloride (53.62g, 500mmol) is heated to 50~55 DEG C and reacts 4~6 hours, and reaction terminates slowly to be cooled to Room temperature be beaten, filtering, ethyl alcohol washing, collect solid it is dry compound 10 (46.81g, 92%).MS (ESI) m/z=400.3 [M+H]+Elemental analysis：Anal.Calcd (%):C 51.93,H 4.75,N 19.27；found:C 51.73H 4.86,N 19.21
Embodiment 13
It hydrogenates and compound 9b (53.36g, 100mmol) is added in bottle, add in methanol (534mL) and dissolve, add in palladium carbon (10%, 2.67g), vacuum switching hydrogen three times, are forced into 45~50 DEG C of reactions 16~24 of temperature in 0.18~0.20Mpa and holding Hour.Reaction terminates cooling diatomite and filters off palladium carbon, and filtrate is heated to 50~55 DEG C, is slowly dropped into 30% methanol hydrochloride solution (36.46g, 300mmol), Slow cooling mashing, filtering, the washing of a small amount of methanol, collect solid it is dry compound 10 (43.25g, yield 85%).
Embodiment 14
10 (50.88g, 100mmol) and n,N-Dimethylformamide (254mL) are added in three-necked flask, after stirring evenly It is cooled to 0~5 DEG C, adds in tetrolic acid (9.25g, 110mmol), add in EDCI (23.00g, 120mmol), N-methylmorpholine is added dropwise (40.46g, 400mmol) reacts 6~8 hours for 25~30 DEG C after adding.Reaction terminates to add in water (254mL), uses dichloromethane (127mL) is extracted 3 times, is merged 10% sodium bicarbonate solution of organic phase (127mL) and is washed 1 time, saturated common salt is washed 2 times (127mL), anhydrous sodium sulfate drying, is beaten after concentration with isopropanol petroleum ether mixed solvent, filtering, dry product (36.31g, 78%).MS (ESI) m/z=
466.2[M+H]+。
Here EDCI can be replaced with HBTU, CDI or DCC.

Claims (10)

1.Acalabrutinib intermediate compound of formula 3, structural formula is as follows：
Wherein, Pg protecting groups are tertbutyloxycarbonyl (Boc) or benzyloxycarbonyl group (Cbz).
The synthetic method of 2.Acalabrutinib intermediate compound of formula 3, it is characterised in that include the following steps：
(1) the chloro- 2- formoxyls acetonitriles of Formula 1 and 2- carry out ring-closure reaction and obtain Formula 2；
(2) chemical formula 2 is obtained into intermediate compound of formula 3 by bromo-reaction；
3. the synthetic method of Acalabrutinib intermediate compound of formula 3 according to claim 2, it is characterised in that institute The alkali used in the ring-closure reaction stated is potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropyl Base ethamine；Reaction dissolvent is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N-Methyl pyrrolidone, acetonitrile, tetrahydrochysene furan It mutters, 2- methyltetrahydrofurans, 1,4- dioxane, toluene, dimethylbenzene or chlorobenzene.
4. the synthetic method of Acalabrutinib intermediate compound of formula 3 according to claim 2, it is characterised in that institute The brominated reagent used in the bromo-reaction stated is selected from bromine, NBS, pyridinium tribromide or C5H6Br2N2O2；Reaction dissolvent is selected from two Chloromethanes, chloroform, tetrahydrofuran, dioxane, acetonitrile, acetic acid, methanol, ethyl alcohol or isopropanol.
The synthetic method of 5.Acalabrutinib, it is characterised in that including Formula 10 and tetrolic acid are carried out condensation reaction Obtain Acalabrutinib formulas 11；
6. the synthetic method of Acalabrutinib according to claim 5, it is characterised in that the conjunction of the Formula 10 Into method, include the following steps：
(1) Formula 7 carries out condensation reaction with 2-aminopyridine and obtains Formula 8；
(2) Formula 6 and Formula 8 obtain compound 9 by Suzuki coupling reactions；
(3) Formula 9 is sloughed into protection and obtains Formula 10；
Wherein, Pg protecting groups are tertbutyloxycarbonyl (Boc) or benzyloxycarbonyl group (Cbz) in Formula 6 and Formula 9.
7. the synthetic method of Acalabrutinib according to claim 6, it is characterised in that the condensation reaction is selected Condensing agent is EDCI/HOBT, HBTU, CDI or DCC；Alkali is selected from diisopropylethylamine, triethylamine or N-methylmorpholine；React molten Agent be selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N-Methyl pyrrolidone, dichloromethane, 1,2- dichloroethanes, Toluene, acetonitrile or 1,4- dioxane；Noble metal catalyst is selected to be selected from palladium, palladium bichloride or Pd in the coupling reaction (dppf)Cl2；Ligand is not selected or selects ligand, and the ligand is selected from triphenylphosphine, tricyclohexyl phosphine, tri-tert-butylphosphine or double (di-t-butyl) Phenylphosphine；Alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate；Reaction dissolvent is selected from N, N- dimethyl second Amide, N,N-dimethylformamide, tetrahydrofuran, 1,4- dioxane, 2- methyltetrahydrofurans or toluene.
8. the synthetic method of Acalabrutinib according to claim 6, it is characterised in that in the step 3, when Pg is During Boc protecting groups, simultaneously one kettle way obtains Formula 10 to Formula 9 with hydrochloric acid into salt for hydrolysis under hydrochloric acid effect；Answer solvent Selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, 1,2- dichloromethane, 1,4- dioxane, toluene, acetic acid second Ester, isopropyl acetate；When Pg is Cbz protecting groups, the first hydro-reduction under palladium catalyst effect of Formula 9, then with hydrochloric acid Formula 10 is obtained into salt；Palladium catalyst is selected from palladium carbon or palladium dydroxide；Reaction dissolvent is selected from methanol, ethyl alcohol, isopropanol, four Hydrogen furans, ethyl acetate, isopropyl acetate.
9. the synthetic method of Acalabrutinib according to claim 6, it is characterised in that the conjunction of the Formula 6 Into method, include the following steps：
(1) Formula 3 carries out condensation reaction with chloroacetaldehyde dimethylacetal and obtains intermediate compound of formula 5；
(2) Formula 5 is deprotected, annulation obtains intermediate compound of formula 6；
Wherein, Pg is tertbutyloxycarbonyl (Boc) or benzyloxycarbonyl group (Cbz).
10. the synthetic method of Acalabrutinib according to claim 9, it is characterised in that the condensation reaction choosing It is potassium carbonate, sodium carbonate, cesium carbonate with alkali, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine；Reaction dissolvent N, N- Dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans, 1,4- dioxane, toluene, Dimethylbenzene, chlorobenzene or acetone；Used in the deprotection, annulation deprotection acid selected from hydrochloric acid, acetic acid, trifluoracetic acid or P-methyl benzenesulfonic acid；The aminating agent of selection is ammonia, ammonium acetate or ammonium formate；Reaction dissolvent is N,N-dimethylformamide, N, N- Dimethylacetylamide, N-Methyl pyrrolidone, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans, 1,4- dioxane, toluene, two Toluene or chlorobenzene.
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