CN107522742B - A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediate - Google Patents
A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediate Download PDFInfo
- Publication number
- CN107522742B CN107522742B CN201710984185.8A CN201710984185A CN107522742B CN 107522742 B CN107522742 B CN 107522742B CN 201710984185 A CN201710984185 A CN 201710984185A CN 107522742 B CN107522742 B CN 107522742B
- Authority
- CN
- China
- Prior art keywords
- preparation
- iodoaniline
- homogeneous
- ethyl acetate
- brigatinib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 229950004272 brigatinib Drugs 0.000 title claims abstract description 12
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 claims abstract description 18
- YOTZYFSGUCFUKA-UHFFFAOYSA-N dimethylphosphine Chemical compound CPC YOTZYFSGUCFUKA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000012043 crude product Substances 0.000 claims abstract description 9
- 238000002955 isolation Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 238000012544 monitoring process Methods 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 10
- 239000003208 petroleum Substances 0.000 claims description 10
- 238000004809 thin layer chromatography Methods 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 238000013019 agitation Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 3
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical class ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 abstract description 10
- 239000002253 acid Substances 0.000 abstract description 5
- 239000011230 binding agent Substances 0.000 abstract description 5
- 238000005859 coupling reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- CEJAHXLRNZJPQH-UHFFFAOYSA-N 2,5-dichloropyrimidine Chemical compound ClC1=CN=C(Cl)N=C1 CEJAHXLRNZJPQH-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 238000001953 recrystallisation Methods 0.000 abstract description 3
- 238000007039 two-step reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 238000001035 drying Methods 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 238000000605 extraction Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 238000005406 washing Methods 0.000 abstract description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- SHEQRWTUXYWGQS-UHFFFAOYSA-N 2-dimethylphosphanylaniline Chemical compound CP(C)C1=CC=CC=C1N SHEQRWTUXYWGQS-UHFFFAOYSA-N 0.000 description 1
- -1 4- methylpiperazine-1-yl Chemical group 0.000 description 1
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019420 lymphoid neoplasm Diseases 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention belongs to technical field of medicine synthesis, and in particular to a kind of homogeneous " one kettle way " preparation method about Brigatinib key intermediate (II).The preparation method includes: that 2- Iodoaniline and dimethyl phosphine are carried out coupling reaction under catalyst, acid binding agent effect, and without isolation directly with 2,4,5- trichloropyrimidines carry out substitution reaction.Then through extraction, washing, drying, filter, be concentrated to get crude product, by being recrystallized to give (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine (II).The present invention replaces two-step reaction using homogeneous " one kettle way ", and centre does not need to isolate and purify, and shortens step and simplifies operation, yield is improved than the prior art；Column chromatographic purifying is replaced with recrystallization simultaneously, reduces solvent consumption and " three wastes " discharge, is suitble to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to one kind is about Brigatinib key intermediate (II)
Homogeneously " one kettle way " preparation method.
Background technique
Brigatinib, trade name Alunbrig, the Ariad drugmaker by now belonging to military field pharmacy research and develop listing,
FDA approval is obtained for the disease progression after gram azoles is for Buddhist nun (Crizotinib) treatment in April, 2017, or Buddhist nun is replaced not to gram azoles
The Locally Advanced or Metastatic Nsclc for the anaplastic lymphoma kinase positive (ALK+) being resistant to.In addition, suitable grinding
Answering disease further includes fibrosarcoma, diffusivity large B cell lymphoid tumor and primary cutaneous type etc..According to Thomson
Reuters data statistics prediction, Brigatinib will obtain 45,330,000 dollars of sales volume in 2017, then year by year on
It rises, is up to 4.78 hundred million dollars to annual sales amount in 2021, has good market prospects.
The chemical name of Brigatinib are as follows: the chloro- N2- of 5- [4- [(4- methylpiperazine-1-yl) piperidin-1-yl] -2- methoxyl group
Phenyl]-N4- [2- (dimethyl Asia phosphono) phenyl] -2,4- pyrimidinediamine (I), structure formula (I) is as follows:
Patent WO2009143389 reports the structure and synthetic method of (I) for the first time, document (J.Med.Chem.2016,
59,4948-4964) and international monopoly US2015225436, WO201665028 etc. also report the synthetic method of (I).Current
The synthetic method about (I) of report is as follows:
At present the synthetic method about key intermediate (II) be by 2- Iodoaniline and dimethyl phosphine palladium acetate/
Under Xantphos catalysis, with K3PO4For acid binding agent, coupling obtains (2- aminophenyl) dimethyl phosphine (IV), then with 2,4,5-
Trichloropyrimidine reacts to obtain (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine (II).Synthetic route is such as
Under:
There is apparent defect in the above-mentioned synthetic method about (II): the 1) synthesis of intermediate (IV) in the actual process
Cheng Fanying not exclusively, low efficiency, need column chromatographic purifying.2) yield is not high, and two-step reaction total recovery is only 49.9%
(J.Med.Chem.2016,59,4948-4964), and operating process is complicated, it is time-consuming and laborious, it is unfavorable for industrialized production.
From the foregoing, it will be observed that the prior art haves the defects that not high yield, low efficiency and cumbersome, it is to influence at present
An important factor for Brigatinib intermediate (II) industrialized production.New preparation method is developed to improve the production of intermediate (II)
Rate and combined coefficient are technical problems urgently to be solved.
Summary of the invention
In view of in existing method there are above-mentioned technical problem, the purpose of the present invention is develop it is a kind of it is easy to operate, high-efficient,
Yield is good, stable product quality and the environmental-friendly preparation method about (II).
" one kettle way " preparation method the present invention provides one kind about Brigatinib key intermediate (II), the system
Preparation Method includes:
2- Iodoaniline and dimethyl phosphine are subjected to coupling reaction under catalyst, acid binding agent effect, without isolation directly
It connects and carries out substitution reaction with 2,4,5- trichloropyrimidine.Then through extraction, washing, drying, filter, be concentrated to get crude product, pass through weight
Crystallization obtains (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine (II).
In preparation method of the present invention, 2- Iodoaniline: dimethyl phosphine: 2,4,5- trichloropyrimidines feed intake mole
Than for 1:1.1:1.2.
Coupling reaction temperature is 80~120 DEG C, preferably 90~100 DEG C.
The catalyst of coupling reaction is selected from palladium acetate/Xantphos, tetrakis triphenylphosphine palladium, palladium acetate/triphenylphosphine, excellent
It is selected as palladium acetate/Xantphos；Acid binding agent is selected from triethylamine, N, and N- diisopropylethylamine, triethylene diamine, 1,8- diaza are double
11 carbon -7- alkene of ring [5.4.0], 4-dimethylaminopyridine, pyridine, N-methylmorpholine, preferably n,N-diisopropylethylamine.2-
Iodoaniline: the molar ratio of acid binding agent is 1:2~2.5, preferably 1:2.2.
In recrystallization method of the present invention, the mixed solvent that selection is made of ethyl acetate and petroleum ether, preferably two
The volume ratio of person is ethyl acetate: petroleum ether=1:2.
Compared with prior art, key intermediate (II) preparation method of the present invention about Brigatinib has
Beneficial effect includes the following aspects: 1) replacing two-step reaction using homogeneous " one kettle way ", centre does not need to isolate and purify, and contracts
Short step simultaneously simplifies operation；2) than prior art raising, (yield of optimum condition is 67.2% to yield, is higher than document
The 49.9% of J.Med.Chem.2016,59,4948-4964 report)；3) column chromatographic purifying is replaced with recrystallization, reduces solvent
Consumption and " three wastes " discharge.Therefore, preparation method of the present invention is easy to operate, efficiency and high income, environmental-friendly, is suitble to
Industrialized production.
Preparation method of the invention needs that otherwise " one kettle way " can not be passed through using homogeneous reaction, i.e. liquid-liquid homogeneous systems
Synthesis is to obtain above-mentioned beneficial effect.
Detailed description of the invention
Fig. 1 is product nucleus magnetic hydrogen spectrum figure in the embodiment of the present invention 1；
Specific embodiment
Embodiment 1
2- Iodoaniline (17.5g, 79.9mmol) and dimethyl phosphine (6.9g, 88.5mmol), palladium acetate is added
(0.3g, 1.3mmol), Xantphos (0.77g, 1.3mmol), n,N-diisopropylethylamine (22.7g, 175.8mmol), DMF
(50mL), magnetic agitation.It under nitrogen protection, is heated to 100 DEG C and reacts 6 hours, run out of through thin-layer chromatography monitoring 2- Iodoaniline
Entirely.It is cooled to room temperature, is added 2,4,5- trichloropyrimidine (17.5g, 95.9mmol), be heated to 75 DEG C and react 6 hours, through thin layer color
Spectrum monitoring fully reacting.It is cooled to room temperature, adds water 300mL, with 5% hydrochloric acid tune pH to 5, ethyl acetate extracts (100mL × 3),
Sodium bicarbonate solution washs (100mL), and saturated sodium chloride solution washs (100mL × 2), and anhydrous sodium sulfate is dry.It filters, it is dense
Contracting, obtains yellow-brown solid crude product, then be recrystallized to give near-white solid 17g with ethyl acetate/petroleum ether (volume ratio 1:2),
Yield 67.3%.Nucleus magnetic hydrogen spectrum data (see Fig. 1) are1H NMR(300MHz,CDCl3) δ 11.56 (s, 1H), 8.66~8.70 (m,
1H), 8.23 (s, 1H), 7.57~7.64 (m, 1H), 7.26~7.34 (m, 1H), 7.16~7.22 (m, 1H), 1.85 (d, J=
15.0Hz,6H).Document (J.Med.Chem.2016,59,4948-4964) value is1H NMR(400MHz,DMSO-d6)δ11.82
(s, 1H), 8.45 (s, 1H), 8.42 (dd, J=4.14,8.28Hz, 1H), 7.47~7.81 (m, 2H), 7.24 (t, J=
7.22Hz, 1H), 1.80 (d, J=13.68Hz, 6H).Therefore, nucleus magnetic hydrogen spectrum data are consistent with document report.
Embodiment 2
2- Iodoaniline (8.6g, 39.3mmol) and dimethyl phosphine (3.4g, 43.6mmol), four (triphenylphosphines) are added
Palladium (0.92g, 0.8mmol), n,N-diisopropylethylamine (11.2g, 86.7mmol), DMF (30mL), magnetic agitation.Nitrogen is protected
Under shield, it is heated to 90 DEG C and reacts 8 hours, it is complete through thin-layer chromatography monitoring 2- Iodoaniline consumption.It is cooled to room temperature, is added 2,4,5-
Trichloropyrimidine (8.6g, 47.0mmol) is heated to 75 DEG C and reacts 6 hours, monitors fully reacting through thin-layer chromatography.It is cooled to room
Temperature adds water 200mL, and with 5% hydrochloric acid tune pH to 5, ethyl acetate extracts (70mL × 3), and sodium bicarbonate solution washs (100mL),
Saturated sodium chloride solution washs (100mL × 2), and anhydrous sodium sulfate is dry.It filters, concentration obtains yellow-brown solid crude product, then use
Ethyl acetate/petroleum ether (volume ratio 1:2) is recrystallized to give near-white solid 6.8g, yield 54.8%.
Embodiment 3
2- Iodoaniline (7.8g, 35.6mmol) and dimethyl phosphine (3.1g, 39.7mmol), palladium acetate is added
(0.13g, 0.58mmol), Xantphos (0.33g, 0.57mmol), n,N-diisopropylethylamine (9.2g, 71.2mmol), DMF
(30mL), magnetic agitation.It under nitrogen protection, is heated to 100 DEG C and reacts 6 hours, run out of through thin-layer chromatography monitoring 2- Iodoaniline
Entirely.It is cooled to room temperature, is added 2,4,5- trichloropyrimidine (7.8g, 42.7mmol), be heated to 75 DEG C and react 6 hours, through thin layer color
Spectrum monitoring fully reacting.It is cooled to room temperature, adds water 200mL, with 5%HCl tune pH to 5, ethyl acetate extracts (70mL × 3), carbon
Sour hydrogen sodium solution washs (100mL), and saturated sodium chloride solution washs (100mL × 2), and anhydrous sodium sulfate is dry.It filters, concentration,
Yellow-brown solid crude product is obtained, then is recrystallized to give near-white solid 6.6g with ethyl acetate/petroleum ether (volume ratio 1:2), is received
Rate 58.8%.
Embodiment 4
2- Iodoaniline (7.8g, 35.6mmol) and dimethyl phosphine (3.1g, 39.7mmol), palladium acetate is added
(0.13g, 0.58mmol), Xantphos (0.33g, 0.57mmol), n,N-diisopropylethylamine (11.5g, 89.0mmol),
DMF (30mL), magnetic agitation.It under nitrogen protection, is heated to 100 DEG C and reacts 6 hours, through thin-layer chromatography monitoring 2- Iodoaniline consumption
Completely.It is cooled to room temperature, is added 2,4,5- trichloropyrimidine (7.8g, 42.7mmol), be heated to 75 DEG C and react 6 hours, through thin layer
Chromatogram monitoring fully reacting.It is cooled to room temperature, adds water 200mL, with 5%HCl tune pH to 5, ethyl acetate extracts (70mL × 3),
Sodium bicarbonate solution washs (100mL), and saturated sodium chloride solution washs (100mL × 2), and anhydrous sodium sulfate is dry.It filters, it is dense
Contracting, obtains yellow-brown solid crude product, then be recrystallized to give near-white solid 6.2g with ethyl acetate/petroleum ether (volume ratio 1:2),
Yield 55.3%.
Embodiment 5
2- Iodoaniline (7.8g, 35.6mmol) and dimethyl phosphine (3.1g, 39.7mmol), palladium acetate is added
(0.13g, 0.58mmol), Xantphos (0.33g, 0.57mmol), n,N-diisopropylethylamine (10.1g, 78.4mmol),
DMF (30mL), magnetic agitation.It under nitrogen protection, is heated to 80 DEG C and reacts 16 hours, through thin-layer chromatography monitoring 2- Iodoaniline consumption
Completely.It is cooled to room temperature, is added 2,4,5- trichloropyrimidine (7.8g, 42.7mmol), be heated to 75 DEG C and react 6 hours, through thin layer
Chromatogram monitoring fully reacting.It is cooled to room temperature, adds water 200mL, with 5%HCl tune pH to 5, ethyl acetate extracts (70mL × 3),
Sodium bicarbonate solution washs (100mL), and saturated sodium chloride solution washs (100mL × 2), and anhydrous sodium sulfate is dry.It filters, it is dense
Contracting, obtains yellow-brown solid crude product, then be recrystallized to give near-white solid 6.4g with ethyl acetate/petroleum ether (volume ratio 1:2),
Yield 56.8%.
Embodiment 6
2- Iodoaniline (7.8g, 35.6mmol) and dimethyl phosphine (3.1g, 39.7mmol), palladium acetate is added
(0.13g, 0.58mmol), Xantphos (0.33g, 0.57mmol), n,N-diisopropylethylamine (10.1g, 78.4mmol),
DMF (30mL), magnetic agitation.It under nitrogen protection, is heated to 120 DEG C and reacts 4 hours, through thin-layer chromatography monitoring 2- Iodoaniline consumption
Completely.It is cooled to room temperature, is added 2,4,5- trichloropyrimidine (7.8g, 42.7mmol), be heated to 75 DEG C and react 6 hours, through thin layer
Chromatogram monitoring fully reacting.It is cooled to room temperature, adds water 200mL, with 5%HCl tune pH to 5, ethyl acetate extracts (70mL × 3),
Sodium bicarbonate solution washs (100mL), and saturated sodium chloride solution washs (100mL × 2), and anhydrous sodium sulfate is dry.It filters, it is dense
Contracting, obtains yellow-brown solid crude product, then be recrystallized to give near-white solid 6.0g with ethyl acetate/petroleum ether (volume ratio 1:2),
Yield 53.6%.
Claims (1)
1. a kind of homogeneous " one kettle way " preparation method about Brigatinib key intermediate, which is characterized in that will
79.9mmol2- Iodoaniline, 88.5mmol dimethyl phosphine, 1.3mmol palladium acetate, 1.3mmol Xantphos,
175.8mmol n,N-diisopropylethylamine is dissolved in 50mLDMF, and uses magnetic agitation；Under nitrogen protection, 100 DEG C are heated to instead
It answers 6 hours, after thin-layer chromatography monitoring 2- Iodoaniline consumption completely, is cooled to room temperature；It is directly added into without isolation
95.9mmol2,4,5- trichloropyrimidines are heated to 75 DEG C and react 6 hours, after thin-layer chromatography monitors fully reacting, are cooled to room
Temperature；300mL is added water, with 5% hydrochloric acid tune pH to 5, is extracted 3 times with 100mL ethyl acetate, is washed with 100mL sodium bicarbonate solution
It washs, is washed 2 times with 100mL saturated sodium chloride solution, it is dry with anhydrous sodium sulfate, then filtered, it is concentrated, obtains yellow-brown solid
Crude product, then carry out being recrystallized to give solid with the ethyl acetate/petroleum ether mixed liquor of ethyl acetate and the volume ratio 1:2 of petroleum ether
Product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710984185.8A CN107522742B (en) | 2017-10-20 | 2017-10-20 | A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710984185.8A CN107522742B (en) | 2017-10-20 | 2017-10-20 | A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107522742A CN107522742A (en) | 2017-12-29 |
| CN107522742B true CN107522742B (en) | 2019-10-18 |
Family
ID=60684901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710984185.8A Active CN107522742B (en) | 2017-10-20 | 2017-10-20 | A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107522742B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108129513A (en) * | 2018-02-01 | 2018-06-08 | 安庆奇创药业有限公司 | A kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate |
| CN110713497A (en) * | 2019-10-30 | 2020-01-21 | 成都海杰亚医药科技有限公司 | Preparation method of Brigatinib intermediate 2-aminophenyldimethylphosphine oxide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103501612A (en) * | 2011-05-04 | 2014-01-08 | 阿里亚德医药股份有限公司 | Compounds for inhibiting cell proliferation in EGFR-driven cancers |
| CN105330698A (en) * | 2014-07-04 | 2016-02-17 | 南京明德新药研发股份有限公司 | Spiro aryl phosphorus oxide or sulfide |
| CN106928275A (en) * | 2015-12-29 | 2017-07-07 | 齐鲁制药有限公司 | The Preparation Method And Their Intermediate and crystal formation of volution amine aryl phosphoric-oxygenic compound |
-
2017
- 2017-10-20 CN CN201710984185.8A patent/CN107522742B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103501612A (en) * | 2011-05-04 | 2014-01-08 | 阿里亚德医药股份有限公司 | Compounds for inhibiting cell proliferation in EGFR-driven cancers |
| CN105330698A (en) * | 2014-07-04 | 2016-02-17 | 南京明德新药研发股份有限公司 | Spiro aryl phosphorus oxide or sulfide |
| CN106928275A (en) * | 2015-12-29 | 2017-07-07 | 齐鲁制药有限公司 | The Preparation Method And Their Intermediate and crystal formation of volution amine aryl phosphoric-oxygenic compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107522742A (en) | 2017-12-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105820110B (en) | Mo Fanselin synthetic methods | |
| CN104926734B (en) | The preparation method of flibanserin | |
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN107522742B (en) | A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediate | |
| CN107778223B (en) | Preparation method of betrixaban maleate | |
| CN103570633B (en) | The preparation method of Gefitinib | |
| CN106187852A (en) | A kind of preparation method of Vonoprazan fumarate intermediate | |
| CN105085484B (en) | A kind of preparation method of Vonoprazan fumarate | |
| CN109134434B (en) | Quinoline or quinazoline compound and preparation method and application thereof | |
| CN104945332A (en) | Preparation method of erlotinib | |
| CN102993121A (en) | Synthetic method for preparing roxatidine acetate hydrochloride with high purity | |
| CN108794414B (en) | Aromatic amido substituted s-triazine compound, preparation and application thereof | |
| CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
| CN105440034A (en) | Preparation method of linagliptin and intermediate thereof | |
| CN106632312B (en) | A kind of related substance of Eliquis, intermediate, preparation method and applications | |
| CN105153169B (en) | A kind of synthetic method of epinastine hydrochloride | |
| CN107698538A (en) | The intermediate 3 of roxatidine acetate hydrochloride（1 piperidine methyl）The new preparation method of phenol | |
| CN108794448A (en) | The preparation method of one koji Ge Lieting and its salt | |
| CN109942462B (en) | Synthesis process of bambuterol hydrochloride | |
| CN102485719A (en) | Preparation method of Imatinib amine | |
| CN109020977A (en) | A kind of preparation method of Acalabrutinib | |
| CN104892596A (en) | Novel method for synthesizing pirenzepine hydrochloride intermediate | |
| CN111171002A (en) | Preparation method of PARP inhibitor intermediate | |
| CN104910101A (en) | Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride | |
| CN109232434A (en) | A kind of new method synthesizing flibanserin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |