CN107522742A - A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediates - Google Patents
A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediates Download PDFInfo
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- CN107522742A CN107522742A CN201710984185.8A CN201710984185A CN107522742A CN 107522742 A CN107522742 A CN 107522742A CN 201710984185 A CN201710984185 A CN 201710984185A CN 107522742 A CN107522742 A CN 107522742A
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- iodoanilines
- dimethyl phosphine
- homogeneous
- binding agent
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- 239000000543 intermediate Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 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
- YOTZYFSGUCFUKA-UHFFFAOYSA-N dimethylphosphine Chemical compound CPC YOTZYFSGUCFUKA-UHFFFAOYSA-N 0.000 claims abstract description 17
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical class ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 9
- 239000011230 binding agent Substances 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000005859 coupling reaction Methods 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- CEJAHXLRNZJPQH-UHFFFAOYSA-N 2,5-dichloropyrimidine Chemical compound ClC1=CN=C(Cl)N=C1 CEJAHXLRNZJPQH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 230000000694 effects Effects 0.000 claims abstract description 3
- 238000002955 isolation Methods 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 23
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical class NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 claims description 19
- 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
- 229910052763 palladium Inorganic materials 0.000 claims description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 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 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003927 aminopyridines Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 238000001953 recrystallisation Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000007039 two-step reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- RRHNGIRRWDWWQQ-UHFFFAOYSA-N n-iodoaniline Chemical class INC1=CC=CC=C1 RRHNGIRRWDWWQQ-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- 239000002024 ethyl acetate extract Substances 0.000 description 4
- 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
- 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-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
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 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
- 150000001336 alkenes Chemical class 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 238000006555 catalytic 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
- 238000005516 engineering process Methods 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
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 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 on Brigatinib key intermediates (II).The preparation method includes：2 Iodoanilines and dimethyl phosphine are subjected to coupling reaction under catalyst, acid binding agent effect, without isolation directly with 2,4,5 trichloropyrimidines carry out substitution reaction.Then through extracting, washing, drying, filtering, being concentrated to give crude product, by being recrystallized to give (2 ((base of 2,5 dichloro pyrimidine 4) amino) phenyl) dimethyl phosphine (II).The present invention replaces two-step reaction using homogeneous " one kettle way ", and centre need not isolate and purify, and shortens step and simplifies operation, yield improves than prior art；Replace column chromatography to purify with recrystallization simultaneously, reduce solvent consumption and " three wastes " discharge, be adapted to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to one kind is on Brigatinib key intermediates (II)
Homogeneously " one kettle way " preparation method.
Background technology
Brigatinib, trade name Alunbrig, listing is researched and developed by the Ariad drugmakers for now belonging to military field pharmacy,
FDA is obtained in April, 2017 and ratifies to be used for the disease progression after gram azoles is for Buddhist nun (Crizotinib) treatment, 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.It is in addition, suitable grinding
Disease is answered also to include fibrosarcoma, diffusivity large B cell lymphoid tumor and primary cutaneous type etc..According to Thomson
Reuters data statistics predicts, Brigatinib in the sales volume that will obtain 45,330,000 dollars in 2017, then year by year on
Rise, be up to 4.78 hundred million dollars to annual sales amount in 2021, there are good market prospects.
Brigatinib's is chemical entitled：The chloro- N2- of 5- [4- [(4- methylpiperazine-1-yls) piperidin-1-yl] -2- methoxyl groups
Phenyl]-N4- [2- (dimethyl Asia phosphono) phenyl] -2,4- pyrimidinediamines (I), structure formula (I) is as follows：
Patent WO2009143389 reports the structure and synthetic method of (I) first, 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 on (I) of report is as follows：
At present the synthetic method on key intermediate (II) be by 2- Iodoanilines and dimethyl phosphine palladium/
Under Xantphos catalysis, with K3PO4For acid binding agent, coupling obtains (2- aminophenyls) dimethyl phosphine (IV), then with 2,4,5-
Trichloropyrimidine reacts to obtain (2- ((2,5- dichloro pyrimidine -4- bases) amino) phenyl) dimethyl phosphine (II).Synthetic route is such as
Under：
The defects of obvious in real process be present in the above-mentioned synthetic method on (II)：1) synthesis of intermediate (IV)
Cheng Fanying is incomplete, efficiency is low, it is necessary to which column chromatography purifies.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, wastes time and energy, is unfavorable for industrialized production.
From the foregoing, it will be observed that prior art is present, yield is not high, efficiency is low and it is cumbersome the defects of, be to influence at present
An important factor for Brigatinib intermediates (II) industrialized production.New preparation method is developed to improve intermediate (II) production
Rate and combined coefficient, it is the technical problem for being badly in need of solving.
The content of the invention
In view of above-mentioned technical problem in existing method be present, the purpose of the present invention be a kind of easy to operate, efficiency high of exploitation,
Yield is good, product quality is stable and the environment-friendly preparation method on (II).
The invention provides " one kettle way " preparation method of one kind on Brigatinib key intermediates (II), the system
Preparation Method includes：
2- Iodoanilines and dimethyl phosphine are subjected to coupling reaction under catalyst, acid binding agent effect, without isolation directly
Connect and carry out substitution reaction with 2,4,5- trichloropyrimidines.Then through extracting, washing, drying, filtering, being concentrated to give crude product, weight is passed through
Crystallization obtains (2- ((2,5- dichloro pyrimidine -4- bases) amino) phenyl) dimethyl phosphine (II).
In preparation method of the present invention, 2- Iodoanilines：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/Xantphos, tetrakis triphenylphosphine palladium, palladium/triphenylphosphine, excellent
Elect palladium/Xantphos as；Acid binding agent is selected from triethylamine, N, and N- diisopropylethylamine, triethylene diamine, 1,8- diazas are double
Carbon -7- the alkene of ring [5.4.0] 11, DMAP, pyridine, preferably N-methylmorpholine, DIPEA.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, from the mixed solvent being made up 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 on Brigatinib has
Beneficial effect includes the following aspects：1) two-step reaction is replaced using homogeneous " one kettle way ", centre need not isolate and purify, and contract
Short step simultaneously simplifies operation；2) than prior art raising, (yield of optimum condition is 67.2% to yield, higher than document
J.Med.Chem.2016,59,4948-4964 report 49.9%)；3) replace column chromatography to purify with recrystallization, reduce solvent
Consumption and " three wastes " discharge.Therefore, preparation method of the present invention is easy to operate, efficiency and high income, environment-friendly, is adapted to
Industrialized production.
The preparation method of the present invention needs to use homogeneous reaction, i.e. liquid-liquid homogeneous systems, otherwise can not pass through " one kettle way "
Synthesize to obtain above-mentioned beneficial effect.
Brief description of the drawings
Fig. 1 is product nucleus magnetic hydrogen spectrum figure in the embodiment of the present invention 1；
Embodiment
Embodiment 1
Add 2- Iodoanilines (17.5g, 79.9mmol) and dimethyl phosphine (6.9g, 88.5mmol), palladium
(0.3g, 1.3mmol), Xantphos (0.77g, 1.3mmol), DIPEA (22.7g, 175.8mmol), DMF
(50mL), magnetic agitation.Under nitrogen protection, it is heated to 100 DEG C and reacts 6 hours, is run out of through thin-layer chromatography monitoring 2- Iodoanilines
Entirely.Room temperature is cooled to, adds 2,4,5- trichloropyrimidines (17.5g, 95.9mmol), 75 DEG C is heated to and reacts 6 hours, through thin layer color
Spectrum monitoring reaction is complete.Room temperature is cooled to, adds water 300mL, pH to 5 is adjusted with 5% hydrochloric acid, ethyl acetate extracts (100mL × 3),
Sodium bicarbonate solution washs (100mL), saturated nacl aqueous solution washing (100mL × 2), anhydrous sodium sulfate drying.Filter, it is dense
Contracting, obtains yellow-brown solid crude product, then with ethyl acetate/petroleum ether (volume ratio 1:2) near-white solid 17g is recrystallized to give,
Yield 67.3%.Nucleus magnetic hydrogen spectrum data are (see Fig. 1)1H 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
Add 2- Iodoanilines (8.6g, 39.3mmol) and dimethyl phosphine (3.4g, 43.6mmol), four (triphenylphosphines)
Palladium (0.92g, 0.8mmol), DIPEA (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 to monitor the consumption of 2- Iodoanilines through thin-layer chromatography.Room temperature is cooled to, adds 2,4,5-
Trichloropyrimidine (8.6g, 47.0mmol), it is heated to 75 DEG C and reacts 6 hours, it is complete through thin-layer chromatography monitoring reaction.It is cooled to room
Temperature, adding water 200mL, pH to 5, ethyl acetate extraction (70mL × 3) are adjusted with 5% hydrochloric acid, sodium bicarbonate solution washs (100mL),
Saturated nacl aqueous solution washs (100mL × 2), anhydrous sodium sulfate drying.Filter, concentration, obtain yellow-brown solid crude product, then use
Ethyl acetate/petroleum ether (volume ratio 1:2) near-white solid 6.8g, yield 54.8% are recrystallized to give.
Embodiment 3
Add 2- Iodoanilines (7.8g, 35.6mmol) and dimethyl phosphine (3.1g, 39.7mmol), palladium
(0.13g, 0.58mmol), Xantphos (0.33g, 0.57mmol), DIPEA (9.2g, 71.2mmol), DMF
(30mL), magnetic agitation.Under nitrogen protection, it is heated to 100 DEG C and reacts 6 hours, is run out of through thin-layer chromatography monitoring 2- Iodoanilines
Entirely.Room temperature is cooled to, adds 2,4,5- trichloropyrimidines (7.8g, 42.7mmol), 75 DEG C is heated to and reacts 6 hours, through thin layer color
Spectrum monitoring reaction is complete.Room temperature is cooled to, adds water 200mL, pH to 5, ethyl acetate extraction (70mL × 3), carbon are adjusted with 5%HCl
Sour hydrogen sodium solution washs (100mL), saturated nacl aqueous solution washing (100mL × 2), anhydrous sodium sulfate drying.Filter, concentration,
Obtain yellow-brown solid crude product, then with ethyl acetate/petroleum ether (volume ratio 1:2) near-white solid 6.6g is recrystallized to give, is received
Rate 58.8%.
Embodiment 4
Add 2- Iodoanilines (7.8g, 35.6mmol) and dimethyl phosphine (3.1g, 39.7mmol), palladium
(0.13g, 0.58mmol), Xantphos (0.33g, 0.57mmol), DIPEA (11.5g, 89.0mmol),
DMF (30mL), magnetic agitation.Under nitrogen protection, it is heated to 100 DEG C and reacts 6 hours, the consumption of 2- Iodoanilines is monitored through thin-layer chromatography
Completely.Room temperature is cooled to, adds 2,4,5- trichloropyrimidines (7.8g, 42.7mmol), 75 DEG C is heated to and reacts 6 hours, through thin layer
Chromatogram monitoring reaction is complete.Room temperature is cooled to, adds water 200mL, pH to 5 is adjusted with 5%HCl, ethyl acetate extracts (70mL × 3),
Sodium bicarbonate solution washs (100mL), saturated nacl aqueous solution washing (100mL × 2), anhydrous sodium sulfate drying.Filter, it is dense
Contracting, obtains yellow-brown solid crude product, then with ethyl acetate/petroleum ether (volume ratio 1:2) near-white solid 6.2g is recrystallized to give,
Yield 55.3%.
Embodiment 5
Add 2- Iodoanilines (7.8g, 35.6mmol) and dimethyl phosphine (3.1g, 39.7mmol), palladium
(0.13g, 0.58mmol), Xantphos (0.33g, 0.57mmol), DIPEA (10.1g, 78.4mmol),
DMF (30mL), magnetic agitation.Under nitrogen protection, it is heated to 80 DEG C and reacts 16 hours, the consumption of 2- Iodoanilines is monitored through thin-layer chromatography
Completely.Room temperature is cooled to, adds 2,4,5- trichloropyrimidines (7.8g, 42.7mmol), 75 DEG C is heated to and reacts 6 hours, through thin layer
Chromatogram monitoring reaction is complete.Room temperature is cooled to, adds water 200mL, pH to 5 is adjusted with 5%HCl, ethyl acetate extracts (70mL × 3),
Sodium bicarbonate solution washs (100mL), saturated nacl aqueous solution washing (100mL × 2), anhydrous sodium sulfate drying.Filter, it is dense
Contracting, obtains yellow-brown solid crude product, then with ethyl acetate/petroleum ether (volume ratio 1:2) near-white solid 6.4g is recrystallized to give,
Yield 56.8%.
Embodiment 6
Add 2- Iodoanilines (7.8g, 35.6mmol) and dimethyl phosphine (3.1g, 39.7mmol), palladium
(0.13g, 0.58mmol), Xantphos (0.33g, 0.57mmol), DIPEA (10.1g, 78.4mmol),
DMF (30mL), magnetic agitation.Under nitrogen protection, it is heated to 120 DEG C and reacts 4 hours, the consumption of 2- Iodoanilines is monitored through thin-layer chromatography
Completely.Room temperature is cooled to, adds 2,4,5- trichloropyrimidines (7.8g, 42.7mmol), 75 DEG C is heated to and reacts 6 hours, through thin layer
Chromatogram monitoring reaction is complete.Room temperature is cooled to, adds water 200mL, pH to 5 is adjusted with 5%HCl, ethyl acetate extracts (70mL × 3),
Sodium bicarbonate solution washs (100mL), saturated nacl aqueous solution washing (100mL × 2), anhydrous sodium sulfate drying.Filter, it is dense
Contracting, obtains yellow-brown solid crude product, then with ethyl acetate/petroleum ether (volume ratio 1:2) near-white solid 6.0g is recrystallized to give,
Yield 53.6%.
Claims (8)
- A kind of 1. homogeneous " one kettle way " preparation method on Brigatinib key intermediates, it is characterised in thatThe preparation method includes following process：2- Iodoanilines and dimethyl phosphine are entered under catalyst, acid binding agent effect Row coupling reaction, without isolation directly with 2,4,5- trichloropyrimidines carry out substitution reaction, then through extracting, washing, drying, taking out Filter, be concentrated to give crude product, then by being recrystallized to give (2- ((2,5- dichloro pyrimidine -4- bases) amino) phenyl) dimethyl phosphine (II)。
- 2. preparation method according to claim 1, it is characterised in that the 2- Iodoanilines：Dimethyl phosphine：2,4,5- The molar ratio of trichloropyrimidine is 1:1.1:1.2.
- 3. preparation method according to claim 1, it is characterised in that the catalyst in following catalyst one Kind：Palladium/Xantphos, tetrakis triphenylphosphine palladium, palladium/triphenylphosphine.
- 4. preparation method according to claim 1, it is characterised in that the 2- Iodoanilines：The molar ratio of acid binding agent For 1:2~2.5.
- 5. preparation method according to claim 4, it is characterised in that the 2- Iodoanilines：The molar ratio of acid binding agent For 1:2.2.
- 6. preparation method according to claim 1, it is characterised in that the acid binding agent in following compounds one Kind：Triethylamine, N, N- diisopropylethylamine, triethylene diamine, the carbon -7- alkene of 1,8- diazabicyclos [5.4.0] 11,4- diformazans Aminopyridine, pyridine, N-methylmorpholine.
- 7. preparation method according to claim 1, it is characterised in that the temperature of the coupling reaction is 80~120 DEG C.
- 8. preparation method according to claim 7, it is characterised in that the temperature of the coupling reaction is 90~100 DEG C.
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| 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 |
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| 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 |
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| 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 |
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