CN111592524B - Preparation method of Enxidani - Google Patents
Preparation method of Enxidani Download PDFInfo
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- CN111592524B CN111592524B CN202010430617.2A CN202010430617A CN111592524B CN 111592524 B CN111592524 B CN 111592524B CN 202010430617 A CN202010430617 A CN 202010430617A CN 111592524 B CN111592524 B CN 111592524B
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- trifluoromethyl
- condensation reaction
- preparation
- triazine
- propanol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006482 condensation reaction Methods 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 17
- LXQMHOKEXZETKB-UHFFFAOYSA-N 1-amino-2-methylpropan-2-ol Chemical compound CC(C)(O)CN LXQMHOKEXZETKB-UHFFFAOYSA-N 0.000 claims abstract description 16
- LYNBZRJTRHTSKI-UHFFFAOYSA-N 2-(trifluoromethyl)pyridin-4-amine Chemical compound NC1=CC=NC(C(F)(F)F)=C1 LYNBZRJTRHTSKI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 15
- -1 tetrafluoroborate Chemical compound 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 claims description 10
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- VHYDMBLRHBILTO-UHFFFAOYSA-N 4-[(2-hydroxy-2-methylpropyl)amino]-6-[6-(trifluoromethyl)pyridin-2-yl]-1H-1,3,5-triazin-2-one Chemical compound CC(C)(CNC1=NC(=O)NC(=N1)C2=NC(=CC=C2)C(F)(F)F)O VHYDMBLRHBILTO-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000012317 TBTU Substances 0.000 description 4
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 4
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012320 chlorinating reagent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 2
- 229940122827 Isocitrate dehydrogenase inhibitor Drugs 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- GSSCQXYNRDFGAV-UHFFFAOYSA-N 2,4-dichloro-6-[6-(trifluoromethyl)pyridin-2-yl]-1,3,5-triazine Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(Cl)N=C(Cl)N=2)=N1 GSSCQXYNRDFGAV-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 description 1
- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- OHJMTUPIZMNBFR-UHFFFAOYSA-N biuret Chemical compound NC(=O)NC(N)=O OHJMTUPIZMNBFR-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- DYLUUSLLRIQKOE-UHFFFAOYSA-N enasidenib Chemical compound N=1C(C=2N=C(C=CC=2)C(F)(F)F)=NC(NCC(C)(O)C)=NC=1NC1=CC=NC(C(F)(F)F)=C1 DYLUUSLLRIQKOE-UHFFFAOYSA-N 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- ORZHZQZYWXEDDL-UHFFFAOYSA-N methanesulfonic acid;2-methyl-1-[[4-[6-(trifluoromethyl)pyridin-2-yl]-6-[[2-(trifluoromethyl)pyridin-4-yl]amino]-1,3,5-triazin-2-yl]amino]propan-2-ol Chemical compound CS(O)(=O)=O.N=1C(C=2N=C(C=CC=2)C(F)(F)F)=NC(NCC(C)(O)C)=NC=1NC1=CC=NC(C(F)(F)F)=C1 ORZHZQZYWXEDDL-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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 application discloses a preparation method of Enantirnib (Enantirnib), which comprises the following steps: the 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione is subjected to condensation reaction with 1-amino-2-methyl-2-propanol and 2-trifluoromethyl-4-aminopyridine in sequence to generate a target compound of Enxidani (I). The preparation method has simple process, mild condition, safety and environmental protection, and provides a new way for industrial production.
Description
Technical Field
The application belongs to the technical field of preparation of raw material medicines and intermediates of organic synthesis route design, and particularly relates to a preparation method of an antitumor medicine Enxidani.
Background
Enxidanib (Enasidinib) is an isocitrate dehydrogenase inhibitor developed from neo-groups together with Agios Pharmaceuticals. The drug was marketed in the united states by approval by the united states Food and Drug Administration (FDA) at month 8 of 2017 under the trade name Idhifa. The medicine is an isocitrate dehydrogenase inhibitor, is also the first marketed oncogenic metabolite synthesis inhibitor, and is used for treating adult recurrent or refractory acute myeloid leukemia carrying isocitrate dehydrogenase gene mutation. Because the medicine is not formally marketed in China and does not have a standard Chinese translated name, the inventor transliterates the medicine into 'Enxidani' here.
The chemical name of Enxidani is: 2-methyl-1- [ [4- (6-trifluoromethyl-2-pyridinyl) -6- [ (2-trifluoromethyl-4-pyridinyl) amino ] -1,3, 5-triazin-2-yl ] amino ] -2-propanol.
International patent WO2013102431A1 and WO2017024134A1 report on the synthesis of Enxidani and analogues thereof. The synthetic route is as follows:
analyzing the synthetic route, the synthetic process comprises the steps of firstly carrying out a cyclic reaction between 6-trifluoromethyl-pyridine-2-methyl formate and biuret to obtain 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione, carrying out a chlorination reaction on the dione compound 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione under the action of chlorinating agents such as phosphorus pentachloride, phosphorus oxychloride and the like to obtain 2, 4-dichloro-6- (6-trifluoromethyl-pyridine-2-yl) -1,3, 5-triazine, and then carrying out a twice substitution reaction on the dichloro-substituted triazine and 1-amino-2-methyl-2-propanol and 2-trifluoromethyl-4-aminopyridine in sequence to finally obtain the target product Enxidebenzol.
It can be seen that, in order to achieve the substituted condensation of the triazine ring and the two side chains, the double chlorination reaction is firstly required to be carried out on the 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione, and the chlorination process inevitably uses chlorinating agents such as phosphorus oxychloride, phosphorus pentachloride and the like, and the use of the phosphorus-containing chlorinating agents inevitably brings certain risks to the ecological environment and production safety.
Therefore, an economic, environment-friendly, green and alternative process route and method which abandons the chlorination reaction process are essential for the economic and technical development of the raw material medicine.
Disclosure of Invention
The application aims to overcome the defects of the prior art, and provides an improved preparation method of Enasidinib according to the synthetic concept of green chemistry, which is simple, convenient, economical and environment-friendly, is beneficial to the industrialized production of the medicine and can promote the development of the economic technology of the raw material medicine.
In order to achieve the above purpose, the main technical scheme provided by the application is as follows: a preparation method of Enxidani (I),
the method comprises the following steps: using 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) and 1-amino-2-methyl-2-propanol to generate 1- [ 4-oxo-6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazin-2-ylamino ] -2-methyl-2-propanol (III) through a first condensation reaction under the action of a condensing agent and an alkali accelerator; the 1- [ 4-oxo-6- (6-trifluoromethyl pyridine-2-yl) -1,3, 5-triazine-2-yl amino ] -2-methyl-2-propanol (III) and 2-trifluoromethyl-4-aminopyridine undergo a second condensation reaction under the action of a condensing agent and an alkali accelerator to generate the Enxidani (I).
The reaction scheme is shown below:
in addition, the application also provides the following auxiliary technical scheme:
the feed molar ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) to 1-amino-2-methyl-2-propanol of the first condensation reaction is 1:1.0-1.2, preferably 1:1.1.
The molar ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) for the first condensation reaction to the condensing agent is 1:1.0-2.0, preferably 1:1.5.
The feeding mole ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) to the alkali accelerator in the first condensation reaction is 1:1.0-2.0, preferably 1:1.5.
The molar ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazin-2-ylamino ] -2-methyl-2-propanol (III) to the 2-trifluoromethyl-4-aminopyridine in the second condensation reaction is 1:1.1-1.5, preferably 1:1.3.
The molar ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazin-2-ylamino ] -2-methyl-2-propanol (III) for the second condensation reaction to the condensing agent is 1:1.0-2.0, preferably 1:1.5.
The molar ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazin-2-ylamino ] -2-methyl-2-propanol (III) and the alkali accelerator is 1:1.0-2.0, preferably 1:1.5.
The condensing agent of the first condensation reaction and the second condensation reaction is N, N, -Dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), N, N ' -Diisopropylcarbodiimide (DIC), 1-hydroxy-benzotriazol (HOBt), O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU), O- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU) or benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate (BOP), preferably benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate (BOP) or O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU).
The alkali promoter of the first condensation reaction and the second condensation reaction is Triethylamine (TEA), pyridine, 2, 6-lutidine, 4-Dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIEA), 1, 5-diazabicyclo [4.3.0] -non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0] -undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2] octane (DABCO), preferably 1, 8-diazabicyclo [5.4.0] -undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] -non-5-ene (DBN).
The solvent of the first condensation reaction and the second condensation reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, dimethyl sulfoxide, N-dimethylformamide or acetonitrile, preferably acetonitrile or N, N-dimethylformamide.
The reaction temperature of the first condensation reaction and the second condensation reaction is 0-100 ℃, preferably 50-80 DEG C
The beneficial effects are that:
according to the preparation method of the Enxidani, disclosed by the application, the known diketone compound is subjected to two condensation reactions, so that the preparation process condition is mild, safe and environment-friendly. Especially, through direct condensation reaction, the chlorination process is omitted, and the use of hazardous chemicals such as phosphorus oxychloride, phosphorus pentachloride and the like is avoided, so that the method is suitable for industrial production.
Detailed Description
The technical scheme of the application is further described in non-limiting detail below with reference to a plurality of preferred embodiments. The synthesis of the starting material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) referred to therein is described in patent WO2017024134A 1.
Embodiment one:
to the reaction flask was added 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) (0.65 g, 2.5 mmol), the condensing agent benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) (1.7 g,3.75 mmol) and 25mL of acetonitrile under nitrogen. Adding alkali promoter 1, 8-diazabicyclo [5.4.0] with stirring]Undec-7-ene (DBU) (0.57 g,3.75 mmol), was warmed to 60℃and reacted for 12 hours. 1-amino-2-methyl-2-propanol (0.25 g,2.75 mmol) was added and the reaction stirred for a further 12 hours, and TLC monitored the end of the reaction. The reaction was quenched with saturated brine and ph=4 to 5 was adjusted with dilute hydrochloric acid. Concentrated under reduced pressure, and the residue was extracted 3 times with ethyl acetate. The organic phases were combined, washed successively with pure water and brine, dried, distilled under reduced pressure to recover the solvent, and the oily residue obtained was recrystallized from ethanol to give 1- [ 4-oxo-6- (6-trifluoromethylpyridin-2-yl) -1,3, 5-triazin-2-ylamino as a yellow solid]0.64g of (E) -2-methyl-2-propanol (III) with the yield of77.8％，EI-MS m/z:330[M+H] + 。
Embodiment two:
under the protection of nitrogen, 1- [ 4-oxo-6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazin-2-ylamino is added into a three-necked flask]-2-methyl-2-propanol (III) (3.29 g,10 mmol), the condensing agent benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) (6.63 g,15 mmol) and acetonitrile 100mL. Adding an alkali promoter 1, 5-diazabicyclo [4.3.0] with stirring]-non-5-ene (DBN) (1.86 g,15 mmol). The temperature was raised to 60℃and the reaction was carried out for 12 hours. 2-trifluoromethyl-4-aminopyridine (2.11 g, 13 mmol) was added and the reaction was continued with stirring for 12 hours, followed by TLC monitoring the end of the reaction. The reaction was quenched with saturated brine and ph=4 to 5 was adjusted with dilute hydrochloric acid. Concentrated under reduced pressure, and the residue was extracted 3 times with ethyl acetate. The organic phase was separated, dried, and the solvent was recovered by distillation under reduced pressure to give a brown solid. Recrystallisation from methanol gives 3.88g of Enxidani (I) as a pale yellow solid in 82.0% yield, EI-MS m/z 474[ M+H ]] + 。
Embodiment III:
6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) (0.65 g, 2.5 mmol), condensing agent O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate (TBTU) (0.8 g,3.75 mmol) and N, N-dimethylformamide (25 mL) were added to the reaction flask under nitrogen. Adding an alkali promoter 1, 5-diazabicyclo [4.3.0] with stirring]-non-5-ene (DBN) (0.47 g,3.75 mmol), warmed to 70 ℃ and reacted for 12 hours. 1-amino-2-methyl-2-propanol (0.25 g,2.75 mmol) was added and the reaction was stirred for 12 hours, followed by TLC monitoring the end of the reaction. The reaction was quenched with saturated brine and ph=4 to 5 was adjusted with dilute hydrochloric acid. Concentrated under reduced pressure, and the residue was extracted 3 times with ethyl acetate. The organic phases are combined, washed with pure water and brine in sequence, dried, distilled under reduced pressure to recover the solvent, and the oily residue obtained is recrystallized from ethanol to obtain yellow solid 1- [ 4-oxo-6- (6-trifluoromethylpyridin-2-yl) -1,3, 5-triazin-2-ylamino]0.58g of (E) -2-methyl-2-propanol (III) with a yield of 70.5%, EI-MS m/z 330[ M+H ]] + 。
Embodiment four:
under the protection of nitrogen, adding 1- [ 4-oxo-6- ] into a three-mouth bottle6-trifluoromethylpyridin-2-yl) -1,3, 5-triazin-2-ylamino]-2-methyl-2-propanol (III) (3.29 g,10 mmol), condensing agent O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate (TBTU) (4.8 g,15 mmol) and N, N-dimethylformamide 50mL. Adding alkali promoter 1, 8-diazabicyclo [5.4.0] with stirring]-deca-7-ene (DBU) (2.28 g,15 mmol). The temperature was raised to 70℃and the reaction was carried out for 12 hours. 2-trifluoromethyl-4-aminopyridine (2.11 g, 13 mmol) was added and the reaction was continued with stirring for 12 hours, followed by TLC monitoring the end of the reaction. The reaction was quenched with saturated brine and ph=4 to 5 was adjusted with dilute hydrochloric acid. Concentrated under reduced pressure, and the residue was extracted 3 times with ethyl acetate. The organic phase was separated, dried, and the solvent was recovered by distillation under reduced pressure to give a brown solid. Recrystallisation from methanol gives 3.62g of Enxidani (I) as a pale yellow solid in 76.5% yield, EI-MS m/z 474[ M+H ]] + ； 1 H NMR(CDCl 3 )δ8.58(m,3H),8.08(m,2H),7.86(m,2H),7.26(s,1H),6.30(t, J 1 ＝8.8Hz,J 2 ＝4.4Hz,1H),3.68(d,J＝4.8Hz,1H),3.59(d,J＝5.2Hz,1H),1.37(s,3H),1.35(s,3H)。
It should be noted that the foregoing description of the preferred embodiments is merely illustrative of the technical concept and features of the present application, and is not intended to limit the scope of the application, as long as the scope of the application is defined by the claims and their equivalents. All equivalent changes or modifications made in accordance with the spirit of the present application should be construed to be included in the scope of the present application.
Claims (9)
1. A preparation method of Enxidanib (Enasidinib), wherein the chemical structural formula of Enxidanib is as follows:
the preparation method is characterized by comprising the following steps: first condensation reaction of 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione and 1-amino-2-methyl-2-propanol under the action of condensing agent benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate or O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate and alkali promoter 1, 8-diazabicyclo [5.4.0] -undec-7-ene or 1, 5-diazabicyclo [4.3.0] -non-5-ene to generate 1- [ 4-oxo-6- (6-trifluoromethylpyridin-2-yl) -1,3, 5-triazine-2-ylamino ] -2-methyl-2-propanol; the 1- [ 4-oxo-6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazin-2-ylamino ] -2-methyl-2-propanol and 2-trifluoromethyl-4-aminopyridine undergo a second condensation reaction under the action of a condensing agent of benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate or O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate and an alkali accelerator of 1, 5-diazabicyclo [4.3.0] -non-5-ene or 1, 8-diazabicyclo [5.4.0] -undec-7-ene to generate the encyclopedia.
2. The process for the preparation of emsidnib according to claim 1, characterized in that: the feeding mole ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione and 1-amino-2-methyl-2-propanol of the first condensation reaction is 1:1.0-1.2.
3. The process for the preparation of emsidnib according to claim 1, characterized in that: the feeding mole ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) and the condensing agent of the first condensation reaction is 1:1.0-2.0.
4. The process for the preparation of emsidnib according to claim 1, characterized in that: the feeding mole ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) and the alkali accelerator in the first condensation reaction is 1:1.0-2.0.
5. The process for the preparation of emsidnib according to claim 1, characterized in that: the feeding mole ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethyl pyridine-2-yl) -1,3, 5-triazine-2-ylamino ] -2-methyl-2-propanol to the 2-trifluoromethyl-4-aminopyridine in the second condensation reaction is 1:1.1-1.5.
6. The process for the preparation of emsidnib according to claim 1, characterized in that: the feeding mole ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethyl pyridine-2-yl) -1,3, 5-triazine-2-amino ] -2-methyl-2-propanol of the second condensation reaction to the condensing agent is 1:1.0-2.0.
7. The process for the preparation of emsidnib according to claim 1, characterized in that: the feeding mole ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethyl pyridine-2-yl) -1,3, 5-triazine-2-amino ] -2-methyl-2-propanol and the alkali accelerator of the second condensation reaction is 1:1.0-2.0.
8. The process for the preparation of emsidnib according to claim 1, characterized in that: the reaction solvents of the first condensation reaction and the second condensation reaction are toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, dimethyl sulfoxide, N-dimethylformamide or acetonitrile.
9. The process for the preparation of emsidnib according to claim 1, characterized in that: the reaction temperature of the first condensation reaction and the second condensation reaction is 0-100 ℃.
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