CN111592524A - Preparation method of Ensidnib - Google Patents
Preparation method of Ensidnib Download PDFInfo
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- CN111592524A CN111592524A CN202010430617.2A CN202010430617A CN111592524A CN 111592524 A CN111592524 A CN 111592524A CN 202010430617 A CN202010430617 A CN 202010430617A CN 111592524 A CN111592524 A CN 111592524A
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- China
- Prior art keywords
- condensation reaction
- triazine
- preparing
- trifluoromethyl
- enzedni
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006482 condensation reaction Methods 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 19
- 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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- -1 tetrafluoroborate Chemical compound 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- 239000002994 raw material 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
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 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 9
- 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
- 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 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 3
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 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 abstract description 4
- 229950010133 enasidenib Drugs 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract 1
- 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
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 238000001035 drying Methods 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
- 238000004821 distillation Methods 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 229940122827 Isocitrate dehydrogenase inhibitor Drugs 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000005406 washing 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
- 238000005160 1H NMR spectroscopy Methods 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
- 208000031261 Acute myeloid leukaemia Diseases 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
- 230000009286 beneficial effect Effects 0.000 description 1
- OHJMTUPIZMNBFR-UHFFFAOYSA-N biuret Chemical compound NC(=O)NC(N)=O OHJMTUPIZMNBFR-UHFFFAOYSA-N 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000013519 translation Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of Ensidnib (Enasidenib), which comprises the following steps: the 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone sequentially reacts with 1-amino-2-methyl-2-propanol and 2-trifluoromethyl-4-aminopyridine through condensation reaction to generate the target compound Ensidnib (I). The preparation method has the advantages of simple process, mild conditions, safety and environmental protection, and provides a new way for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates thereof, and particularly relates to a preparation method of an anti-tumor medicine Ensidnib.
Background
Ensidnib (Enasidenib) is an isocitrate dehydrogenase inhibitor developed by the noval group together with Agios Pharmaceuticals. The drug was marketed in the united states by the U.S. Food and Drug Administration (FDA) in 2017 at 8 months under the trade name of idifa. The drug is an isocitrate dehydrogenase inhibitor and is also the first carcinogenic metabolite synthesis inhibitor on the market, and is used for treating adult recurrent or refractory acute myeloid leukemia carrying isocitrate dehydrogenase gene mutation. Because the medicine is not yet on the market formally in China and does not have a standard Chinese translation name, the applicant translates the medicine into 'Ensidney' here.
The chemical name of encydeni 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 patents WO2013102431a1 and WO2017024134a1 report synthetic methods for enzideneand and analogues thereof. The synthetic route is as follows:
analyzing the synthesis route, firstly, 6-trifluoromethyl-pyridine-2-methyl formate reacts with biuret to generate a ring to obtain 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone, the diketone compound 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone reacts with chlorinating agents such as phosphorus pentachloride and phosphorus oxychloride to obtain 2, 4-dichloro-6- (6-trifluoromethylpyridine-2-yl) -1,3, 5-triazine, and the dichloro-substituted triazine sequentially reacts with 1-amino-2-methyl-2-propanol and 2-trifluoromethyl-4-aminopyridine to generate two parts And carrying out secondary substitution reaction to finally obtain the target product Ensidney.
Therefore, in order to realize the substitution condensation of the triazine ring and two side chains, 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone needs to be subjected to a double chlorination reaction, and chlorination processes inevitably use chlorination reagents such as phosphorus oxychloride and phosphorus pentachloride, and the use of the phosphorus chlorination reagents inevitably brings certain risks to the ecological environment and the production safety.
Therefore, an economic, environment-friendly, green and alternative process route and method which abandon the chlorination reaction process are sought, and the economic and technical development of the bulk drug is crucial.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides an improved Ensidnib (Enasidenib) preparation method according to a green chemical synthesis concept, wherein the preparation method is simple, convenient, economic and environment-friendly, is beneficial to industrial production of the medicine, and can promote the development of the economic technology of the raw medicine.
In order to achieve the purpose, the main technical scheme provided by the invention is as follows: a preparation method of Ensidnib (I),
the method comprises the following steps: performing a first condensation reaction of 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) and 1-amino-2-methyl-2-propanol under the action of a condensing agent and an alkali promoter to generate 1- [ 4-oxo-6- (6-trifluoromethylpyridin-2-yl) -1,3, 5-trizin-2-ylamino ] -2-methyl-2-propanol (III); the 1- [ 4-oxo-6- (6-trifluoromethylpyridine-2-yl) -1,3, 5-triazine-2-amino ] -2-methyl-2-propanol (III) and 2-trifluoromethyl-4-aminopyridine are subjected to a second condensation reaction under the action of a condensing agent and an alkali promoter to generate the Ensidnib (I).
The reaction scheme is schematically as follows:
in addition, the invention also provides the following auxiliary technical scheme:
the charging molar ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) and 1-amino-2-methyl-2-propanol in the first condensation reaction is 1: 1.0-1.2, preferably 1: 1.1.
The feeding molar ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone (II) for the first condensation reaction to the condensing agent is 1: 1.0-2.0, preferably 1: 1.5.
The feeding molar ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone (II) for the first condensation reaction to the alkali promoter is 1: 1.0-2.0, and preferably 1: 1.5.
The feeding molar ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethylpyridin-2-yl) -1,3, 5-triazin-2-ylamino ] -2-methyl-2-propanol (III) and 2-trifluoromethyl-4-aminopyridine in the second condensation reaction is 1: 1.1-1.5, preferably 1: 1.3.
The feeding molar ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethylpyridin-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 feeding molar ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethylpyridin-2-yl) -1,3, 5-triazin-2-ylamino ] -2-methyl-2-propanol (III) of the second condensation reaction to the alkali promoter is 1: 1.0-2.0, preferably 1: 1.5.
The condensing agent for the first and second condensation reactions is N, N '-Dicyclohexylcarbodiimide (DCC), Carbonyldiimidazole (CDI), N, N' -Diisopropylcarbodiimide (DIC), 1-hydroxy-benzotriazole (HOBt), O-benzotriazole-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-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), preferably benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) or O-benzotriazol-N, n, N' -tetramethyluronium tetrafluoroborate (TBTU).
The basic accelerator for the first and 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
Has the advantages that:
according to the preparation method of Ensidney, the condition of the preparation process is mild, safe and environment-friendly through the condensation reaction of the known diketone compound twice. Particularly, the direct condensation reaction saves the chlorination process, avoids the use of hazardous chemicals such as phosphorus oxychloride and phosphorus pentachloride, and is suitable for industrial production.
Detailed Description
The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments. The synthesis method of the starting material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone (II) involved in the method can be found in the report of the patent WO2017024134A 1.
The first embodiment is as follows:
under the protection of nitrogen, 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) (0.65g, 2.5mmol), the condensing agent benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) (1.7g, 3.75mmol) and acetonitrile 25mL were added to a reaction flask. Adding alkali accelerator 1, 8-diazabicyclo [5.4.0] under stirring]Undec-7-ene (DBU) (0.57g, 3.75mmol), warmed to 60 ℃ and reacted for 12 hours. 1-amino-2-methyl-2-propanol (0.25g,2.75mmol) was added and the reaction was stirred for an additional 12 hours and monitored by TLC for completion. The reaction was quenched with saturated saline and the pH was adjusted to 4-5 with dilute hydrochloric acid. Concentrating under reduced pressure, and extracting the residue with ethyl acetate for 3 times. Combining organic phases, washing with pure water and brine in sequence, drying, distilling under reduced pressure to recover the solvent, recrystallizing the obtained oily residue with ethanol to obtain yellow solid 1- [ 4-oxo-6- (6-trifluoromethylpyridin-2-yl) -1,3, 5-triazin-2-ylamino]0.64g of (III) -2-methyl-2-propanol (III), yield 77.8%, EI-MS M/z 330[ M + H ]]+。
Example two:
adding 1- [ 4-oxo-6- (6-trifluoromethylpyridine-2-yl) -1,3, 5-triazine-2-yl amino into a three-neck bottle under the protection of nitrogen]-2-methyl-2-propanol (III) (3.29g, 10mmol), the condensing agent benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) (6.63g, 15mmol), and acetonitrile 100 mL. Adding alkali accelerator 1, 5-diazabicyclo [4.3.0] under stirring]-non-5-ene (DBN) (1.86g, 15 mmol). The temperature is raised to 60 ℃ and the reaction is carried out for 12 hours. 2-trifluoromethyl-4-aminopyridine (2.11g, 13mmol) was added and the reaction was stirred for an additional 12 h and monitored by TLC for completion. The reaction was quenched with saturated saline and the pH was adjusted to 4-5 with dilute hydrochloric acid. Concentrating under reduced pressure, and extracting the residue with ethyl acetate for 3 times. Separating out an organic phase, drying, and recovering the solvent by reduced pressure distillation to obtain a brown solid. Recrystallizing with methanol to obtain pale yellow solid Ensidney (I)3.88g with yield of 82.0%, EI-MS M/z: 474[ M + H ]]+。
Example three:
under the protection of nitrogen, 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-dione (II) (0.65g, 2.5mmol), a condensing agent O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.8g, 3.75mmol) and 25mL of N, N-dimethylformamide are added into a reaction bottle. Adding alkali accelerator 1, 5-diazabicyclo [4.3.0] under stirring]-non-5-ene (DBN) (0.47g, 3.75mmol), warmed to 70 ℃ and reacted for 12 hours. 1-amino-2-methyl-2-propanol (0.25g,2.75mmol) was added and the reaction was continued for 12 hours with stirring and the end of the reaction was monitored by TLC. The reaction was quenched with saturated saline and the pH was adjusted to 4-5 with dilute hydrochloric acid. Concentrating under reduced pressure, and extracting the residue with ethyl acetate for 3 times. Combining organic phases, washing with pure water and brine in sequence, drying, recovering the solvent by reduced pressure distillation, recrystallizing the obtained oily residue with ethanol to obtain yellow solid 1- [ 4-oxo-6- (6-trifluoromethylpyridin-2-yl) -1,3, 5-triazin-2-ylamino]0.58g of (III) -2-methyl-2-propanol (III), yield 70.5%, EI-MS M/z 330[ M + H ]]+。
Example four:
adding 1- [ 4-oxo-6- (6-trifluoromethylpyridine-2-yl) -1,3, 5-triazine-2-yl amino into a three-neck bottle under the protection of nitrogen]-2-methyl-2-propanol (III) (3.29g, 10mmol), condensing agent O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate (TBTU) (4.8g, 15mmol) and N, N-dimethylformamide 50 mL. Adding alkali accelerator 1, 8-diazabicyclo [5.4.0] under stirring]-unde-7-ene (DBU) (2.28g, 15 mmol). The temperature is raised to 70 ℃ and the reaction is carried out for 12 hours. 2-trifluoromethyl-4-aminopyridine (2.11g, 13mmol) was added and the reaction was stirred for an additional 12 h and monitored by TLC for completion. The reaction was quenched with saturated saline and the pH was adjusted to 4-5 with dilute hydrochloric acid. Concentrating under reduced pressure, and extracting the residue with ethyl acetate for 3 times. Separating out an organic phase, drying, and recovering the solvent by reduced pressure distillation to obtain a brown solid. Recrystallizing with methanol to obtain pale yellow solid Ensidney (I)3.62g with yield of 76.5%, EI-MS M/z: 474[ M + H ]]+；1H NMR(CDCl3)8.58(m,3H),8.08(m,2H),7.86(m,2H),7.26(s,1H),6.30(t, J1＝8.8Hz,J2＝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 above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (11)
1. A method for preparing enzidenib (enasidinib), wherein the chemical structure of enzidenib is as follows:
the preparation method is characterized by comprising the following steps: performing a first condensation reaction on 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone and 1-amino-2-methyl-2-propanol under the action of a condensing agent and an alkali promoter to generate 1- [ 4-oxo-6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazine-2-ylamino ] -2-methyl-2-propanol; the 1- [ 4-oxo-6- (6-trifluoromethylpyridine-2-yl) -1,3, 5-triazine-2-ylamino ] -2-methyl-2-propanol and 2-trifluoromethyl-4-aminopyridine are subjected to a second condensation reaction under the action of a condensing agent and an alkali promoter to generate the encystednib.
2. The method of claim 1, wherein the step of preparing the enzedni comprises: the feeding molar ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone and 1-amino-2-methyl-2-propanol in the first condensation reaction is 1: 1.0-1.2.
3. The method of claim 1, wherein the step of preparing the enzedni comprises: the feeding molar ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone (II) for the first condensation reaction to the condensing agent is 1: 1.0-2.0.
4. The method of claim 1, wherein the step of preparing the enzedni comprises: the feeding molar ratio of the raw material 6- (6-trifluoromethyl-2-yl) -1,3, 5-triazine-2, 4-diketone (II) for the first condensation reaction to the alkali promoter is 1: 1.0-2.0.
5. The method of claim 1, wherein the step of preparing the enzedni comprises: the feeding molar ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethylpyridine-2-yl) -1,3, 5-triazine-2-ylamino ] -2-methyl-2-propanol for the second condensation reaction to 2-trifluoromethyl-4-aminopyridine is 1: 1.1-1.5.
6. The method of claim 1, wherein the step of preparing the enzedni comprises: the feeding molar ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethylpyridine-2-yl) -1,3, 5-triazine-2-ylamino ] -2-methyl-2-propanol of the second condensation reaction to the condensing agent is 1: 1.0-2.0.
7. The method of claim 1, wherein the step of preparing the enzedni comprises: the feeding molar ratio of the raw material 1- [ 4-oxo-6- (6-trifluoromethylpyridine-2-yl) -1,3, 5-triazine-2-ylamino ] -2-methyl-2-propanol of the second condensation reaction to the alkali promoter is 1: 1.0-2.0.
8. The method of claim 1, wherein the step of preparing the enzedni comprises: the condensing agent for the first condensation reaction and the second condensation reaction is N, N-dicyclohexylcarbodiimide, carbonyldiimidazole, N, N ' -diisopropylcarbodiimide, 1-hydroxy-benzotriazole, O-benzotriazole-N, N, N ', N ' -tetramethylurea tetrafluoroborate, O- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, benzotriazole-N, N, N ', N ' -tetramethylurea hexafluorophosphate or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate.
9. The method of claim 1, wherein the step of preparing the enzedni comprises: the alkali accelerator for the first condensation reaction and the second condensation reaction is triethylamine, pyridine, 2, 6-lutidine, 4-dimethylaminopyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1, 5-diazabicyclo [4.3.0] -non-5-ene, 1, 8-diazabicyclo [5.4.0] -undec-7-ene or 1, 4-diazabicyclo [2.2.2] octane.
10. The method of claim 1, wherein the step of preparing the enzedni comprises: the reaction 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.
11. The method of claim 1, wherein the step of preparing the enzedni comprises: the reaction temperature of the first condensation reaction and the second condensation reaction is 0-100 ℃.
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