CN107021965B - A method of synthesis -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines - Google Patents
A method of synthesis -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines Download PDFInfo
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- CN107021965B CN107021965B CN201710343490.9A CN201710343490A CN107021965B CN 107021965 B CN107021965 B CN 107021965B CN 201710343490 A CN201710343490 A CN 201710343490A CN 107021965 B CN107021965 B CN 107021965B
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- 238000000034 method Methods 0.000 title claims abstract description 32
- FPEAARFNXIWCTP-UHFFFAOYSA-N 5,6,7,8-tetrahydro-1,6-naphthyridine Chemical class C1=CC=C2CNCCC2=N1 FPEAARFNXIWCTP-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title description 4
- 238000003786 synthesis reaction Methods 0.000 title description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 36
- 230000004224 protection Effects 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 23
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims abstract description 10
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 9
- 125000003368 amide group Chemical group 0.000 claims abstract description 8
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 238000006880 cross-coupling reaction Methods 0.000 claims abstract description 3
- 238000010189 synthetic method Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N [chloro(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Cl)C1=CC=CC=C1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
- 229940073608 benzyl chloride Drugs 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 2
- 238000004440 column chromatography Methods 0.000 claims 1
- -1 cylite Chemical compound 0.000 claims 1
- XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 abstract description 7
- 150000001540 azides Chemical class 0.000 abstract description 5
- 230000001988 toxicity Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 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 description 8
- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 150000005056 1,6-naphthyridines Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BBUVDDPUURMFOX-SAABIXHNSA-N AMG-925 Chemical compound C1C[C@@H](C)CC[C@@H]1N1C2=NC(NC=3N=C4CCN(CC4=CC=3)C(=O)CO)=NC=C2C2=CC=NC=C21 BBUVDDPUURMFOX-SAABIXHNSA-N 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 101001052849 Homo sapiens Tyrosine-protein kinase Fer Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100024537 Tyrosine-protein kinase Fer Human genes 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of methods for synthesizing -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines; specific step is as follows for the synthetic method: (1) halogenated -5 2-, 6,7,8- tetrahydros -1; the 2- halogenated -5 of 6 protections, 7,8- tri- hydrogen -1,6- naphthyridines are made by amido protecting reaction for 6- naphthyridines；With carbamate, -2 amine of 5,7,8- tri- hydrogen -1,6- naphthyridines of double protections is made by palladium catalysed cross coupling reaction under alkaline condition for the 2- halogenated -5 of (2) 6 protections, 7,8- tri- hydrogen -1,6- naphthyridines；(3) -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines is made by deprotection reaction in double -2 amine of tri- hydrogen -1,6- naphthyridines of protection 5,7,8-.The entire technical process of the present invention all uses conventional reagent, avoids the azide big using toxicity and environmental hazard, reaction condition is mild, more safety and environmental protection.
Description
Technical field
The present invention relates to the synthesis technical fields of medicine intermediate, more particularly, to one kind with 2- halogenated -5,6,7,8- tetra-
Hydrogen -1,6- naphthyridines is that raw material passes through amido protecting reaction, coupling reaction, the process of deprotection reaction, and 5,6,7,8- tetrahydros-are made
The method of -2 amine of 1,6- naphthyridines.
Background technique
- 2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines is the tyrosine kinase 3 of Cyclin dependent kinase 4 and FMS sample
The main mother nucleus structure of double inhibitor AMG925.The intermediate is during one kind of the antitumor and anti-leukocythemia new drug of research is important
Mesosome, existing literature WO2008149163A2 report the specific solution of the compound, and this method is with 1,6- naphthyridines -2- formic acid
Hydro-reduction is first passed through for raw material and obtains 5,6,7,8- tetrahydro -1,6- naphthyridines -2- formic acid, then upper Boc protects amino, then passes through
Curtis is reset, and finally deprotection obtains 5,6,7,8- tetrahydro -1,6- naphthyridines -2- amine, and this method uses in Curtis rearrangement
Azide has the danger of explosion, while azide has stronger toxicity, larger to environmental hazard.
Summary of the invention
In view of the above-mentioned problems existing in the prior art, the applicant provides a kind of 5,6,7,8- tetrahydro -1 of synthesis,
The method of -2 amine of 6- naphthyridines.The present invention using the halogenated -5,6,7,8- tetrahydro -1,6- naphthyridines of 2- as raw material by amido protecting and
Then deprotection obtains 5,6,7,8- tetrahydro -1,6- naphthyridines -2- amine for BuckWald coupling, avoids using toxicity and environmental hazard
Biggish azide, more safety and environmental protection.
Technical scheme is as follows:
A kind of method synthesizing -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines, the method includes following processes:
Wherein, X is chlorine, bromine or iodine；R1For benzyl, benzhydryl, trityl orR2For C1-5It is straight
Chain or branched alkyl or benzyl；
Specific step is as follows for the synthetic method:
(1) the 2- halogen of 6 protections is made by amido protecting reaction for the halogenated -5,6,7,8- tetrahydro -1,6- naphthyridines (2) of 2-
The i.e. compound 3 of generation three hydrogen -1,6- naphthyridines of -5,7,8-；
(2) 6 protection halogenated -5,7,8- tri- hydrogen -1,6- naphthyridines (3) of 2- under alkaline condition with carbamate (4),
Tri- -2 amine of hydrogen -1,6- naphthyridines of 5,7,8-, that is, compound 5 of double protections is made by palladium catalysed cross coupling reaction；
(3) it is 5,6,7 that compound 1, which is made, by deprotection reaction in double -2 amine (5) of tri- hydrogen -1,6- naphthyridines of protection 5,7,8-,
- 2 amine of 8- tetrahydro -1,6- naphthyridines.
The detailed process of the reaction of amido protecting described in step (1) are as follows: by the halogenated -5,6,7,8- tetrahydro -1,6- naphthyridines of 2-
(1) it is dissolved in the solution for forming 0.01-0.2g/mL in solvent, the alkali of 1.5-5 equivalent is added, is slowly added under the conditions of -10-30 DEG C
The protection reagent for entering 1-2 equivalent, then reacts 1-12h at 0-80 DEG C, and after reaction, revolving removes solvent, direct column layer
It analyses or is diluted with water, extracted with ethyl acetate or methylene chloride, organic phase saturated sodium bicarbonate, dilute hydrochloric acid and saturated common salt
Water washing, dry, concentration removes solvent and obtains halogenated -5,7,8- tri- hydrogen -1,6- naphthyridines of 2-, that is, compound 3 of 6 protections.
The solvent be methylene chloride, ethyl acetate, tetrahydrofuran, 1,4- dioxane, N,N-dimethylformamide or
One of dimethyl sulfoxide etc. is a variety of；The alkali is triethylamine, diisopropylethylamine, N-methylmorpholine, sodium carbonate, carbonic acid
One of potassium, cesium carbonate are a variety of；The protection reagent is benzyl chloride, cylite, diphenyl methyl chloride, triphenyl chloromethane
One in alkane, Boc acid anhydrides, methylchloroformate, ethyl chloroformate, isopropyl chlorocarbonate, isobutylchloroformate or benzyl chloroformate
Kind.
The process of coupling reaction described in step (2) are as follows: the halogenated three hydrogen -1,6- naphthyridines of -5,7,8- of 2- for protecting 6
(3) it is dissolved in the solution for forming 0.01-0.2g/mL in solvent, sequentially adds the carbamate (4) of 1.1-3 equivalent, 0.01-0.2
The palladium catalyst of equivalent, the X ligand antphos of 0.02-0.4 equivalent, the alkali of 1-3 equivalent add under the protection of inert gas
Heat arrives 80-120 DEG C of reaction 2-12h, and reaction solution is diluted with water after reaction, is extracted with ethyl acetate or methylene chloride, extraction
Organic phase saturated common salt water washing, dry, concentration removes solvent and obtains crude product, chromatographs or be recrystallized to give double protections by column
Tri- -2 amine of hydrogen -1,6- naphthyridines of 5,7,8-, that is, compound 5.
The solvent is in tetrahydrofuran, 1,4- dioxane, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide
It is one or more；The palladium catalyst is Pd2(dba)3Or tetra-triphenylphosphine palladium；The alkali is potassium carbonate or cesium carbonate solid.
Deprotection reaction described in step (3), which refers to, removes ammonia by the catalyzing hydrolysis or catalytic hydrogenation reaction of acid or alkali
The protecting group of base.
The present invention is beneficial to be had the technical effect that
It is raw material by amido protecting reaction, coupling reaction and deprotection using the halogenated -5,6,7,8- tetrahydro -1,6- naphthyridines of 2-
The process of reaction, entire technical process all use conventional reagent, avoid the azide big using toxicity and environmental hazard, reaction
Mild condition, more safety and environmental protection.
Detailed description of the invention
Fig. 1 is the schematic diagram of reaction process of the present invention.
Specific embodiment
With reference to the accompanying drawings and examples, the present invention is specifically described.
Embodiment 1
A kind of method synthesizing -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines, described method includes following steps:
(1) in 250mL single port bottle, chloro- 5,6,7,8- Tetrahydronaphthyridderivates 20.0g and 14.0g triethylamine of 2- is dissolved in 50mL
The solution is stirred cooling by methylene chloride under ice salt bath, and 27.2g Boc is added dropwise dropwise2O reacts at room temperature 1h after being added dropwise,
The dilution of 50mL methylene chloride is added, is successively washed twice with the dilute hydrochloric acid of 1mol/L, saturated sodium bicarbonate washed once and be saturated
Brine It is primary, and organic phase is dried, filtered with anhydrous magnesium sulfate, and filtrate is spin-dried for obtaining that 30.9g is light yellow shape object, i.e. 2-
Chloro- 6- tertbutyloxycarbonyl -5,7, tri- hydrogen -1,6- naphthyridines of 8-, yield 97%, LCMS (ESI): m/z 269 (M+H)+,169(M-
100)+。
(2) the chloro- three hydrogen -1,6- naphthyridines 7.0g of 6- tertbutyloxycarbonyl -5,7,8- of 2- made from step (1) is weighed in 250mL
In single port bottle, 100mL dioxane stirring and dissolving is added, then sequentially adds 9.3g BocNH2, 1.5g Xantphos,
17.0g Cs2CO3, and 1.2g Pd2(dba)3, then cold by reaction mixture heating reflux reaction 7h under nitrogen protection
But room temperature is arrived, the dilution of 500mL water is added, is extracted in three times with 300mL ethyl acetate, organic phase is washed with 100mL saturated common salt
It washs once, is then dried, filtered with anhydrous sodium sulfate, be spin-dried for obtaining crude product, crude product uses PE:EA=50:1 through silica gel column chromatography
8.0g yellow solid, i.e. 2- tert-butoxy formamido -6- tertbutyloxycarbonyl -5,7, tri- hydrogen -1,6- of 8- are arrived in~10:1 elution
Naphthyridines, yield 87%, LCMS (ESI): m/z 350 (M+H)+。
(3) three hydrogen -1,6- naphthalene of 2- tert-butoxy formamido -6- tertbutyloxycarbonyl -5,7,8- made from step (2) is weighed
Pyridine 8.0g is added 200mL HCl/MeOH (20~30%) in 250ml single port bottle, is heated to 50 DEG C and is stirred to react overnight, instead
Rear directly rotate solvent should be removed completely, the mashing of 25mL ethyl acetate is then added, 3.9g off-white powder is obtained by filtration, i.e. institute
State -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines, yield 76%, LCMS (ESI): m/z 150 (M+H)+。1H NMR(400MHz,
DMSO) δ 9.79 (b, 2H), 8.01 (b, 1H), 7.76 (d, J=9.1Hz, 1H), 6.91 (d, J=9.1Hz, 1H), 4.13 (s,
2H), 3.06 (t, J=6.0Hz, 2H).
Embodiment 2
A kind of method synthesizing -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines, described method includes following steps:
(1) in 250mL single port bottle, bromo- 5,6,7,8- Tetrahydronaphthyridderivates 5.0g of 2-, potassium carbonate 6.5g, chlorination are sequentially added
Benzyl 5.9g and acetonitrile 50mL.Heating reflux reaction is stayed overnight, and is filtered after fully reacting, and filtrate revolving removes solvent and crosses column, uses EA:PE
=1:20-1:10 elutes to obtain 6.3g white solid, i.e. the bromo- 6- benzyl -5,7 of 2-, tri- hydrogen -1,6- naphthyridines of 8-, yield 89%,
LCMS (ESI): m/z 303,305 (M+H)+。
(2) the bromo- three hydrogen -1,6- naphthyridines 5.0g of 6- benzyl -5,7,8- of 2- made from step (1) is weighed in 100mL single port bottle
In, 50mL DMF stirring and dissolving is added, then sequentially adds 3.7g benzyq carbamate, 3.7g Xantphos, 6.8g K2CO3,
With 3.5g tetra-triphenylphosphine palladium, which is heated to 120 DEG C of reaction 4h under nitrogen protection, is then cooled to room
Temperature is added the dilution of 300mL water, is extracted in three times with 200mL ethyl acetate, and organic phase washed once with 100mL saturated salt solution,
Then it is dried, filtered with anhydrous sodium sulfate, is spin-dried for obtaining crude product, crude product is washed through silica gel column chromatography with PE:EA=20:1~10:1
It is de- to arrive 4.8g off-white powder, i.e. 2- benzyloxyformamido -6- benzyl -5,7, tri- hydrogen -1,6- naphthyridines of 8-, yield 78%,
LCMS(ESI):m/z 374(M+H)+。
(3) weigh step (2) made from three hydrogen -1,6- naphthyridines 2.0g of 2- benzyloxyformamido -6- benzyl -5,7,8- in
In 100ml single port bottle, 50mL MeOH stirring and dissolving is added, is added under 0.2g 10%Pd/C nitrogen atmosphere and reaction 3h is stirred at room temperature.
Diatomite filtering is padded after fully reacting, filtrate is spin-dried for obtaining 0.79g white solid, i.e., described 5,6,7,8- tetrahydro -1,6- naphthyridines -
2 amine, yield 99%, LCMS (ESI): m/z 150 (M+H)+。
Embodiment 3
A kind of method synthesizing -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines, described method includes following steps:
(1) in 250mL single port bottle, chloro- 5,6,7,8- Tetrahydronaphthyridderivates 10.0g and 9.2g DIEA of 2- is dissolved in 50mL
THF is cooled to -10~-5 DEG C, and 11.1g benzyl chloroformate is added dropwise dropwise, reacts at room temperature 2h after being added dropwise.After fully reacting,
The dilution of 200mL water is added, is extracted in three times with 200mL ethyl acetate, the dilute hydrochloric acid of organic phase 1mol/L, saturated sodium bicarbonate
It respectively washed once with saturated salt solution, anhydrous magnesium sulfate dries, filters, and filtrate is spin-dried for obtaining that 16.3g is light yellow shape object, i.e. 2-
Chloro- 6- benzyloxycarbonyl group -5,7, tri- hydrogen -1,6- naphthyridines of 8-, yield 91%, LCMS (ESI): m/z 303,305 (M+H)+。
(2) it is bored in 100mL to weigh the chloro- three hydrogen -1,6- naphthyridines 3.0g of 6- benzyloxycarbonyl group -5,7,8- of 2- made from step (1)
In tank, 50mL THF stirring and dissolving is added, then sequentially adds 1.8g benzyq carbamate, 1.1g Xantphos, 2.7g
K2CO3, and 0.9g Pd2(dba)3, which is heated to 100 DEG C of reactions overnight under nitrogen protection, is then cooled down
To room temperature, diatomite filtering, the crude product after filtrate concentration are padded, crude product is eluted through silica gel column chromatography with PE:EA=50:1~10:1
Arrive 3.8g white solid, i.e. 2- benzyloxyformamido -6- benzyloxycarbonyl group -5,7, tri- hydrogen -1,6- naphthyridines of 8-, yield 92%,
LCMS(ESI):m/z 418(M+H)+。
(3) three hydrogen -1,6- naphthyridines of 2- benzyloxyformamido -6- benzyloxycarbonyl group -5,7,8- made from step (2) is weighed
50mL MeOH stirring and dissolving is added in 100ml single port bottle in 3.0g, is added under 0.3g 10%Pd/C nitrogen atmosphere and is stirred at room temperature instead
It should stay overnight, pad diatomite filtering after fully reacting, filtrate is spin-dried for obtaining 1.0g white solid, yield 94%, and LCMS (ESI): m/z
150(M+H)+。
Embodiment 4
A kind of method synthesizing -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines, described method includes following steps:
(1) in 250mL single port bottle, chloro- 5,6,7,8- Tetrahydronaphthyridderivates 5.0g and 3.6g TEA of 2- is dissolved in 50mL DMF,
- 10~-5 DEG C are cooled to, 3.5g ethyl chloroformate is added dropwise dropwise, reacts at room temperature 1h after being added dropwise.After fully reacting, it is added
The dilution of 300mL water, is extracted, the dilute hydrochloric acid of organic phase 1mol/L in three times with 150mL ethyl acetate, saturated sodium bicarbonate and full
It respectively washed once with saline solution, anhydrous magnesium sulfate dries, filters, and filtrate is spin-dried for obtaining that 6.7g is light yellow shape object, the i.e. chloro- 6- of 2-
Carbethoxyl group -5,7, tri- hydrogen -1,6- naphthyridines of 8-, yield 94%, LCMS (ESI): m/z 241,243 (M+H)+。
(2) it is mono- in 100mL to weigh the chloro- three hydrogen -1,6- naphthyridines 4.0g of 6- carbethoxyl group -5,7,8- of 2- made from step (1)
In mouth bottle, 60mL DMSO stirring and dissolving is added, then sequentially adds 2.9g urethanes, 1.9g Xantphos, 10.8g
Cs2CO3, and 0.8g Pd2(dba)3, which is heated to 100 DEG C of reaction 8h under nitrogen protection, is then cooled to
Room temperature is added the dilution of 300mL water, is extracted in three times with 200mL ethyl acetate, organic phase 100mL saturated common salt water washing one
It is secondary, it is then dried, filtered with anhydrous sodium sulfate, is spin-dried for obtaining crude product, crude product is through silica gel column chromatography, with PE:EA=50:1~10:
4.2g off-white powder, i.e. 2- (ethoxymethyl) amide groups -6- carbethoxyl group -5,7 are arrived in 1 elution, and tri- hydrogen -1,6- naphthyridines of 8- is received
Rate 86%, LCMS (ESI): m/z 294 (M+H)+。
(3) 2- (ethoxymethyl) amide groups -6- carbethoxyl group -5,7 made from weighing step (2), tri- hydrogen -1,6- naphthyridines of 8-,
10mL THF stirring and dissolving is added in 1.0g in 100mL single port bottle, weighs 0.43g LiOH.H2O is dissolved in 3mL water, then plus
Enter into reaction flask, reaction is stirred at room temperature overnight.THF is evaporated off in fully reacting back spin, the dilution of 10mL water is added, with 50mL acetic acid
Ethyl ester extracts in three times, and organic phase washed once with saturated salt solution, anhydrous sodium sulfate dry deep-frying, and filtering is spin-dried for obtaining 0.4g class white
Color solid, yield 79%, LCMS (ESI): m/z 150 (M+H)+。
Claims (3)
1. a kind of method for synthesizing -2 amine of 5,6,7,8- tetrahydro -1,6- naphthyridines, it is characterised in that the method includes following processes:
Wherein, X is chlorine, bromine or iodine；R1For benzyl, benzhydryl,Or trityl；R2For C1-5Straight chain or branch
Alkyl group or benzyl；
Specific step is as follows for the synthetic method:
(1) 2- halogenated -5 of 6 protections is made by amido protecting reaction for the halogenated -5,6,7,8- tetrahydro -1,6- naphthyridines (2) of 2-,
The i.e. compound 3 of tri- hydrogen -1,6- naphthyridines of 7,8-；
Halogenated -5,7,8- tri- hydrogen -1,6- naphthyridines (3) of 2- of (2) 6 protections passes through under alkaline condition with carbamate (4)
Tri- -2 amine of hydrogen -1,6- naphthyridines of 5,7,8-, that is, compound 5 of double protections is made in palladium catalysed cross coupling reaction；
(3) it is 5,6,7,8- tetra- that compound 1, which is made, by deprotection reaction in double -2 amine (5) of tri- hydrogen -1,6- naphthyridines of protection 5,7,8-
- 2 amine of hydrogen -1,6- naphthyridines；
The detailed process of the reaction of amido protecting described in step (1) are as follows: the halogenated -5,6,7,8- tetrahydro -1,6- naphthyridines (1) of 2- is molten
The solution that 0.01-0.2g/mL is formed in solvent, is added the alkali of 1.5-5 equivalent, is slowly added to 1-2 under the conditions of -10-30 DEG C
The protection reagent of equivalent, then reacts 1-12h at 0-80 DEG C, and after reaction, revolving removes solvent, direct column chromatography or
It is diluted with water, is extracted with ethyl acetate or methylene chloride, organic phase saturated sodium bicarbonate, dilute hydrochloric acid and saturated common salt washing
It washs, dry, concentration removes solvent and obtains halogenated -5,7,8- tri- hydrogen -1,6- naphthyridines of 2-, that is, compound 3 of 6 protections；
The protection reagent be benzyl chloride, cylite, diphenyl methyl chloride, triphenylchloromethane, Boc acid anhydrides, methylchloroformate,
One of ethyl chloroformate, isopropyl chlorocarbonate, isobutylchloroformate or benzyl chloroformate；
The process of coupling reaction described in step (2) are as follows: the halogenated three hydrogen -1,6- naphthyridines (3) of -5,7,8- of 2- for protecting 6 is molten
The solution that 0.01-0.2g/mL is formed in solvent, sequentially adds the carbamate (4) of 1.1-3 equivalent, 0.01-0.2 equivalent
Palladium catalyst, the X ligand antphos of 0.02-0.4 equivalent, the alkali of 1-3 equivalent is heated under the protection of inert gas
80-120 DEG C of reaction 2-12h, reaction solution is diluted with water after reaction, is extracted with ethyl acetate or methylene chloride, is extracted organic
Saturated common salt water washing is mutually used, dry, concentration removes solvent and obtains crude product, the 5 of double protections are chromatographed or are recrystallized to give by column,
Tri- -2 amine of hydrogen -1,6- naphthyridines of 7,8-, that is, compound 5；The solvent is tetrahydrofuran, 1,4- dioxane, acetonitrile, N, N- diformazan
One of base formamide or dimethyl sulfoxide are a variety of；The palladium catalyst is Pd2(dba)3Or tetra-triphenylphosphine palladium；Institute
Stating alkali is potassium carbonate or cesium carbonate solid.
2. according to the method described in claim 1, it is characterized in that the solvent be methylene chloride, ethyl acetate, tetrahydrofuran,
One of 1,4- dioxane, N,N-dimethylformamide or dimethyl sulfoxide etc. are a variety of；The alkali is triethylamine, two different
One of propylethylamine, N-methylmorpholine, sodium carbonate, potassium carbonate, cesium carbonate are a variety of.
3. according to the method described in claim 1, it is characterized in that deprotection reaction described in step (3) refers to through acid or alkali
Catalyzing hydrolysis or catalytic hydrogenation reaction removal amino protecting group.
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| CN103703000A (en) * | 2011-03-23 | 2014-04-02 | 安姆根有限公司 | Fused tricyclic dual inhibitors of CDK4/6 and FLT3 |
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| CN103703000A (en) * | 2011-03-23 | 2014-04-02 | 安姆根有限公司 | Fused tricyclic dual inhibitors of CDK4/6 and FLT3 |
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