CN107400082A - A kind of preparation method of substituted piperidine derivative - Google Patents
A kind of preparation method of substituted piperidine derivative Download PDFInfo
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- CN107400082A CN107400082A CN201610340767.8A CN201610340767A CN107400082A CN 107400082 A CN107400082 A CN 107400082A CN 201610340767 A CN201610340767 A CN 201610340767A CN 107400082 A CN107400082 A CN 107400082A
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- prepare compound
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- xylene
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- 150000003053 piperidines Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 238000003379 elimination reaction Methods 0.000 claims abstract description 10
- 230000000977 initiatory effect Effects 0.000 claims abstract description 4
- 239000000463 material Substances 0.000 claims abstract description 4
- 230000008030 elimination Effects 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 8
- 238000006266 etherification reaction Methods 0.000 claims description 8
- 238000006146 oximation reaction Methods 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 7
- 229940125898 compound 5 Drugs 0.000 claims description 7
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- XBXHCBLBYQEYTI-UHFFFAOYSA-N piperidin-4-ylmethanol Chemical class OCC1CCNCC1 XBXHCBLBYQEYTI-UHFFFAOYSA-N 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 8
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims 8
- 239000000203 mixture Substances 0.000 claims 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 4
- 229940113088 dimethylacetamide Drugs 0.000 claims 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims 4
- 238000000034 method Methods 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 3
- 229910019213 POCl3 Inorganic materials 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims 1
- 229910000564 Raney nickel Inorganic materials 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- -1 (2 (amino methyl) 6 methylphenoxy) methyl Chemical group 0.000 abstract description 4
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- YNKMHABLMGIIFX-UHFFFAOYSA-N benzaldehyde;methane Chemical compound C.O=CC1=CC=CC=C1 YNKMHABLMGIIFX-UHFFFAOYSA-N 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000000926 separation method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- ZWJHFFKODHFICU-UHFFFAOYSA-N 2-(hydroxyiminomethyl)-6-methylphenol Chemical class CC1=CC=CC(C=NO)=C1O ZWJHFFKODHFICU-UHFFFAOYSA-N 0.000 description 1
- IPPQNXSAJZOTJZ-UHFFFAOYSA-N 3-methylsalicylaldehyde Chemical class CC1=CC=CC(C=O)=C1O IPPQNXSAJZOTJZ-UHFFFAOYSA-N 0.000 description 1
- KYOJTNGIXPOUGI-UHFFFAOYSA-N CC(C)(C)OC(N1CCC(COc2c(C)cccc2CN)CC1)=O Chemical compound CC(C)(C)OC(N1CCC(COc2c(C)cccc2CN)CC1)=O KYOJTNGIXPOUGI-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a kind of preparation method of substituted piperidine derivative 4 ((2 (amino methyl) 6 methylphenoxy) methyl) piperidinyl-1 carboxylic acid tert-butyl ester, using the tolyl aldehyde of 2 hydroxyl 3 as initiation material, target product is obtained by oximate, elimination, etherificate, catalytic hydrogenation reaction, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of substituted piperidine derivative 4- ((2- (ammonia
Ylmethyl) -6- methylphenoxies) methyl) and piperidines -1- carboxylic acid tert-butyl esters preparation method.
Technical background
Compound 4- ((2- (amino methyl) -6- methylphenoxies) methyl) piperidines -1- carboxylic acid tert-butyl esters, structural formula are：
The derivative of this compound 4- ((2- (amino methyl) -6- methylphenoxies) methyl) piperidines -1- carboxylic acid tert-butyl esters and correlation
Thing has extensive use in pharmaceutical chemistry and organic synthesis.4- ((2- (amino methyl) -6- methylphenoxies) methyl) at present
The synthesis of piperidines -1- carboxylic acid tert-butyl esters is more difficult.Therefore it is easy to get, it is necessary to develop a raw material, easy to operate, reaction is easy to
Control, the suitable synthetic method of overall yield.
The content of the invention
The invention discloses a kind of substituted piperidine derivative 4- ((2- (amino methyl) -6- methylphenoxies) methyl) piperidines -1-
The preparation method of carboxylic acid tert-butyl ester, using 2- hydroxy-3-methyls benzaldehyde as initiation material, by oximate, elimination, it is etherified, urges
Change hydrogenation reaction and obtain target product 5, synthesis step is as follows：
(1) using 2- hydroxy-3-methyls benzaldehyde as initiation material, 2 are obtained by oximation reaction；
(2) elimination reaction is carried out 2, obtains 3；
(3) 3 progress etherification reactions are obtained 4；
(4) 4 progress catalytic hydrogenation reactions are obtained 5；
In a preferred embodiment, the reagent used in described oximation reaction prepare compound 2 is selected from hydroxylamine hydrochloride；It is described
Elimination reaction prepare compound 3 used in reagent be selected from acetic anhydride；Reagent used in described etherification reaction prepare compound 4
Selected from 4- (hydroxymethyl) piperidines -1- t-butyl formates；Catalyst used in described catalytic hydrogenation reaction prepare compound 5
Selected from palladium carbon.
In a preferred embodiment, the solvent used in described oximation reaction prepare compound 2 is selected from ethanol；Described disappears
Except the solvent used in reaction prepare compound 3 is selected from acetic anhydride；Solvent used in described etherification reaction prepare compound 4 is selected from
Tetrahydrofuran；Solvent used in described catalytic hydrogenation reaction prepare compound 5 is selected from methanol.
In a preferred embodiment, the reaction temperature used in described oximation reaction prepare compound 2 is room temperature；Described
Temperature used in elimination reaction prepare compound 3 is the reflux temperature of solvent；Used in described etherification reaction prepare compound 4
Temperature is room temperature；Temperature used in described catalytic hydrogenation reaction prepare compound 5 is room temperature.
The present invention relates to a kind of substituted piperidine derivative 4- ((2- (amino methyl) -6- methylphenoxies) methyl) piperidines -1-
The preparation method of the preparation method of carboxylic acid tert-butyl ester, reported currently without other Patents documents.
The present invention is further described by the following embodiment, and these descriptions are not to make further limit to present invention
It is fixed.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or be correspondingly improved, still belong to
Within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 2- hydroxy-3-methyls benzaldehyde formaldoxime
30g 2- hydroxy-3-methyl benzaldehydes are added in 270ml ethanol, 17g hydroxylamine hydrochlorides is added, is stirred overnight at room temperature,
Cooling, water and ethyl acetate are added, extract liquid separation, collect organic phase, dried, concentration, obtain 23g 2- hydroxy-3-methyl benzene
Formaldoxime.
(2) synthesis of 2- hydroxy-3-methyls benzonitrile
23g 2- hydroxy-3-methyl benzaldoximes are added in 195ml acetic anhydride, are heated to reflux stirring 2 hours, are concentrated,
Residue is poured into frozen water, ethyl acetate extraction liquid separation is added, collects organic phase, dry, concentration, cross post separation and obtain
17g 2- hydroxy-3-methyl benzonitriles.
(3) synthesis of 4- ((2- cyano group -6- methylphenoxies) methyl) piperidines -1- t-butyl formates
15g 2- hydroxy-3-methyl benzonitriles are added in 2000ml tetrahydrofurans, sequentially add 20g 4- (hydroxymethyl) piperazine
Pyridine -1- t-butyl formates, 45g triphenylphosphines, 38g diisopropyl azodiformates, it is stirred at room temperature 22 hours, concentrates, it is remaining
Silica gel post separation obtains 18g 4- ((2- cyano group -6- methylphenoxies) methyl) piperidines -1- t-butyl formates on thing.
(4) synthesis of 4- ((2- (amino methyl) -6- methylphenoxies) methyl) piperidines -1- carboxylic acid tert-butyl esters
18g 4- ((2- cyano group -6- methylphenoxies) methyl) piperidines -1- t-butyl formates are added in 180ml methanol,
The palladium carbons of 1g 10% are added, leads to hydrogen, is stirred at room temperature 24 hours, are filtered, filtrate is collected, concentration, obtains 9g 4- ((2-
(amino methyl) -6- methylphenoxies) methyl) piperidines -1- carboxylic acid tert-butyl esters.
Claims (5)
1. a kind of substituted piperidine derivative 4- ((2- (amino methyl) -6- methylphenoxies) methyl) piperidines -1- carboxylic acid tert-butyl esters
Preparation method, using 2- hydroxy-3-methyls benzaldehyde as initiation material, by oximate, elimination, etherificate, catalytic hydrogenation reaction
Target product 5 is obtained, synthetic route is as follows,
2. method according to claim 1, it is characterised in that the reagent used in described oximation reaction prepare compound 2 is selected from salt
Sour azanol；The one kind or two of reagent in acetic anhydride, POCl3 used in described elimination reaction prepare compound 3
The mixture of kind；Reagent used in described etherification reaction prepare compound 4 is selected from 4- (hydroxymethyl) piperidines -1- formic acid
The tert-butyl ester；Catalyst used in described catalytic hydrogenation reaction prepare compound 5 is selected from palladium carbon, palladium dydroxide, Raney's nickel
In one or more of mixtures in one or more of mixtures.
3. method according to claim 1, it is characterised in that the solvent used in described oximation reaction prepare compound 2 is selected from first
Alcohol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, two
One kind in toluene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile, acetic acid or
Several mixtures；Solvent used in described elimination reaction prepare compound 3 is selected from methanol, ethanol, normal propyl alcohol, different
Propyl alcohol, acetic anhydride, POCl3, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, a diformazan
One or more of mixtures in benzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, water；It is described
Etherification reaction prepare compound 4 used in solvent be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, two
The ring of oxygen six, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- dimethyl methyls
One or more of mixtures in acid amides, DMAC N,N' dimethyl acetamide, acetonitrile, POCl3；Described catalytic hydrogenation
React prepare compound 5 used in solvent be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane,
Dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N-
One or more of mixtures in dimethyl acetamide, acetic acid, water.
4. method according to claim 1, it is characterised in that the reaction temperature used in described oximation reaction prepare compound 2 is
The reflux temperature of 0 DEG C~solvent；Temperature used in described elimination reaction prepare compound 3 is the backflow temperature of 0 DEG C~solvent
Degree；Temperature used in described etherification reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described catalytic hydrogenation
Temperature used in reaction prepare compound 5 is the reflux temperature of 0 DEG C~solvent.
5. method according to claim 1, it is characterised in that the reaction temperature used in described oximation reaction prepare compound 2 is
Room temperature；Temperature used in described elimination reaction prepare compound 3 is the reflux temperature of solvent；Described etherification reaction system
Temperature used in standby compound 4 is room temperature；Temperature used in described catalytic hydrogenation reaction prepare compound 5 is room temperature.
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| CN201610340767.8A CN107400082A (en) | 2016-05-19 | 2016-05-19 | A kind of preparation method of substituted piperidine derivative |
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| CN201610340767.8A CN107400082A (en) | 2016-05-19 | 2016-05-19 | A kind of preparation method of substituted piperidine derivative |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012136111A1 (en) * | 2011-04-02 | 2012-10-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Phenylpropionic acid compound, preparation method therefor and medicinal use thereof |
| CN103930416A (en) * | 2011-09-09 | 2014-07-16 | 默克专利股份公司 | Benzonitrile derivatives as kinase inhibitors |
| CN104520300A (en) * | 2012-06-04 | 2015-04-15 | 第一三共株式会社 | Imidazo[1,2-b]pyridazine derivative as kinase inhibitor |
-
2016
- 2016-05-19 CN CN201610340767.8A patent/CN107400082A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012136111A1 (en) * | 2011-04-02 | 2012-10-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Phenylpropionic acid compound, preparation method therefor and medicinal use thereof |
| CN103930416A (en) * | 2011-09-09 | 2014-07-16 | 默克专利股份公司 | Benzonitrile derivatives as kinase inhibitors |
| CN104520300A (en) * | 2012-06-04 | 2015-04-15 | 第一三共株式会社 | Imidazo[1,2-b]pyridazine derivative as kinase inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| 姚其正等: "氰基的还原", 《药物合成反应》 * |
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