CN103483250B - Preparation method of 5-aminomethyl nicotinic acid - Google Patents
Preparation method of 5-aminomethyl nicotinic acid Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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Abstract
The invention provides a preparation method of 5-aminomethyl nicotinic acid. The method comprises the steps of: (1) subjecting 5-substituted nicotinate and a cyanide salt to coupling reaction to obtain 5-cyanonicotinate; (2) reducing the 5-cyanonicotinate by a reducing agent to obtain 5-aminomethyl nicotinate; and (3) letting the 5-aminomethyl nicotinate undergo hydrolysis reaction under an acidic condition or alkaline condition, thus obtaining the 5-aminomethyl nicotinic acid. The method has the advantages of simple process, mild condition, safe operation, and high yield.
Description
Technical field
The invention belongs to the field of chemical synthesis, particularly a kind of preparation method of 5-aminomethyl nicotinic acid.
Background technology
5-aminomethyl nicotinic acid is a kind of important medicine intermediate.Existing 5-aminomethyl nicotinic acid obtains by the reduction of 5-cyano methyl nicotinic acid usually, and 5--cyano methyl nicotinic acid has following several method to obtain usually: (1) null method: under the chloro dehydrated reagent effects such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, the acyl group in 5-formamyl nicotinic acid or oximido dewater to obtain 5--cyano methyl nicotinic acid; This reaction is fiercer very fast and corrodibility is high, as patent WO2006/589A1 and document J.Med.Chem, and 52 (10), 3381,2009, all disclose and obtain 5-aminomethyl nicotinic acid by acyl group through the method that phosphorus trichloride dewaters; (2) amino group is 5-cyano group nicotinic acid by oxidation style: under the effect of oxidizing agent sodium hypochlorite, perosmic anhydride or nickel peroxide; The method reaction is fiercer, operationally has potential explosion safety hidden danger; As document Synth.Commun.27,3559,1997 and Synthesis544,2001, all disclose the technique adopting clorox and perosmic anhydride as oxygenant respectively.
Summary of the invention
Goal of the invention: the preparation method that the object of the present invention is to provide the 5-aminomethyl nicotinic acid that technique is simple, reaction conditions is gentle.
Technical scheme: the preparation method of a kind of 5-aminomethyl nicotinic acid provided by the invention, comprises the following steps:
(1) 5 nicotinate (compound 3) replaced and cyanogen salt linked reaction, obtained 5-cyano group nicotinate (compound 4);
(2) 5-cyano group nicotinate (compound 4) is through reductive agent reduction, obtains 5-aminomethyl nicotinate (compound 5);
(3) 5-aminomethyl nicotinate (compound 5) in acid condition or alkaline condition issue raw hydrolysis reaction, obtain 5-aminomethyl nicotinic acid.
In step (1), described cyanogen salt is metal cyano sources or organic cyano source, and described metal cyano sources includes but not limited to sodium cyanide, potassium cyanide, zinc cyanide, ferriferro cyanide, and described organic cyano source includes but not limited to third level natural division, 2-cyanogen propyl alcohol; 5 nicotinates (compound 3) replaced are 1:(0.5-2.0 with the mol ratio of cyanogen salt); Temperature of reaction is 0 DEG C of reflux temperature to solvent; The preferred boiling point of reaction solvent is the solvent of more than 55 DEG C, more preferably toluene, normal heptane, tetrahydrofuran (THF), DMF, N,N-dimethylacetamide, acetonitrile or dimethyl sulfoxide (DMSO); Reaction times is 0.5-48h, preferred 1-24h; Also comprise catalyzer in reaction system, described catalyzer is selected from one or more in basic catalyst, metal catalyst and ligand catalyst; Described basic catalyst comprises mineral alkali and organic bases, and described mineral alkali includes but not limited to salt of wormwood, sodium carbonate and hydrolith, and described organic bases includes but not limited to triethylamine, Tetramethyl Ethylene Diamine and N, N'-dimethyl-ethylenediamine; Described metal catalyst includes but not limited to one or more in zinc, palladium, copper, sylvite, zinc salt, palladium salt, mantoquita, palladium derivative, copper derivative, one or more in preferred palladium carbon, three (dibenzalacetone) two palladium, tetra-triphenylphosphine palladium, palladium, two (two (diphenylphosphine) ferrocene of 1,1'-) palladium chloride, potassiumiodide and cuprous iodide; Described ligand catalyst includes but not limited to one or more Phosphine ligands, preferably 1,2-two (diphenylphosphine) ethane, 1,1'-two (diphenylphosphine) ferrocene, four triphenylphosphines and 2-dicyclohexyl phosphorus-2', one or more in 4', 6'-tri isopropyl biphenyl; The mol ratio of catalyzer and reaction substrate is (0.5-20): 100, more preferably (1-10): 100.
In step (2), described reductive agent is any reductive agent of the hydrogen that can produce on the spot, include but not limited to hydrogen, hydrazine hydrate, formic acid or formate, the mol ratio of 5-cyano group nicotinate, formic acid or formate, reductive agent is 1:(10-30), described formate includes but not limited to ammonium formiate and alkali metal formate; Temperature of reaction is that room temperature is to solvent reflux temperature; Reaction times is 3-48h, preferred 12-24h.
In step (3), hydrolyzed under acidic conditions reaction pH is 0-3, and temperature of reaction is room temperature, and the reaction times is 1-24h; Hydrolyzed under basic conditions reaction pH is 10-14, and temperature of reaction is room temperature, and the reaction times is 1-24h.
Reaction equation is as follows:
Wherein,
L is leavings group, the one in preferred halogen (as chlorine, bromine, iodine, fluorine) and OTs;
R
1for straight chain, side chain, cycloalkyl or aryl.
Wherein, 5 nicotinates (compound 3) replaced, for commercially available, also can adopt following two kinds of methods to obtain:
The nicotinic acid (compound 2) that method 1:5 position replaces and alcohol reflux esterification in acid condition, obtain 5 nicotinates (compound 3) replaced;
Wherein, the substituting group of 5 nicotinic acid replaced is leavings group, preferred halogen or OTs; Alcohol, except as except reactant, also can be used as reaction solvent, and therefore the consumption of alcohol should be greater than 5 nicotinic acid consumptions replaced, and preferably, the mol ratio of 5 nicotinic acid replaced and alcohol is 1:(1.1-100); Temperature of reaction is the reflux temperature that room temperature arrives solvent; Reaction times is 0.5-48h, preferred 1-24h; Reaction system pH is 0-5, preferred 0-2.
Method 2:5-bromo-nicotinic acid (compound 2) and acyl chlorides reagent generation acyl chloride reaction, product and alcohol esterification, obtain 5 nicotinates (compound 3) replaced;
Wherein, the substituting group of 5 nicotinic acid replaced is leavings group, preferred halogen or OTs; In acyl chloride reaction, described acyl chlorides reagent is oxalyl chloride or sulfur oxychloride, and 5-bromo-nicotinic acid (compound 2) is 1:(1-3 with the mol ratio of acyl chlorides reagent), temperature of reaction is 0-10 DEG C, and the reaction times is 1-3h; In esterification, the mol ratio of acyl chloride reaction product and alcohol is 1:(1-3), temperature of reaction is-5 to 5 DEG C, and the reaction times is 0.5-1h.
Beneficial effect: the preparation method of 5-aminomethyl nicotinic acid provided by the invention, technique is simple, mild condition, operational safety, yield are high.
Embodiment
According to following embodiment, the present invention may be better understood.But those skilled in the art will readily understand, concrete material proportion, processing condition and result thereof described by embodiment only for illustration of the present invention, and should can not limit the present invention described in detail in claims yet.
The preparation of embodiment 1 5-aminomethyl nicotinic acid
The preparation of 5-aminomethyl nicotinic acid, comprises the following steps:
(1) preparation of 5-bromo-nicotinic acid methyl esters
In three-necked bottle, add 20.20g5-bromo-nicotinic acid, 240 ml methanol successively, then add the dense H of 98%
2sO
4adjust pH value of reaction system to be 0, heating makes back flow reaction 24h, and HPLC detects raw material and transforms completely; Cooling, concentrated, add frozen water, adjust solution ph to alkalescence, extraction into ethyl acetate, concentrating under reduced pressure removing volatile matter, obtains 5-bromo-nicotinic acid methyl esters 19.48g, yield 91%.
(2) preparation of 5-cyano group nicotinic acid methyl ester
17.00g5-bromo-nicotinic acid methyl esters, 300mg potassiumiodide, 5.50g zinc cyanide, 4.50g tetra-triphenylphosphine palladium, 2.00g1 is added respectively in clean, that nitrogen purging is crossed three-necked bottle, 1'-two (diphenylphosphine) ferrocene, 130mL N, N-N,N-DIMETHYLACETAMIDE, be warming up to 100 DEG C of reaction 1h, HPLC detection raw materials under nitrogen protection to transform completely; Naturally cooling, adds saturated aqueous common salt 500mL, ethyl acetate 300mL, stirs 1h, and filter, the appropriate ethyl acetate of filter cake washs three times.Filtrate merges, and frozen water washing organic phase twice, separates organic phase, add normal hexane 200mL, appropriate anhydrous sodium sulfate drying.After being concentrated into the precipitation of minute white solid, under minus 20 degrees, slowly stir 4h.Filter, with the n-hexane filter cake containing 5% ethyl acetate, merging filtrate, concentrating under reduced pressure removing volatile matter, obtains 5-cyano group nicotinic acid methyl ester 10.76g, yield 84%.
1H NMR(300M Hz,CDCl
3)δ(ppm)4.00(s,3H),8.56(s,1H),9.03(ds,J=1.8Hz,1H),9.39(ds,J=1.8Hz,1H);MS:[M+H]+163.
(3) preparation of 5-aminomethyl nicotinic acid methyl ester: add 5.00g5-cyano group nicotinic acid methyl ester in autoclave, 125mL methyl alcohol, 20mL acetic acid, 2.00g palladium carbon, H
2purge autoclave three times, under hydrogen 8bar, react 24h, it is complete that HPLC detects raw material completely consumed; Filter, concentrating under reduced pressure removing volatile matter, column chromatography obtains 5-aminomethyl nicotinic acid methyl ester 2.15g, yield 42%.
1H NMR(300M Hz,CDCl
3)δ(ppm)3.96(s,3H),3.98(s,2H),8.29(m,1H),8.74(d,J=2.1Hz,1H),9.11(d,J=1.8Hz,1H);MS:[M+H]+167.
(4) preparation of 5-aminomethyl nicotinic acid: add 2.00g5-aminomethyl nicotinic acid methyl ester, 8mL methyl alcohol and 10mL water in single neck bottle successively, the aqueous sodium hydroxide solution dripping 1M after mixing adjusts reaction system pH to 13, and it is complete that reaction 12h, HPLC detect raw material consumption; Concentrating under reduced pressure; Below 10 DEG C, add sal enixum 3.30g in the alkaline aqueous solution of gained, freeze-drying obtains solid in batches, and solid chloroform dissolves, and insolubles filters, and filtrate concentrates to obtain 5-aminomethyl nicotinic acid 1.78g, yield 97%.
1h NMR (300M Hz, CDCl
3) δ (ppm): (please supplement); MS:[M+H]+: (please supplement)
The preparation of embodiment 2 5-aminomethyl nicotinic acid
The preparation of 5-aminomethyl nicotinic acid, comprises the following steps:
(1) preparation of 5-chlorine apellagrin ethyl ester
In three-necked bottle, add 0.2mol5-chlorine apellagrin, 20mmol ethanol successively, then add the dense H of 98%
2sO
4adjust pH value of reaction system to be 5, room temperature reaction 48h, HPLC detect raw material and transform completely; Cooling, concentrated, add frozen water, adjust solution ph to alkalescence, extraction into ethyl acetate, concentrating under reduced pressure removing volatile matter, obtains 5-chlorine apellagrin ethyl ester.
(2) preparation of 5-cyano group nicotinic acid methyl ester
0.1mol5-chlorine apellagrin ethyl ester, 0.05mol sodium cyanide, 0.5mmol two (1 is added respectively in clean, that nitrogen purging is crossed three-necked bottle, two (diphenylphosphine) ferrocene of 1'-) palladium chloride, 130mL N, dinethylformamide, nitrogen protection lower 0 DEG C of reaction 48h, HPLC detect raw material and transform completely; Naturally cooling, adds saturated aqueous common salt 500mL, ethyl acetate 300mL, stirs 1h, and filter, the appropriate ethyl acetate of filter cake washs three times.Filtrate merges, and frozen water washing organic phase twice, separates organic phase, add normal hexane 200mL, appropriate anhydrous sodium sulfate drying.After being concentrated into the precipitation of minute white solid, under minus 20 degrees, slowly stir 4h.Filter, with the n-hexane filter cake containing 5% ethyl acetate, merging filtrate, concentrating under reduced pressure removing volatile matter, obtains 5-cyano group nicotinic acid methyl ester.
1H NMR(300M Hz,CDCl
3)δ(ppm)4.00(s,3H),8.56(s,1H),9.03(ds,J=1.8Hz,1H),9.39(ds,J=1.8Hz,1H);MS:[M+H]+163.
(3) preparation of 5-aminomethyl nicotinic acid methyl ester: add 50mmol5-cyano group nicotinic acid methyl ester in autoclave, 125mL methyl alcohol, 50mmol sodium formiate, 50mmol hydrazine hydrate, it is complete that room temperature reaction 24h, HPLC detect raw material completely consumed; Filter, concentrating under reduced pressure removing volatile matter, column chromatography obtains 5-aminomethyl nicotinic acid methyl ester.
1H NMR(300M Hz,CDCl
3)δ(ppm)3.96(s,3H),3.98(s,2H),8.29(m,1H),8.74(d,J=2.1Hz,1H),9.11(d,J=1.8Hz,1H);MS:[M+H]+167.
(4) preparation of 5-aminomethyl nicotinic acid: add 50mmol5-aminomethyl nicotinic acid methyl ester, 20mL methyl alcohol and 20mL water in single neck bottle successively, the aqueous sodium hydroxide solution dripping 1M after mixing adjusts reaction system pH to 14, it is complete that room temperature reaction 1h, HPLC detect raw material consumption; Concentrating under reduced pressure; Below 10 DEG C, add sal enixum 10mmol in the alkaline aqueous solution of gained, freeze-drying obtains solid in batches, and solid chloroform dissolves, and insolubles filters, and filtrate concentrates to obtain 5-aminomethyl nicotinic acid.
The preparation of embodiment 3 5-aminomethyl nicotinic acid
The preparation of 5-aminomethyl nicotinic acid, comprises the following steps:
(1) preparation of 5-fluorine nicotinic acid ethyl ester
In three-necked bottle, add 0.2mol5-fluorine nicotinic acid, 2.2mmol methyl alcohol successively, then add the dense H of 98%
2sO
4adjust pH value of reaction system to be 1, back flow reaction 1h, HPLC detect raw material and transform completely; Cooling, concentrated, add frozen water, adjust solution ph to alkalescence, extraction into ethyl acetate, concentrating under reduced pressure removing volatile matter, obtains 5-fluorine nicotinic acid methyl esters.
(2) preparation of 5-cyano group nicotinic acid methyl ester
0.1mol5-fluorine nicotinic acid methyl esters, 0.1mol ferriferro cyanide, triethylamine 1mmol, zinc 1mmol, palladium carbon 1mmol, four triphenylphosphine 1mmol, 130mL methyl-sulphoxides are added respectively in clean, that nitrogen purging is crossed three-necked bottle, be warming up to 55 DEG C of reaction 24h, HPLC detection raw materials under nitrogen protection to transform completely; Naturally cooling, adds saturated aqueous common salt 500mL, ethyl acetate 300mL, stirs 1h, and filter, the appropriate ethyl acetate of filter cake washs three times.Filtrate merges, and frozen water washing organic phase twice, separates organic phase, add normal hexane 200mL, appropriate anhydrous sodium sulfate drying.After being concentrated into the precipitation of minute white solid, under minus 20 degrees, slowly stir 4h.Filter, with the n-hexane filter cake containing 5% ethyl acetate, merging filtrate, concentrating under reduced pressure removing volatile matter, obtains 5-cyano group nicotinic acid methyl ester.
(3) preparation of 5-aminomethyl nicotinic acid methyl ester: add 50mmol5-cyano group nicotinic acid methyl ester in autoclave, 125mL methyl alcohol, 25mmol ammonium formiate, 25mmol hydrazine hydrate, it is complete that back flow reaction 12h, HPLC detect raw material completely consumed; Filter, concentrating under reduced pressure removing volatile matter, column chromatography obtains 5-aminomethyl nicotinic acid methyl ester.
1H NMR(300M Hz,CDCl
3)δ(ppm)3.96(s,3H),3.98(s,2H),8.29(m,1H),8.74(d,J=2.1Hz,1H),9.11(d,J=1.8Hz,1H);MS:[M+H]+167.
(4) preparation of 5-aminomethyl nicotinic acid: add 50mmol5-aminomethyl nicotinic acid methyl ester, 20mL methyl alcohol and 20mL water in single neck bottle successively, the aqueous sodium hydroxide solution dripping 1M after mixing adjusts reaction system pH to 12, it is complete that room temperature reaction 24h, HPLC detect raw material consumption; Concentrating under reduced pressure; Below 10 DEG C, add sal enixum 10mmol in the alkaline aqueous solution of gained, freeze-drying obtains solid in batches, and solid chloroform dissolves, and insolubles filters, and filtrate concentrates to obtain 5-aminomethyl nicotinic acid.
The preparation of embodiment 4 5-aminomethyl nicotinic acid
The preparation of 5-aminomethyl nicotinic acid, comprises the following steps:
(1) preparation of 5-bromo-nicotinic acid ethyl ester
In three-necked bottle, add 0.2mol5-bromo-nicotinic acid, 10mmol methyl alcohol successively, then add the dense H of 98%
2sO
4adjust pH value of reaction system to be 0, back flow reaction 0.5h, HPLC detect raw material and transform completely; Cooling, concentrated, add frozen water, adjust solution ph to alkalescence, extraction into ethyl acetate, concentrating under reduced pressure removing volatile matter, obtains 5-bromo-nicotinic acid methyl esters.
(2) preparation of 5-cyano group nicotinic acid methyl ester
0.1mol5-bromo-nicotinic acid methyl esters, 0.1mol sodium cyanide, Tetramethyl Ethylene Diamine 2mmol, palladium 2mmol, three (dibenzalacetone) two palladium 1mmol, cuprous iodide 10mmol, 130mL toluene is added respectively in clean, that nitrogen purging is crossed three-necked bottle, under nitrogen protection, back flow reaction 0.5h, HPLC detection raw material transforms completely; Naturally cooling, adds saturated aqueous common salt 500mL, ethyl acetate 300mL, stirs 1h, and filter, the appropriate ethyl acetate of filter cake washs three times.Filtrate merges, and frozen water washing organic phase twice, separates organic phase, add normal hexane 200mL, appropriate anhydrous sodium sulfate drying.After being concentrated into the precipitation of minute white solid, under minus 20 degrees, slowly stir 4h.Filter, with the n-hexane filter cake containing 5% ethyl acetate, merging filtrate, concentrating under reduced pressure removing volatile matter, obtains 5-cyano group nicotinic acid methyl ester.
(3) preparation of 5-aminomethyl nicotinic acid methyl ester: add 50mmol5-cyano group nicotinic acid methyl ester in autoclave, 125mL methyl alcohol, 50mmol ammonium formiate, 100mmol hydrazine hydrate, it is complete that room temperature reaction 48h, HPLC detect raw material completely consumed; Filter, concentrating under reduced pressure removing volatile matter, column chromatography obtains 5-aminomethyl nicotinic acid methyl ester.
1H NMR(300M Hz,CDCl
3)δ(ppm)3.96(s,3H),3.98(s,2H),8.29(m,1H),8.74(d,J=2.1Hz,1H),9.11(d,J=1.8Hz,1H);MS:[M+H]+167.
(4) preparation of 5-aminomethyl nicotinic acid: add 50mmol5-aminomethyl nicotinic acid methyl ester, 20mL methyl alcohol and 20mL water in single neck bottle successively, the aqueous hydrochloric acid dripping 1M after mixing adjusts reaction system pH to 0, and it is complete that room temperature reaction 1h, HPLC detect raw material consumption; Concentrating under reduced pressure; Below 10 DEG C, add sal enixum 10mmol in the alkaline aqueous solution of gained, freeze-drying obtains solid in batches, and solid chloroform dissolves, and insolubles filters, and filtrate concentrates to obtain 5-aminomethyl nicotinic acid.
The preparation of embodiment 5 5-aminomethyl nicotinic acid
The preparation of 5-aminomethyl nicotinic acid, comprises the following steps:
(1) preparation of 5-bromo-nicotinic acid methyl esters:
0.2mol5-bromo-nicotinic acid, ethylene dichloride 180mL and 1mL DMF is added respectively in three-necked bottle; Slowly oxalyl chloride 0.2mol is dripped, 10 DEG C of reactions 1h, then stirring at room temperature 2h under ice-water bath; In the reactor of drying, add 0.2mol methyl alcohol, then slowly drip chloride compounds at-5 DEG C ,-5 DEG C of reaction 1h, then rise to stirring at room temperature.Cooling, add frozen water, tune solution ph is weakly alkaline, dichloromethane extraction, and concentrating under reduced pressure removing volatile matter, obtains 5-bromo-nicotinic acid methyl esters.
(2) preparation of 5-cyano group nicotinic acid methyl ester
0.1mol5-bromo-nicotinic acid methyl esters, 0.2mol methyl silicon cyanogen, 0.3mmol N is added respectively in clean, that nitrogen purging is crossed three-necked bottle, N-dimethyl-ethylenediamine, 0.5mmol copper, 0.2mmol1,2-two (diphenylphosphine) ethane, 130mL tetrahydrofuran (THF), under nitrogen protection, back flow reaction 24h, HPLC detection raw material transforms completely; Naturally cooling, adds saturated aqueous common salt 500mL, ethyl acetate 300mL, stirs 1h, and filter, the appropriate ethyl acetate of filter cake washs three times.Filtrate merges, and frozen water washing organic phase twice, separates organic phase, add normal hexane 200mL, appropriate anhydrous sodium sulfate drying.After being concentrated into the precipitation of minute white solid, under minus 20 degrees, slowly stir 4h.Filter, with the n-hexane filter cake containing 5% ethyl acetate, merging filtrate, concentrating under reduced pressure removing volatile matter.
(3) preparation of 5-aminomethyl nicotinic acid methyl ester: add 50mmol5-cyano group nicotinic acid methyl ester, 125mL methyl alcohol, 100mmol ammonium formiate in autoclave, the completely consumed of 40 DEG C of reaction 24h, HPLC detection raw materials is complete; Filter, concentrating under reduced pressure removing volatile matter, column chromatography obtains 5-aminomethyl nicotinic acid methyl ester.
1H NMR(300M Hz,CDCl
3)δ(ppm)3.96(s,3H),3.98(s,2H),8.29(m,1H),8.74(d,J=2.1Hz,1H),9.11(d,J=1.8Hz,1H);MS:[M+H]+167.
(4) preparation of 5-aminomethyl nicotinic acid: add 50mmol5-aminomethyl nicotinic acid methyl ester, 20mL methyl alcohol and 20mL water in single neck bottle successively, the aqueous hydrochloric acid dripping 1M after mixing adjusts reaction system pH to 3, and it is complete that room temperature reaction 24h, HPLC detect raw material consumption; Concentrating under reduced pressure; Below 10 DEG C, add sal enixum 10mmol in the alkaline aqueous solution of gained, freeze-drying obtains solid in batches, and solid chloroform dissolves, and insolubles filters, and filtrate concentrates to obtain 5-aminomethyl nicotinic acid.
The preparation of embodiment 6 5-aminomethyl nicotinic acid
The preparation of 5-aminomethyl nicotinic acid, comprises the following steps:
(1) preparation of 5-bromo-nicotinic acid methyl esters:
0.2mol5-bromo-nicotinic acid, ethylene dichloride 180mL and 1mL DMF is added respectively in three-necked bottle; Slowly oxalyl chloride 0.6mol is dripped, 0 DEG C of reaction 3h, then stirring at room temperature 2h under ice-water bath; In the reactor of drying, add 0.6mol methyl alcohol, then slowly drip chloride compounds at-5 DEG C, 5 DEG C of reaction 0.5h, then rise to stirring at room temperature.Cooling, add frozen water, tune solution ph is weakly alkaline, dichloromethane extraction, and concentrating under reduced pressure removing volatile matter, obtains 5-bromo-nicotinic acid methyl esters.
(2) preparation of 5-cyano group nicotinic acid methyl ester
0.1mol5-bromo-nicotinic acid methyl esters, 0.1mol2-cyanogen propyl alcohol, 2mmol cupric chloride, 1mmol Palladous chloride, 1mmol ferrocenyl cycloimine palladium palladium, 2mmol palladium, 130mL acetonitrile is added respectively in clean, that nitrogen purging is crossed three-necked bottle, under nitrogen protection, back flow reaction 12h, HPLC detection raw material transforms completely; Naturally cooling, adds saturated aqueous common salt 500mL, ethyl acetate 300mL, stirs 1h, and filter, the appropriate ethyl acetate of filter cake washs three times.Filtrate merges, and frozen water washing organic phase twice, separates organic phase, add normal hexane 200mL, appropriate anhydrous sodium sulfate drying.After being concentrated into the precipitation of minute white solid, under minus 20 degrees, slowly stir 4h.Filter, with the n-hexane filter cake containing 5% ethyl acetate, merging filtrate, concentrating under reduced pressure removing volatile matter, obtains 5-cyano group nicotinic acid methyl ester.
(3) preparation of 5-aminomethyl nicotinic acid methyl ester: add 50mmol5-cyano group nicotinic acid methyl ester 125mL methyl alcohol, 50mmol formic acid, 2.00g palladium carbon in autoclave, H
2purge autoclave three times, under hydrogen 8bar, the completely consumed of room temperature reaction 12h, HPLC detection raw material is complete; Filter, concentrating under reduced pressure removing volatile matter, column chromatography obtains 5-aminomethyl nicotinic acid methyl ester.
1HNMR(300M Hz,CDCl
3)δ(ppm)3.96(s,3H),3.98(s,2H),8.29(m,1H),8.74(d,J=2.1Hz,1H),9.11(d,J=1.8Hz,1H);MS:[M+H]+167.
(4) preparation of 5-aminomethyl nicotinic acid: add 50mmol5-aminomethyl nicotinic acid methyl ester, 20mL methyl alcohol and 20mL water in single neck bottle successively, the aqueous hydrochloric acid dripping 1M after mixing adjusts reaction system pH to 2, and it is complete that room temperature reaction 12h, HPLC detect raw material consumption; Concentrating under reduced pressure; Below 10 DEG C, add sal enixum 10mmol in the alkaline aqueous solution of gained, freeze-drying obtains solid in batches, and solid chloroform dissolves, and insolubles filters, and filtrate concentrates to obtain 5-aminomethyl nicotinic acid.
The preparation of embodiment 7 5-aminomethyl nicotinic acid
The preparation of 5-aminomethyl nicotinic acid, comprises the following steps:
(1) preparation of 5-bromo-nicotinic acid methyl esters
0.2mol5-bromo-nicotinic acid, ethylene dichloride 180mL and 1mL DMF is added respectively in three-necked bottle; Slowly sulfur oxychloride 0.2mol is dripped, 0 DEG C of reaction 3h, then stirring at room temperature 2h under ice-water bath; In the reactor of drying, add 0.2mol methyl alcohol, then slowly drip chloride compounds at-5 DEG C ,-5 DEG C of reaction 1h, then rise to stirring at room temperature.Cooling, add frozen water, tune solution ph is weakly alkaline, dichloromethane extraction, and concentrating under reduced pressure removing volatile matter, obtains 5-bromo-nicotinic acid methyl esters.
(2) preparation of 5-cyano group nicotinic acid methyl ester
0.1mol5-bromo-nicotinic acid methyl esters, 0.1mol sodium cyanide, 10mmol2-dicyclohexyl phosphorus-2' is added respectively in clean, that nitrogen purging is crossed three-necked bottle, 4', 6'-tri isopropyl biphenyl, 130mL normal heptane, under nitrogen protection, back flow reaction 0.5h, HPLC detection raw material transforms completely; Naturally cooling, adds saturated aqueous common salt 500mL, ethyl acetate 300mL, stirs 1h, and filter, the appropriate ethyl acetate of filter cake washs three times.Filtrate merges, and frozen water washing organic phase twice, separates organic phase, add normal hexane 200mL, appropriate anhydrous sodium sulfate drying.After being concentrated into the precipitation of minute white solid, under minus 20 degrees, slowly stir 4h.Filter, with the n-hexane filter cake containing 5% ethyl acetate, merging filtrate, concentrating under reduced pressure removing volatile matter, obtains 5-cyano group nicotinic acid methyl ester 10.76g, yield 84%.
(3) preparation of 5-aminomethyl nicotinic acid methyl ester: add 50mmol5-cyano group nicotinic acid methyl ester, 125mL methyl alcohol, 50mmol ammonium formiate, 2.00g palladium carbon in autoclave, H2 purges autoclave three times, under hydrogen 8bar, the completely consumed of 40 DEG C of reaction 3h, HPLC detection raw materials is complete; Filter, concentrating under reduced pressure removing volatile matter, column chromatography obtains 5-aminomethyl nicotinic acid methyl ester.
1HNMR(300M Hz,CDCl
3)δ(ppm)3.96(s,3H),3.98(s,2H),8.29(m,1H),8.74(d,J=2.1Hz,1H),9.11(d,J=1.8Hz,1H);MS:[M+H]+167.
(4) preparation of 5-aminomethyl nicotinic acid: add 50mmol5-aminomethyl nicotinic acid methyl ester, 20mL methyl alcohol and 20mL water in single neck bottle successively, the aqueous hydrochloric acid dripping 1M after mixing adjusts reaction system pH to 2, and it is complete that room temperature reaction 12h, HPLC detect raw material consumption; Concentrating under reduced pressure; Below 10 DEG C, add sal enixum 10mmol in the alkaline aqueous solution of gained, freeze-drying obtains solid in batches, and solid chloroform dissolves, and insolubles filters, and filtrate concentrates to obtain 5-aminomethyl nicotinic acid.
The preparation of embodiment 8 5-aminomethyl nicotinic acid
The preparation of 5-aminomethyl nicotinic acid, comprises the following steps:
(1) preparation of 5-bromo-nicotinic acid methyl esters
0.2mol5-bromo-nicotinic acid, ethylene dichloride 180mL and 1mL DMF is added respectively in three-necked bottle; Slowly sulfur oxychloride 0.6mol is dripped, 10 DEG C of reactions 1h, then stirring at room temperature 2h under ice-water bath; In the reactor of drying, add 0.6mol methyl alcohol, then slowly drip chloride compounds at-5 DEG C, 5 DEG C of reaction 0.5h, then rise to stirring at room temperature.Cooling, add frozen water, tune solution ph is weakly alkaline, dichloromethane extraction, and concentrating under reduced pressure removing volatile matter, obtains 5-bromo-nicotinic acid methyl esters.
(2) preparation of 5-cyano group nicotinic acid methyl ester
0.1mol5-bromo-nicotinic acid methyl esters, 0.1mol sodium cyanide, 10mmol2-dicyclohexyl phosphorus-2' is added respectively in clean, that nitrogen purging is crossed three-necked bottle, 4', 6'-tri isopropyl biphenyl, 130mL normal heptane, under nitrogen protection, back flow reaction 0.5h, HPLC detection raw material transforms completely; Naturally cooling, adds saturated aqueous common salt 500mL, ethyl acetate 300mL, stirs 1h, and filter, the appropriate ethyl acetate of filter cake washs three times.Filtrate merges, and frozen water washing organic phase twice, separates organic phase, add normal hexane 200mL, appropriate anhydrous sodium sulfate drying.After being concentrated into the precipitation of minute white solid, under minus 20 degrees, slowly stir 4h.Filter, with the n-hexane filter cake containing 5% ethyl acetate, merging filtrate, concentrating under reduced pressure removing volatile matter, obtains 5-cyano group nicotinic acid methyl ester 10.76g, yield 84%.
(3) preparation of 5-aminomethyl nicotinic acid methyl ester: add 50mmol5-cyano group nicotinic acid methyl ester, 125mL methyl alcohol, 100mmol ammonium formiate, 2.00g palladium carbon in autoclave, H
2purge autoclave three times, under hydrogen 8bar, the completely consumed of 40 DEG C of reaction 3h, HPLC detection raw materials is complete; Filter, concentrating under reduced pressure removing volatile matter, column chromatography obtains 5-aminomethyl nicotinic acid methyl ester.
1HNMR(300M Hz,CDCl
3)δ(ppm)3.96(s,3H),3.98(s,2H),8.29(m,1H),8.74(d,J=2.1Hz,1H),9.11(d,J=1.8Hz,1H);MS:[M+H]+167.
(4) preparation of 5-aminomethyl nicotinic acid: add 50mmol5-aminomethyl nicotinic acid methyl ester, 20mL methyl alcohol and 20mL water in single neck bottle successively, the aqueous hydrochloric acid dripping 1M after mixing adjusts reaction system pH to 2, and it is complete that room temperature reaction 12h, HPLC detect raw material consumption; Concentrating under reduced pressure; Below 10 DEG C, add sal enixum 10mmol in the alkaline aqueous solution of gained, freeze-drying obtains solid in batches, and solid chloroform dissolves, and insolubles filters, and filtrate concentrates to obtain 5-aminomethyl nicotinic acid.
Claims (1)
1. a preparation method for 5-aminomethyl nicotinic acid, is characterized in that: comprise the following steps:
(1) 5 nicotinate and cyanogen salt linked reaction replaced, obtained 5-cyano group nicotinate; Wherein, described cyanogen salt is metal cyano sources or organic cyano source; The mol ratio of 5 nicotinates replaced and cyanogen salt is 1:(0.5-2.0); Temperature of reaction is 0 DEG C of reflux temperature to solvent; Reaction times is 0.5-48h; Also comprise catalyzer in reaction system, described catalyzer is selected from one or more in basic catalyst, metal catalyst and ligand catalyst; The mol ratio of catalyzer and reaction substrate is (0.5-20): 100;
(2) 5-cyano group nicotinate reduces through reductive agent, obtains 5-aminomethyl nicotinate; Wherein, described reductive agent is selected from hydrogen, hydrazine hydrate, formic acid or formate, and the mol ratio of 5-cyano group nicotinate, reductive agent is 1:(10-30); Temperature of reaction is that room temperature is to solvent reflux temperature; Reaction times is 3h-48h;
(3) there is hydrolysis reaction in the basic conditions in 5-aminomethyl nicotinate, obtains 5-aminomethyl nicotinic acid; Wherein, hydrolyzed under basic conditions reaction pH is 10-14, and temperature of reaction is room temperature, and the reaction times is 1-24h.
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| WO2012161965A1 (en) * | 2011-05-26 | 2012-11-29 | Eli Lilly And Company | Novel imidazole derivatives useful for the treatment of arthritis |
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| WO2012161965A1 (en) * | 2011-05-26 | 2012-11-29 | Eli Lilly And Company | Novel imidazole derivatives useful for the treatment of arthritis |
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