CN110981794A - Synthetic method of nicotinate - Google Patents
Synthetic method of nicotinate Download PDFInfo
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- CN110981794A CN110981794A CN201911320125.1A CN201911320125A CN110981794A CN 110981794 A CN110981794 A CN 110981794A CN 201911320125 A CN201911320125 A CN 201911320125A CN 110981794 A CN110981794 A CN 110981794A
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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
- C07D213/80—Acids; Esters in position 3
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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
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Abstract
The invention belongs to the technical field of compound preparation, and particularly relates to (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate and a synthesis method thereof, which comprises the following steps: (1) adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into a reaction kettle, stirring uniformly, then sequentially dropwise adding a mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran, reacting at 50-60 ℃ until the mass concentration of the 4-cyano-3-trifluoromethylaniline/(R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide is less than or equal to 12-18%, then adding water and toluene, layering, collecting an organic phase, concentrating and crystallizing to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-methylpropanamide The synthetic method of the invention is simple and the preparation cost is low.
Description
Technical Field
The invention belongs to the technical field of compound preparation, and particularly relates to a synthesis method of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate.
Background
(S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate is used for the treatment of acute or chronic muscle wasting, and also for the prevention of bone related disorders, for the treatment of muscle wasting, muscle wasting caused by cancer, AIDS, nephropathy, burn diseases, anemia, obesity, diabetes, etc., the existing (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate synthesis processes such as CN 103772238A, a new aromatic propionamide compound containing ester group, its preparation method and use are disclosed, its preparation method is to use the nicotinic anhydride to esterify in pyridine solution, the utilization rate of nicotinic acid is low, nicotinic acid and pyridine need secondary recovery; meanwhile, the target compound is purified by column chromatography separation, so that the synthesis cost is high and the processing technology is complex.
Disclosure of Invention
The invention aims to provide a synthetic method of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate, which has simple process and low cost.
Based on the purpose, the invention adopts the following technical scheme:
a method of synthesizing (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate comprising the steps of:
(1) adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into a reaction kettle, stirring uniformly, then sequentially dropwise adding a mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran, reacting at 50-60 ℃ until the mass concentration of the 4-cyano-3-trifluoromethylaniline/(R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide is less than or equal to 12-18%, then adding water and toluene, layering, collecting an organic phase, concentrating and crystallizing to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-methylpropanamide -2-hydroxy-2-methylpropionamide, the chemical reaction formula being:
(2) adding into a reaction kettleIsopropanol, (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] obtained in step (1)]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3Stirring and heating to reflux, reacting to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]The mass concentration of the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is less than or equal to 0.5-2%, then methyl tert-butyl ether and water are added for stirring and layering, an organic phase is taken, the organic phase is collected, concentrated and crystallized to obtain the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, and the chemical reaction formula is as follows:
(3) under the protection of nitrogen, adding nicotinic acid and toluene into a reaction kettle, heating to reflux, distilling off and adding 10-15% of the total mass of the toluene, cooling to 40-60 ℃, dropwise adding oxalyl chloride, heating to 100 ℃ and 120 ℃, stirring for 2-3h, then adding the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide obtained in the step (2), dropwise adding triethylamine, heating to reflux and reacting until the mass concentration of the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide/(S) -1- ((4-cyano-3- (trifluoromethyl) The mass concentration of the phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate is less than or equal to 0.5 to 2 percent, the temperature is reduced, water and ethyl acetate are added, the mixture is stirred and layered, an upper organic phase is collected, concentrated and refined to obtain (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate,
the chemical reaction formula is as follows:
further, in the step (1), adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into the reaction kettle, wherein the mass ratio of the (R) -3-bromo-2-hydroxy-2-methylpropanoic acid to the N, N-dimethylformamide to the tetrahydrofuran is 1-5 kg: 10-15 kg: 6-10 kg; after being uniformly stirred, the mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran is sequentially dripped, and the mass ratio of the thionyl chloride, the N, N-diisopropylethylamine, the 4-cyano-3-trifluoromethylaniline and the tetrahydrofuran is 1-4 kg: 6-10 kg; the mass ratio of the (R) -3-bromine-2-hydroxyl-2-methylpropanoic acid, the thionyl chloride, the water and the toluene is 1-5kg, 1-4kg, 2-8kg, 5-9 kg.
Further, in the step (2), isopropanol, (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3The mass ratio of the methyl tert-butyl ether to the water is as follows: 5-9kg, 1-4kg, 0.5-3kg, 15-19kg, and 14-18 kg.
Further, in the step (3), the weight ratio of nicotinic acid, toluene, oxalyl chloride, (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, triethylamine, water and ethyl acetate is as follows: 1-4kg, 25-30kg, 0.5-3kg, 1-4kg, 2-6kg, 10-15kg, 9-12 kg.
Further, the concentration in the step (1) is that the organic phase is washed by water and combined, and then is concentrated by reduced pressure distillation until no distillate is produced, so as to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropionamide crude product, the mass ratio of water to thionyl chloride in the washing is 2-8 kg: 1-4kg, the crystallization is that toluene is added into the concentrated (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropionamide crude product, the mass ratio of the toluene to tetrahydrofuran is 10-20 kg: 6-10kg, the temperature is reduced and the stirring is carried out for 2-3h, and filter cake is obtained after filtration, washing the filter cake with toluene at a mass ratio of toluene to tetrahydrofuran of 1-5 kg: 6-10kg, and drying the filter cake to obtain crystalline R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide.
Further, in the concentration in the step (2), the organic phase is added with water for layering, and the organic phase is concentrated by reduced pressure distillation until no distillate exists, so as to obtain a crude product of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide, the mass ratio of the added water to the isopropanol is 12-20 kg: 5-10kg, the crystallization is realized by adding toluene and methyl tert-butyl ether, the mass ratio of the toluene, the methyl tert-butyl ether to the isopropanol is 6-10 kg: 0.5-2 kg: 5-9kg, heating and stirring, cooling and crystallizing, stirring for 2-3h, carrying out suction filtration, washing a filter cake by using toluene, the mass ratio of the toluene to the isopropanol is 1-4 kg: 5-9kg, drying at 40-50 deg.C for 3-4h to obtain crystallized (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide.
Further, the concentration in the step (3) is to add silica gel into the organic phase, the mass ratio of the silica gel to triethylamine is 1-4 kg: 2-6kg, stir uniformly, filter and wash, then add the silica gel into the filtrate, the mass ratio of the silica gel to triethylamine is 1-4 kg: 2-6kg, stir, filter, wash and concentrate under reduced pressure, the refining is to add isopropanol into the concentrated concentrate, the mass ratio of the isopropanol to triethylamine is 4-8 kg: 2-6kg, stir and heat up to 40-50 ℃, add active carbon, the mass ratio of the active carbon to triethylamine is 0.1-4 kg: 2-6kg, stir uniformly, filter and wash, drop water into the filtrate, the mass ratio of the water to triethylamine is 8-12 kg: 2-6kg, cool to 20-30 ℃, stirring for 2-3h, dripping water, cooling to 0-10 deg.C, stirring for 2-3h, filtering, washing the filter cake with water at a mass ratio of 1-4 kg: 2-6kg, collecting the filter cake, and drying at 40-70 deg.C to obtain refined (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate.
Further, the method comprises a step (4) of adding the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate obtained in the step (3) and isopropanol into a reaction kettle, uniformly stirring, filtering, washing with purified water, and drying to obtain the purified (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate, wherein the chemical reaction formula is as follows:
the invention greatly reduces the consumption of nicotinic acid, and simultaneously uses the triethylamine which is cheap and easy to obtain to replace pyridine; in the purification process, a recrystallization purification method is adopted. Simple manufacture, low cost and contribution to industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate;
FIGS. 3 and 4 are infrared spectra of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate;
FIG. 5 is a UV spectrum of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate;
Detailed Description
Example 1:
an (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate having the formula:
a synthetic method of the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate comprises the following steps:
(1) adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into a reaction kettle, stirring uniformly, then sequentially dropwise adding a mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran, reacting at 50 ℃ until the mass concentration of the 4-cyano-3-trifluoromethylaniline/(R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide is less than or equal to 12%, then adding water and toluene, layering, collecting an organic phase, concentrating and crystallizing to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methacrylamide 2-methylpropionamide, the chemical reaction formula is as follows:
adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into a reaction kettle in the step (1), wherein the mass ratio of the (R) -3-bromo-2-hydroxy-2-methylpropanoic acid to the N, N-dimethylformamide to the tetrahydrofuran is 1 kg: 10 kg: 6 kg; after being uniformly stirred, the mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran is sequentially dripped, and the mass ratio of the thionyl chloride to the N, N-diisopropylethylamine to the 4-cyano-3-trifluoromethylaniline to the tetrahydrofuran is 1 kg: 6 kg; the mass ratio of the (R) -3-bromine-2-hydroxyl-2-methylpropanoic acid, the thionyl chloride, the water and the toluene is 1 kg: 2 kg: 5 kg.
The concentration in the step (1) is to wash the organic phase, combine the organic phase and concentrate the organic phase by reduced pressure distillation until no distillate is obtained, thus obtaining (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropionamide crude product, wherein the mass ratio of water to thionyl chloride in the washing is 2 kg: 1kg, the crystallization is to add toluene into the concentrated (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropionamide crude product, the mass ratio of the toluene to tetrahydrofuran is 10 kg: 6kg, cool and stir the crude product for 2h, filter the obtained filter cake after filtration, wash the filter cake with toluene, the mass ratio of the toluene to tetrahydrofuran is 1 kg: 6kg, drying the filter cake to obtain the crystallized R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide.
(2) Adding isopropanol into a reaction kettle, and adding the (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl group obtained in the step (1)]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3Stirring and heating to reflux, reacting to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl](S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide in a mass concentration of (E) -3-bromo-2-hydroxy-2-methylpropanamideAdding methyl tert-butyl ether and water, stirring for layering, collecting organic phase, concentrating, crystallizing to obtain (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide,
the chemical reaction formula is as follows:
in the step (2), isopropanol and (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3The mass ratio of the methyl tert-butyl ether to the water is as follows: 5-9kg, 1-4kg, 0.5-3kg, 15kg and 14 kg.
The concentration in the step (2) is to add water into the organic phase for layering, and concentrate the organic phase to no distillate through reduced pressure distillation, so as to obtain a crude product of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide, wherein the mass ratio of the added water to isopropanol is 12 kg: 5kg, the crystallization is to add toluene and methyl tert-butyl ether, the mass ratio of the toluene, the methyl tert-butyl ether and the isopropanol is 6 kg: 0.5 kg: 5kg, heat up and stir, cool down and crystallize, stir for 2h, pump filter, wash the filter cake with toluene, the mass ratio of the toluene to the isopropanol is 1 kg: 5kg, and dry the filter cake for 3h at 40 ℃ so as to obtain crystallized (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) - 2-hydroxy-2-methylpropionamide.
(3) Under the protection of nitrogen, adding nicotinic acid and toluene into a reaction kettle, heating to reflux, distilling off and adding 10-15% of the total mass of the toluene, cooling to 40 ℃, dropwise adding oxalyl chloride, heating to 100 ℃, stirring for 2h, then adding (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide obtained in the step (2), dropwise adding triethylamine, heating to reflux and reacting until the mass concentration of the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide/(S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- Cooling after the mass concentration of the (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate is less than or equal to 0.5 percent, adding water and ethyl acetate, stirring and layering, collecting an upper organic phase, concentrating and refining to obtain the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate,
the chemical reaction formula is as follows:
in the step (3), the mass ratio of nicotinic acid, toluene, oxalyl chloride, (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, triethylamine, water and ethyl acetate is as follows: 1 kg: 25 kg: 0.5 kg: 1 kg: 2 kg: 10 kg: 9 kg.
The concentration in the step (3) is to add silica gel into an organic phase, the mass ratio of the silica gel to triethylamine is 1 kg: 2kg, stir uniformly, filter and wash, then add the silica gel into a filtrate, the mass ratio of the silica gel to the triethylamine is 1 kg: 2kg, stir, filter, wash and concentrate under reduced pressure, the refining is to add isopropanol into a concentrated concentrate, the mass ratio of the isopropanol to the triethylamine is 4 kg: 2kg, stir and heat to 40-50 ℃, add activated carbon, the mass ratio of the activated carbon to the triethylamine is 0.1 kg: 2kg, stir uniformly, filter and wash, drip water into the filtrate, the mass ratio of the water to the triethylamine is 8 kg: 2kg, cool to 20 ℃, stir for 2h, then drip water, the mass ratio of the water to the triethylamine is 2 kg: 2kg, cool to 0 ℃, stir for 2h, filter, wash a filter cake with water, the mass ratio of the water to the triethylamine is 1 kg: 2kg, collecting the filter cake, and drying at 40 deg.C to obtain refined (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate.
And a step (4) of adding the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate obtained in the step (3) and isopropanol into a reaction kettle, uniformly stirring, filtering, washing with purified water for six times, and drying to obtain the purified (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate, wherein the chemical reaction formula is as follows:
the mass ratio of the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate to the isopropanol to the purified water for the first washing to the purified water for the second washing to the purified water for the third washing to the purified water for the fourth washing to the purified water for the fifth washing to the purified water for the sixth washing is 0.5kg to 1kg to 0.5kg to 0.3kg to 0.5kg to 2kg to 0.2kg, so as to obtain the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate, the yield is 88.7 percent
Example 2:
(S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate,
the structural formula is as follows:
a synthetic method of the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate comprises the following steps:
(1) adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into a reaction kettle, stirring uniformly, then sequentially dropwise adding a mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran, reacting at 60 ℃ until the mass concentration of the 4-cyano-3-trifluoromethylaniline/(R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide is less than or equal to 18%, then adding water and toluene, layering, collecting an organic phase, concentrating and crystallizing to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methacrylamide 2-methylpropionamide, the chemical reaction formula is as follows:
adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into a reaction kettle in the step (1), wherein the mass ratio of the (R) -3-bromo-2-hydroxy-2-methylpropanoic acid to the N, N-dimethylformamide to the tetrahydrofuran is 5 kg: 15 kg: 10 kg; after being uniformly stirred, the mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran is sequentially dripped, and the mass ratio of the thionyl chloride to the N, N-diisopropylethylamine to the 4-cyano-3-trifluoromethylaniline to the tetrahydrofuran is 4 kg: 10 kg; the mass ratio of the (R) -3-bromine-2-hydroxyl-2-methylpropanoic acid, the thionyl chloride, the water and the toluene is 5kg, 4kg, 8kg and 9 kg.
The concentration in the step (1) is that organic phases are washed by water and combined together and then concentrated by reduced pressure distillation until no distillate is obtained, thus obtaining (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropionamide crude product, the mass ratio of water to thionyl chloride in the washing is 8 kg: 4kg, the crystallization is that toluene is added into the concentrated (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropionamide crude product, the mass ratio of the toluene to tetrahydrofuran is 20 kg: 10kg, the mixture is cooled and stirred for 3h, filter cake is obtained after filtration, the filter cake is washed by toluene, the mass ratio of the toluene to tetrahydrofuran is 5 kg: 10kg, drying the filter cake to obtain the crystallized R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide.
(2) Adding isopropanol into a reaction kettle, and adding the (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl group obtained in the step (1)]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3Stirring and heating to reflux, reacting to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]The mass concentration of the (E) -3-bromo-2-hydroxy-2-methylpropanamide/(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is less than or equal to 2%, then methyl tert-butyl ether and water are added for stirring and layering, an organic phase is taken, the organic phase is collected, concentrated and crystallized to obtain the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, and the chemical reaction formula is as follows:
in the step (2), isopropanol and (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3The mass ratio of the methyl tert-butyl ether to the water is as follows: 9 kg: 4 kg: 3 kg: 19 kg: 18 kg.
The concentration in the step (2) is to add water into the organic phase for layering, and concentrate the organic phase to no distillate through reduced pressure distillation, so as to obtain a crude product of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide, wherein the mass ratio of the added water to the isopropanol is 20 kg: 10kg, the crystallization is to add toluene and methyl tert-butyl ether, the mass ratio of the toluene, the methyl tert-butyl ether and the isopropanol is 10 kg: 2 kg: 9kg, heat up and stir, cool down and crystallize, stir for 3h, pump filter, wash a filter cake with toluene, the mass ratio of the toluene to the isopropanol is 4 kg: 9kg, and dry the filter cake for 4h at 50 ℃ so as to obtain crystallized (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) - 2-hydroxy-2-methylpropionamide.
(3) Under the protection of nitrogen, adding nicotinic acid and toluene into a reaction kettle, heating to reflux, distilling off and adding 10-15% of the total mass of the toluene, cooling to 50 ℃, dropwise adding oxalyl chloride, heating to 110 ℃, stirring for 3h, then adding (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide obtained in the step (2), dropwise adding triethylamine, heating to reflux and reacting until the mass concentration of the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide/(S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- Cooling after the mass concentration of the (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate is less than or equal to 2 percent, adding water and ethyl acetate, stirring and layering, collecting the upper organic phase, concentrating and refining to obtain the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate,
the chemical reaction formula is as follows:
in the step (3), the mass ratio of nicotinic acid, toluene, oxalyl chloride, (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, triethylamine, water and ethyl acetate is as follows: 4 kg: 30 kg: 3 kg: 4 kg: 6 kg: 15 kg: 12 kg.
The concentration in the step (3) is to add silica gel into an organic phase, the mass ratio of the silica gel to triethylamine is 4 kg: 6kg, stir uniformly, filter and wash, then add the silica gel into a filtrate, the mass ratio of the silica gel to the triethylamine is 4 kg: 6kg, stir, filter, wash and concentrate under reduced pressure, the refining is to add isopropanol into a concentrated concentrate, the mass ratio of the isopropanol to the triethylamine is 8 kg: 6kg, stir and heat to 50 ℃, add activated carbon, the mass ratio of the activated carbon to the triethylamine is 4 kg: 6kg, stir uniformly, filter and wash, add water into the filtrate dropwise, the mass ratio of the water to the triethylamine is 12 kg: 6kg, cool to 30 ℃, stir for 3h, then add water dropwise, the mass ratio of the water to the triethylamine is 6 kg: 6kg, cool to 10 ℃, stir for 3h, filter, wash a filter cake with water, the mass ratio of the water to the triethylamine is 4 kg: 6kg, collecting the filter cake, and drying at 70 deg.C to obtain refined (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate.
And a step (4) of adding the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate obtained in the step (3) and isopropanol into a reaction kettle, uniformly stirring, filtering, washing with purified water for six times, and drying to obtain the purified (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate, wherein the chemical reaction formula is as follows:
the mass ratio of the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate to the isopropanol to the purified water for the first washing, the purified water for the second washing, the purified water for the third washing, the purified water for the fourth washing, the purified water for the fifth washing and the purified water for the sixth washing is 1.2 kg: 4 kg: 2 kg: 3 kg: 4 kg: 5 kg: 3 kg. To obtain (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate with a yield of 87.2%
Example 3:
an (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate having the formula:
a synthetic method of the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate comprises the following steps:
(1) adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into a reaction kettle, stirring uniformly, then sequentially dropwise adding a mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran, reacting at 55 ℃ until the mass concentration of the 4-cyano-3-trifluoromethylaniline/(R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide is less than or equal to 15%, then adding water and toluene, layering, collecting an organic phase, concentrating and crystallizing to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methacrylamide 2-methylpropionamide, the chemical reaction formula is as follows:
adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into a reaction kettle in the step (1), wherein the mass ratio of the (R) -3-bromo-2-hydroxy-2-methylpropanoic acid to the N, N-dimethylformamide to the tetrahydrofuran is 3 kg: 12 kg: 8.01 kg; after uniformly stirring, sequentially dropwise adding a mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran, wherein the mass ratio of the thionyl chloride to the N, N-diisopropylethylamine to the 4-cyano-3-trifluoromethylaniline to the tetrahydrofuran is as follows: 2.34kg, 2.76kg, 8.01 kg; the mass ratio of the (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, the thionyl chloride, the water and the toluene is 3kg, 2.34kg, 6kg and 7.8 kg.
The concentration in the step (1) is to wash the organic phase, combine the organic phase and concentrate the organic phase by reduced pressure distillation until no distillate is obtained, thus obtaining (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropionamide crude product, wherein the mass ratio of water to thionyl chloride in the washing is 6 kg: 2.34kg, the crystallization is to add toluene into the concentrated (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropionamide crude product, the mass ratio of the toluene to tetrahydrofuran is 15.6 kg: 8.01kg, cool and stir the mixture for 2 to 3h, filter the obtained filter cake after filtration, wash the filter cake with toluene, the mass ratio of the toluene to tetrahydrofuran is 3.9 kg: 8.01kg, drying the filter cake to obtain the crystallized R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide.
(2) Adding isopropanol into a reaction kettle, and adding the (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl group obtained in the step (1)]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3Stirring and heating to reflux, reacting to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]The mass concentration of the (E) -3-bromo-2-hydroxy-2-methylpropanamide/(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide is less than or equal to 1 percent, then methyl tert-butyl ether and water are added for stirring and layering, an organic phase is taken, the organic phase is collected, concentrated and crystallized to obtain the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, and the chemical reaction formula is as follows:
in the step (2), isopropanol and (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3Methyl tert-butylThe mass ratio of the butyl ether to the water is as follows: 7.79 kg: 3.3 kg: 1.18 kg: 1.98 kg: 17.09 kg: 16.5 kg.
The concentration in the step (2) is to add water into the organic phase for layering, and concentrate the organic phase by reduced pressure distillation until no distillate is generated, thus obtaining (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide crude product, the mass ratio of the added water to the isopropanol is 16.5 kg: 7.79kg, the crystallization is to add toluene and methyl tert-butyl ether, the mass ratio of the toluene to the methyl tert-butyl ether to the isopropanol is 8.58 kg: 0.73 kg: 7.79kg, the temperature is raised and the stirring is carried out, the temperature is reduced and the crystallization is carried out, the stirring is carried out for 2.5h, the suction filtration is carried out, the filter cake is washed by toluene, the mass ratio of the toluene to the isopropanol is 2.87 kg: 7.79kg, and the drying is carried out for 3.5h at the temperature of 45 ℃, thus obtaining the crystallized (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4- 2-hydroxy-2-methylpropionamide.
(3) Under the protection of nitrogen, nicotinic acid and toluene are added into a reaction kettle and heated to reflux, 12 percent of toluene is evaporated, oxalyl chloride is cooled to 60 ℃, the temperature is raised to 120 ℃, the mixture is stirred for 2.5h, then (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide obtained in the step (2) is added, triethylamine is added, and the mixture is heated and refluxed until (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide/(S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) - Cooling after 2-methyl-1-oxoprop-2-yl nicotinate is less than or equal to 1 percent, adding water and ethyl acetate, stirring and layering, collecting the upper organic phase, concentrating and refining to obtain (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate,
the chemical reaction formula is as follows:
in the step (3), the mass ratio of nicotinic acid, toluene, oxalyl chloride, (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, triethylamine, water and ethyl acetate is as follows: 2.53 kg: 27.71 kg: 1.37 kg: 2 kg: 4.16 kg: 13 kg: 11.72 kg.
The concentration in the step (3) is to add silica gel into an organic phase, the mass ratio of the silica gel to triethylamine is 2 kg: 4.16kg, stir uniformly, filter and wash, then add silica gel into a filtrate, the mass ratio of the silica gel to the triethylamine is 2 kg: 4.16kg, stir, filter, wash and concentrate under reduced pressure, the refining is to add isopropanol into the concentrated concentrate, the mass ratio of the isopropanol to the triethylamine is 6.28 kg: 4.16kg, stir and heat up to 45 ℃, add activated carbon, the mass ratio of the activated carbon to the triethylamine is 0.2 kg: 4.16kg, stir uniformly, filter and wash, drop water into the filtrate, the mass ratio of the water to the triethylamine is 10 kg: 4.16kg, cool to 25 ℃, stir for 2.5h, drop water, the mass ratio of the water to the triethylamine is 4 kg: 4.16kg, cool to 0-10 ℃, stir for 2.5h, filter, wash a filter cake with water, the mass ratio of the water to the triethylamine is 2: 4.16kg, the filter cake was collected and dried at 50 ℃ to give refined (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-ylnicotinate.
Further comprising a step (4) of adding the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate obtained in the step (3) and isopropanol into a reaction kettle, uniformly stirring, filtering, washing with purified water for six times, and drying to obtain purified (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate,
the chemical reaction formula is as follows:
the mass ratio of the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate to the isopropanol to the purified water for the first washing, the purified water for the second washing, the purified water for the third washing, the purified water for the fourth washing, the purified water for the fifth washing and the purified water for the sixth washing is 0.91kg to 2.86kg to 1.82kg to 0.91kg to 1.82kg to 3.64kg to 0.91 kg. To obtain (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate with a yield of 89.9%.
Test example 1:
(S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate, prepared in example 2, of formula: c25H17F3N4O4Molecular weight: 494.43.
subjecting to NMR spectroscopy with VARIAN 400 NMR spectrometer with deuterated chloroform (CDCl)3) The results are shown in table 1 below and fig. 1:
TABLE 1 nuclear magnetic resonance1H spectrum data column
Table:
as can be seen from table 1 above and from figure 1,1the H spectrum shows 12 groups of 17 hydrogens; hydrogen at δ 9.31 is a group of single peaks, the number of protons is 1, and the assignment is hydrogen at position 12; hydrogen at delta 8.78-8.80 is a group of multiple peaks, and the total number of protons is 1: ascribed to hydrogen at position 28; the hydrogen at delta 8.55 is a group of single peaks, the proton number is 1, and the assignment is 26-position hydrogen; hydrogen at delta 8.08 is a group of single peaks, the proton number is 1, the assignment is 14-position hydrogen, delta 8.32-8.33, 7.94-7.95, 7.81-7.83, 7.50-7.59 are multiple groups of peaks, the proton number is 6, the assignment is 2, 6, 17, 18, 29, 30-position hydrogen; the hydrogen at delta 6.96-6.98 is a group of doublets, the number of protons is 2, and the assignment is the hydrogen at 3, 5 positions; hydrogen at delta 4.60-4.83 is a group of multiplets, the number of protons is 2, and the assignment is 9-position hydrogen; the hydrogen at δ 2.01 is a group of single peaks, the number of protons is 3, and the assignment is to be a hydrogen at position 22. Thus, the NMR data for (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate prepared in example 1 are consistent with the chemical structure.
Test example 2:
NMR carbon Spectroscopy of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate prepared in example 1 using a BRUKERAV-300 NMR spectrometer in deuterated chloroform (CDCl)3) The results are shown in table 2 below and fig. 2:
TABLE 2 NMR13C spectral data List
As can be seen from Table 2 above and FIG. 2, the molecular structure of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate has 25 carbons, and the product thereof13The C spectrum shows 25 groups of carbon peaks, consistent with its molecular structure.
Wherein, the carbon peak of delta 168.90 can be assigned as 11-position carbon; a carbon peak of δ 163.67, assignable to carbon 24; a carbon peak of δ 161.01, assignable as carbon at position 4; carbons of δ 153.92, 150.69, 141.60, 137.61, 135.75, 134.12, 134.00, 133.74, 133.48, 125.42, 123.71, 123.09, 122.63, 118.70, 117.99, 117.96, 115.44, which can be assigned to positions I, 2, 6, 7, 13, 14, 15, 16, 17, 18, 19, 20, 25, 26, 28, 29, 30; δ 105.10, carbon 14.72, assignable as carbons at positions 3, 5; δ 82.64, assignable to carbon number 10; δ 69.77, which can be assigned to carbon 9; a carbon peak of δ 20.25, assignable to carbon 22; therefore, the nuclear magnetic resonance carbon spectrum data of the product is consistent with the chemical structure of the product.
Test example 3:
mass spectrometry of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate prepared in example 2 using a Waters ACQULTY QDa Mass spectrometer with ESI as the ion source and ESI as the mass spectrometry measurement]+Having a mass to charge ratio m/z of493, a spectrum shown in FIG. 3, obtained from the above, and determined to correspond to the molecular weight of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate (molecular formula C25H17F3N4O4, molecular weight 494), and the chemical structure of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate corresponds to that of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy).
Test example 4:
infrared spectroscopy of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate prepared in example 2 was performed using a Perkin Elmer Spectrum 400, compressed with KBr, and the results are given in Table 3 and FIG. 4.
TABLE 3 Infrared Spectrum data List
As shown in Table 3 and FIG. 4, 3426cm-1 is NH stretching vibration absorption of amide, indicating that the structure contains amide group; 1605cm-1、1507cm-1、1428cm-1The stretching vibration absorption of the aromatic ring C-H is realized, and the aromatic ring is contained in the description structure; 2228cm-1The deformation vibration absorption of cyano C [ identical to ] N shows that the structure contains cyano; 1731cm-1The structure contains an ester group, which is a deformation shock absorption of C ═ O in the ester group. The product prepared in example 2 corresponds to the chemical structure of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate, as described above.
Test example 5:
the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate obtained in example 2 was subjected to UV spectroscopy using Shimadzu UV-2450 in acetonitrile as solvent, and the results are shown in Table 4 and FIG. 5.
Table 1 ultraviolet spectra data tabulation
As shown by table 4 above and fig. 5, in acetonitrile solution: λ max is 270.00nm, 248.50nm, 195.50 nm. The ultraviolet absorption spectrum of lambda min-258.50 nm and 229.00nm shows that the product contains ester and amide structures. The above UV spectral data correspond to the structure of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate.
Claims (8)
- A process for the synthesis of (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate comprising the steps of:(1) adding (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide and tetrahydrofuran into a reaction kettle, stirring uniformly, then sequentially dropwise adding a mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran, reacting at 50-60 ℃ until the mass concentration of the 4-cyano-3-trifluoromethylaniline/(R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide is less than or equal to 12-18%, then adding water and toluene, layering, collecting an organic phase, concentrating and crystallizing to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-methylpropanamide -2-hydroxy-2-methylpropanamide;(2) adding isopropanol into a reaction kettle, and adding the (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl group obtained in the step (1)]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3Stirring and heating to reflux, reacting to obtain (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]The mass concentration of the 3-bromo-2-hydroxy-2-methylpropionamide/(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide is less than or equal to 0.5-2%, methyl tert-butyl ether and water are added for stirring and layering, an organic phase is taken, the organic phase is collected, concentrated and crystallized to obtain (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide;(3) under the protection of nitrogen, adding nicotinic acid and toluene into a reaction kettle, heating to reflux, distilling off and adding 10-15% of the total mass of the toluene, cooling to 40-60 ℃, dropwise adding oxalyl chloride, heating to 100 ℃ and 120 ℃, stirring for 2-3h, then adding the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide obtained in the step (2), dropwise adding triethylamine, heating to reflux and reacting until the mass concentration of the (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide/(S) -1- ((4-cyano-3- (trifluoromethyl) And (2) after the mass concentration of the phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate is less than or equal to 0.5-2%, cooling, adding water and ethyl acetate, stirring for layering, collecting an upper organic phase, concentrating and refining to obtain the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate.
- 2. The method for synthesizing (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate according to claim 1, wherein in step (1) (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide, tetrahydrofuran are added to a reaction vessel, and the mass ratio of (R) -3-bromo-2-hydroxy-2-methylpropanoic acid, N-dimethylformamide, tetrahydrofuran is 1-5 kg: 10-15 kg: 6-10 kg; after being uniformly stirred, the mixed solution of thionyl chloride, N-diisopropylethylamine, 4-cyano-3-trifluoromethylaniline and tetrahydrofuran is sequentially dripped, and the mass ratio of the thionyl chloride, the N, N-diisopropylethylamine, the 4-cyano-3-trifluoromethylaniline and the tetrahydrofuran is 1-4 kg: 6-10 kg; the mass ratio of the (R) -3-bromine-2-hydroxyl-2-methylpropanoic acid, the thionyl chloride, the water and the toluene is 1-5kg, 1-4kg, 2-8kg, 5-9 kg.
- 3. The method of synthesizing (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate of claim 1, wherein isopropanol, (R) -N- [ 4-cyano-3- (trifluoromethyl) benzene in step (2)Base of]-3-bromo-2-hydroxy-2-methylpropionamide, 4-cyanophenol, Na2CO3The mass ratio of the methyl tert-butyl ether to the water is as follows: 5-9kg, 1-4kg, 0.5-3kg, 15-19kg, and 14-18 kg.
- 4. The method for synthesizing (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate according to claim 1, wherein the mass ratio of nicotinic acid, toluene, oxalyl chloride, (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, triethylamine, water and ethyl acetate in step (3) is: 1-4kg, 25-30kg, 0.5-3kg, 1-4kg, 2-6kg, 10-15kg, 9-12 kg.
- 5. The method for synthesizing (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2-yl nicotinate according to claim 1, wherein the concentration in step (1) is carried out by washing the organic phase with water, combining the organic phase and concentrating the organic phase by reduced pressure distillation to obtain the crude (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropanamide, the mass ratio of the water to the thionyl chloride in the washing is 2-8 kg: 1-4kg, and the crystallization is carried out to obtain the concentrated (R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-methyl-2-oxopropan-yl nicotinate Adding toluene into the crude product of the-bromo-2-hydroxy-2-methylpropionamide, wherein the mass ratio of the toluene to the tetrahydrofuran is 10-20 kg: 6-10kg, cooling and stirring for 2-3h, filtering to obtain a filter cake, washing the filter cake with toluene, wherein the mass ratio of the toluene to the tetrahydrofuran is 1-5 kg: 6-10kg, and drying the filter cake to obtain the crystallized R) -N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3-bromo-2-hydroxy-2-methylpropionamide.
- 6. The method for synthesizing (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate according to claim 1, wherein the concentration in step (2) is to add water to the organic phase for separation and to concentrate to no distillate by distillation under reduced pressure to obtain a crude product of (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide, the mass ratio of the added water to the isopropanol is 12-20 kg: 5-10kg, the crystallization is to add toluene and methyl tert-butyl ether, the mass ratio of the toluene to the methyl tert-butyl ether to the isopropanol is 6-10 kg: 0.5-2 kg: 5-9kg, the mixture is heated and stirred, cooled and crystallized, stirred for 2-3h, filtered, the filter cake is washed by the toluene, the mass ratio of the toluene to the isopropanol is 1-4 kg: 5-9kg, and the mixture is dried for 3-4h at the temperature of 40-50 ℃ to obtain the crystallized (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-cyanophenoxy) -2-hydroxy-2-methylpropionamide.
- 7. The method for synthesizing (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate according to claim 1, wherein the concentration in step (3) is performed by adding an organic phase to silica gel having a mass ratio of 1-4 kg: 2-6kg to triethylamine, stirring uniformly, filtering and washing, adding silica gel having a mass ratio of 1-4 kg: 2-6kg to the filtrate, stirring, filtering, washing, and concentrating under reduced pressure, the purification is performed by adding isopropanol having a mass ratio of 4-8 kg: 2-6kg to the concentrate after concentration, stirring and heating to 40-50 ℃, adding active carbon, wherein the mass ratio of the active carbon to triethylamine is 0.1-4 kg: 2-6kg, stirring uniformly, filtering, washing, dripping water into filtrate, wherein the mass ratio of the water to the triethylamine is 8-12 kg: 2-6kg, cooling to 20-30 ℃, stirring for 2-3h, dripping water, wherein the mass ratio of the water to the triethylamine is 2-6 kg: 2-6kg, cooling to 0-10 ℃, stirring for 2-3h, filtering, washing filter cakes with water, wherein the mass ratio of the water to the triethylamine is 1-4 kg: 2-6kg, collecting the filter cakes, drying at 40-70 ℃ to obtain refined (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxopropan-2 -a nicotinate ester.
- 8. The method for synthesizing (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate according to claim 1, further comprising the step (4) of adding the (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3- (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate obtained in the step (3) and isopropanol to a reaction kettle, stirring them uniformly and filtering them, washing them with purified water, and drying them to obtain the purified (S) -1- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -3-yl nicotinate - (4-cyanophenoxy) -2-methyl-1-oxoprop-2-yl nicotinate.
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