CN110845397B - Synthesis method of maleic acid dimethylindidine impurity - Google Patents
Synthesis method of maleic acid dimethylindidine impurity Download PDFInfo
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- CN110845397B CN110845397B CN201911200384.0A CN201911200384A CN110845397B CN 110845397 B CN110845397 B CN 110845397B CN 201911200384 A CN201911200384 A CN 201911200384A CN 110845397 B CN110845397 B CN 110845397B
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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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
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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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
Abstract
The invention relates to the technical field of impurity synthesis of known compounds, and particularly discloses a synthesis method of a maleic acid dimethindidine impurity H. The synthesis method of the impurity H comprises the following steps: 2- [2- (dimethylamino) ethyl ] -1-indanone and methyl halide are subjected to Hofmann elimination reaction under alkaline conditions to generate a compound 1 (2-vinyl-2, 3-dihydro-1H-indene-1-one); carrying out nucleophilic reaction on the compound 1 and 2-ethylpyridine, and then carrying out addition reaction on the compound 1 and concentrated hydrochloric acid to generate a compound 2 (2- {1- [2- (1-chloroethyl) -1H-inden-3-yl ] ethyl } pyridine); the compound 2 undergoes elimination reaction with sodium methoxide to produce a compound 3 (impurity H). The method for synthesizing the impurity H provided by the invention not only fills the blank of the prior art, but also is simple and high in impurity H content.
Description
Technical Field
The invention relates to the technical field of impurity synthesis of known compounds, in particular to a synthesis method of a maleic acid dimethindidine impurity.
Background
Difindadine maleate was developed by Kurarian Smick company and marketed in the early 60 s of the last century under the trade name of Fenistil and is used for treating pruritus caused by dermatitis, urticaria, insect bites, sunburn and surface burns. Loxofenadine can be administered both locally and systemically. To date, difindidine has been marketed in several countries and regions such as switzerland, spain, portugal, belgium, austria, the netherlands, italy, russia, germany, india and chinese hong kong.
The molecular formula of the maleic acid dimethylinddine is as follows: c20H24N2The chemical name is:
n, N-dimethyl-2- (3- (1- (pyridin-2-yl) ethyl) -1H-inden-2-yl) ethylamine or
N, N-dimethyl-2- (3- (1- (pyridine-2-yl) ethyl) -1H-inden-2-yl) ethanamine with the structural formula:
the impurity H is a main process byproduct impurity discovered by the inventor in the process of synthesizing the maleic acid dimetindedine, and the molecular formula of the impurity is C18H17N，
The structural formula is as follows:
the main principle of its generation:in the reaction process of synthesizing the maleic acid dimethylinddine, C-N bonds are broken through high-temperature reaction to obtain an impurity H.
The quality standard of finished product of raw material medicine established by European Union clearly limits the limit of impurity H, and the content of the impurity H is less than 0.2 percent, so the synthesis method is difficult to synthesize, and no document reports the synthesis method.
The higher content of the impurity H can cause the standard exceeding of the maleic acid dimethylindidine impurity, and the unqualified quality of the finished product is caused. Therefore, the directional synthesis of the impurity and the establishment of an analysis method of the impurity have important significance on the quality control of the maleic acid dimethindidine bulk drug.
Disclosure of Invention
In order to fill the blank in the prior art, the invention aims to provide a synthetic method of a maleic acid dimethindidine impurity, and particularly relates to a synthetic method of an impurity H.
The synthesis method of the impurity H comprises the following steps:
specifically, the method comprises the following steps:
(1) synthesis of Compound 1 (chemical name: 2-vinyl-2, 3-dihydro-1H-inden-1-one)
Dissolving 2- [2- (dimethylamino) ethyl ] -1-indanone in absolute ethyl alcohol, dropwise adding methyl halide (the methyl halide is any one of methyl chloride, methyl bromide and methyl iodide, preferably methyl iodide), precipitating salt, filtering, adding toluene, carrying out reflux reaction for 12-20h at 90-120 ℃ under alkaline conditions (the alkali used in the alkaline conditions is any one of sodium hydroxide, potassium hydroxide and silver oxide, preferably sodium hydroxide, more preferably 20 wt% sodium hydroxide), cooling, filtering, separating filtrate layers, taking organic layers, adding toluene into water layers, extracting, combining the organic layers, drying and concentrating to obtain the compound 1. The proportion of the raw material 2- [2- (dimethylamino) ethyl ] -1-indanone to the halogenated methane is 1mol (1.0-1.15 mol).
(2) Synthesis of Compound 2 (chemical name: 2- {1- [2- (1-chloroethyl) -1H-inden-3-yl ] ethyl } pyridine)
Dissolving 2-ethylpyridine in tetrahydrofuran, dropwise adding 1.0-2.0mol/L (preferably 1.6mol/L) of butyl lithium (preferably n-butyllithium) n-hexane solution at 0-10 ℃ under the protection of nitrogen, and reacting for 1-3h (preferably 2h) after the addition is finished. Dissolving compound 1 in tetrahydrofuran, adding dropwise into the reaction system, reacting at 0-10 deg.C for 5-8 hr (preferably 6 hr), adding dropwise water, quenching, layering, sequentially adding water and concentrated hydrochloric acid to the organic layer, layering, collecting the aqueous layer, and reflux reacting at 60-80 deg.C (preferably 75 deg.C) for 2-4 hr (preferably 3 hr). Cooling, adjusting pH of the reaction solution to 9-10, adding ethyl acetate to extract and layer, drying the organic layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain compound 2. The molar ratio of the raw material compounds 1, 2-ethylpyridine and butyllithium is preferably 1:4: 4.
(3) Synthesis of Compound 3
Uniformly mixing the compound 2, sodium methoxide and methanol, heating to 60-80 ℃ for reaction for 2-4h, cooling, concentrating to remove methanol, adding ethyl acetate and water, stirring, standing for layering, extracting a water layer with ethyl acetate, combining organic layers, drying, concentrating, mixing the obtained oily substance (namely the crude product) with silica gel, wherein the mass ratio of the silica gel to the crude oily substance is preferably 2: adding dichloromethane, uniformly mixing, concentrating to obtain a mixture of a crude product and silica gel, and then separating the concentrated material by column chromatography: silica gel is paved on the lower layer of the silica gel column, and the mass of the silica gel is as follows: the mass ratio of the crude product to the silica gel is 5:1, then the mixture of the crude product and the silica gel is paved, then a layer (preferably 2cm thick) of silica gel is added, and the mixture is compacted; eluting with eluting agent methanol, monitoring by TLC, collecting impurity H eluate, and concentrating under reduced pressure to obtain compound 3 (impurity H); the molar ratio of the compound 2 to the sodium methoxide is preferably 1: 1.85.
Compared with the prior art, the invention has the advantages and beneficial effects that:
1. provides a method for synthesizing an impurity H, and fills the blank in the prior art.
2. The synthesis method of the impurity H is simple, and the obtained impurity H is high in content.
Drawings
Fig. 1 is a graph showing purity of compound 1 prepared in example 1 by HPLC and the results.
Fig. 2 is a graph showing purity of compound 2 prepared in example 1 by HPLC and the results.
Fig. 3 is a graph showing purity of compound 3 prepared in example 1 by HPLC and the results.
FIG. 4 is a drawing of Compound 3 prepared in example 11H-NMR spectrum.
1H NMR(600MHz,DMSO)δ8.68(dd,J＝5.3,1.0Hz,1H),8.12(t,J＝7.2Hz,1H),7.65(d,J＝8.0Hz,1H),7.61–7.53(m,1H),7.42(d,J＝6.9Hz,1H),7.16–7.04(m,3H),6.99(dd,J＝17.2,10.8Hz,1H),5.57(dd,J＝17.2,1.5Hz,1H),5.28(dd,J＝10.7,1.5Hz,1H),4.88(q,J＝7.2Hz,1H),3.62(d,J＝2.1Hz,2H),1.74(d,J＝7.2Hz,3H).
Detailed Description
The applicants will now further describe the synthesis of the present invention in detail with reference to specific examples, but it should be understood that the following examples are only illustrative and not intended to limit the scope of the invention as claimed in the claims.
In the following examples, the starting materials used are commercially available products, and the concentration of concentrated hydrochloric acid is 36 to 38 wt%.
Example 1:
a synthetic method of a maleic acid dimethylindidine impurity H comprises the following steps:
(1) synthesis of Compound 1:
taking 10.0g (0.0492mol) of 2- [2- (dimethylamino) ethyl ] -1-indanone, adding the mixture into a 250mL three-necked bottle, adding 50mL of absolute ethyl alcohol, stirring, dropwise adding 7.2g (0.0507mol) of methyl iodide at room temperature, separating out a solid, filtering, adding the obtained solid into the 250mL three-necked bottle, adding 100mL of toluene, adding 120mL of a 20% sodium hydroxide aqueous solution by mass fraction, heating to 100 ℃, carrying out reflux reaction for 16h, cooling to 20 ℃, filtering out the solid, carrying out layering, adding 50mL of toluene into an aqueous layer, extracting for 1 time, combining organic layers, adding 10g of anhydrous sodium sulfate, drying, and concentrating at 60 ℃ under reduced pressure to obtain 6.8g (0.0430mol) of compound 1. Yield: 87% and 95.60% pure by HPLC.
(2) Synthesis of Compound 2:
18.3g (0.171mol) of 2-ethylpyridine is put into a 250mL three-necked flask, 34mL of tetrahydrofuran is added and stirred to dissolve, 106mL (0.170mol) of n-hexane solution of 1.6mol/L n-butyllithium is slowly dropped under the protection of nitrogen at 0 ℃, and the reaction is carried out for 2h at 5-10 ℃. Taking 6.8g (0.0430mol) of the compound 1, adding 34mL of tetrahydrofuran for dissolving, slowly dropwise adding into a reaction system, reacting for 6h at 5-10 ℃ after dropwise adding, dropwise adding 150mL of water for quenching reaction, layering, adding 60mL of water into an organic layer, dropwise adding 60mL of concentrated hydrochloric acid, stirring, standing, layering, collecting a water layer, heating the water layer to 75 ℃, refluxing, and reacting for 3 h. Cooling to 10 ℃, dropwise adding a 30% sodium hydroxide aqueous solution to adjust the pH of the reaction solution to 9-10, adding 100mL of ethyl acetate, extracting and separating layers, collecting an organic layer, drying the organic layer with 10g of anhydrous sodium sulfate, and concentrating under reduced pressure at 60 ℃ to obtain 11.0g (0.0388mol) of compound 2, wherein the yield is as follows: 90% pure by HPLC 84.75%.
(3) Synthesis of Compound 3:
adding 11.0g (0.0388mol) of compound 2 into a 250mL three-necked flask, adding 12.9g (0.0717mol) of 30 wt% sodium methoxide methanol solution and 40mL of methanol, stirring to dissolve, heating to 70 ℃, reacting for 3h, cooling to 50 ℃, and concentrating under reduced pressure to dryness. Adding 100mL of ethyl acetate and 100mL of water, stirring, standing for layering, extracting a water layer for 1 time by using 50mL of ethyl acetate, combining organic layers, drying by using 10g of anhydrous sodium sulfate, concentrating at 50 ℃ under reduced pressure to obtain 10g of oily matter, adding 20g of silica gel (the silica gel is 200 meshes), adding 100mL of dichloromethane, uniformly mixing, concentrating to dryness, and then carrying out column chromatography separation on the concentrated material: 150g of silica gel is paved on the lower layer of the silica gel column, then a mixed sample of the silica gel and the crude product is paved on the upper layer of the silica gel, a layer of silica gel with the thickness of 2cm is added on the sample, and the sample is compacted; eluting with methanol eluting agent, monitoring by TLC, collecting impurity H eluate, and concentrating under reduced pressure to obtain impurity H, to obtain 6.2g of compound 3(0.0251mol), with yield of 65%, and purity of 98.55% by HPLC.
By subjecting Compound 3 to nuclear magnetic detection1H-NMR spectrum (see FIG. 4) confirmed that the molecular formula and structural formula are:
Claims (3)
1. a method for synthesizing an impurity H, wherein the structural formula of the impurity H is shown in the specification
the methyl halide is any one of methyl chloride, methyl bromide and methyl iodide;
the alkali used in the alkaline condition is any one of sodium hydroxide, potassium hydroxide and silver oxide;
the synthesis method comprises the following steps:
(1) synthesis of Compound 1
Dissolving 2- [2- (dimethylamino) ethyl ] -1-indanone in absolute ethyl alcohol, dropwise adding methyl halide, separating out salt, filtering, adding toluene, carrying out reflux reaction at 90-120 ℃ for 12-20h under an alkaline condition, cooling, filtering, layering filtrate, taking an organic layer, drying and concentrating to obtain a compound 1;
(2) synthesis of Compound 2
Dissolving 2-ethylpyridine in tetrahydrofuran, dropwise adding 1.0-2.0mol/L butyl lithium n-hexane solution at 0-10 ℃ under the protection of nitrogen, and reacting for 1-3h after the addition is finished; dissolving compound 1 in tetrahydrofuran, dropwise adding into a reaction system, reacting at 0-10 deg.C for 5-8h, dropwise adding water, quenching, reacting, layering, sequentially adding water and concentrated hydrochloric acid into an organic layer, layering, collecting a water layer, and reflux-reacting at 60-80 deg.C for 2-4 h; cooling, adjusting pH of the reaction solution to 9-10, adding ethyl acetate, extracting and layering, drying the organic layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain compound 2;
(3) synthesis of Compound 3
Uniformly mixing a compound 2, sodium methoxide and methanol, heating to 60-80 ℃, reacting for 2-4h, cooling, concentrating to remove methanol, adding ethyl acetate and water, stirring, standing for layering, extracting a water layer with ethyl acetate, combining organic layers, drying, concentrating, mixing the obtained oily matter with silica gel, wherein the mass ratio of the silica gel to the oily matter is 2:1, adding dichloromethane, uniformly mixing, concentrating to obtain a mixture of a crude product and the silica gel, and then separating the mixture of the concentrated crude product and the silica gel by column chromatography: silica gel is paved on the lower layer of the silica gel column, and the mass of the silica gel is as follows: the mass ratio of the crude product to the mixture of silica gel is 5:1, then the mixture of the crude product and the silica gel is paved, then a layer of silica gel is added, and the mixture is compacted; eluting with eluting agent methanol, monitoring by TLC, collecting impurity H eluate, and concentrating under reduced pressure to obtain compound 3, i.e. impurity H;
in the step (1), the molar ratio of the 2- [2- (dimethylamino) ethyl ] -1-indanone to the halogenated methane is 1: (1.0-1.15), wherein the molar ratio of the compound 1, the 2-ethylpyridine and the butyl lithium in the step (2) is 1:4:4, wherein the molar ratio of the compound 2 to the sodium methoxide in the step (3) is 1: 1.85.
2. the synthesis method according to claim 1, wherein the alkali used in the alkaline condition in the step (1) is sodium hydroxide.
3. The method according to claim 1, wherein the butyllithium in the step (2) is n-butyllithium.
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