CN108727212B - Synthesis of mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide - Google Patents
Synthesis of mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide Download PDFInfo
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Abstract
The invention discloses a synthesis method of a mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenyl acetamide, which comprises the steps of firstly carrying out esterification reaction on R-mandelic acid and triphosgene in a solvent in the presence of alkali to generate an lactide intermediate I; and then carrying out acylation reaction on the intermediate I and 4-nitrophenylethylamine in a solvent to obtain a target product. The synthesis method avoids using expensive EDCI and HOBt, has the advantages of easily obtained raw materials, low cost, simple operation and less impurities, and is suitable for industrial production.
Description
Technical Field
The invention relates to a synthesis method of a mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, belonging to the field of drug synthesis.
Background
Mirabegron belongs to an aromatic ethanolamine receptor agonist and is approved to be on the market by the U.S. Food and Drug Administration (FDA) at 6 months of 2012. Mirabegron was developed by astela medicine (astella) japan, and the pharmaceutical company, san francisco, (later incorporated into astela medicine) filed a patent for the compound of mirabegron in japan 10.17 days 1997, and the chemical structure of mirabegron is as follows:
the patent (EP1440969, EP1559427, WO2015044965A1) relates to a method for synthesizing a mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, wherein R-mandelic acid raw material reacts with 4-nitrophenylethylamine hydrochloride to obtain (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, and the specific synthetic route is as follows:
at present, the route is a main method for synthesizing the mirabegron intermediate (II), R-mandelic acid can be reacted in one step to obtain the intermediate (II), but in the first condensation reaction method A, expensive 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and N-hydroxybenzotriazole (HOBt) are used, and a plurality of condensation byproducts are generated, and after-treatment, water washing, acid washing, alkali washing, hydrochloric acid washing and toluene recrystallization are needed, so that the toxicity is high, the after-treatment steps are complicated, and a large amount of three wastes are easily generated. In the method B, the condensation yield is low, the product purity is not high, the chemical purity of the intermediate (I) reported in WO2015044965A1 is 98.65%, and the post-treatment is complicated.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a synthesis method of a mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide. The synthesis method avoids using expensive EDCI and HOBt, has the advantages of easily obtained raw materials, low cost, simple operation and less impurities, and is suitable for industrial production.
The synthesis of the mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide comprises the following steps:
s1, esterification: carrying out esterification reaction on R-mandelic acid and triphosgene in a solvent in the presence of alkali to generate a lactide intermediate I;
s2, acylation reaction: and carrying out acylation reaction on the intermediate I and 4-nitrophenylethylamine in a solvent to obtain a target product.
The synthesis of the mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide specifically comprises the following steps:
s1, esterification: adding R-mandelic acid, alkali, triphosgene and solvent into a three-neck flask, reacting for 5-8h at 15-30 ℃, and controlling the reaction by TLC (thin layer chromatography); cooling to room temperature after the reaction is finished, concentrating the solvent in vacuum, adding ethyl acetate and water into the residue, stirring for half an hour, standing for layering, drying an organic phase, and concentrating to obtain a white solid, namely an intermediate I;
s2, acylation reaction: dissolving the intermediate I in a solvent, adding 4-nitrophenylethylamine, reacting at 40-70 ℃, after TLC (thin layer chromatography) controlled reaction, cooling to room temperature, concentrating the solvent in vacuum, adding methanol for dissolving at 50 ℃, naturally cooling for crystallization for 12 hours, filtering, washing with methanol, and drying to obtain a target product, namely the mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, which is a white solid.
In step S1, the solvent is one or more of acetonitrile, DMF, DMSO, acetone, THF, and 1, 4-dioxane, wherein the preferred solvent is acetonitrile.
In step S1, the base is one or more of potassium carbonate, triethylamine, pyridine, DMAP, and DIEA, wherein the preferred base is triethylamine.
In step S1, the reaction temperature is 25 ℃ and the reaction time is 6 h.
In step S1, the molar ratio of R-mandelic acid to triphosgene is 1.0: 1.0-1.2, preferably 1.0: 1.1; the molar ratio of the R-mandelic acid to the base is 1.0: 2.0-2.2, preferably 1.0: 2.1.
In step S2, the solvent is one or more of acetonitrile, DMF, DMSO, acetone, THF, and 1, 4-dioxane, and preferably the solvent is acetone.
In step S2, the reaction temperature was 56 ℃.
In step S2, the molar ratio of the intermediate I to the 4-nitrophenylethylamine is 1.0:1.0 to 1.2, preferably 1.0: 1.1.
The synthetic route of the invention is as follows:
the invention has the beneficial effects that:
the invention uses cheap and easily obtained R-mandelic acid as raw material to react with triphosgene to obtain an intermediate I with a yield of 99%; the intermediate I reacts with 4-nitrophenylethylamine to generate a target product, the yield is 91%, and the purity is 99.73%.
The method avoids using expensive EDCI and HOBt and generating a large amount of industrial wastewater, reduces the production cost, has simple and convenient operation, simple post-treatment, less impurities, high yield and high industrial operation feasibility, and is beneficial to large-scale industrial production.
Detailed Description
Example 1:
preparation of intermediate I: under mechanical stirring, adding 15.2g R-mandelic acid, 22.2g triethylamine and 32.5g triphosgene 150mL acetonitrile into a 250mL three-necked bottle, reacting for 6h at 25 ℃, cooling to room temperature after TLC controlled reaction is finished, filtering, concentrating the solvent in vacuum, adding 150mL ethyl acetate and 150mL water into the residue, stirring for half an hour, standing for layering, drying the organic phase, and concentrating to obtain a white solid 17.7g, namely an intermediate I, with the yield of 99%.1H NMR(400MHz,CDCl3)d 6.02(s,1H),7.40-7.46(m,5H)。
Preparation of a target product: dissolving 8.9g of the intermediate I in 90mL of acetone, adding 9.1g of 4-nitrophenylethylamine, reacting for 3 hours at 56 ℃, after TLC (thin layer chromatography) control reaction is finished, concentrating the solvent at room temperature in vacuum, adding 30mL of methanol, dissolving at 50 ℃, naturally cooling, crystallizing for 12 hours, filtering, washing with 15mL of methanol, and drying to obtain 13.6g of white solid, namely the labetalone intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, wherein the yield is 91% and the purity is 99.73%.1H NMR(400MHz,CDCl3)8.04(d,J＝8.6Hz,2H),7.31(ddd,J＝7.2,5.9,3.4Hz,5H),7.15(d,J＝8.6Hz,2H),6.34(s,1H),4.95(d,J＝3.4Hz,1H),3.75(d,J＝3.5Hz,1H),3.62–3.42(m,2H),2.95–2.77(m,2H).
Example 2:
preparation of intermediate I: under the mechanical stirring, 30g R-mandelic acid, 60g potassium carbonate and 65g triphosgene 300mL DMF are added into a 500mL three-necked bottle, the mixture reacts for 5 hours at the temperature of 30 ℃, TLC (thin layer chromatography) is used for controlling the reaction to be finished, the mixture is cooled to room temperature, filtered, the solvent is concentrated in vacuum, 300mL ethyl acetate and 300mL water are added into the residue, the mixture is stirred for half an hour, the mixture is kept stand for layering, the organic phase is dried, and the white solid 35.5g, namely the intermediate I, is obtained by concentration, and the yield is 99.
Preparation of a target product: dissolving 18g of the intermediate I in 150mL of THF, adding 18.2g of 4-nitrophenylethylamine, reacting for 3 hours at 40 ℃, after TLC controlled reaction is finished, concentrating the solvent at room temperature in vacuum, adding 60mL of methanol, dissolving at 50 ℃, naturally cooling, crystallizing for 12 hours, filtering, washing with 30mL of methanol, and drying to obtain 13.7g of white solid, namely the mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, wherein the yield is 92% and the purity is 99.78%.
Example 3:
preparation of intermediate I: under mechanical stirring, 30g R-mandelic acid, 26g DMAP and 65g triphosgene 300mL acetonitrile are added into a 500mL three-necked bottle, the mixture reacts for 8 hours at 15 ℃, TLC is used for controlling the reaction to be finished, the mixture is cooled to room temperature, filtered, the solvent is concentrated in vacuum, 300mL ethyl acetate and 300mL water are added into the residue, the mixture is stirred for half an hour, the mixture is kept stand for layering, the organic phase is dried, and the white solid 35.5g, namely the intermediate I, is obtained by concentration, and the yield is 99%.
Preparation of a target product: dissolving 18g of the intermediate I in 150mL of acetonitrile, adding 18.2g of 4-nitrophenylethylamine, reacting at 70 ℃ for 3 hours, after TLC (thin layer chromatography) controlled reaction is finished, concentrating the solvent in vacuum at room temperature, adding 60mL of methanol, dissolving at 50 ℃, naturally cooling and crystallizing for 12 hours, filtering, washing with 30mL of methanol, and drying to obtain 13.4g of white solid, namely the labetalone intermediate (R) -2-hydroxy-N- (4-nitrophenyl ethyl) -2-phenyl acetamide, wherein the yield is 92% and the purity is 99.31%.
Although the present invention has been described with reference to the specific embodiments, it should be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Claims (7)
1. The synthesis of the mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide is characterized by comprising the following steps:
s1, esterification: adding R-mandelic acid, alkali, triphosgene and solvent into a three-neck flask, reacting for 5-8h at 15-30 ℃, and controlling the reaction by TLC (thin layer chromatography); cooling to room temperature after the reaction is finished, concentrating the solvent in vacuum, adding ethyl acetate and water into the residue, stirring for half an hour, standing for layering, drying an organic phase, and concentrating to obtain a white solid, namely an intermediate I;
s2, acylation reaction: dissolving the intermediate I in a solvent, adding 4-nitrophenylethylamine, reacting at 40-70 ℃, after TLC (thin layer chromatography) controlled reaction is finished, cooling to room temperature, concentrating the solvent in vacuum, adding methanol for dissolving at 50 ℃, naturally cooling and crystallizing for 12 hours, filtering, washing with methanol, and drying to obtain a target product;
in the step S1, the molar ratio of R-mandelic acid to triphosgene is 1.0: 1.0-1.2; the molar ratio of the R-mandelic acid to the alkali is 1.0: 2.0-2.2;
in step S2, the molar ratio of the intermediate I to the 4-nitrophenylethylamine is 1.0: 1.0-1.2.
2. The synthesis of claim 1, wherein:
in step S1, the solvent is one or more of acetonitrile, DMF, DMSO, acetone, THF, and 1, 4-dioxane.
3. The synthesis of claim 1, wherein:
in step S1, the base is one or more of potassium carbonate, triethylamine, pyridine, DMAP, and DIEA.
4. The synthesis of claim 1, wherein:
in step S1, the reaction temperature is 25 ℃ and the reaction time is 6 h.
5. The synthesis of claim 1, wherein:
in step S1, the molar ratio of R-mandelic acid to triphosgene is 1.0: 1.1; the molar ratio of R-mandelic acid to base was 1.0: 2.1.
6. The synthesis of claim 1, wherein:
in step S2, the solvent is one or more of acetonitrile, DMF, DMSO, acetone, THF, and 1, 4-dioxane.
7. The synthesis of claim 1, wherein:
in step S2, the reaction temperature was 56 ℃.
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| CN105801438A (en) * | 2016-04-12 | 2016-07-27 | 济南大学 | Synthetic method of mirabegron intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105801438A (en) * | 2016-04-12 | 2016-07-27 | 济南大学 | Synthetic method of mirabegron intermediate |
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| (1-Naphthyl)(trifluoromethyl) O-Carboxy Anhydride as a Chiral Derivatizing Agent: Eclipsed Conformation Enforced by Hydrogen Bonding;Olivier Thillaye du Boullay等;《ORGANIC LETTERS》;20080925;第10卷(第20期);4669-4672 * |
| An efficient synthetic approach towards fully functionalized tetronic acids: the use of 1,3-dioxolane-2,4-diones as novel protected-activated synthons of a-hydroxy acids;Kyriakos C. Prousis等;《Tetrahedron》;20150910(第71期);8637-8648 * |
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