CN102358725B - Preparation method of intermediate of isoxazole compound - Google Patents
Preparation method of intermediate of isoxazole compound Download PDFInfo
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- CN102358725B CN102358725B CN 201110346676 CN201110346676A CN102358725B CN 102358725 B CN102358725 B CN 102358725B CN 201110346676 CN201110346676 CN 201110346676 CN 201110346676 A CN201110346676 A CN 201110346676A CN 102358725 B CN102358725 B CN 102358725B
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Abstract
The invention relates to a preparation method of an important intermediate 2-amino-N-2,2,2-trifluoroethyl acetamide (IV) and its salts for preparing isoxazole compounds, and the method adopts N-butoxycarbonyl glycine as a raw material, and obtains the product through several steps of routine reactions.
Description
Technical field:
The present invention relates to a kind of important intermediate 2-amino-N-2 of isoxazole class compound, the preparation method of 2,2-trifluoroethyl ethanamide (IV) and salt thereof.
Background technology:
2-amino-N-2,2,2-trifluoroethyl ethanamide is the important intermediate of a class isoxazole class compound, is widely used in fields such as people's medication, agricultural chemicals, veterinary drug, especially for preparation isoxazoles veterinary drug, this type of veterinary drug is mainly as sterilant, miticide.
Patent documentation WO2010070068 discloses the preparation method of the trifluoroacetate of compound (IV).It is raw material that document adopts the N-t-butoxycarbonyl glycine, makes catalyzer with phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus (PyBOP), in the presence of alkali, carries out condensation with trifluoro ethamine.Its shortcoming is the PyBOP expensive price, be difficult for buying, and the amount that needs is very big, the ingredient proportion of it and raw material N-t-butoxycarbonyl glycine is 3.26: 1 (weight ratio), the yield in this step has only 53%, and then under normal condition, take off tertbutyloxycarbonyl (Boc) with trifluoroacetic acid, obtain product.
Summary of the invention:
At the problem that above-mentioned prior art exists, the object of the invention is to provide the preparation method of a kind of compound (IV), and this method has overcome the defective of prior art, has improved yield, has saved cost, makes it to have more the advantage of suitability for industrialized production.
The invention provides the preparation method of compound (IV),
It is characterized in that: adopt N-t-butoxycarbonyl glycine (I) to be raw material, in the presence of alkali, this alkali is preferably organic bases, as N-methylmorpholine, triethylamine, diisopropylethylamine etc., carry out condensation reaction with relatively cheap isobutyl chlorocarbonate that is easy to get, obtain compound (II).Compound (II) is without purifying, and direct and trifluoro ethamine reaction obtains compound (III).Compound (III) again with common acid, tertbutyloxycarbonyl (Boc) is taken off in reactions such as example hydrochloric acid, sulfuric acid, trifluoroacetic acid, obtains product (IV).
Specific embodiment:
Embodiment 1
The preparation of N-t-butoxycarbonyl glycine (I)
Add sodium hydroxide solution (containing 25g sodium hydroxide) in reaction flask, 40g glycine and 200g tetrahydrofuran (THF) add tert-Butyl dicarbonate 130g again, and stirring reaction to raw material disappears, solvent evaporated, re-adjustment PH＜6.Use dichloromethane extraction, anhydrous sodium sulfate drying filters, and solvent evaporated gets white solid 92.5g, and yield is that 94.3%, HPLC purity is 95.2%.
Embodiment 2
[(2,2,2-trifluoroethyl formamyl)-methyl]-carboxylamine tertiary butyl ester
Add 40g compound (I) in reaction flask, the 400g methylene dichloride is cooled to-30 ℃, adds the 28gN-methylmorpholine, drips the 37g isobutyl chlorocarbonate again, insulation reaction 2 hours.Drip 25g trifluoro ethamine (diluting with methylene dichloride) again in the reaction system of above-mentioned inclusion compound (II), the HPLC monitoring reacts completely, add saturated aqueous common salt again and told basic phase, washing, drying is filtered, filtrate steams solvent, obtain white solid 54.5g, yield 95.7%, HPLC purity is 97.8%.
Embodiment 3
2-amino-N-2, the preparation of the hydrochloride (IV-a) of 2,2-trifluoroethyl ethanamide (IV)
Add compound (III) 50g in reaction flask, methylene dichloride 200g stirs and is cooled to 20 ℃.Another reaction flask adds 35g sodium-chlor, the 80g concentrated hydrochloric acid, drip the 125g vitriol oil again, the hydrogen chloride gas of generation is by after the drying, feeds in the above-mentioned reaction flask that contains compound (III), middle control reacts completely, refilter washing, the dry hydrochloride 34.6g that gets compound (IV), yield is that 93%, HPLC purity is 98.7%
Embodiment 4
2-amino-N-2, the preparation of 2,2-trifluoroethyl ethanamide (IV)
In reaction flask, add the 19.5g compound (IV-a) with ethanolic soln 100mL 1N sodium hydroxide, stirring at room 3h filters, washing, the filtrate evaporate to dryness obtains light yellow oil 14.6g (2-amino-N-2,2,2-trifluoroethyl ethanamide), yield is 93.6%, and purity is 99.8%.
Claims (5)
1. the preparation method of a formula (III) compound,
This method comprises: the reaction of compound and trifluoro ethamine shown in the formula (II), obtain formula (III) compound,
2. method according to claim 1,
The preparation method who it is characterized in that compound shown in the formula (II) is: under the alkali existence condition, and the reaction of compound and isobutyl chlorocarbonate shown in the formula (I) and make formula (II) compound,
。
3. according to each described method of claim 1-2, it is characterized in that compound (II) does not pass through purifying, directly carries out next step reaction.
4. according to each described method of claim 1-2, the compound of preparation (III) takes off Boc again and prepares compound (IV) and salt thereof,
5. method according to claim 4 is characterized in that the salt of compound (IV) refers to the hydrochloride of compound (IV).
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201110346676 CN102358725B (en) | 2011-11-04 | 2011-11-04 | Preparation method of intermediate of isoxazole compound |
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| CN 201110346676 CN102358725B (en) | 2011-11-04 | 2011-11-04 | Preparation method of intermediate of isoxazole compound |
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| CN102358725A CN102358725A (en) | 2012-02-22 |
| CN102358725B true CN102358725B (en) | 2013-08-14 |
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| CN 201110346676 Active CN102358725B (en) | 2011-11-04 | 2011-11-04 | Preparation method of intermediate of isoxazole compound |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020222158A1 (en) * | 2019-04-30 | 2020-11-05 | Hikal Limited | Process for the preparation of 2-amino-n-(2,2,2-trifluoroethyl)-acetamide and salts thereof |
| CN114014784A (en) * | 2021-12-10 | 2022-02-08 | 许昌学院 | Novel chiral or achiral monofluoroethylamine compound, preparation method and application |
| CN115772091B (en) * | 2023-01-05 | 2023-06-23 | 济南久隆医药科技有限公司 | Synthesis method of 2-amino-N- (2, 2-trifluoroethyl) acetamide |
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| JP5403205B2 (en) * | 2007-10-29 | 2014-01-29 | 日産化学工業株式会社 | Process for producing 2-amino-N- (2,2,2-trifluoroethyl) acetamide compound or a salt thereof |
| HUE015568T4 (en) * | 2008-12-19 | 2017-10-30 | Elanco Tiergesundheit Ag | Isoxazoline derivatives and their use as pesticide |
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Non-Patent Citations (1)
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| JP特开2009-173621A 2009.08.06 |
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