CN107353222A - The method for preparing 2 amino Ns (2,2,2 trifluoroethyl) acetamide - Google Patents
The method for preparing 2 amino Ns (2,2,2 trifluoroethyl) acetamide Download PDFInfo
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- CN107353222A CN107353222A CN201710546605.4A CN201710546605A CN107353222A CN 107353222 A CN107353222 A CN 107353222A CN 201710546605 A CN201710546605 A CN 201710546605A CN 107353222 A CN107353222 A CN 107353222A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The method for preparing 2 amino Ns (2,2,2 trifluoroethyl) acetamide and its salt.2 amino Ns (2 of preparation of the present invention; 2; 2 trifluoroethyls) acetamide and its salt method; it is the glycine and trifluoroethylamine or its reactant salt generation acid amides using the protection of N phthalyls; protection group, which is sloughed, under hydrazine hydrate effect obtains 2 amino Ns (2; 2; 2 trifluoroethyls) acetamide crude product; the crude product can obtain 2 amino Ns (2 with acid through salt-forming reaction; 2,2 trifluoroethyls) acetamide salt, finally again plus alkali dissociates 2 pure amino Ns (2; 2,2 trifluoroethyls) acetamide.The deprotection reaction reagent price that the present invention uses is cheap, simple to operate, it is not necessary to uses inflammable and explosive hydrogen, reaction temperature can be achieved from room temperature to solvent reflux temperature, and reaction condition is gentle, is very suitable for the production of commercial plant.
Description
Technical field
The present invention is the method on preparing 2- amino-N- (2,2,2- trifluoroethyl) acetamides and its salt.
Background technology
2- amino-N- (2,2,2- trifluoroethyl) acetamide, is generally stabilized, is synthesizing new wide spectrum in a salt form
Desinsection veterinary drug fluorine thunder Rana（fluralaner）Key intermediate.Fluorine thunder Rana belongs to isoxazolines animal pesticides, passes through
Disturb γ-aminobutyric acid（GABA）Gate chloride channel plays a role, with phenyl pyrazoles, cyclopentadiene and macrolide
The animal pesticides such as class are compared, and in molecular structure, action site, selectivity and cross resistance etc., there were significant differences,
With to mammalian safe, insecticidal activity is high the characteristics of.
At present, E.I.Du Pont Company is reported on 2- amino-N- (2,2,2- trifluoro second in the patent CN103124721B of China
Base) acetamide two synthetic routes（Route 1 and route 2）.
Route 1：
This route is using N- carbobenzoxyglycines as raw material and condensing agent carbonyl dimidazoles（CDI）, the intermediate of formation without
It need to separate directly with trifluoroethylamine hydrochloric acid reactant salt, it is via the hydrogenolysis with hydrogen to remove the benzyl protecting group particularly useful method
Effect, it need to generally use noble metal catalyst and carry out hydrogenolysis in the case where pressurization is passed through hydrogen, also solid supported noble metal can be used to urge
Agent and hydrogen donor（That is ammonium formate or cyclohexadiene）Realized by hydrogen migration, the best way is urged by hydrogen and palladium carbon
The combination of change removes this protection group.
Route 2：
Chloracetyl chloride under -5 to 0 DEG C of temperature conditionss, is added drop-wise to trifluoroethylamine by this route using chloracetyl chloride as initiation material
In the mixture of carbonic acid alkali（Using ethyl acetate and the mixed solvent of water）Stirring reaction, obtained chloroacetamide, then with two
Benzylamine using methanol as solvent, is heated to reflux, finally under the conditions of tertiary amine base, such as after addition triethylamine or diisopropylethylamine
The benzyl is removed with hydrogen hydrogenolysis, hydrogenolysis needs to carry out at a temperature of 5~10MPa pressure and 50~80 DEG C.
Two synthetic routes of the patent report are required for using noble metal catalyst in the protection group on sloughing amino,
Catalyst it is expensive, meanwhile, also need to carry out in compressive reaction kettle using inflammable and explosive hydrogen in reaction, it is seen then that should
Synthetic route is harsher in large-scale production conditional, there is the problem of essential safety and higher cost, in produce reality
In have certain limitation.
The content of the invention
Present invention aims at provide a kind of 2- amino-N- (2,2,2- trifluoroethyl) acetamide（Compound 1）And its salt
Preparation method, to improve the deficiency of above-mentioned route.
To achieve these goals, the method that the present invention uses is as follows：
The method for preparing 2- amino-N- (2,2,2- trifluoroethyl) acetamide, 2- amino-N- (2,2,2- trifluoroethyl) acetamide
Chemical structural formula（1）For：
Methods described includes：
In the basic conditions, using phthalyl glycine（2）,
With trifluoroethylamine（3）Or the salt of trifluoroethylamine carries out amidation process under action of coupling agents,
Generate 2-（1,3- dioxo -1,3- DIHYDRO-ISOINDOL -2- bases）- N- (2,2,2- trifluoroethyl)-acetamide（4）,
Then deprotection reaction is carried out, sloughs phthalyl, obtains the crude product of compound 1, then obtained into salt refining with acid
To the salt of compound 1, the salt of compound 1 most afterwards through plus alkali after dissociate pure compound 1.
In the basic conditions, it is to need to add under conditions of organic base, organic base is pyridine, piperidines, N, N- dimethyl benzenes
One or more of mixtures in amine, triethylamine, diisopropylethylamine, N-methylmorpholine.
3rd, the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 1, its feature
It is, the acid group in the salt of compound 3 includes Cl-、SO4 2-、NO3 -、H2PO4 -、CH3COO-、HCOO-。
The coupling agent is condensing agent or carboxylic acid activating agent.
Coupling agent is condensing agent or carboxylic acid activating agent, and condensing agent is carbodiimide class N, N'- dicyclohexylcarbodiimide
(DCC), N, N'- DIC (DIC), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate
And salt 2- (7- azos BTA)-N, N, N', (EDC.HCl) N'- tetramethylurea hexafluorophosphoric acid esters（HATU）, O- benzene
And triazole-tetramethylurea hexafluorophosphoric acid ester (HBTU), hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl（PyBOP）
In one or more of mixtures.
Coupling agent is condensing agent or carboxylic acid activating agent, carboxylic acid activating agent's N, N'- carbonyl dimidazoles (CDI), mesyl chloride,
In paratoluensulfonyl chloride, 4-Nitrobenzenesulfonyl chloride, thionyl chloride, chlorination sulfone, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene
One or more of mixtures.
When condensing agent is carbodiimide class, need to add catalyst in reaction, catalyst is DMAP
(DMAP), 4- pyrollidinopyridines（4-PPY）, one or more of mixtures in I-hydroxybenzotriazole (HOBT).
The solvent of amidation process is dichloromethane, chloroform, dichloroethanes, N,N-dimethylformamide, methanol, second
One or more of mixtures in alcohol, isopropanol, ethyl acetate, acetonitrile.
Deprotection reaction reagent is hydrazine hydrate or its arbitrary proportion mixture with water,
The solvent of deprotection reaction is one or more of mixtures in ethanol, methanol, isopropanol.
Advantages of the present invention：The present invention is anti-using the glycine and trifluoroethylamine or its salt of N- phthalyls protection
Acid amides should be generated, sloughing protection group under hydrazine hydrate effect obtains the crude product of 2- amino-N- (2,2,2- trifluoroethyl) acetamide,
The crude product can obtain the salt of 2- amino-N- (2,2,2- trifluoroethyl) acetamide with acid through salt-forming reaction, finally add alkali to dissociate again
Go out pure 2- amino-N- (2,2,2- trifluoroethyl) acetamide.The deprotection reaction reagent price that the present invention uses is cheap, operation
Simply, it is not necessary to use inflammable and explosive hydrogen, reaction temperature can be achieved from room temperature to solvent reflux temperature, reaction condition temperature
Be very suitable for the production of commercial plant.
Embodiment
The following example is only used for the description of the invention, definitely not limits the invention.
Embodiment one：
1）2-（1,3- dioxo -1,3- DIHYDRO-ISOINDOL -2- bases）- N- (2,2,2- trifluoroethyl)-acetamide（Compound 4）
Preparation
By phthalyl glycine（5.00 g, 0.024 mol）It is dissolved in DMAP (0.44 g, 0.0036 mol)
200ml dichloromethane, less than 0 DEG C is cooled to, adds DCC (5.59 g, 0.0288 mol), stirring reaction 30 minutes at 0 DEG C
Afterwards, trifluoroethylamine hydrochloride is added（3.52 g, 0.026 mol）And triethylamine（6.7 ml, 0.048 mol）, continue
React 12 hours at room temperature.Less than 0 DEG C is cooled to, is filtered to remove white precipitate, filtrate is washed with 200ml, separates organic phase, nothing
Water magnesium sulfate is dried, and filtering, is concentrated crystallization, is obtained 4.25g compounds 4 (yield 60.9%).1H NMR(DMSO-d6) ：8.94
(tr, J=6.0Hz, 1H), 7.94-7.88(m, 4H), 4.29(s, 2H), 3.99-3.90(m, 2H)。
2) 2- amino-N- (2,2,2- trifluoroethyl) acetamide（Compound 1）Preparation
Compound 4 is added in reaction bulb（4 g, 0.014 mol）, 100ml ethanol and 80% hydrazine hydrate（1.3 ml,
0.021mol）, after stirring 24 hours at room temperature, it is filtered to remove white precipitate, filtrate rotates to dry to obtain white solid.It is solid to white
80ml ethyl acetate is added in body, is stirred at room temperature 1 hour, is filtered to remove insoluble matter, hydrogen chloride gas is passed through into filtrate, is analysed
Go out white flock crystal.Filtering, obtain the hydrochloride of compound 1.
The hydrochloride of compound 1 is dissolved in 20ml water, pH values are adjusted to 9~10,40ml with saturated sodium carbonate solution
Ethyl acetate is extracted, and organic phase is dried with anhydrous magnesium sulfate, filtering, rotates to dry to obtain 1.87g compounds 1 (yield 85.7%).1H
NMR(DMSO-d6)：9.25(tr,J=6.0Hz, 1H), 8.30(s, 3H), 4.04-3.95(m, 2H), 3.64(s,
2H)。
Embodiment two：
1）2-（1,3- dioxo -1,3- DIHYDRO-ISOINDOL -2- bases）- N- (2,2,2- trifluoroethyl)-acetamide（Compound 4）
Preparation
By phthalyl glycine（5.00 g, 0.024 mol）100ml DMFs are dissolved in, it is different to add two
Propylethylamine（12.5ml, 0.072mol）And HATU（13.69g, 0.036mol）, stirring reaction after 1 hour at room temperature, then
Add trifluoroethylamine（2.38g, 0.024 mol）, continue to react 18 hours at room temperature.Revolving removes solvent, adds 100ml
Ethyl acetate is stirred 30 minutes, is washed with 300ml, separates organic phase, and anhydrous magnesium sulfate is dried, and filtering, is concentrated crystallization, is obtained
5.12g compounds 4 (yield 73.4%).
2) preparation of 2- amino-N- (2,2,2- trifluoroethyl) acetamide
Compound 4 is added in reaction bulb（4.58 g, 0.016 mol）, 160ml ethanol and 40% hydrazine hydrate（4.0 ml,
0.032mol）, after stirring 8 hours at 40 DEG C, white precipitate is filtered to remove, filtrate rotates to dry to obtain white solid.It is solid to white
100ml ethyl acetate is added in body, is stirred at room temperature 1 hour, is filtered to remove insoluble matter, hydrogen chloride gas is passed through into filtrate, is analysed
Go out white flock crystal.Filtering, obtain the hydrochloride of compound 1.
The hydrochloride of compound 1 is dissolved in 25ml water, pH values are adjusted to 9~10 with saturated sodium carbonate solution, with 50
Ml ethyl acetate is extracted, and organic phase is dried with anhydrous magnesium sulfate, filtering, rotates to dry to obtain 2.21g compounds 1（Yield 88.6%）.
Embodiment three：
1）2-（1,3- dioxo -1,3- DIHYDRO-ISOINDOL -2- bases）- N- (2,2,2- trifluoroethyl)-acetamide（Compound 4）
Preparation
By phthalyl glycine（5.00 g, 0.024 mol）Be dissolved in 200ml ethyl acetate, add CDI (3.89 g,
0.024 mol), after stirring 1 hour at room temperature, add triethylamine（5.0 ml, 0.036mol）With trifluoroethylamine hydrochloride
（3.52 g, 0.026 mol）, continue to react 12 hours at room temperature.Reacted with 50ml 1N hydrochloric acids, separate organic phase,
Washed with 200ml, anhydrous magnesium sulfate is dried, and filtering, revolving removes solvent, obtains 5.13g compounds 4 (yield 73.5%).
2) 2- amino-N- (2,2,2- trifluoroethyl) acetamide（Compound 1）Preparation
Compound 4 is added in reaction bulb（4.58 g, 0.016 mol）, 60ml methanol and 80% hydrazine hydrate（1.3 ml,
0.021mol）, after stirring 24 hours at room temperature, it is filtered to remove white precipitate, filtrate rotates to dry to obtain white solid.It is solid to white
80ml ethyl acetate is added in body, is stirred at room temperature 1 hour, is filtered to remove insoluble matter, hydrogen chloride gas is passed through into filtrate, is separated out
White flock crystal.Filtering, obtain the hydrochloride of compound 1.
The hydrochloride of compound 1 is dissolved in 20ml water, pH value is adjusted to 9~10,40ml second with saturated sodium carbonate solution
Acetoacetic ester is extracted, and organic phase is dried with anhydrous magnesium sulfate, filtering, rotates to dry to obtain 1.78g compounds 1 (yield 71.3%).
Claims (10)
1. prepare the method for 2- amino-N- (2,2,2- trifluoroethyl) acetamide, 2- amino-N- (2,2,2- trifluoroethyl) acetyl
The chemical structural formula of amine（1）For：
It is characterized in that methods described includes：
In the basic conditions, using phthalyl glycine（2）,
With trifluoroethylamine（3）Or the salt of trifluoroethylamine carries out amidation process under action of coupling agents,
Generate 2-（1,3- dioxo -1,3- DIHYDRO-ISOINDOL -2- bases）- N- (2,2,2- trifluoroethyl)-acetamide（4）,
Then deprotection reaction is carried out, sloughs phthalyl, obtains the crude product of compound 1, then obtained into salt refining with acid
To the salt of compound 1, the salt of compound 1 most afterwards through plus alkali after dissociate pure compound 1.
2. the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 1, its feature exist
In, in the basic conditions, be need add organic base under conditions of, organic base be pyridine, piperidines, DMA, three
One or more of mixtures in ethamine, diisopropylethylamine, N-methylmorpholine.
3. the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 1, its feature exist
In the acid group in the salt of compound 3 includes Cl-、SO4 2-、NO3 -、H2PO4 -、CH3COO-、HCOO-。
4. the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 1, its feature exist
In the coupling agent is condensing agent or carboxylic acid activating agent.
5. the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 4, its feature exist
In, coupling agent be condensing agent or carboxylic acid activating agent, condensing agent be carbodiimide class N, N'- dicyclohexylcarbodiimide (DCC),
N, N'- DIC (DIC), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl)
With salt 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters（HATU）, O- BTAs-
Tetramethylurea hexafluorophosphoric acid ester (HBTU), hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl（PyBOP）In one kind
Or several mixture.
6. the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 4, its feature exist
In, coupling agent be condensing agent or carboxylic acid activating agent, carboxylic acid activating agent's N, N'- carbonyl dimidazoles (CDI), mesyl chloride, to first
One kind in benzene sulfonyl chloride, 4-Nitrobenzenesulfonyl chloride, thionyl chloride, chlorination sulfone, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene
Or several mixture.
7. the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 5, its feature exist
In, when condensing agent is carbodiimide class, needed in reaction add catalyst, catalyst be DMAP (DMAP), 4-
Pyrollidinopyridine（4-PPY）, one or more of mixtures in I-hydroxybenzotriazole (HOBT).
8. the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 1, its feature exist
In the solvent of, amidation process be dichloromethane, it is chloroform, dichloroethanes, DMF, methanol, ethanol, different
One or more of mixtures in propyl alcohol, ethyl acetate, acetonitrile.
9. the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 1, its feature exist
In deprotection reaction reagent is hydrazine hydrate or its arbitrary proportion mixture with water.
10. the method for preparation 2- amino-N- (2,2,2- trifluoroethyl) acetamide according to claim 1, its feature exist
In the solvent of deprotection reaction is one or more of mixtures in ethanol, methanol, isopropanol.
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Cited By (6)
| 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 |
| CN113121383A (en) * | 2021-04-22 | 2021-07-16 | 江苏慧聚药业有限公司 | Related substances of Aforana and frailana synthesized building blocks and synthesis method thereof |
| CN114057594A (en) * | 2020-07-31 | 2022-02-18 | 广东东阳光药业有限公司 | Process for preparing 2-amino-N- (2,2, 2-trifluoroethyl) acetamide or its salt |
| CN114414678A (en) * | 2021-12-27 | 2022-04-29 | 丽珠集团新北江制药股份有限公司 | Analysis method for related impurities of isoxazoline veterinary drug intermediate ammonium salt |
| CN115772091A (en) * | 2023-01-05 | 2023-03-10 | 济南久隆医药科技有限公司 | Synthesis method of 2-amino-N- (2, 2-trifluoroethyl) acetamide |
| TWI821107B (en) * | 2022-01-28 | 2023-11-01 | 日商日本曹達股份有限公司 | Method for producing amide compounds |
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| JP2009173621A (en) * | 2007-10-29 | 2009-08-06 | Nissan Chem Ind Ltd | Method for producing 2-amino-n-(2,2,2,-trifluoroethyl)acetamide compound or salt thereof |
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2017
- 2017-07-06 CN CN201710546605.4A patent/CN107353222A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009173621A (en) * | 2007-10-29 | 2009-08-06 | Nissan Chem Ind Ltd | Method for producing 2-amino-n-(2,2,2,-trifluoroethyl)acetamide compound or salt thereof |
Cited By (7)
| 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 |
| CN114057594A (en) * | 2020-07-31 | 2022-02-18 | 广东东阳光药业有限公司 | Process for preparing 2-amino-N- (2,2, 2-trifluoroethyl) acetamide or its salt |
| CN113121383A (en) * | 2021-04-22 | 2021-07-16 | 江苏慧聚药业有限公司 | Related substances of Aforana and frailana synthesized building blocks and synthesis method thereof |
| CN114414678A (en) * | 2021-12-27 | 2022-04-29 | 丽珠集团新北江制药股份有限公司 | Analysis method for related impurities of isoxazoline veterinary drug intermediate ammonium salt |
| TWI821107B (en) * | 2022-01-28 | 2023-11-01 | 日商日本曹達股份有限公司 | Method for producing amide compounds |
| CN115772091A (en) * | 2023-01-05 | 2023-03-10 | 济南久隆医药科技有限公司 | Synthesis method of 2-amino-N- (2, 2-trifluoroethyl) acetamide |
| 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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