CN103396380A - Preparation method of (E)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic aid - Google Patents
Preparation method of (E)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic aid Download PDFInfo
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Abstract
The invention provides a preparation method of (E)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic aid. The method comprises the following steps: carrying out an oximation reaction of 2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide derivative with nitrite under the catalysis of hydrochloric acid, carrying out an etherification reaction of the obtained substance with an ethylating reagent in the presence of an alkali, and hydrolyzing the obtained material in the alkali to prepare (E)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic aid. The preparation method has the advantages of less reactions steps, mild conditions, simple operation, good reaction selectivity, high yield, large scientific research and enforcement values, and large social and economic benefits.
Description
(1) technical field
The present invention relates to the trans body of a kind of ceftaroline side-chain acid---the preparation method of (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid.
(2) background technology
The qualitative and quantitative analysis of medicine and related impurities thereof is an important step of modern pharmaceutical engineering field; The success of impurity of the drug is synthetic can make the analysis of medicine and related impurities thereof more accurate, quick.Impurity of the drug has the characteristics such as added value is high, profit large, small scale as commodity selling.Cynnematin, because its special chemical structure causes its chemical stability poor, easily produces the characteristics such as impurity in synthetic and storage process.In the cynnematin that contains oximido series side chain, (E)-oximido cephalo isomer is the important impurity in the cynnematin production process.The cynnematin impurity that tradition contains (E)-oximido series side chain is mainly obtained by the method for its Z-type isomer by illumination, and there are the shortcomings such as by product is more, content is not ideal enough in the method.
CPT (Ceftaroline) belong to the 5th generation cephalosporin analog antibiotic, by Japan's military field pharmacy (Takeda Pharmaceutical) company exploitation, and examine and ratifies it and go on the market in the U.S. by U.S. FDA in October, 2010.Similar with other cynnematin that contains oximido series side chain, the trans body of CPT (E-isomer of Ceftaroline) is one of important potential impurity during CPT is produced,
(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I) is one of key intermediate for preparing the trans body of CPT to the trans body of ceftaroline side-chain acid---(E)-2-.At present, less about the synthetic method bibliographical information of the trans body of ceftaroline side-chain acid (I), associated document mainly contains:
1, document J.Antibiot., 1984,27 (5): 557-571 has reported take ethoxycarbonyl carbonamidine hydrobromate as raw material, through six steps such as cyclization, amino acidylate, oxidation, carbonyl imidization, alkaline hydrolysis, makes the trans body of ceftaroline side-chain acid.The trans body of ceftaroline side-chain acid prepared by the method finally only obtains with by-product form, and yield is lower, is unfavorable for a large amount of preparations.
2, Bull.Chem.Soc.Jpn., 1994,67,1701-1707 has reported so that (5-amino-1,2,4-thiadiazoles-3-yl)-methyl acetate derivative is starting raw material, through oximate, methylate, be hydrolyzed and obtain the trans body of Cefozopran side-chain acid---and (5-amino-1 for-(E)-2-, 2,4-thiadiazoles-3-yl)-2-methoxy imino guanidine-acetic acid.
(3) summary of the invention
The objective of the invention is to overcome the shortcoming of prior art, synthesis step is few, reaction conditions is gentle, selectivity is better, yield is higher, be easy to the preparation method of the trans bodies of ceftaroline side-chain acid of preparation in a large number to provide one.
The preparation method of a kind of (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid as shown in the formula (I) of the present invention design, its reaction formula is as follows:
The preparation method that the present invention adopts comprises the steps:
(1) (5-amino-1 by the 2-shown in formula (II), 2, 4-thiadiazoles-3-yl) acetamide derivative, mass concentration is that 30%～37% mixed in hydrochloric acid is in organic solvent A, in (at preferred 25 ℃～40 ℃ temperature) at 25 ℃～65 ℃ temperature, drip nitrous acid ester R-O-N=O, insulation reaction, TLC follows the tracks of and detects to reacting completely, gained reaction solution a concentrating under reduced pressure (concentrating under reduced pressure at 25 ℃～65 ℃ temperature usually), to remove excessive nitrous acid ester and to reclaim organic solvent A, in residuum, add organic solvent B, alkaline matter and ethylization reagent, at 5 ℃～60 ℃ temperature, (at preferred 20 ℃～40 ℃ temperature) carry out etherification reaction, TLC follows the tracks of and detects to reacting completely, gained reaction solution b makes (the E)-2-shown in formula (III) through aftertreatment, and (5-amino-1, 2, 4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative, in described nitrous acid ester R-O-N=O, R is C
3～C
6alkyl, described ethylization reagent is monochloroethane, monobromethane, iodoethane or ethyl sulfate, (5-amino-1 for 2-shown in described formula (II), the amount of substance of the HCl that 2,4-thiadiazoles-3-yl) contains in acetamide derivative, hydrochloric acid, nitrous acid ester, alkaline matter, ethylization reagent is than being 1.0:0.05～0.8:1.0～8.0:1.0～10.0:1.0～10.0,
(2) (5-amino-1 for (the E)-2-shown in the formula (III) that step (1) is obtained, 2, the aqueous solution of 4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative and mineral alkali, in 30 ℃～100 ℃ (preferred 60 ℃～90 ℃) reactions that are hydrolyzed, TLC follows the tracks of and detects to reacting completely; Gained reaction solution c makes (the E)-2-shown in formula (I) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid through aftertreatment; (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1:2～20 with the ratio of the amount of substance of mineral alkali to (E)-2-shown in described formula (III);
Formula (II) or (III) in, R
1, R
2Independent separately is C
1～C
6Alkyl, preferred R
1For methyl or tertiary butyl, preferred R
2For methyl.
In described step (1), nitrous acid ester is preferably nitrous acid isopropyl ester or Isopentyl nitrite, more preferably nitrous acid isopropyl ester.
In described step (1), described alkaline matter is one or more the combination in sodium carbonate, salt of wormwood, Quilonum Retard, triethylamine, tri-n-butylamine, pyridine, 2-picoline, piperidines, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, be preferably salt of wormwood or triethylamine, more preferably triethylamine.
In described step (1), described organic solvent A is ethyl acetate, ether, methyl tertiary butyl ether, acetone, 2-butanone, methylene dichloride, trichloromethane, benzene, toluene, 1,1-ethylene dichloride, 1,2-ethylene dichloride, tetrahydrofuran (THF), 1, the combination of one or more arbitrary proportions in the 4-dioxane, be preferably tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or ethyl acetate, most preferably tetrahydrofuran (THF).
In described step (1), described organic solvent B is acetonitrile, 1,4-dioxane, N, dinethylformamide, N, the combination of one or more arbitrary proportions in N-N,N-DIMETHYLACETAMIDE, methyl alcohol, ethanol, the trimethyl carbinol, acetone, tetramethylene sulfone, be preferably acetonitrile or DMF, most preferably acetonitrile.
In described step (1), the quality consumption of organic solvent A is generally 2～15 times of the 2-shown in formula (II) (5-amino-1,2,4-thiadiazoles-3-yl) acetamide derivative quality, preferred 4～10 times.The quality of described organic solvent B is generally 2～15 times of the 2-shown in formula (II) (5-amino-1,2,4-thiadiazoles-3-yl) acetamide derivative quality, preferred 3～10 times.
In described step (1), described ethylization reagent is preferably monobromethane, iodoethane or ethyl sulfate, more preferably monobromethane or ethyl sulfate, most preferably monobromethane.
In described step (1), the temperature of (5-amino-1,2, the 4-thiadiazoles-3-yl) acetamide derivative of the 2-shown in described formula (II) and nitrous acid ester reaction is preferably 25 ℃～40 ℃; The temperature of described etherification reaction is preferably 20 ℃～40 ℃.
In described step (1), (5-amino-1 for 2-shown in formula (II), 2, the amount of substance of the HCl that 4-thiadiazoles-3-yl) contains in acetamide derivative, hydrochloric acid, nitrous acid ester, alkaline matter, ethylization reagent is than being 1.0:0.05～0.8:1.0～8.0:1.0～10.0:1.0～10.0, be preferably 1.0:0.1～0.5:1.5～7.0:1.5～5.0:1.0～5.0, more preferably 1.0:0.1～0.5:1.5～4.0:1.5～4.0:1.0～2.5.
In described step (1), described reaction solution b post-treating method is: after reaction finishes, in reaction solution b, add water and methylene dichloride, standing separatory after stirring, get organic layer drying, evaporated under reduced pressure, make (the E)-2-shown in formula (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative.
In described step (1), in reaction solution b, add water and methylene dichloride, the quality consumption of water is generally 5～15 times of the 2-shown in formula (II) (5-amino-1,2,4-thiadiazoles-3-yl) acetamide derivative quality, preferred 7～12 times.The quality consumption of methylene dichloride is generally 5～15 times of the 2-shown in formula (II) (5-amino-1,2,4-thiadiazoles-3-yl) acetamide derivative quality, preferred 8～12 times.
In described step (2), described mineral alkali is the combination of one or more arbitrary proportions in lithium hydroxide, sodium hydroxide, potassium hydroxide or hydrated barta, is preferably sodium hydroxide or potassium hydroxide, most preferably sodium hydroxide.
In described step (2), in the aqueous solution of described mineral alkali, the mass concentration of mineral alkali is 0.5～30%, and is preferred 5～25%, more preferably 8%～20%.
In described step (2), (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1:2～20 with the ratio of the amount of substance of mineral alkali to (the E)-2-shown in formula (III), is preferably 1:4～10.
In described step (2), (the E)-2-shown in formula (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative and the mineral alkali temperature of reacting that is hydrolyzed is preferably 60 ℃～90 ℃, more preferably 70 ℃～85 ℃.
In described step (2), described reaction solution c post-treating method is: after reaction finishes, reaction solution c is cooled to 0～10 ℃, it with mass concentration, is the pH value to 2～3 of 5%～25% hydrochloric acid conditioned reaction system, there is solid to separate out, suction filtration, filter cake makes (the E)-2-shown in formula (I) through vacuum-drying, and (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid.
In the inventive method, utilize TLC to follow the tracks of the detection reaction process, detect to raw material reaction and get final product fully.General, the time of (5-amino-1,2, the 4-thiadiazoles-3-yl) acetamide derivative of the 2-shown in step (1) Chinese style (II) and nitrous acid ester reaction is generally 1～10 hour; The reaction times of etherification reaction is generally 5～20 hours.In step (2), (the E)-2-shown in formula (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative and mineral alkali reaction times of reacting that is hydrolyzed is generally 10～48 hours.
Further, recommend preparation method of the present invention to carry out in accordance with the following steps:
(1) (5-amino-1 by the 2-shown in formula (II), 2, 4-thiadiazoles-3-yl) acetamide derivative, mass concentration is that 30%～37% mixed in hydrochloric acid is in tetrahydrofuran (THF), at 25 ℃～40 ℃ temperature, drip nitrous acid isopropyl ester, insulation reaction, TLC follows the tracks of and detects to reacting completely, gained reaction solution a concentrating under reduced pressure, in residuum, add acetonitrile, triethylamine and monobromethane, at 20 ℃～40 ℃ temperature, carry out etherification reaction, TLC follows the tracks of and detects to reacting completely, in gained reaction solution b, add water and methylene dichloride, standing separatory after stirring, get the organic layer drying, evaporated under reduced pressure, (5-amino-1 to make (the E)-2-shown in formula (III), 2, 4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative, (5-amino-1 for 2-shown in described formula (II), the amount of substance of the HCl that 2,4-thiadiazoles-3-yl) contains in acetamide derivative, hydrochloric acid, nitrous acid isopropyl ester, triethylamine, monobromethane is than being 1.0:0.1～0.5:1.5～4.0:1.5～4.0:1.0～2.5,
(2) (5-amino-1 for (the E)-2-shown in the formula (III) that step (1) is obtained, 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative mixes with the aqueous sodium hydroxide solution of mass concentration 8%～20%, the reaction that is hydrolyzed at 60 ℃～90 ℃ temperature, TLC follows the tracks of and detects to reacting completely; Gained reaction solution c is cooled to 0～10 ℃, it with mass concentration, is the pH value to 2～3 of 5%～25% hydrochloric acid conditioned reaction system, there is solid to separate out, suction filtration, filter cake makes (the E)-2-shown in formula (I) through vacuum-drying, and (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid; (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1:4～10 with the ratio of the amount of substance of mineral alkali to (E)-2-shown in described formula (III);
In formula (II), (III), R
1For methyl or tertiary butyl, R
2For methyl.
Compared with prior art, beneficial effect of the present invention is embodied in:
A) invent a kind of novel method for preparing the trans body of ceftaroline side-chain acid, had originality.
The stereoselectivity of the trans-isomer(ide) that b) in route of the present invention, oximation reaction generates is higher, intermediate is after simple separation, without further refining, can be directly used in next step hydrolysis reaction, make to higher yields the trans body of ceftaroline side-chain acid, product HPLC content >=98.0%, maleinoid body content<0.5%.
C) raw material is easy to get, easy and simple to handle, reaction conditions is gentle, stereoselectivity is better, yield is higher, has larger scientific research, implementary value and economic results in society.
(4) accompanying drawing explanation
Fig. 1 is the single crystal structure figure that the embodiment of the present invention 1 obtains (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide.
Fig. 2 is that the embodiment of the present invention 1 obtains (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide
1The H-NMR spectrogram.
Fig. 3 is that the embodiment of the present invention 5 obtains (E)-N-ethanoyl-2-(5-acetamido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide
1The H-NMR spectrogram.
Fig. 4 is the trans body of ceftaroline side-chain acid that the embodiment of the present invention 1 obtains--(E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid
1The H-NMR spectrogram.
Fig. 5 is the trans body of ceftaroline side-chain acid that the embodiment of the present invention 1 obtains--the HPLC spectrogram of (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid.
(5) embodiment
Below with specific embodiment, technical scheme of the present invention is described, but protection scope of the present invention is not limited to this; The structural formula of the compound that relates in following examples (IIa), (IIIa), (IIb), (IIIb) is as follows:
Embodiment 1:
(1) synthesizing of (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa)
The 250mL there-necked flask adds N-ethanoyl-2-(5-pivaloyl amido-1 successively, 2,4-thiadiazoles-3-yl) ethanamide (IIa) (25.0g, 0.088mol), mass concentration is 37% hydrochloric acid (1.0g, 0.01mol), tetrahydrofuran (THF) (100g), under constantly stirring, in 25 ℃, drips nitrous acid isopropyl ester (23g, 0.258mol), constant temperature, TLC follows the tracks of, and reacts and reacts completely in 3 hours; In 25 ℃～40 ℃ lower concentrating under reduced pressure, remove excessive nitrous acid isopropyl ester and reclaim tetrahydrofuran (THF), in residuum, add acetonitrile (80g), triethylamine (13.3g, 0.132mol), monobromethane (14.0g, 0.13mol), reaction under 25 ℃, TLC follows the tracks of, and reacts completely in 20 hours; In reaction solution, add water (200g) and methylene dichloride (200g); stirring, standing separatory, organic layer is through anhydrous sodium sulfate drying, filtration, and the filtrate decompression evaporate to dryness obtains (E)-N-ethanoyl-2-(5-pivaloyl amido-1; 2; 4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa), white solid, weight 21.1g; with raw material (IIa), calculate; yield 70.0%, fusing point: 183.5 ℃～185.4 ℃
1H NMR (400MHz, DMSO-d
6) δ (ppm) 12.96 (s, 1H), 10.97 (s, 1H), 4.28 (q, J=7.0Hz, 2H), 2.23 (s, 3H), 1.33 – 1.22 (m, 12H).
1The H-NMR spectrogram is shown in accompanying drawing 2.
(2) synthesizing of (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I)
(E)-N-ethanoyl-2-(the 5-pivaloyl amido-1 that adds step (1) gained in the 500mL there-necked flask, 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa) (21.0g, 0.061mol), mass concentration is 5% NaOH solution (293.6g, 0.367mol), 80 ℃ of stirring reactions, TLC follows the tracks of, and reacts completely in 20 hours; Reaction solution is cooled to 5 ℃, with the hydrochloric acid that mass concentration is 5%, adjusts system pH to 2～3, has solid to separate out, suction filtration, the filter cake of gained obtains (E)-2-through vacuum-drying, and (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I), light yellow solid, weight 9.7g, calculate with intermediate (IIIa), yield 73.0%, fusing point: 147.0 ℃～148.7 ℃, HPLC content 99.0%
1H NMR (400MHz, DMSO-d
6) δ (ppm) 8.14 (s, 2H), 4.18 (q, J=7.0Hz, 2H), 1.19 (t, J=7.0Hz, 3H).
1The H-NMR spectrogram is shown in accompanying drawing 4, and the HPLC spectrogram is shown in accompanying drawing 5.
Embodiment 2:
(1) synthesizing of (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa)
In the 500mL there-necked flask, add successively N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl) ethanamide (25.0g, 0.088mol), mass concentration is in 37% aqueous hydrochloric acid (2.0g, 0.02mol), tetrahydrofuran (THF) (250.0g), under stirring, in 30 ℃, drips nitrous acid isopropyl ester (30.0g, 0.337mol), isothermal reaction, TLC follows the tracks of, and reacts completely in 2.5 hours; Remove tetrahydrofuran (THF) under reduced pressure in 30 ℃, in residuum, add DMF (100g), salt of wormwood (18.0g, 0.132mol), monobromethane (14.0g, 0.13mol), 25 ℃ of reactions, TLC follows the tracks of, and reacts completely in 15 hours; In reaction solution, add water (250g) and methylene dichloride (300g); stirring, standing separatory; organic layer filters after anhydrous sodium sulfate drying, the filtrate decompression evaporate to dryness obtains (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2; 4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa); white solid, 21.6g, calculate with raw material (IIa); yield 72.0%, fusing point: 183.8 ℃～186.0 ℃.
(2) synthesizing of (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I)
In the 250mL there-necked flask, add step (1) gained (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa) (21.6g, 0.0635mol) and mass concentration be 20% NaOH solution (50.4g, 0.253mol), 85 ℃ of reactions, TLC follows the tracks of, and reacts completely in 24 hours; Reaction solution is cooled to 5 ℃, with the hydrochloric acid that mass concentration is 5%, adjusts system pH to 2～3, has solid to separate out, suction filtration, filter cake obtains (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I) through vacuum-drying, light yellow solid, weight 8.6g, calculate yield 62.7% with intermediate (IIIa), fusing point: 147.2 ℃～149.0 ℃, HPLC content 99.0%.
Embodiment 3:
(1) synthesizing of (E)-N-ethanoyl-2-(5-acetamido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIb)
In the 500mL there-necked flask, add successively N-ethanoyl-2-(5-acetamido-1,2,4-thiadiazoles-3-yl) ethanamide (IIb) (21.3g, 0.088mol), mass concentration is 37% hydrochloric acid (1.0g, 0.01mol), tetrahydrofuran (THF) (150.0g), under stirring, in 35 ℃, drips nitrous acid isopropyl ester (15.4g, 0.176mol), 35 ℃ of reactions, TLC follows the tracks of, and reacts completely in 1.5 hours; Remove tetrahydrofuran (THF) under reduced pressure, in residuum, add acetonitrile (150g), triethylamine (13.3g, 0.132mol), monobromethane (14.0g, 0.13mol), 35 ℃ of reactions, TLC follows the tracks of, and reacts completely in 17 hours; In reaction solution, add water (150g) and methylene dichloride (200g); stirring, separatory, organic layer filters after anhydrous sodium sulfate drying, and the filtrate decompression evaporate to dryness obtains (E)-N-ethanoyl-2-(5-acetamido-1; 2; 4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIb), light yellow solid, weight 17.6g; with raw material (IIb), calculate; yield 57.1%, fusing point: 177.3 ℃～179.6 ℃
1H NMR (400MHz, CDCl
3) δ=10.98 (s, 1H), 9.97 (s, 1H), 4.16 (q, J=7.1Hz, 2H), 2.58 (s, 3H), 2.35 (s, 3H), 1.21 (t, J=7.2Hz, 3H).
(2) synthesizing of (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I)
In the 500mL there-necked flask, add step (1) gained (E)-N-ethanoyl-2-(5-acetamido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIb) (17.4g, 0.058mol) and mass concentration be 8%KOH solution (284.0g, 0.406mol), 80 ℃ of reactions, TLC follows the tracks of, and 25h reacts completely; Reaction solution is cooled to 5 ℃, with mass concentration, is that 5% dilute hydrochloric acid is adjusted system pH to 2～3, has solid to separate out, suction filtration, the gained filter cake obtains (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I) through vacuum-drying, light yellow solid, weight 8.8g, calculate yield 70.0% with intermediate (IIIb), fusing point: 147.3 ℃～148.9 ℃, HPLC content 98.1%.
Embodiment 4:
(1) synthesizing of (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa)
In the 500mL there-necked flask, add successively N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl) ethanamide (IIa) (25.0g, 0.088mol), mass concentration are 37% aqueous hydrochloric acid (4.46g, 0.044mol), 1,4-dioxane (250g), under stirring, in 25 ℃, drip Isopentyl nitrite (15.4g, 0.132mol), isothermal reaction, TLC follows the tracks of, and reacts completely in 5 hours; Remove Isosorbide-5-Nitrae-dioxane under reduced pressure, add acetonitrile (250g), triethylamine (35.5g, 0.352mol) and ethyl sulfate (15.2g, 0.11mol), 40 ℃ of reactions, TLC follows the tracks of, and reacts completely in 15 hours; In reaction solution, add water (200g) and methylene dichloride (300g); stirring, separatory; organic layer filters after anhydrous sodium sulfate drying, the filtrate decompression evaporate to dryness obtains (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2; 4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa); white solid, weight 22.5g, calculate with raw material (IIIa); yield 75.0%, fusing point: 183.3 ℃～184.7 ℃.
(2) synthesizing of (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I)
(E)-N-ethanoyl-2-(the 5-pivaloyl amido-1 that adds step (1) gained in the 1L there-necked flask, 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa) (22.5g, 0.066mol) with mass concentration be 10% NaOH solution (396g, 0.99mol), 70 ℃ of reactions, TLC follows the tracks of, and reacts completely in 38 hours; Reaction solution is cooled to 5 ℃, with mass concentration, is that 5% dilute hydrochloric acid is adjusted system pH to 2～3, has solid to separate out, suction filtration, the gained filter cake obtains (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I) through vacuum-drying, light yellow solid, weight 10.3g, calculate yield 72.0% with intermediate (IIIa), fusing point: 147.6 ℃～149.0 ℃, HPLC content 98.8%.
Embodiment 5:
(1) synthesizing of (E)-N-ethanoyl-2-(5-acetamido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIb)
In the 500mL there-necked flask, add successively N-ethanoyl-2-(5-acetamido-1,2,4-thiadiazoles-3-yl) ethanamide (IIb) (21.3g, 0.088mol), mass concentration is 37% aqueous hydrochloric acid (1.73g, 0.0176mol), ethyl acetate (250g), under stirring, in 30 ℃, drips nitrous acid isopropyl ester (39.2g, 0.44mol), 30 ℃ of reactions, TLC follows the tracks of, and reacts completely in 2 hours; Remove ethyl acetate under reduced pressure, in residuum, add acetonitrile (180g), triethylamine (10.8g, 0.107mol), iodoethane (15.2g, 0.097mol), 40 ℃ of reactions, TLC follows the tracks of, and reacts completely in 14 hours; In reaction solution, add water (200g) and methylene dichloride (300g); stirring, separatory; organic layer is through anhydrous sodium sulfate drying, filtration, and the filtrate decompression evaporate to dryness obtains (E)-N-ethanoyl-2-(5-acetamido-1,2; 4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIb); light yellow solid, weight 15.8g, calculate with raw material (IIb); yield 60.0%, fusing point: 176.9 ℃～178.7 ℃.
1The H-NMR spectrogram is shown in accompanying drawing 3.
(2) synthesizing of (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I)
In the 500mL there-necked flask, add step (1) gained (E)-N-ethanoyl-2-(5-acetamido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIb) (15.8g, 0.0528mol) and mass concentration be 15% NaOH solution (140.8g, 0.528mol), 85 ℃ of reactions, TLC follows the tracks of, and reacts completely in 30 hours; Reaction solution is cooled to 5 ℃, with mass concentration, is that 5% dilute hydrochloric acid is adjusted system pH to 2～3, has solid to separate out, suction filtration, filter cake obtains (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I) through vacuum-drying, light yellow solid, weight 3.64g, calculate yield 32.0% with intermediate (IIIb), fusing point: 147.3 ℃～149.1 ℃, HPLC content 99.1%.
Embodiment 6
(1) synthesizing of (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa)
In the 500mL there-necked flask, add successively N-ethanoyl-2-(5-pivaloyl amido-1,2,4-thiadiazoles-3-yl) ethanamide (25.0g, 0.088mol), mass concentration are 37% hydrochloric acid soln (2.6g, 0.0264mol), 1,4-dioxane (250g), under 25 ℃, drip nitrous acid isopropyl ester (54.9g, 0.616mol), constant temperature, TLC follows the tracks of, and reacts and reacts completely in 3 hours; Remove Isosorbide-5-Nitrae-dioxane under reduced pressure, in residuum, add acetonitrile (250g), salt of wormwood (35.9g, 0.264mol), monobromethane (23.8g, 0.22mol), 40 ℃ of reactions, TLC follows the tracks of, and reacts completely in 13 hours; In reaction solution, add water (300g) and methylene dichloride (300g); stirring, separatory; organic layer is through anhydrous sodium sulfate drying, filtration, and the filtrate decompression evaporate to dryness obtains (E)-N-ethanoyl-2-(5-pivaloyl amido-1,2; 4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa); white solid, weight 20.1g, calculate with raw material (IIa); yield 67.0%, fusing point: 183.6 ℃～185.7 ℃.
(2) synthesizing of (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I)
(E)-N-ethanoyl-2-(the 5-pivaloyl amido-1 that adds step (1) gained in the 500mL there-necked flask, 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup ethanamide (IIIa) (20.1g, 0.059mol) with mass concentration be 25% KOH solution (321g, 0.59mol), 80 ℃ of reactions, TLC follows the tracks of, and reacts completely in 28 hours; Reaction solution is cooled to 5 ℃, with mass concentration, is that 5% dilute hydrochloric acid is adjusted system pH to 2～3, has solid to separate out, suction filtration, filter cake obtains (E)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid (I) through vacuum-drying, light yellow solid, weight 9.3g, calculate yield 73.1% with intermediate (IIIa), fusing point: 147.8 ℃～149.4 ℃, HPLC content 98.7%.
Claims (10)
1. the preparation method of (the E)-2-shown in a formula (I) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid, is characterized in that described method comprises the steps:
(1) (5-amino-1 by the 2-shown in formula (II), 2, 4-thiadiazoles-3-yl) acetamide derivative, mass concentration is that 30%～37% mixed in hydrochloric acid is in organic solvent A, at 25 ℃～65 ℃ temperature, drip nitrous acid ester R-O-N=O, insulation reaction, TLC follows the tracks of and detects to reacting completely, gained reaction solution a concentrating under reduced pressure, in residuum, add organic solvent B, alkaline matter and ethylization reagent, at 5 ℃～60 ℃ temperature, carry out etherification reaction, TLC follows the tracks of and detects to reacting completely, gained reaction solution b makes (the E)-2-shown in formula (III) through aftertreatment, and (5-amino-1, 2, 4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative, in described nitrous acid ester R-O-N=O, R is C
3～C
6alkyl, described ethylization reagent is monochloroethane, monobromethane, iodoethane or ethyl sulfate, (5-amino-1 for 2-shown in described formula (II), the amount of substance of the HCl that 2,4-thiadiazoles-3-yl) contains in acetamide derivative, hydrochloric acid, nitrous acid ester, alkaline matter, ethylization reagent is than being 1.0:0.05～0.8:1.0～8.0:1.0～10.0:1.0～10.0,
(2) (5-amino-1 for (the E)-2-shown in the formula (III) that step (1) is obtained, 2, the aqueous solution of 4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative and mineral alkali, the reaction that is hydrolyzed at 30 ℃～100 ℃ temperature, TLC follows the tracks of and detects to reacting completely; Gained reaction solution c makes (the E)-2-shown in formula (I) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid through aftertreatment; (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1:2～20 with the ratio of the amount of substance of mineral alkali to (E)-2-shown in described formula (III);
Formula (II) or (III) in, R
1, R
2Independent separately is C
1～C
6Alkyl.
2. the method for claim 1, it is characterized in that in described step (1), described alkaline matter is one or more the combination in sodium carbonate, salt of wormwood, Quilonum Retard, triethylamine, tri-n-butylamine, pyridine, 2-picoline, piperidines, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide.
3. the method for claim 1, is characterized in that in described step (1), described alkaline matter is salt of wormwood or triethylamine.
4. the method for claim 1, it is characterized in that in described step (1), described organic solvent A is ethyl acetate, ether, methyl tertiary butyl ether, acetonitrile, acetone, 2-butanone, methylene dichloride, trichloromethane, benzene, toluene, 1,1-ethylene dichloride, 1, the combination of one or more arbitrary proportions in 2-ethylene dichloride, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane; Described organic solvent B is the combination of one or more arbitrary proportions in acetonitrile, Isosorbide-5-Nitrae-dioxane, DMF, N,N-dimethylacetamide, methyl alcohol, ethanol, the trimethyl carbinol, acetone, tetramethylene sulfone.
5. the method for claim 1, is characterized in that in described step (2), described mineral alkali is the combination of one or more arbitrary proportions in lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrated barta.
6. the method for claim 1, is characterized in that in described step (2), and in the aqueous solution of described mineral alkali, the mass concentration of mineral alkali is 0.5～30%.
7. the method for claim 1, is characterized in that in described formula (II) or formula (III) R
1For methyl or tertiary butyl, R
2For methyl.
8. the method for claim 1, it is characterized in that in described step (1), described reaction solution b post-treating method is: after reaction finishes, in reaction solution b, add water and methylene dichloride, standing separatory after stirring, get organic layer drying, evaporated under reduced pressure, and (5-amino-1 to make (the E)-2-shown in formula (III), 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative.
9. the method for claim 1, it is characterized in that in described step (2), described reaction solution c post-treating method is: after reaction finishes, reaction solution c is cooled to 0～10 ℃, with mass concentration, is the pH value to 2～3 of 5%～25% hydrochloric acid conditioned reaction system, has solid to separate out, suction filtration, filter cake makes (the E)-2-shown in formula (I) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid through vacuum-drying.
10. the method for claim 1 is characterized in that described method carries out in accordance with the following steps:
(1) (5-amino-1 by the 2-shown in formula (II), 2, 4-thiadiazoles-3-yl) acetamide derivative, mass concentration is that 30%～37% mixed in hydrochloric acid is in tetrahydrofuran (THF), at 25 ℃～40 ℃ temperature, drip nitrous acid isopropyl ester, insulation reaction, TLC follows the tracks of and detects to reacting completely, gained reaction solution a concentrating under reduced pressure, in residuum, add acetonitrile, triethylamine and monobromethane, at 20 ℃～40 ℃ temperature, carry out etherification reaction, TLC follows the tracks of and detects to reacting completely, in gained reaction solution b, add water and methylene dichloride, standing separatory after stirring, get the organic layer drying, evaporated under reduced pressure, (5-amino-1 to make (the E)-2-shown in formula (III), 2, 4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative, (5-amino-1 for 2-shown in described formula (II), the amount of substance of the HCl that 2,4-thiadiazoles-3-yl) contains in acetamide derivative, hydrochloric acid, nitrous acid isopropyl ester, triethylamine, monobromethane is than being 1.0:0.1～0.5:1.5～4.0:1.5～4.0:1.0～2.5,
(2) (5-amino-1 for (the E)-2-shown in the formula (III) that step (1) is obtained, 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative mixes with the aqueous sodium hydroxide solution of mass concentration 8%～20%, the reaction that is hydrolyzed at 60 ℃～90 ℃ temperature, TLC follows the tracks of and detects to reacting completely; Gained reaction solution c is cooled to 0～10 ℃, it with mass concentration, is the pH value to 2～3 of 5%～25% hydrochloric acid conditioned reaction system, there is solid to separate out, suction filtration, filter cake makes (the E)-2-shown in formula (I) through vacuum-drying, and (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetic acid; (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1:4～10 with the ratio of the amount of substance of mineral alkali to (E)-2-shown in described formula (III);
In formula (II), (III), R
1For methyl or tertiary butyl, R
2For methyl.
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