CN105330612A - Synthesis process of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid - Google Patents
Synthesis process of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid Download PDFInfo
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- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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Abstract
The invention relates to a synthesis process of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid. With cyanoacetamide serving as a starting material, 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid is obtained through a hydroxyl oximation reaction, a methylation reaction, a cyclization reaction, a nitrile hydrolysis reaction and the like. Particularly, due to the fact that hydroxyapatite is added in the fifth step to serve as a catalyst, the yield of the intermediate product 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetonitrile and the total yield of the final product 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid can be effectively increased, and compared with the total yield not exceeding 9% in the prior art, the total yield of the technical scheme reaches 13% or so and is substantially increased; cost is lowered; industrial large-scale application is facilitated.
Description
Technical field
The present invention relates to a kind of synthesis technique of Cefozopran intermediate, be specifically related to the synthesis technique of a kind of 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid.
Background technology
Cefozopran (Cefozopran) is forth generation cephalosporins, broad-spectrum antibacterial action is had to gram-negative bacteria and gram positive organism, particularly there is potent antibacterial effect to the various bacteriums of Cordycepps in staphylococcus, streptococcus, intestines, influenza, have the faecalis of resistance to most cynnematin, green pus bacterium also has stronger antimicrbial power.2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetic acid be synthesis Cefozopran important intermediate, therefore, therefore 2-(5-amino-1 is studied, 2,4-thiadiazoles-3-base) the significant and using value of the synthetic method of-2-methoxyimino acetic acid.
The people such as Lu Hongguo (" synthesis of 2-(5-amino-1; 2; 4-thiadiazoles-3-base)-2-methoxyimino acetic acid ", " Chinese practical medical magazine ", 7th volume the 9th phase in 2007) disclose a kind of 2-(5-amino-1,2,4-thiadiazoles-3-base) synthetic method of-2-methoxyimino acetic acid, take malonamide nitrile as starting raw material, through hydroxyl oximate, methylate, cyclization, the obtained 2-of the reaction such as nitrile solution (5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetic acid, total recovery 8.8%.
A kind of 2-(5-amino-1 is prior art discloses although above-mentioned, 2,4-thiadiazoles-3-base) synthesis technique of-2-methoxyimino acetic acid, can meet certain needs, but in process of the present invention, contriver finds that the technical scheme of above-mentioned prior art also comes with some shortcomings and shortcoming, such as total recovery only has 8.8%, yield is on the low side, causes cost high, is unfavorable for industrial large-scale application.
Therefore, the synthesis technique for 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid exists and further improves and optimize demand, and this is the power that is accomplished of the present invention and starting point place just.
Summary of the invention
In order to overcome the above-mentioned technical problem that prior art exists, after a large amount of further investigations, thus provide a kind of 2-(5-amino-1,2,4-thiadiazoles-3-base) synthesis technique of-2-methoxyimino acetic acid, total recovery obtains and significantly improves, and reduces cost, is conducive to industrial large-scale application.
The synthesis technique of a kind of 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid, comprises the following steps:
Step one, adds malonamide nitrile, Sodium Nitrite and water in reaction flask, be warming up to 30 ~ 35 DEG C, stirs, temperature control 30 ~ 35 DEG C drips glacial acetic acid, and drip and finish, 30 ~ 35 DEG C are reacted, then room temperature is chilled to, suction filtration, dry light yellow solid 2-hydroxyl oximido-2-Malonamide nitrile;
Step 2, adds 2-hydroxyl oximido-2-Malonamide nitrile, water, sodium carbonate and methyl alcohol in reaction flask, stir, drip methyl-sulfate at 10 ~ 15 DEG C, drip to finish and react at 20 ~ 25 DEG C, be chilled to less than 15 DEG C, suction filtration, dry pink solid 2-methoxyimino-2-Malonamide nitrile;
Step 3, adds 2-methoxyimino-2-Malonamide nitrile, anhydrous sodium sulphate and acetonitrile in reaction flask, stir, drip phosphorus oxychloride at being no more than 30 DEG C, drip and finish, back flow reaction, be chilled to room temperature, reaction solution is poured in frozen water, dichloromethane extraction, sodium hydrogen carbonate solution washing organic phase, anhydrous sodium sulfate drying, suction filtration, is concentrated into dry, obtains brown oily matter 2-methoxyimino propane dinitrile;
Step 4, adds ammoniacal liquor, water and ammonium chloride in reaction flask, stir, drip 2-methoxyimino propane dinitrile at being no more than-5 DEG C, finish, react at being no more than-5 DEG C, reaction solution is poured in ethyl acetate, suction filtration, filtrate leaves standstill, and divides and gets organic over anhydrous dried over sodium sulfate, suction filtration, glacial acetic acid adjusts pH to being no more than 4.5, crystallization, and filtration cakes torrefaction obtains light tan solid 2-methoxyimino-3-amino-3-imino-propionitrile;
Step 5, adds 2-methoxyimino-3-amino-3-imino-propionitrile, potassium thiocyanate, methyl alcohol and hydroxyapatite in reaction flask, stir, drip triethylamine being no more than at 0 DEG C, drip and finish, be cooled to and be no more than-10 DEG C, drip bromine, drip to finish and react being no more than-10 DEG C, by reacting liquid filtering, filtrate is poured in frozen water, stir suction filtration, dry light tan solid 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetonitrile;
Step 6, adds aceticanhydride in reaction flask, is warming up to 30 ~ 35 DEG C, drip formic acid under stirring, 30 ~ 35 DEG C are reacted, and add 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile, be warming up to 55 ~ 60 DEG C and react, be chilled to and be no more than 5 DEG C, drip isopropyl ether, stir, suction filtration, dry light tan solid 2-(5-formamido group-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile;
Step 7,2-(5-formamido group-1 is added in reaction flask, 2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile, sodium hydroxide and water, stir, be warming up to more than 60 DEG C and react, be cooled to 15 ~ 20 DEG C again, dripping hydrochloric acid adjusts pH to be neutral, adds ethyl acetate, continues to drip hydrochloric acid and adjusts below pH to 0.5, leave standstill, separate organic layer, anhydrous sodium sulfate drying, suction filtration, be concentrated into dry, dry white solid 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid.
Preferably, in step 5, the weight ratio of described 2-methoxyimino-3-amino-3-imino-propionitrile, potassium thiocyanate, methyl alcohol, hydroxyapatite, triethylamine and bromine is 90:84:936:(3 ~ 8): 183:125, more preferably 90:84:936:5:183:125.
Preferably, in step one, described malonamide nitrile, Sodium Nitrite, water and glacial acetic acid mole ratio be 15:18:278:35.
Preferably, in step 2, the ratio of the weight of described 2-hydroxyl oximido-2-Malonamide nitrile, water, sodium carbonate, methyl alcohol, methyl-sulfate is 25:165:42:130:77.
Preferably, in step 3, the weight ratio of described 2-methoxyimino-2-Malonamide nitrile, anhydrous sodium sulphate, acetonitrile, phosphorus oxychloride is 30:33:47:82.
Preferably, in step 4, the weight ratio of described ammoniacal liquor, water, ammonium chloride, 2-methoxyimino propane dinitrile is 23:30:4:10.
Preferably, in step 6, the weight ratio of described aceticanhydride, formic acid, 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetonitrile, isopropyl ether is 135:90:40:144.
Preferably, in step 7, the weight ratio of described 2-(5-formamido group-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile, sodium hydroxide is 6:6.4.
Compared with prior art, technical scheme provided by the invention has following beneficial effect: by taking malonamide nitrile as starting raw material, through hydroxyl oximate, methylate, cyclization, the obtained 2-of the reaction such as nitrile solution (5-amino-1, 2, 4-thiadiazoles-3-base)-2-methoxyimino acetic acid, especially in step 5, hydroxyapatite is added as catalyzer, effectively can improve intermediate product 2-(5-amino-1, 2, 4-thiadiazoles-3-base) yield of-2-methoxyimino acetonitrile and final product 2-(5-amino-1, 2, 4-thiadiazoles-3-base) total recovery of-2-methoxyimino acetic acid, the total recovery of 9% is no more than compared to prior art, the total recovery of technical scheme provided by the invention reaches about 13%, significantly improve total recovery, reduce cost, be conducive to industrial large-scale application.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art and understand the present invention further, but not limit the present invention in any form.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.
Embodiment 1
The present embodiment relates to the synthesis technique of a kind of 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid, is made up of following steps:
Step one, malonamide nitrile (25g, 0.3mol), Sodium Nitrite (25g, 0.36mol) and water 100ml is added in reaction flask, be warming up to 30 DEG C, stir, temperature control 30 DEG C drips glacial acetic acid 40ml, drips and finishes, constant temperature 30 DEG C reaction 2h, be chilled to room temperature, suction filtration, 70 DEG C of dry light yellow solid 2-hydroxyl oximido-2-Malonamide nitriles;
Step 2,2-hydroxyl oximido-2-Malonamide nitrile (25g is added in reaction flask, 0.22mol), water 165ml, sodium carbonate 42g and methyl alcohol 165ml, stir, at 13 DEG C, drip methyl-sulfate 58ml, drip and finish, 3h is reacted at 25 DEG C, be chilled to less than 15 DEG C, suction filtration, 70 DEG C of dry pink solid 2-methoxyimino-2-Malonamide nitriles;
Step 3, adds 2-methoxyimino-2-Malonamide nitrile (30g), anhydrous sodium sulphate 33g and acetonitrile 60ml in reaction flask, stir, drip phosphorus oxychloride 50ml at 30 DEG C, drip and finish, back flow reaction 4h, be chilled to room temperature, reaction solution is poured in 300ml frozen water, and methylene dichloride 100ml × 3 extract, sodium hydrogen carbonate solution washing organic phase, anhydrous sodium sulfate drying, suction filtration, is concentrated into dry, obtains brown oily matter 2-methoxyimino propane dinitrile;
Step 4, adds ammoniacal liquor 25ml (density 0.91g/ml), water 30ml and ammonium chloride 4g in reaction flask, stir, drip 2-methoxyimino propane dinitrile (10g) at-5 DEG C, finish ,-5 DEG C of isothermal reaction 3h, reaction solution is poured in ethyl acetate 40ml, suction filtration, filtrate leaves standstill, and divides and gets organic over anhydrous dried over sodium sulfate, suction filtration, glacial acetic acid adjusts pH to 4.5, crystallization, and filter cake 60 DEG C is dry obtains light tan solid 2-methoxyimino-3-amino-3-imino-propionitrile;
Step 5,2-methoxyimino-3-amino-3-imino-propionitrile (9g), potassium thiocyanate 8.4g, methyl alcohol 120ml and hydroxyapatite 0.3g is added in reaction flask, stir, triethylamine 25ml is dripped at 0 DEG C, drip and finish, be cooled to-10 DEG C, drip bromine 12.5g, drip and finish-10 DEG C of reaction 3h, by reacting liquid filtering, filtrate is poured in 300ml frozen water, stir suction filtration, 70 DEG C of dry light tan solid 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile, yield 96.7%;
Step 6, adds aceticanhydride 25ml in reaction flask, be warming up to 33 DEG C, stir lower dropping formic acid 18g, 33 DEG C of reaction 1h, add 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile (8g), be warming up to 60 DEG C of reaction 2.5h, be chilled to 5 DEG C, drip isopropyl ether 40ml, stir, suction filtration, 60 DEG C of dry light tan solid 2-(5-formamido group-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitriles;
Step 7,2-(5-formamido group-1 is added in reaction flask, 2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile (6g) and 2mol/L sodium hydroxide 80ml, stir, be warming up to 60 DEG C of reaction 1.2h, be cooled to 15 DEG C, drip 6mol/L hydrochloric acid and adjust pH to 7, add ethyl acetate 50ml, continue to drip 6mol/L hydrochloric acid and adjust pH to 0.5, leave standstill, separate organic layer, anhydrous sodium sulfate drying, suction filtration, be concentrated into dry, 60 DEG C of dry white solid 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid.
By adopting the scheme of embodiment 1, being starting raw material by 25g malonamide nitrile, finally obtaining 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid 8.0g, total recovery 13.2%, purity 98.9%, MS:m/z=202 (M
+),
1h-NMR (DMSO-d
6, 500MHz) and δ: 8.30 (s, 2H), 4.04 (s, 3H).
Embodiment 2
The present embodiment relates to the synthesis technique of a kind of 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid, is made up of following steps:
Step one, malonamide nitrile (25g, 0.3mol), Sodium Nitrite (25g, 0.36mol) and water 100ml is added in reaction flask, be warming up to 35 DEG C, stir, temperature control 35 DEG C drips glacial acetic acid 40ml, drips and finishes, constant temperature 35 DEG C reaction 2h, be chilled to room temperature, suction filtration, 70 DEG C of dry light yellow solid 2-hydroxyl oximido-2-Malonamide nitriles;
Step 2,2-hydroxyl oximido-2-Malonamide nitrile (25g is added in reaction flask, 0.22mol), water 165ml, sodium carbonate 42g and methyl alcohol 165ml, stir, at 15 DEG C, drip methyl-sulfate 58ml, drip and finish, 3h is reacted at 20 DEG C, be chilled to less than 15 DEG C, suction filtration, 70 DEG C of dry pink solid 2-methoxyimino-2-Malonamide nitriles;
Step 3, adds 2-methoxyimino-2-Malonamide nitrile (30g), anhydrous sodium sulphate 33g and acetonitrile 60ml in reaction flask, stir, drip phosphorus oxychloride 50ml at 30 DEG C, drip and finish, back flow reaction 4h, be chilled to room temperature, reaction solution is poured in 300ml frozen water, and methylene dichloride 100ml × 3 extract, sodium hydrogen carbonate solution washing organic phase, anhydrous sodium sulfate drying, suction filtration, is concentrated into dry, obtains brown oily matter 2-methoxyimino propane dinitrile;
Step 4, adds ammoniacal liquor 25ml (density 0.91g/ml), water 30ml and ammonium chloride 4g in reaction flask, stir, drip 2-methoxyimino propane dinitrile (10g) at-5 DEG C, finish ,-5 DEG C of isothermal reaction 3h, reaction solution is poured in ethyl acetate 40ml, suction filtration, filtrate leaves standstill, and divides and gets organic over anhydrous dried over sodium sulfate, suction filtration, glacial acetic acid adjusts pH to 4.5, crystallization, and filter cake 60 DEG C is dry obtains light tan solid 2-methoxyimino-3-amino-3-imino-propionitrile;
Step 5,2-methoxyimino-3-amino-3-imino-propionitrile (9g), potassium thiocyanate 8.4g, methyl alcohol 120ml and hydroxyapatite 0.5g is added in reaction flask, stir, triethylamine 25ml is dripped at 0 DEG C, drip and finish, be cooled to-10 DEG C, drip bromine 12.5g, drip and finish-10 DEG C of reaction 3h, by reacting liquid filtering, filtrate is poured in 300ml frozen water, stir suction filtration, 70 DEG C of dry light tan solid 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile, yield 96.1%;
Step 6, adds aceticanhydride 25ml in reaction flask, be warming up to 35 DEG C, stir lower dropping formic acid 18g, 35 DEG C of reaction 1h, add 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile (8g), be warming up to 55 DEG C of reaction 2.5h, be chilled to 5 DEG C, drip isopropyl ether 40ml, stir, suction filtration, 60 DEG C of dry light tan solid 2-(5-formamido group-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitriles;
Step 7,2-(5-formamido group-1 is added in reaction flask, 2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile (6g) and 2mol/L sodium hydroxide 80ml, stir, be warming up to 60 DEG C of reaction 1.2h, be cooled to 20 DEG C, drip 6mol/L hydrochloric acid and adjust pH to 7, add ethyl acetate 50ml, continue to drip 6mol/L hydrochloric acid and adjust pH to 0.5, leave standstill, separate organic layer, anhydrous sodium sulfate drying, suction filtration, be concentrated into dry, 60 DEG C of dry white solid 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid.
By adopting the scheme of embodiment 2, being starting raw material by 25g malonamide nitrile, finally obtaining 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid 8.0g, total recovery 13.1%, purity 99.1%, MS:m/z=202 (M
+),
1h-NMR (DMSO-d
6, 500MHz) and δ: 8.31 (s, 2H), 4.05 (s, 3H).
Embodiment 3
The present embodiment relates to the synthesis technique of a kind of 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid, is made up of following steps:
Step one, malonamide nitrile (25g, 0.3mol), Sodium Nitrite (25g, 0.36mol) and water 100ml is added in reaction flask, be warming up to 33 DEG C, stir, temperature control 33 DEG C drips glacial acetic acid 40ml, drips and finishes, constant temperature 33 DEG C reaction 2h, be chilled to room temperature, suction filtration, 70 DEG C of dry light yellow solid 2-hydroxyl oximido-2-Malonamide nitriles;
Step 2,2-hydroxyl oximido-2-Malonamide nitrile (25g is added in reaction flask, 0.22mol), water 165ml, sodium carbonate 42g and methyl alcohol 165ml, stir, at 10 DEG C, drip methyl-sulfate 58ml, drip and finish, 3h is reacted at 23 DEG C, be chilled to less than 15 DEG C, suction filtration, 70 DEG C of dry pink solid 2-methoxyimino-2-Malonamide nitriles;
Step 3, adds 2-methoxyimino-2-Malonamide nitrile (30g), anhydrous sodium sulphate 33g and acetonitrile 60ml in reaction flask, stir, drip phosphorus oxychloride 50ml at 30 DEG C, drip and finish, back flow reaction 4h, be chilled to room temperature, reaction solution is poured in 300ml frozen water, and methylene dichloride 100ml × 3 extract, sodium hydrogen carbonate solution washing organic phase, anhydrous sodium sulfate drying, suction filtration, is concentrated into dry, obtains brown oily matter 2-methoxyimino propane dinitrile;
Step 4, adds ammoniacal liquor 25ml (density 0.91g/ml), water 30ml and ammonium chloride 4g in reaction flask, stir, drip 2-methoxyimino propane dinitrile (10g) at-5 DEG C, finish ,-5 DEG C of isothermal reaction 3h, reaction solution is poured in ethyl acetate 40ml, suction filtration, filtrate leaves standstill, and divides and gets organic over anhydrous dried over sodium sulfate, suction filtration, glacial acetic acid adjusts pH to 4.5, crystallization, and filter cake 60 DEG C is dry obtains light tan solid 2-methoxyimino-3-amino-3-imino-propionitrile;
Step 5,2-methoxyimino-3-amino-3-imino-propionitrile (9g), potassium thiocyanate 8.4g, methyl alcohol 120ml and hydroxyapatite 0.8g is added in reaction flask, stir, triethylamine 25ml is dripped at 0 DEG C, drip and finish, be cooled to-10 DEG C, drip bromine 12.5g, drip and finish-10 DEG C of reaction 3h, by reacting liquid filtering, filtrate is poured in 300ml frozen water, stir suction filtration, 70 DEG C of dry light tan solid 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile, yield 96.2%;
Step 6, adds aceticanhydride 25ml in reaction flask, be warming up to 30 DEG C, stir lower dropping formic acid 18g, 30 DEG C of reaction 1h, add 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile (8g), be warming up to 57 DEG C of reaction 2.5h, be chilled to 5 DEG C, drip isopropyl ether 40ml, stir, suction filtration, 60 DEG C of dry light tan solid 2-(5-formamido group-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitriles;
Step 7,2-(5-formamido group-1 is added in reaction flask, 2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile (6g) and 2mol/L sodium hydroxide 80ml, stir, be warming up to 60 DEG C of reaction 1.2h, be cooled to 18 DEG C, drip 6mol/L hydrochloric acid and adjust pH to 7, add ethyl acetate 50ml, continue to drip 6mol/L hydrochloric acid and adjust pH to 0.5, leave standstill, separate organic layer, anhydrous sodium sulfate drying, suction filtration, be concentrated into dry, 60 DEG C of dry white solid 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid.
By adopting the scheme of embodiment 3, being starting raw material by 25g malonamide nitrile, finally obtaining 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid 7.8g, total recovery 12.8%, purity 98.8%, MS:m/z=202 (M
+),
1h-NMR (DMSO-d
6, 500MHz) and δ: 8.32 (s, 2H), 4.02 (s, 3H).
Comparative example 1
This comparative example is with the difference of embodiment 1: in step 5, do not add hydroxyapatite, the independent yield of step 5 is 65.1%, be starting raw material by 25g malonamide nitrile, finally obtain 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetic acid 5.4g, total recovery 8.9%, purity 98.5%, MS:m/z=202 (M
+),
1h-NMR (DMSO-d
6, 500MHz) and δ: 8.30 (s, 2H), 4.06 (s, 3H).
Comparative example 2
This comparative example is with the difference of embodiment 2: in step 5, do not add hydroxyapatite, the independent yield of step 5 is 64.8%, be starting raw material by 25g malonamide nitrile, finally obtain 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetic acid 5.4g, total recovery 8.8%, purity 98.7%, MS:m/z=202 (M
+),
1h-NMR (DMSO-d
6, 500MHz) and δ: 8.33 (s, 2H), 4.04 (s, 3H).
Comparative example 3
This comparative example is with the difference of embodiment 3: in step 5, do not add hydroxyapatite, the independent yield of step 5 is 65.3%, be starting raw material by 25g malonamide nitrile, finally obtain 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetic acid 5.3g, total recovery 8.7%, purity 98.9%, MS:m/z=202 (M
+),
1h-NMR (DMSO-d
6, 500MHz) and δ: 8.35 (s, 2H), 4.01 (s, 3H).
Analysis of conclusion
Implement above-described embodiment 1-3 and comparative example 1-3 respectively, and add up total recovery and the purity of 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid, and the independent yield of step 5.The independent yield of step 5 of comparative example 1-3 is about 65%, and total recovery is also no more than 9%, and in embodiment 1-3, the independent yield of step 5 is more than 96%, and the total recovery of acquisition is all about 13%.Relative to comparative example 1-3, the total recovery of embodiment 1-3 improves at least 40%, increase rate is beyond expectation, this illustrates hydroxyapatite as catalyzer to the (5-amino-1 of 2-in step 5, 2, 4-thiadiazoles-3-base) this intermediate of-2-methoxyimino acetonitrile formation efficiency have vital impact, especially 2-methoxyimino-3-amino-3-imino-propionitrile, potassium thiocyanate, methyl alcohol, hydroxyapatite, the weight ratio of triethylamine and bromine is 90:84:936:(3 ~ 8): successful during 183:125, wherein weight ratio is 90:84:936:5:183:125, 2-(5-amino-1, 2, 4-thiadiazoles-3-base) total recovery of-2-methoxyimino acetic acid is 27.2%, can be used as most preferred embodiment.
Above specific embodiment provided by the invention is described.It is to be appreciated that the present invention is not limited to above-mentioned particular implementation, those skilled in the art can make various distortion or amendment within the scope of the claims, and this does not affect flesh and blood of the present invention.
Claims (9)
1. the synthesis technique of 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid, is characterized in that, comprise the following steps:
Step one, adds malonamide nitrile, Sodium Nitrite and water in reaction flask, be warming up to 30 ~ 35 DEG C, stirs, temperature control 30 ~ 35 DEG C drips glacial acetic acid, and drip and finish, 30 ~ 35 DEG C are reacted, then room temperature is chilled to, suction filtration, dry light yellow solid 2-hydroxyl oximido-2-Malonamide nitrile;
Step 2, adds 2-hydroxyl oximido-2-Malonamide nitrile, water, sodium carbonate and methyl alcohol in reaction flask, stir, drip methyl-sulfate at 10 ~ 15 DEG C, drip to finish and react at 20 ~ 25 DEG C, be chilled to less than 15 DEG C, suction filtration, dry pink solid 2-methoxyimino-2-Malonamide nitrile;
Step 3, adds 2-methoxyimino-2-Malonamide nitrile, anhydrous sodium sulphate and acetonitrile in reaction flask, stir, drip phosphorus oxychloride at being no more than 30 DEG C, drip and finish, back flow reaction, be chilled to room temperature, reaction solution is poured in frozen water, dichloromethane extraction, sodium hydrogen carbonate solution washing organic phase, anhydrous sodium sulfate drying, suction filtration, is concentrated into dry, obtains brown oily matter 2-methoxyimino propane dinitrile;
Step 4, adds ammoniacal liquor, water and ammonium chloride in reaction flask, stir, drip 2-methoxyimino propane dinitrile at being no more than-5 DEG C, finish, react at being no more than-5 DEG C, reaction solution is poured in ethyl acetate, suction filtration, filtrate leaves standstill, and divides and gets organic over anhydrous dried over sodium sulfate, suction filtration, glacial acetic acid adjusts pH to being no more than 4.5, crystallization, and filtration cakes torrefaction obtains light tan solid 2-methoxyimino-3-amino-3-imino-propionitrile;
Step 5, adds 2-methoxyimino-3-amino-3-imino-propionitrile, potassium thiocyanate, methyl alcohol and hydroxyapatite in reaction flask, stir, drip triethylamine being no more than at 0 DEG C, drip and finish, be cooled to and be no more than-10 DEG C, drip bromine, drip to finish and react being no more than-10 DEG C, by reacting liquid filtering, filtrate is poured in frozen water, stir suction filtration, dry light tan solid 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetonitrile;
Step 6, adds aceticanhydride in reaction flask, is warming up to 30 ~ 35 DEG C, drip formic acid under stirring, 30 ~ 35 DEG C are reacted, and add 2-(5-amino-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile, be warming up to 55 ~ 60 DEG C and react, be chilled to and be no more than 5 DEG C, drip isopropyl ether, stir, suction filtration, dry light tan solid 2-(5-formamido group-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile;
Step 7,2-(5-formamido group-1 is added in reaction flask, 2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile, sodium hydroxide and water, stir, be warming up to more than 60 DEG C and react, be cooled to 15 ~ 20 DEG C again, dripping hydrochloric acid adjusts pH to be neutral, adds ethyl acetate, continues to drip hydrochloric acid and adjusts below pH to 0.5, leave standstill, separate organic layer, anhydrous sodium sulfate drying, suction filtration, be concentrated into dry, dry white solid 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetic acid.
2. synthesis technique as claimed in claim 1, it is characterized in that, in step 5, the weight ratio of described 2-methoxyimino-3-amino-3-imino-propionitrile, potassium thiocyanate, methyl alcohol, hydroxyapatite, triethylamine and bromine is 90:84:936:(3 ~ 8): 183:125.
3. synthesis technique as claimed in claim 2, it is characterized in that, in step 5, the weight ratio of described 2-methoxyimino-3-amino-3-imino-propionitrile, potassium thiocyanate, methyl alcohol, hydroxyapatite, triethylamine and bromine is 90:84:936:5:183:125.
4. synthesis technique as claimed in claim 1, is characterized in that, in step one, described malonamide nitrile, Sodium Nitrite, water and glacial acetic acid mole ratio be 15:18:278:35.
5. synthesis technique as claimed in claim 1, it is characterized in that, in step 2, the ratio of the weight of described 2-hydroxyl oximido-2-Malonamide nitrile, water, sodium carbonate, methyl alcohol, methyl-sulfate is 25:165:42:130:77.
6. synthesis technique as claimed in claim 1, it is characterized in that, in step 3, the weight ratio of described 2-methoxyimino-2-Malonamide nitrile, anhydrous sodium sulphate, acetonitrile, phosphorus oxychloride is 30:33:47:82.
7. synthesis technique as claimed in claim 1, it is characterized in that, in step 4, the weight ratio of described ammoniacal liquor, water, ammonium chloride, 2-methoxyimino propane dinitrile is 23:30:4:10.
8. synthesis technique as claimed in claim 1, is characterized in that, in step 6, the weight ratio of described aceticanhydride, formic acid, 2-(amino-1,2, the 4-thiadiazoles of 5--3-base)-2-methoxyimino acetonitrile, isopropyl ether is 135:90:40:144.
9. synthesis technique as claimed in claim 1, it is characterized in that, in step 7, the weight ratio of described 2-(5-formamido group-1,2,4-thiadiazoles-3-base)-2-methoxyimino acetonitrile, sodium hydroxide is 6:6.4.
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| WO2020010988A1 (en) * | 2018-07-13 | 2020-01-16 | 沈阳中化农药化工研发有限公司 | Method for preparing propanedinitrile oxime ether compound and intermediate compound |
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| WO2020010988A1 (en) * | 2018-07-13 | 2020-01-16 | 沈阳中化农药化工研发有限公司 | Method for preparing propanedinitrile oxime ether compound and intermediate compound |
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| US11952355B2 (en) | 2018-07-13 | 2024-04-09 | Shenyang Sinochem Agrochemicals R&D Co., Ltd. | Method of preparing malononitrile oxime ether compound and intermediate compound |
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