CN104829556A - Method for preparing 2-hydroxy-amino-1,3,4-thiadiazole from solid phosgene and thiosemicarbazide - Google Patents

Method for preparing 2-hydroxy-amino-1,3,4-thiadiazole from solid phosgene and thiosemicarbazide Download PDF

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Publication number
CN104829556A
CN104829556A CN201510227237.8A CN201510227237A CN104829556A CN 104829556 A CN104829556 A CN 104829556A CN 201510227237 A CN201510227237 A CN 201510227237A CN 104829556 A CN104829556 A CN 104829556A
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thiadiazoles
hydroxyl
amido
reaction
thiosemicarbazide
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CN104829556B (en
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焦岩
张明道
陈敏东
蔡正松
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Shanxi bizhou Biotechnology Co.,Ltd.
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Nanjing University of Information Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the preparation of 2-hydroxy-5-amino-1,3,4-thiadiazole. The preparation method comprises the following steps: taking thiosemicarbazide as the substrate, then adding thiosemicarbazide into a dichloromethane solution containing solid phosgene and triethanolamine, then adding a saturated potassium hydroxide solution, mixing, stirring to carry out reactions, and extracting the reaction products by ethyl acetate to obtain the target product. The provided novel method prepares 2-hydroxy-5-amino-1,3,4-thiadiazole from solid phosgene and thiosemicarbazide, has the advantages of mild conditions, convenience, low cost, high yield, and convenient and efficient post treatment, and is suitable for industrial production. The prepared 2-hydroxy-5-amino-1,3,4-thiadiazole can be used to prepare 1,3,4-thiadiazole drugs.

Description

A kind of method being prepared 2-hydroxyl-5-amido-1,3,4-thiadiazoles by solid phosgene and thiosemicarbazide reaction
Technical field
The present invention relates to the method that one prepares 2-hydroxyl-5-amido-1,3,4-thiadiazoles (2-Hydroxyl-5-amino-1,3,4-thiodiazole).
Background technology
1,3, the organic molecule of 4-thiadiazoles structure is present in multiple marketed drug and drug candidate molecule, such as disulfonamide ayerlucil, cephalosporin analog antibiotic cefazedone, for the people such as antibacterials .Yang Hu detailed overview nearly ten years 1,3, the synthesis of 4-thiadiazoles and the application (Chem.Rev.2014,114,5572-5610) at medicine, agricultural and Material Field thereof.In addition, Chinese patent CN1639141A reports a series of 1,3, the synthesis of 4-thiadiazole compound and application, (F irrigates root etc., new thiadiazoles is with oxadiazole and the purposes as phosphodiesterase-7 inhibitors thereof) with the application having studied such material in great detail and to suppress at phosphodiesterase-7 (PDE-7) field, for the treatment of the disease that T cell is correlated with.
1; 3; the preparation of 4-thiadiazoles is mainly through thiosemicarbazone derivative, acylhydrazine, sulfydryl triazole and 1; 3,4-oxadiazole, four kinds of materials have come as substrate reactions, and F irrigates the people such as root (CN1639141A) and also uses wherein three kinds of methods to synthesize 1 respectively; 3; 4-thiadiazoles, current most widely used method has come with the condensation of thiosemicarbazone derivative and carboxylic acid derivative, and synthesis comprises: 1, with thiosemicarbazone derivative, carboxylic acid derivative and POCl 3at 95 DEG C, heat 5h, form 1,3,4-Thiadiazole.2, at 75 DEG C, react 18h with thiosemicarbazide and aldehyde, then oxidizing reaction 19h obtains 1,3,4-thiadiazoles derivative at 75 DEG C.3, three is generate intermediate with acyl chlorides and thiosemicarbazide reaction, then to obtain 1,3,4-thiadiazoles through closing ring under red precipitate induction.The problems such as this several method reaction conditions is all comparatively harsh, long reaction time, and Heating temperature is high, phosphorus oxychloride and red precipitate toxicity are comparatively large simultaneously, can to environment.
Summary of the invention
The problem to be solved in the present invention is: existing 1,3,4-thiadiazoles preparation method long reaction time, and reaction conditions is comparatively harsh, the problem that environmental pollution is heavy.
For solving above technical problem, technical scheme provided by the invention is: prepare 1 with thiosemicarbazide and solid phosgene reaction, 3,4-thiadiazoles, reaction (comprises trolamine at organic bases, triethylamine or pyridine) and mineral alkali (for KOH) promotion under carry out, reaction solvent for use can be methylene dichloride, DMF (DMF) or tetrahydrofuran (THF) (THF), temperature of reaction is room temperature, reaction times is short, aftertreatment is simply efficient, and productive rate is higher, is expected to the requirement meeting industry member production.
Synthetic method 1: the present invention take thiosemicarbazide as substrate, by solid phosgene reaction under trolamine and potassium hydroxide exist, prepare the method for 1,3,4-thiadiazoles, its key step is:
Under the water-cooled condition of ice, in the dichloromethane solution of solid phosgene, carefully add trolamine, then add thiosemicarbazide and saturated potassium hydroxide solution, at room temperature react, be obtained by reacting 2-hydroxyl-5-amido-1,3,4-thiadiazoles, reaction formula is as follows:
Experiment of the present invention is at room temperature carried out, reacting the solvent used is methylene dichloride/water=1/1 (v/v), the feed way of reaction is solid phosgene, trolamine, thiosemicarbazide and potassium hydroxide, the aftertreatment of reaction adopts extraction into ethyl acetate, dry steam seasoning after saturated sodium bicarbonate solution washing.
Synthetic method 2: change the trolamine in synthetic method 1 into triethylamine, the feed ratio of reaction is, solid phosgene: triethylamine: the mol ratio of thiosemicarbazide is 1.67:20:1, and step, with synthetic method 1, obtains target product equally.
Synthetic method 3: change the trolamine in synthetic method 1 into pyridine, KOH saturated solution changes KOH solid particulate into, dichloromethane solvent changes DMF into, the feed ratio of reaction is, solid phosgene: pyridine: thiosemicarbazide: the mol ratio of potassium hydroxide is 0.5:1.5:1:2, step, with synthetic method 1, obtains target product equally.
Synthetic method 4: change the DMF in synthetic method 3 into THF, the feed ratio of reaction is, solid phosgene: pyridine: thiosemicarbazide: the mol ratio of potassium hydroxide is 0.5:1.5:1:2, and step, with synthetic method 3, obtains target product equally.
Reaction product through fusing point test, 1hNMR method and ESI-MS method are determined.
Beneficial effect:
The invention provides a kind of easy low cost and prepare 2-hydroxyl-5-amino-1,3, the novel method of 4-thiadiazoles, take thiosemicarbazide as substrate, to solid phosgene be added, in the dichloromethane solution of trolamine, then add saturated potassium hydroxide solution, mix and blend reacts, and obtains target compound after extraction into ethyl acetate.The method reaction conditions is gentle, and easy, low cost, productive rate is high, aftertreatment simple and effective, meets industrial needs, and product can be used as preparation 1,3,4-thiadiazole medicine.
Embodiment
Embodiment 1:
In 50ml single port bottle, add the dichloromethane solution of solid phosgene, wherein solid phosgene is 2.37g (12mmol), and in dichloromethane solution, methylene dichloride and water are respectively 10mL.
Under the water-cooled condition of ice, in the dichloromethane solution of solid phosgene, carefully add reaction raw materials trolamine; Wherein trolamine is 3.18ml (24mmol).
And then reaction raw materials thiosemicarbazide and saturated potassium hydroxide solution is added in gained reaction solution, wherein thiosemicarbazide is 1.82g (20mol), and saturated potassium hydroxide solution is 10mL.
By the mixed reaction solution of above-mentioned steps gained stirring reaction in ice-water bath, TLC follows the tracks of, and solution, in yellow, reacts the milk yellow of solution appeared cloudy after 15 minutes.5 hours, stop stirring rear layering, upper strata was clear yellow, and lower floor is turbid whitish powder.TLC point plate, R f(thiosemicarbazide)=0.12, R f(product)=0.58 (developping agent is methyl alcohol: ethyl acetate=1:4.5).Separatory, is extracted with ethyl acetate water layer, merges organic phase, and with water, saturated sodium bicarbonate washs, and anhydrous magnesium sulfate drying, suction filtration revolves steaming, obtains faint yellow solid 1.52 grams, productive rate 50%.
Embodiment 2:
In 150ml flask, add triethylamine, thiosemicarbazide, methylene dichloride, wherein triethylamine is 4mL (40mmol), and wherein thiosemicarbazide is 0.18g (2mol), and dichloromethane solvent is 5mL.
In frozen water cooling, under the condition of magnetic agitation, the careful dichloromethane solution dripping solid phosgene in above-mentioned dichloromethane solution; Wherein solid phosgene is 1g (3.3mmol), and dichloromethane solvent is 5mL.
And then saturated potassium hydroxide solution is added in gained reaction solution, saturated potassium hydroxide solution is 5mL.
By the mixed reaction solution of above-mentioned steps gained stirring reaction in ice-water bath, be slowly warmed up to room temperature (25 DEG C), after 12 hours, layering after static mixer, separatory, with 15mL dichloromethane extraction water layer, in triplicate, merge organic phase, with the water washing of 15mL saturated common salt, repeat twice, anhydrous sodium sulfate drying, suction filtration revolves steaming, obtains faint yellow solid 0.09 gram, productive rate 40%.
Embodiment 3:
In 150ml flask, add pyridine, DMF, wherein pyridine is 1.2mL (15mmol), and DMF solvent is 10mL.
In frozen water cooling, under the condition of magnetic agitation, in above-mentioned solution, add solid phosgene powder in batches; Wherein solid phosgene is 1.5g (5mmol).
And then in gained reaction solution, add thiosemicarbazide, potassium hydroxide pellet, wherein thiosemicarbazide is 0.91g (10mmol), and potassium hydroxide is 1.12 grams (20mmol).
The mixed reaction solution of above-mentioned steps gained is warmed up to room temperature (25 DEG C), stirring reaction is after 24 hours, acetic acid neutralization reaction liquid is to neutral, evaporated under reduced pressure solvent, dissolve with ethanol, filters evaporate to dryness again, silica gel column chromatography (1:1=ethyl acetate: sherwood oil drip washing), obtain faint yellow solid 0.64 gram, productive rate 55%.
Product structure is analyzed: product fusing point is 177-179 DEG C. 1h NMR (400MHz, CDCl 3) δ 11.27 (s, 1H ,-OH), 6.47 (s, 1H ,-NH 2), these two groups of reactive hydrogens can disappear containing the situation of a small amount of water in the sample to which.LC-MS：calculatedC 2H 3O 1N 3S 1，117.13，found 118.1。ESI-Ms:116.0. from analytical results, products therefrom confirms as 2-hydroxyl-5-amido-1,3,4-thiadiazoles.

Claims (10)

1. prepare 2-hydroxyl-5-amino-1 for one kind, 3, the method of 4-thiadiazoles, it is characterized in that: its preparation process is as follows: in reaction vessel, add reaction raw materials and reaction solvent, described reaction raw materials is solid phosgene and thiosemicarbazide, reacts and carries out under the promotion of organic bases and mineral alkali, and obtaining product after mix and blend reaction is 2-hydroxyl-5-amino-1,3,4-thiadiazoles.
2. the method preparing 2-hydroxyl-5-amido-1,3,4-thiadiazoles according to claim 1, is characterized in that: add the condition of the required material of reaction under the water-cooled condition of ice.
3. the method preparing 2-hydroxyl-5-amido-1,3,4-thiadiazoles according to claim 1, is characterized in that: the condition of carrying out reacting is room temperature.
4. the method preparing 2-hydroxyl-5-amido-1,3,4-thiadiazoles according to claim 1, it is characterized in that: described organic bases is trolamine, triethylamine or pyridine, described mineral alkali is KOH.
5. prepare the method for 2-hydroxyl-5-amido-1,3,4-thiadiazoles as claimed in claim 1, it is characterized in that: described reaction solvent is methylene dichloride, DMF (DMF) or tetrahydrofuran (THF) (THF).
6. prepare the method for 2-hydroxyl-5-amido-1,3,4-thiadiazoles as claimed in claim 1, it is characterized in that: its preparation process is as follows:
(1) in reaction vessel, first add the dichloromethane solution of solid phosgene;
(2) under the water-cooled condition of ice, add trolamine, then add reaction raw materials thiosemicarbazide and saturated potassium hydroxide solution; (3) mixed reaction solution of above-mentioned steps gained at room temperature reacts, and obtains 2-hydroxyl-5-amido-1,3,4-thiadiazoles.
7. prepare the method for 2-hydroxyl-5-amido-1,3,4-thiadiazoles as claimed in claim 1, it is characterized in that: its preparation process is as follows:
(1) first in reaction vessel, triethylamine is added, thiosemicarbazide and methylene dichloride;
(2) under the water-cooled condition of ice, drip the dichloromethane solution of solid phosgene, and then add saturated potassium hydroxide solution;
(3) mixed reaction solution of above-mentioned steps gained reacts, and obtains 2-hydroxyl-5-amido-1,3,4-thiadiazoles.
8. prepare the method for 2-hydroxyl-5-amido-1,3,4-thiadiazoles as claimed in claim 1, it is characterized in that: its preparation process is as follows:
(1) in reaction vessel, first add DMF or the THF solution of pyridine;
(2) then reaction raw materials solid phosgene, thiosemicarbazide and potassium hydroxide is added under the water-cooled condition of ice;
(3) mixed reaction solution of above-mentioned steps gained reacts, and obtains 2-hydroxyl-5-amido-1,3,4-thiadiazoles.
9. prepare the method for 2-hydroxyl-5-amido-1,3,4-thiadiazoles as claimed in claim 6, it is characterized in that: in step (1), in described dichloromethane solution, the volume ratio of methylene dichloride and water is 1:1.
10. prepare the method for 2-hydroxyl-5-amido-1,3,4-thiadiazoles as claimed in claim 1, it is characterized in that: also comprise post-processing step, described post-processing step is: adopt extraction into ethyl acetate, merges organic phase, with water, saturated sodium bicarbonate washing, final drying evaporate to dryness.
CN201510227237.8A 2015-05-06 2015-05-06 A kind of method that the thiadiazoles of 2 hydroxyl, 5 amino 1,3,4 is prepared by solid phosgene and thiosemicarbazides reaction Active CN104829556B (en)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN112321583A (en) * 2020-12-02 2021-02-05 安徽理工大学 Synthesis method of 1,2, 4-thiadiazole compound
CN112321583B (en) * 2020-12-02 2023-05-09 安徽理工大学 Synthesis method of 1,2, 4-thiadiazole compound

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