CN117603156A - Synthesis method of pinoxaden intermediate N-acetyl- [1,4,5] -oxydiazepam - Google Patents
Synthesis method of pinoxaden intermediate N-acetyl- [1,4,5] -oxydiazepam Download PDFInfo
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- CN117603156A CN117603156A CN202311563874.3A CN202311563874A CN117603156A CN 117603156 A CN117603156 A CN 117603156A CN 202311563874 A CN202311563874 A CN 202311563874A CN 117603156 A CN117603156 A CN 117603156A
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- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 239000005597 Pinoxaden Substances 0.000 title abstract description 5
- MGOHCFMYLBAPRN-UHFFFAOYSA-N pinoxaden Chemical compound CCC1=CC(C)=CC(CC)=C1C(C1=O)=C(OC(=O)C(C)(C)C)N2N1CCOCC2 MGOHCFMYLBAPRN-UHFFFAOYSA-N 0.000 title abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 23
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 69
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 24
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 22
- ZNSMNVMLTJELDZ-UHFFFAOYSA-N Bis(2-chloroethyl)ether Chemical compound ClCCOCCCl ZNSMNVMLTJELDZ-UHFFFAOYSA-N 0.000 claims description 13
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- WTAGBGKFGMJZNM-UHFFFAOYSA-N n,n-diethyl-3-phenylpropan-1-amine;hydrochloride Chemical compound Cl.CCN(CC)CCCC1=CC=CC=C1 WTAGBGKFGMJZNM-UHFFFAOYSA-N 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- UDYGXWPMSJPFDG-UHFFFAOYSA-M benzyl(tributyl)azanium;bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 UDYGXWPMSJPFDG-UHFFFAOYSA-M 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- GNMJFQWRASXXMS-UHFFFAOYSA-M trimethyl(phenyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)C1=CC=CC=C1 GNMJFQWRASXXMS-UHFFFAOYSA-M 0.000 claims description 2
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 239000002904 solvent Substances 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 5
- 229910052736 halogen Inorganic materials 0.000 abstract description 5
- 150000002367 halogens Chemical class 0.000 abstract description 5
- 125000006239 protecting group Chemical group 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000007789 gas Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 150000002429 hydrazines Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- FOZVXADQAHVUSV-UHFFFAOYSA-N 1-bromo-2-(2-bromoethoxy)ethane Chemical compound BrCCOCCBr FOZVXADQAHVUSV-UHFFFAOYSA-N 0.000 description 1
- CEGQKEWSEGCYRS-UHFFFAOYSA-N 2-(2-methylsulfonyloxyethoxy)ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCOCCOS(C)(=O)=O CEGQKEWSEGCYRS-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- -1 monosubstituted hydrazine Chemical class 0.000 description 1
- 239000012011 nucleophilic catalyst Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- TYSZETYVESRFNT-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate Chemical compound CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C TYSZETYVESRFNT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
- C07D273/06—Seven-membered rings
Abstract
The invention discloses a synthetic method of pinoxaden intermediate N-acetyl- [1,4,5] -oxydiazepane. The synthesis method of the invention is that acethydrazide is taken as a raw material, dissolved in a solvent and added with a phase transfer catalyst, and then cyclized with 2,2' -disubstituted diethyl ether in the presence of an alkaline reagent to obtain N-acetyl- [1,4,5] -oxydiazepin, the N-acetyl- [1,4,5] -oxydiazepin is dissolved in the solvent and introduced with anhydrous halogen acid gas to remove protective groups, thus obtaining the product [1,4,5] -oxydiazepin. The method has the advantages of simple reaction system, low-cost and easily-obtained raw materials, environmental friendliness, simple and convenient post-treatment operation and high atom utilization rate, is suitable for industrial production, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing pinoxaden intermediate N-acetyl- [1,4,5] -oxydiazepane.
Background
Pinoxaden is a very widely used herbicide, and [1,4,5] -oxydiazepane is an important intermediate in the production and preparation process.
In patent WO99047525 is disclosed a process for the preparation of N, N '-di-tert-butoxycarbonyl- [1,4,5] -oxydiazepin by the cyclization of diethylene glycol dimesylate with N, N' -di-tert-butoxycarbonyl hydrazine under the action of sodium hydride, which is subjected to acid-catalyzed deprotection to give [1,4,5] -oxydiazepin dihydrobromide, which process uses a solvent with a low flash point of diethyl ether, presents a safety hazard and uses an expensive Boc protecting group.
Patent WO03051853 discloses the cyclization of N, N ' -diacylhydrazine with 2,2' -disubstituted diethyl ether to give N, N ' -diacylhydrazine- [1,4,5] -oxydiazepine which avoids the use of expensive and high molecular weight Boc protecting groups and the relatively dangerous methanesulfonyl chloride. However, the method has the problems of large solvent consumption, complicated reaction steps and long reaction period.
Disclosure of Invention
The invention aims to provide a more efficient and simple synthesis method of [1,4,5] -oxydiazepine compounds, in particular to a synthesis method of N-acetyl- [1,4,5] -oxydiazepine.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a synthesis method of N-acetyl- [1,4,5] -oxydiazepane, which comprises the following steps: uniformly dispersing an alkaline reagent, acetylhydrazine, a phase transfer catalyst and 2,2' -disubstituted diethyl ether in an organic solvent to construct a reaction system, carrying out cyclization reaction for 4-7 hours (particularly preferably, carrying out cyclization reaction for 5 hours at 100 ℃) at 55-125 ℃ (preferably, 75-105 ℃), and separating and purifying the obtained reaction solution to obtain the N-acetyl- [1,4,5] -oxydiazepine;
the phase transfer catalyst is one or more than two of tetrabutylammonium bromide, benzyl triethylamine chloride, benzyl tributylammonium bromide, phenyl trimethyl ammonium bromide and tetradecyl trimethyl ammonium chloride (preferably tetrabutylammonium bromide); the 2,2' -disubstituted diethyl ether is one or more of 2,2' -dichloro diethyl ether, 2' -dibromodiethyl ether and 2,2' -dimethyl sulfonyl diethyl ether (preferably 2,2' -dichloro diethyl ether); the organic solvent is one or more than two of N, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone (preferably N, N-dimethylformamide); the mol ratio of the acethydrazide, the alkaline reagent, the phase transfer catalyst and the 2,2' -disubstituted diethyl ether is 1:1-4:0.01-0.1:1-3, preferably 1:1.5-3:0.01-0.05:1.5-2.5, most preferably 1:3:0.05:2.
further, the alkaline agent is one or more of sodium carbonate, potassium phosphate and potassium hydroxide (preferably potassium hydroxide).
Further, the resulting isolation was purified as: and cooling the reaction liquid to room temperature, filtering, washing a filter cake with N, N-dimethylformamide, merging obtained filtrate, evaporating and concentrating, cooling to 0 ℃, separating out solid, filtering, washing the obtained filter cake with N-amyl alcohol, and drying to obtain the N-acetyl- [1,4,5] -oxydiazepine.
The compound is then dissolved in a solvent, a halogen acid gas is passed through the solution at a temperature of about 55 ℃, and when the mass of the solution is unchanged, the mixture is allowed to continue at that temperature for about 7 hours, degassed, cooled, filtered, and washed to give the halogen acid salt of [1,4,5] -oxydiazepine.
Preferably, the organic solvent is N, N-dimethylformamide. Still further, the volume of the organic solvent is 6-15mL/g (preferably 8-12mL/g, 10mL/g in one embodiment of the invention) based on the mass of the acethydrazide.
The second step of the invention is that N-acetyl- [1,4,5] -oxydiazepine is dissolved in a solvent, halogen acid gas is introduced, and protective groups are removed at 25-75 ℃ to obtain the [1,4,5] -oxydiazepine compound. The solvent is methanol, diethylene glycol, n-amyl alcohol, ethylene glycol, ethanol, preferably methanol or ethanol. The reaction temperature is preferably 35-55 ℃. The halogen acid gas is hydrogen chloride gas or hydrogen bromide gas.
Wherein potassium iodide, a nucleophilic catalyst, may be added in order to further increase the yield of the first-step cyclization reaction. That is, preferably, the reaction system further comprises potassium iodide, and the molar ratio of the potassium iodide to the acethydrazide is 0.01-0.2:1 (preferably 0.05:1)
The invention particularly recommends that the method is: uniformly dispersing an alkaline reagent, acetylhydrazine, a phase transfer catalyst and 2,2' -disubstituted diethyl ether in an organic solvent to construct a reaction system, carrying out cyclization reaction for 5 hours at 100 ℃, and separating and purifying the obtained reaction solution to obtain the N-acetyl- [1,4,5] -oxydiazepine;
the phase transfer catalyst is tetrabutylammonium bromide; the 2,2 '-disubstituted diethyl ether is 2,2' -dichlorodiethyl ether; the molar ratio of the acethydrazide, the alkaline reagent, the phase transfer catalyst, the 2,2' -disubstituted diethyl ether and the potassium iodide is 1:3:0.05:2:0.05.
compared with the prior art, the invention has the beneficial effects that: compared with the document (WO 03051853) and the like, the invention avoids the use of disubstituted hydrazine by adopting monosubstituted hydrazine as a raw material, improves the atomic utilization rate and has higher yield compared with the disubstituted hydrazine. Meanwhile, the raw materials are cheap and easy to obtain, the reaction conditions are safe, the production cost is low, and the large-scale production is easy.
Drawings
FIG. 1 is a mass spectrum of N-acetyl- [1,4,5] -oxydiazepane as the product of example 1 of the present invention.
Detailed Description
The technical scheme of the invention is further specifically described below through specific embodiments and with reference to the accompanying drawings.
Example 1:
9.24g (67 mmol) of powdered potassium carbonate was added to 2g of acetylhydrazine (26 mmol) and 20ml of N, N-dimethylformamide, stirred uniformly, 7.64g (52 mmol) of 2,2' -dichlorodiethyl ether and 0.43g (1.3 mmol) of tetrabutylammonium bromide were added, reacted at 100℃for 5 hours, cooled to room temperature, filtered, the filter residue was washed with N, N-dimethylformamide, the obtained filtrate was distilled off to obtain an oily yellow liquid, the temperature was lowered to 0℃to precipitate the product N-acetyl- [1,4,5] -oxydiazepin, filtered, washed with N-amyl alcohol and dried to obtain 2.76g of a white solid (yield 71.8%, purity 99%).
Example 2:
3.75g (67 mmol) of powdered potassium hydroxide was added to 2g of acetylhydrazine (26 mmol) and 20ml of N, N-dimethylformamide, stirred uniformly, 7.64g (52 mmol) of 2,2' -dichlorodiethyl ether and 0.43g (1.3 mmol) of tetrabutylammonium bromide were added, the mixture was heated to 100℃for reaction for 5 hours, cooled to room temperature, filtered, the filtration residue was washed with N, N-dimethylformamide, and the obtained filtrate was distilled off to obtain an oily yellow liquid, the temperature was lowered to 0℃to precipitate the product N-acetyl- [1,4,5] -oxydiazepin, filtered, washed with N-amyl alcohol and dried to obtain 3.05g of a white solid (yield 79.1%, purity 99%).
Example 3:
9.24g (67 mmol) of powdered potassium carbonate was added to 2g of acetylhydrazine (26 mmol) and 20ml of N, N-dimethylformamide, stirred uniformly, 7.64g (52 mmol) of 2,2' -dichlorodiethyl ether and 0.43g (1.3 mmol) of tetrabutylammonium bromide were added, the reaction was carried out at 80℃for 5 hours, cooled to room temperature, filtered, the filtration residue was washed with N, N-dimethylformamide, the obtained filtrate was distilled off to obtain an oily yellow liquid, the temperature was lowered to 0℃to precipitate the product N-acetyl- [1,4,5] -oxydiazepin, filtered, washed with N-amyl alcohol and dried to obtain 1.82g of a white solid (yield 47.2%, purity 99%).
Example 4:
9.24g (67 mmol) of powdered potassium carbonate was added to 2g of acetylhydrazine (26 mmol) and 20ml of N, N-dimethylformamide, stirred uniformly, 7.64g (52 mmol) of 2,2' -dichlorodiethyl ether and 0.30g (1.3 mmol) of benzyl triethylamine chloride were added, the mixture was heated to 100℃for 5 hours, cooled to room temperature, filtered, the filter residue was washed with N, N-dimethylformamide, the obtained filtrate was distilled off to obtain an oily yellow liquid, the temperature was lowered to 0℃to precipitate the product N-acetyl- [1,4,5] -oxydiazepin, filtered, washed with N-amyl alcohol and dried to obtain 2.71g of a white solid (yield 70.4%, purity 98%).
Example 5:
11.09g (80 mmol) of powdered potassium carbonate was added to 2g of acetylhydrazine (26 mmol) and 20ml of N, N-dimethylformamide, stirred uniformly, 7.64g (52 mmol) of 2,2' -dichlorodiethyl ether and 0.43g (1.3 mmol) of tetrabutylammonium bromide were added, reacted at 100℃for 5 hours, cooled to room temperature, filtered, the filter residue was washed with N, N-dimethylformamide, the obtained filtrate was distilled off to obtain an oily yellow liquid, the temperature was lowered to 0℃to precipitate the product N-acetyl- [1,4,5] -oxydiazepin, filtered, washed with N-amyl alcohol and dried to obtain 3.11g of a white solid (yield 80.8%, purity 99%).
Example 6:
powdered potassium hydroxide (4.5 g) (80 mmol) was added to 2g of acetylhydrazine (26 mmol) and 20ml of N, N-dimethylformamide, stirred uniformly, 7.64g (52 mmol) of 2,2' -dichlorodiethyl ether and 0.43g (1.3 mmol) of tetrabutylammonium bromide were then added, the reaction was carried out at 100℃for 5 hours, cooled to room temperature, filtered, the filtration residue was washed with N, N-dimethylformamide, and the obtained filtrate was distilled off to obtain an oily yellow liquid, the temperature was lowered to 0℃to precipitate the product N-acetyl- [1,4,5] -oxydiazepin, filtered, washed with N-amyl alcohol and dried to obtain 3.54g of a white solid (yield 92.0%, purity 98%).
Example 7:
powdered potassium hydroxide (4.5 g) (80 mmol) was added to 2g of acetylhydrazine (26 mmol) and 20ml of N, N-dimethylformamide, stirred uniformly, 7.64g (52 mmol) of 2,2' -dichlorodiethyl ether, 0.43g (1.3 mmol) of tetrabutylammonium bromide and 0.22g (1.3 mmol) of potassium iodide were then added, the mixture was heated to 100℃for reaction for 5 hours, cooled to room temperature, filtered, the filtration residue was washed with N, N-dimethylformamide, the obtained filtrate was distilled off to give an oily yellow liquid, the temperature was lowered to 0℃to precipitate the product N-acetyl- [1,4,5] -oxydiazepane, filtered, washed with N-amyl alcohol and dried to give 3.66g (yield 95.0%, purity 98%) of white solid.
Example 8:
powdered potassium hydroxide (4.5 g) (80 mmol) was added to 2g of acetylhydrazine (26 mmol) and 20ml of N, N-dimethylformamide, stirred uniformly, then added with 2,2' -dibromodiethyl ether (12.4 g) (52 mmol) and tetrabutylammonium bromide (0.43 g) (1.3 mmol), reacted at 100℃for 5 hours, cooled to room temperature, filtered, the filter residue was washed with N, N-dimethylformamide, the obtained filtrate was distilled off to obtain an oily yellow liquid, the temperature was lowered to 0℃to precipitate the product N-acetyl- [1,4,5] -oxydiazepin, filtered, washed with N-amyl alcohol and dried to obtain 3.38g of a white solid (yield 87.8%, purity 97%).
Example 9:
n-acetyl- [1,4,5]Oxydiazepan (2 g,14 mmol) was added to 4ml of methanol and after heating to 55℃anhydrous hydrogen chloride gas was introduced until the weight of the solution was unchanged. The reaction mixture was then allowed to continue at this temperature for 7 hours. The reaction suspension was purged with nitrogen at 40℃for 30min, cooled, filtered at 10℃and the residue was washed with isopropyl acetate and dried to give 2.16g of a white solid in 89.2% yield and 99% purity. 1 H NMR(400MHz,DMSO-d 6 )δ7.45(s,4H),3.79-3.76(m,4H),3.22-3.20(m,4H)。 13 C NMR(101MHz,DMSO)δ67.6,50.2。
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the invention in any way, but other variations and modifications are possible without exceeding the technical solutions described in the claims.
Claims (10)
1. A method for synthesizing N-acetyl- [1,4,5] -oxydiazepane, which is characterized by comprising the following steps: uniformly dispersing an alkaline reagent, acetylhydrazine, a phase transfer catalyst and 2,2' -disubstituted diethyl ether in an organic solvent to construct a reaction system, carrying out cyclization reaction for 4-7 hours at 55-125 ℃, and separating and purifying the obtained reaction solution to obtain the N-acetyl- [1,4,5] -oxydiazepine;
the phase transfer catalyst is one or more than two of tetrabutylammonium bromide, benzyl triethylamine chloride, benzyl tributylammonium bromide, phenyl trimethyl ammonium bromide and tetradecyl trimethyl ammonium chloride; the 2,2 '-disubstituted diethyl ether is one or more than two of 2,2' -dichloro diethyl ether, 2 '-dibromodiethyl ether and 2,2' -dimethyl sulfonyl diethyl ether; the organic solvent is one or more than two of N, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone; the mol ratio of the acethydrazide, the alkaline reagent, the phase transfer catalyst and the 2,2' -disubstituted diethyl ether is 1:1-4:0.01-0.1:1-3.
2. The method for synthesizing the N-acetyl- [1,4,5] -oxydiazepine according to claim 1, wherein the method comprises the following steps: the alkaline reagent is one or more of sodium carbonate, potassium phosphate and potassium hydroxide.
3. The method for synthesizing the N-acetyl- [1,4,5] -oxydiazepine according to claim 2, wherein the method comprises the following steps: the alkaline reagent is potassium hydroxide.
4. The process for the synthesis of N-acetyl- [1,4,5] -oxydiazepane according to claim 1, characterized in that the isolation obtained is purified: and cooling the reaction liquid to room temperature, filtering, washing a filter cake with N, N-dimethylformamide, merging obtained filtrate, evaporating and concentrating, cooling to 0 ℃, separating out solid, filtering, washing the obtained filter cake with N-amyl alcohol, and drying to obtain the N-acetyl- [1,4,5] -oxydiazepine.
5. The method for synthesizing the N-acetyl- [1,4,5] -oxydiazepine according to claim 1, wherein the method comprises the following steps: the organic solvent is N, N-dimethylformamide.
6. The method for synthesizing the N-acetyl- [1,4,5] -oxydiazepine according to claim 1, wherein the method comprises the following steps: the volume of the organic solvent is 6-15mL/g based on the mass of the acethydrazide.
7. The method for synthesizing the N-acetyl- [1,4,5] -oxydiazepine according to claim 1, wherein the method comprises the following steps: the reaction system also comprises potassium iodide, wherein the molar ratio of the potassium iodide to the acethydrazide is 0.01-0.2:1.
8. the method for synthesizing the N-acetyl- [1,4,5] -oxydiazepine according to claim 1, wherein the method comprises the following steps: the phase transfer catalyst is tetrabutylammonium bromide.
9. The method for synthesizing the N-acetyl- [1,4,5] -oxydiazepine according to claim 1, wherein the method comprises the following steps: the 2,2 '-disubstituted diethyl ether is 2,2' -dichlorodiethyl ether.
10. A process for the synthesis of N-acetyl- [1,4,5] -oxydiazepane according to claim 1, characterized in that it comprises: uniformly dispersing an alkaline reagent, acetylhydrazine, a phase transfer catalyst and 2,2' -disubstituted diethyl ether in an organic solvent to construct a reaction system, carrying out cyclization reaction for 5 hours at 100 ℃, and separating and purifying the obtained reaction solution to obtain the N-acetyl- [1,4,5] -oxydiazepine;
the phase transfer catalyst is tetrabutylammonium bromide; the 2,2 '-disubstituted diethyl ether is 2,2' -dichlorodiethyl ether; the molar ratio of the acethydrazide, the alkaline reagent, the phase transfer catalyst, the 2,2' -disubstituted diethyl ether and the potassium iodide is 1:3:0.05:2:0.05.
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