DESC:FIELD
The present disclosure relates to a process for preparing 1,4,5-hexahydro-oxadiazepine hydrochloride.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
1,4,5-Hexahydro oxadiazepine hydrochloride is a useful intermediate in the preparation of herbicides. Various methods for preparing 1,4,5-Hexahydro oxadiazepine hydrochloride and its derivatives are known.

However, the known processes for preparing 1,4,5-Hexahydro oxadiazepine hydrochloride are complex, time consuming, use expensive raw material and are labour intensive. Further, the yield and purity of 1,4,5-Hexahydro oxadiazepine hydrochloride obtained using these conventional processes is low and hence they are not commercially feasible.
Therefore, there is felt a need for a process for preparing 1,4,5-hexahydro oxadiazepine hydrochloride that mitigates the drawbacks mentioned hereinabove.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for preparing 1,4,5-hexahydro oxadiazepine hydrochloride.
Still another object of the present disclosure is to provide a process for preparing 1,4,5-hexahydro oxadiazepine hydrochloride in high yield and with high purity.
Yet another object of the present disclosure is to provide a simple, efficient, and economic process for preparing 1,4,5-hexahydro oxadiazepine hydrochloride.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure provides a process for preparing 1,4,5-hexahydro oxadiazepine hydrochloride. The process comprises acetylating hydrazine, by adding hydrazine to ethyl acetate under stirring, at a temperature in the range of 25 °C to 35 °C to obtain mono acetyl hydrazine. The mono acetyl hydrazine is further acetylated, by slowly adding acetic anhydride to the mono acetyl hydrazine, at a temperature in the range of 25 °C to 35 °C to obtain N,N’-diacetylhydrazine. Separately, diethylene glycol is chlorinated using a chlorinating agent, in the presence of a catalyst in a halogenated fluid medium, at a temperature in the range of 50 °C to 90 °C to obtain 2,2’-dichlorodiethyl ether. 2,2’ dichlorodiethyl ether is reacted with N,N’-diacetylhydrazine, by using a phase transfer catalyst, a base and a nucleophillic catalyst in a fluid medium to obtain 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine. 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine is treated with a salt forming agent to obtain 1,4,5-hexahydro oxadiazepine hydrochloride salt.
The molar ratio of hydrazine to ethyl acetate is in the range of 1:1 to 1:1.2, and the molar ratio of hydrazine to acetic anhydride is in the range of 1:0.95 to 1:1.05.
The phase transfer catalyst is tetrabutyl ammonium bromide in an amount in the range of 1 mole% to 5 mole% with respect to N,N’-diacetylhydrazine.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING
The process for preparing 1,4,5-hexahydro oxadiazepine hydrochloride of present disclosure will now be described with the help of the accompanying drawing, in which:
Figure-1 illustrates the X-ray powder diffractogram (X-RPD) of the crystalline form of oxadiazepine hydrochloride, obtained by the process of the present disclosure; and
Figure-2 illustrates the FTIR spectra of the crystalline form of oxadiazepine hydrochloride, obtained by the process of the present disclosure.
DETAILED DESCRIPTION
Embodiments, of the present disclosure, will now be described with reference to the accompanying drawing.
Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details, are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc.,when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
Conventional processes for preparing 1,4,5-hexahydro oxadiazepine hydrochloride are complex, use expensive raw material, are time consuming, labour intensive and provide low yields. Hence the methods known in the art are not suitable for large scale production of 1,4,5-hexahydro oxadiazepine hydrochloride.
The present disclosure provides a simple, efficient and economic process for the preparation of 1,4,5-hexahydro oxadiazepine hydrochloride with high yield and high purity.
In an aspect, the present disclosure provides a process for preparing 1,4,5-hexahydro-oxadiazepine hydrochloride.
The process is hereinafter described in detail.
The process for preparing 1,4,5-hexahydro oxadiazepine hydrochloride comprises the following steps:
Step I: Synthesis of diacetyl hydrazine from hydrazine.
The schematic representation of the synthesis of N,N’-diacetylhydrazine in accordance with the present disclosure is given below as scheme-I.

In the first step hydrazine is acetylatedg, by adding hydrazine to ethyl acetate under stirring, at a temperature in the range of 25 °C to 35 °C to obtain a solution comprising mono acetyl hydrazine. of the so obtained mono acetyl hydrazine in the solution, is further acetylated by slowly adding acetic anhydride to the solution, at a temperature in the range of 25 °C to 35 °C to obtain N,N’-diacetylhydrazine.
In an embodiment, an hydrazine solution is mixed with ethyl acetate and stirred for four hours at a temperature in the range of 25°C to 30 °C to obtain a clear solution. The so obtained clear solution is continuously further stirred at 25°C to 30 °C for 3 to 5 hours, followed by the slow addition of acetic anhydride at a temperature in the range of 25 °C to 30 °C. The consumption of mono acetyl hydrazine is monitored by Gas Liquid Chromatography (GLC). After complete consumption of the mono acetyl hydrazine, the work up of the mixture comprising N,N’-diacetylhydrazine is carried out using known methods.
The so obtained mixture comprising N,N’-diacetylhydrazine is continuously stirred for 3 to 4 hours. Chlorobenzene is added to the reaction mixture at a temperature in the range of 25 °C to 30 °C, and stirred for 0.5 hour to 1.5 hour. After complete addition of chlorobenzene, the mixture comprising N,N’-diacetylhydrazine, is cooled while stirring, to a temperature in the range of 0 °C to 1 °C to obtain a slurry comprising N, N’-diacetylhydrazine. The slurry is filtered to obtain N,N’-diacetylhydrazine having a purity in the range of 97.5% to 99.5 % and a filtrate. In an exemplary embodiment, the purity of N,N’-diacetylhydrazine is 99.2 %
The filtrate obtained from the first filtration is concentrated under reduced pressure. The concentrated filtrate is cooled to a temperature in the range of 0 °C to 5 °C and filtered to obtain a residue (N,N’-diacetylhydrazine) and a second filtrate. The residue is washed with monochlorobenzene and dried to obtain N,N’-diacetylhydrazine having purity in the range of 96.5% to 98.5%. In an exemplary embodiment, the purity of N,N’-diacetylhydrazine is 98.3%.
The second filtrate obtained is concentrated to obtain N,N’-diacetylhydrazine having purity in the range of 86.5 to 88.5%. In an exemplary embodiment, the purity is 88%.
In view of same, maximum product purity is reached.
In accordance with the present disclosure, the molar ratio of hydrazine to ethyl acetate is in the range of 1:1 to 1:1.2, and the molar ratio of hydrazine to acetic anhydride is in the range of 1:0.95 to 1:1.05.
The present disclosure uses ethyl acetate as solvent, as well as a reactant for acetylation of hydrazine. Further, by using abundantly available, cost effective acetylating agent like ethyl acetate as a reagent to form mono acetyl hydrazine, the present disclosure limits the use of toxic, expensive and regulated chemicals such as acetic anhydride. Thus, the present disclosure, which does not use any organic solvent is simple, economic and environmental friendly.
Step II: Synthesis of 2,2’-dichlorodiethyl ether.
The schematic representation of synthesis of 2,2’-dichlorodiethyl ether in accordance with the present disclosure is provided below in Scheme-II.

Separately, in a second step, diethylene glycol is chlorinated using a chlorinating agent, in the presence of a catalyst in a halogenated fluid medium, at a temperature in the range of 50 °C to 90 °C to obtain 2,2’-dichlorodiethyl ether.
In an embodiment, diethylene glycol is mixed with a catalyst in a halogenated fluid medium to obtain a clear solution.
In accordance with the present disclosure, the amount of halogenated fluid medium is in the range of 175 ml to 225 ml per mole of diethylene glycol.
In accordance with the present disclosure, the halogenated fluid medium is selected from ethylene dichloride (EDC), monochlorobenzene (MCB), and dichloromethane (DMC). In an exemplary embodiment the halogenated fluid medium is ethylene dichloride (EDC).
In accordance with the embodiments of the present disclosure, the catalyst is selected from dimethylformamide (DMF), and pyridine. In an exemplary embodiment the catalyst is dimethylformamide (DMF).
The catalyst is in the range of 0.05 mole% to 0.5 mole%.
The so obtained clear solution is heated at a temperature in the range of 65 °C to 75°C to obtain a heated solution. A chlorinating agent is slowly added below the surface of the heated solution for 8 hours to 10 hours to obtain a mixture comprising 2,2’-dichlorodiethyl ether.
In accordance with the present disclosure, the ratio of the diethylene glycol to the chlorinating agent is in the range of 1:1 to 1:1.1.
In accordance with the present disclosure, the chlorinating agent is thionyl chloride (SOCl2).
The gases released from the reaction mixture during the reaction are absorbed in an alkali scrubber.
The consumption of diethylene glycol is monitored by Gas Liquid Chromatography (GLC). After completion of the reaction, the work up of the mixture comprising 2,2’-dichlorodiethyl ether is carried out using known methods.
The work up of the mixture comprising 2,2’-dichlorodiethyl ether is carried out by bubbling an inert gas below the surface of the product mixture to drive off the gases in the alkali scrubber. Further, alkali metal carbonate is added to the mixture comprising 2,2’-dichlorodiethyl ether, under continuous stirring and the mixture comprising 2,2’-dichlorodiethyl ether is fractionated over a column packed with ceramics to obtain a fraction containing 2,2’-dichlorodiethyl ether at a temperature in the range of 70 °C to 80°C and at a predetermined pressure. In an exemplary embodiment, the predetermined pressure is 40 mm and the inert gas is nitrogen. The alkali metal carbonate is selected from sodium carbonate and potassium carbonate. In an exemplary embodiment, the alkali metal carbonate is sodium carbonate.
The 2,2’- dichlorodiethyl ether obtained has a purity in the range of 97% to 99% and a yield in the range of 81% to 85%.
In an exemplary embodiment, the purity of 2,2’-dichlorodiethyl ether is 98.5 % and the yield is 83%.
Step-III: Synthesis of 4,5-diacetyl-hexahydro-1,4,5-oxadizepine
The schematic representation of the synthesis of 4,5-diacetyl-hexahydro-1,4,5-oxadizepine in accordance with the present disclosure is given below as scheme III.

2,2’ dichlorodiethyl ether is reacted with N,N’-diacetylhydrazine, using a phase transfer catalyst, a base and a nucleophillic catalyst in a fluid medium to obtain 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine.
In an embodiment, N,N’-diacetylhydrazine is dissolved in a fluid medium under continuous stirring to obtain a clear solution. A base is added to the clear solution under continuous stirring for a time period in the range of 10 minutes to 15 minutes, followed by the addition of 2,2’- dichlorodiethyl ether obtained in step-II under continuous stirring to obtain a reaction mixture.
The fluid medium is selected from dimethyl sulphoxide (DMSO) and dimethyl formamide (DMF).
In an exemplary embodiment the fluid medium is dimethyl sulphoxide (DMSO).
In accordance with the present disclosure, the phase transfer catalyst is tetrabutyl ammonium bromide in an amount in the range of 1 mole% to 5 mole% with respect to N,N’-diacetylhydrazine.
The base is selected from sodium carbonate (Na2CO3), and potassium carbonate (K2CO3). In an exemplary embodiment the base is sodium carbonate (Na2CO3).
In accordance with the present disclosure, the nucleophillic catalyst is potassium Iodide (KI) in an amount in the range of 1 mole% to 5 mole% with respect to N,N’-diacetylhydrazine.
A mixture of a phase transfer catalyst and nucleophillic catalyst is added to the so obtained reaction mixture. The reaction mixture is heated at a temperature in range of 72°C to 76°C to obtain a heated reaction mixture.
Powdered base is added in portions to the heated reaction mixture at a temperature in the range of 72°C to 78 °C in 3 hours to 4 hours to obtain a slurry comprising base. The reaction is monitored for the consumption of N,N’-diacetylhydrazine, by Gas Liquid Chromatography (GLC). After completion of the reaction, the work up of the so obtained product mixture comprising 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine is carried out using known methods.
The so obtained product mixture comprising 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine, is cooled to a temperature in the range of 15 °C to 25 °C, under continuous stirring for a time period in the range of 0.5 hour to 1.5 hour to obtain a product slurry. The slurry is filtered to obtain a filtrate and a residue. The residue is washed with DMSO and dried. The filtrate and wash mixture is concentrated at a temperature in the range of 125 °C to 135 °C and a predetermined pressure to obtain a concentrated mixture of 4,5-diacetyl-hexahydro-1,4,5-oxadizepine. In an exemplary embodiment, the predetermined pressure is 5 mm.
Step-IV: Synthesis of 1,4,5-hexahydro oxadiazepine hydrochloride
The schematic representation of the synthesis of 1,4,5-hexahydro oxadiazepine hydrochloride in accordance with an embodiment of the present disclosure is given below:

In this step, 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine is treated with a salt forming agent to obtain 1,4,5-hexahydro oxadiazepine hydrochloride salt.
In accordance with the present disclosure, the salt forming agent is hydrogen chloride (HCl).
The concentrated mixture obtained in step-III is mixed in diethylene glycol to obtain a slurry. The slurry is heated at a temperature in the range of 40°C to 45°C and then dry HCl gas is passed below the surface of the slurry at a temperature in a range of 45°C to 50 °C for a time period in the range of 10 hours to 12 hours. Thereafter, the slurry is continuously stirred at a temperature in a range of 50°C to 55 °C, for a time period in the range of 10 hours to 16 hours. The reaction is monitored by Gas Liquid Chromatography (GLC). After completion of the reaction, the work up of the so obtained mixture comprising 1,4,5-hexahydro oxadiazepine hydrochloride salt is carried out using known methods.
Nitrogen gas is bubbled through the slurry below surface to drive off the dissolved HCl gas at a temperature in a range of 50 °C to 55 °C. The slurry is cooled to a temperature in a range of 0 °C to 1°C and filtered to obtain a residue and a filtrate. The residue is resuspended in 0.8 ml to 1 ml of isopropyl alcohol per gram of residue and dried under reduced pressure at a temperature in the range 50 °C to 55 °C to obtain 1,4,5–hexahydro oxadiazepine hydrochloride having a yield in a range of 36% to 50%. In an exemplary embodiment, the yield of 1,4,5–hexahydro oxadiazepine hydrochloride is 38%.
In another exemplary embodiment, the yield of 1,4,5–hexahydro oxadiazepine hydrochloride is 47%.
The Diethylene glycol is recovered and used in step-IV. The filtrate obtained in step-IV is concentrated and mixed with diethylene glycol filtrate obtained in the first step. The filtrate is stirred with methanol in a range 0.2 ml to 0.8 ml of methanol per ml of filtrate, under reflux for 10 hours to 12 hours. The reaction is monitored by Gas Liquid Chromatography (GLC). After completion of the reaction, the work up of the so obtained 1,4,5-hexahydro oxadiazepine hydrochloride salt is carried out using known methods.
The mixture comprising 1,4,5-hexahydro oxadiazepine hydrochloride salt is concentrated to recover methanol and distilled under reduced pressure at a temperature in a range of 130 °C to 140 °C, at a predetermined pressure to obtain a distillate. In an embodiment, the predetermined pressure is 2 mm. In an embodiment, the recovered distillate is used in step-IV instead of fresh diethylene glycol to obtain 1,4,5–hexahydro oxadiazepine hydrochloride with a yield of 42%.
The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial scale.
Experimental details:
Experiment 1: Synthesis of 1,4,5 –hexahydro oxadiazepine hydrochloride from hydrazine and diethylene glycol.
Step-I: - Synthesis of N, N’-diacetylhydrazine.
Aqueous hydrazine (1255 gms, 20 moles) was added to ethyl acetate (1936 gms, 22 moles) under continuous stirring over 5 hours at a temperature of 27 °C and the resultant mixture was maintained at 27 °C for 4 hours to obtain a clear solution containing mono acetyl hydrazine. Acetic anhydride (2040 gms) was added to the above solution over 2 hours at a temperature of 30 °C and the reaction mixture was stirred for 4 hours to obtain a slurry containing N,N’-diacetyl hydrazine. The reaction was monitored by GLC (gas liquid chromatography) for 4 hours until the mono acetyl hydrazine content in the slurry was reduced to <1%. Chlorobenzene (200 ml/mole of N,N’-diacetyl hydrazine) was added to the slurry and the diluted slurry was equilibrated at 30°C for 1 hour. The equilibrated slurry was cooled to 0 °C under continuous stirring. The cooled slurry was filtered to collect solids comprising crude N, N’-diacetylhydrazine and a first filtrate. The crude N, N’-diacetylhydrazine was washed with chilled monochlorobenzene (MCB) and dried to obtain N, N’-diacetylhydrazine [Yield=1850 gm; purity (GLC) = 99.2%].
The first filtrate obtained was combined with the MCB wash to obtain a mixture. The so obtained mixture was concentrated under continuous stirring and reduced pressure, by distilling out MCB to obtain a concentrated mass. The concentrated mass was cooled to 0 °C and filtered to obtain a residue of solids (product) and a second filtrate. The residue of solids was dried to obtain N, N’-diacetylhydrazine [Yield=318 gm; purity (GLC) = 98.3%]. The second filtrate was further concentrated by distilling out MCB to obtain N,N’-diacetylhydrazine [Yield=85 gm; purity (GLC) = 88%]
Step-II: - Synthesis of 2,2’-dichlorodiethyl ether.
Diethylene glycol (530 gms, 5 moles) was mixed with 1,2-dichloroethane (1000 ml, 200 ml/mole of DEG) followed by mixing dimethyl formamide (10 ml) to obtain a clear solution. The clear solution was heated to 70 °C to obtain a heated solution. Thionyl chloride (1190 gms, or 2 moles of thionyl chloride per mole of diethylene glycol) was slowly added into the heated solution, over 10 hours and the reaction mixture was maintained at 70 °C for 4 hours to obtain a mixture comprising 2,2’-dichlorodiethyl ether. The gases released from the reaction mixture were scrubbed in an alkali scrubber. The reaction was monitored by GLC (Gas Liquid Chromatography). After completion of the reaction, nitrogen gas was bubbled into the mixture comprising 2,2’-dichlorodiethyl ether to drive off the off gases in the scrubber. Sodium carbonate (25 gms) was added to the scrubbed mixture under continuous stirring to obtain a slurry. The slurry comprising comprising 2,2’-dichlorodiethyl ether was subjected to distillation using a 1’ fractionation column packed with ceramics to collect a fraction at 75 °C and at 40 mm Hg that contained 2,2’-dichlorodiethyl ether [Yield=602 gm (83%); purity (GLC)=98.5%].
Step-III: - Preparation of 4,5-diacetyl-hexhydro-1,4,5-oxadiazepine.
N, N’ diacetylhydrazine (292 gms/ 2.5 moles) was mixed with DMSO (3000 gms/1200 gms/mole) under continuous stirring in a reactor to obtain a clear solution. Potassium carbonate (690 gms/5 moles) was added to the clear solution under continuous stirring over 15 minutes, followed by addition of 2,2’-dichlorodiethyl ether (450 gms/3 moles), under continuous stirring to obtain a slurry. A mixture of tetrabutyl ammonium bromide (2 mole%) and potassium iodide (2 mole%) was added to the slurry and the resultant mixture was heated to 75 °C. Potassium hydroxide (335 gms/5 moles) was added in portions to the heated mixture at 75 °C over 4 hours to obtain a slurry containing diacetyl oxadiazepine. The heated mixture was monitored by Gas Liquid Chromatography (GLC) for the formation of diacetyl oxadiazepine. After completion of the reaction the heated mixture was cooled to 20 °C under continuous stirring for 1 hour. The cooled product mixture was filtered to obtain solids of diacetyl oxadiazepine and a filtrate. The solids of diacetyl oxadiazepine were washed with DMSO and dried. The filtrate and the DMSO wash were distilled at 130 °C under a reduced pressure of 5mm to obtain a concentrated mass of 4,5-diacetyl-1,4,5 –hexahydro oxadiazepine [Yield=479 gms]
Step-IV: - Preparation of 1,4,5 –hexahydro oxadiazepine hydrochloride.
Example-1:
The concentrated mass of 4,5-Diacetyl-1,4,5–hexahydro oxadiazepine (240 gms, 1.25 mole) obtained in step-III was mixed in diethylene glycol (312 ml, 250 ml/mole of 4,5-diacetyl-1,4,5-hexahydro-oxadiazepine) to form a slurry. The slurry was heated to 45 °C and dry HCl gas (3.5 mole/mole) was passed into the slurry at 45 °C for 12 hours, and the slurry was maintained at 50-55 °C for 16 hours to obtain a product mixture. The reaction was monitored by Gas Liquid Chromatography (GLC) for the formation of oxadiazepine. Nitrogen was bubbled through the product mixture to remove dissolved HCl gas at 55 °C till no HCl gas was detected in the scrubber. The product mixture was cooled to 0 °C and filtered to obtain a crude oxadiazepine.HCl. The crude oxadiazepine.HCl was suspended in 1 ml of isopropyl alcohol per gm of oxadiazepine.HCl, at 0 °C for 1 hour to obtain oxadiazepine slurry. The oxadiazepine slurry was filtered to obtain a solid containing wet oxadiazepine.HCl and a filtrate of isopropyl alcohol. The solid was dried under reduced pressure at 55°C to obtain 1,4,5-hexahydro oxadiazepine hydrochloride [Yield=85gm; yield on purity starting from N,N’-diacetyl hydrazine = 38%]
The isopropyl alcohol filtrate obtained was concentrated and mixed with the filtrate. The filtrate was stirred with 0.5 ml of methanol per ml of filtrate, under reflux, for 12 hours to obtain a reaction mass. The reaction was monitored by Gas Liquid Chromatography (GLC). The reaction mass was concentrated to recover methanol and methyl acetate. The concentrated mass was further distilled off under reduced pressure of 2 mm at 135°C to obtain a distillate. The distillate was used in step 4 instead of fresh diethylene glycol.
The X-ray powder diffractogram (X-PRD) of the crystalline form of 1,4,5–hexahydro oxadiazepine hydrochloride synthesized by the process of the present disclosure is represented in Figure-1.
2 theta I/Io
15.430 100
18.980 64
19.930 21
21.330 19
22.590 25
24.070 96
24.420 19
26.230 55
29.260 50
30.790 17
31.140 52
32.870 27
35.310 29
36.270 17
37.000 16
The FTIR spectrum of the crystalline form of 1,4,5–hexahydro oxadiazepine hydrochloride synthesized by the process of the present disclosure is represented in Figure-2.
Example-2:
Concentrated mass of 4,5-diacetyl-1,4,5–hexahydro oxadiazepine (1.625 kg, 9.41 moles) obtained in step-III was dissolved in recovered diethylene glycol (2.353 litres, 250 ml/mole of diacetyl-oxadiazepine) to form a slurry. The slurry was heated to 45 °C and dry HCl gas (3.5 mole/mole of oxediazepin) was passed into the slurry at 45 °C, for 31 hours, and the slurry was equilibrated at 60 °C for 16 hours to obtain a product mixture. The reaction was monitored by Gas Liquid Chromatography (GLC) for the formation of oxadiazepine. Nitrogen was bubbled through the product mixture to remove dissolved HCl gas at 60 °C till no HCl gas was detected in the scrubber. The product mixture was cooled to 0 °C and filtered to obtain a crude oxadiazepine. The crude oxadiazepine was suspended in 1 ml of isopropyl alcohol per gm of oxadiazepine, at 0 °C for 1 hour to obtain oxadiazepine slurry. The oxadiazepine slurry was filtered to obtain a solid containing wet oxadiazepine and a filtrate of isopropyl alcohol. The solid was dried under reduced pressure at 55 °C to obtain 1,4,5-hexahydro oxadiazepine hydrochloride [Yield = 860 gms; yield on purity starting from N,N’-diacetyl hydrazine = 47%].
TECHNICAL ADVANCEMENTS
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of:
- a simple process for preparation of 1,4,5–hexahydro oxadiazepine hydrochloride; and
- a process that provides comparatively high yield and high purity of 1,4,5 –hexahydro oxadiazepine hydrochloride.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.
The numerical values given for various physical parameters, dimensions and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.
While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.
,CLAIMS:We Claim
1. A process for preparing 1,4,5-hexahydro oxadiazepine hydrochloride, said process comprising the following steps:
i) acetylating hydrazine, by adding hydrazine to ethyl acetate under stirring, at a temperature in the range of 25 °C to 35 °C to obtain mono acetyl hydrazine;
ii) acetylating mono acetyl hydrazine, by slowly adding acetic anhydride to mono acetyl hydrazine, at a temperature in the range of 25 °C to 35 °C to obtain N,N’-diacetylhydrazine;
iii) separately, chlorinating diethylene glycol using a chlorinating agent, in the presence of a catalyst in a halogenated fluid medium, at a temperature in the range of 50 °C to 90 °C to obtain 2,2’-dichlorodiethyl ether;
iv) reacting 2,2’ dichlorodiethyl ether with N,N’-diacetylhydrazine, using a phase transfer catalyst, a base and a nucleophillic catalyst in a fluid medium to obtain 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine; and
v) treating 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine with a salt forming agent to obtain 1,4,5-hexahydro oxadiazepine hydrochloride salt.
2. The process as claimed in claim 1, wherein the molar ratio of the hydrazine to the ethyl acetate is in the range of 1:1 to 1:1.2, and the molar ratio of the hydrazine to the acetic anhydride is in the range of 1:0.95 to 1:1.05.
3. The process as claimed in claim 1, wherein the halogenated fluid medium is selected from ethylene dichloride (EDC), monochlorobenzene (MCB), and dichloromethane (DMC).
4. The process as claimed in claim 1, wherein the catalyst is dimethylformamide (DMF), in an amount in the range of 0.05 mole% to 0.5 mole%.
5. The process as claimed in claim 1, wherein the ratio of the diethylene glycol to the chlorinating agent is in the range of 1:1 to 1:1.1.
6. The process as claimed in claim 1, wherein the chlorinating agent is thionyl chloride (SOCl2).
7. The process as claimed in claim 1, wherein the phase transfer catalyst is tetrabutyl ammonium bromide in an amount in the range of 1 mole% to 5 mole% with respect to N,N’-diacetylhydrazine.
8. The process as claimed in claim 1, wherein the base is selected from sodium carbonate (Na2CO3), and potassium carbonate (K2CO3).
9. The process as claimed in claim 1, wherein the nucleophillic catalyst is potassium Iodide (KI) in an amount in the range of 1 mole% to 5 mole% with respect to N,N’-diacetylhydrazine.
10. The process as claimed in claim 1, wherein the salt forming agent is hydrogen chloride (HCl).