DESC:FIELD
The present disclosure relates to a process for preparing an intermediate pharmaceutical compound, particularly 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
Eliglustat is an active pharmaceutical ingredient (API), which is used for the treatment of type 1 Gaucher disease. Eliglustat is synthesized from 2, 3-dihydro-1, 4-benzodioxine-6-carbaldehyde (represented by Formula A). Therefore, the quality of Formula A will significantly impact the quality of the final API.

Conventionally, several methods are reported for the synthesis of Formula A. However, these methods are associated with drawbacks such as low yield and low purity. Further, these methods involve tedious purification processes, hazardous reaction conditions and high cost.
Conventionally, the compound is manufactured by a dealkylation process at temperatures ranging from 0°C to 20°C using chloroform as a solvent. Further, the reaction work up uses organic solvents such as petroleum ether resulting in tedious operations and high costs.
There is, therefore, felt a need to provide a process for preparation of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (Formula A) which obviates the drawbacks mentioned hereinabove. Particularly, it is desired that the process involves simple operations, easy purification, low production costs and is environmentally friendly.
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 simple and economical process for preparing 2, 3-dihydro-1, 4-benzodioxine-6-carbaldehyde (Formula A).
Yet another object of the present disclosure is to provide an environment friendly process for preparing 2,3-dihydro-benzioxine-6-carbaldehyde.
Still another object of the present disclosure is to provide a process for preparing 2, 3-dihydro-1, 4-benzodioxine-6-carbaldehyde (Formula A) with relatively high yield and high purity.
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
In accordance with the present disclosure, there is provided a process for preparing 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde, the process comprising the following steps
i) dealkylating 4-hydroxy-3-methoxybenzaldehyde with aluminium chloride and pyridine, using dichloromethane as a solvent, to obtain 3,4-dihydroxybenzaldehyde,
ii) etherifying 3,4-dihydroxybenzaldehyde with 1,2-dichloroethane and potassium carbonate using a fluid medium, to obtain a product mixture comprising 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde,
iii) separating 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde from the product mixture to obtain 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde.
The dealkylation in step (i) is carried out at a temperature in the range of 35 °C to 45 °C for 22 hours to 26 hours under continuous stirring.
The etherification in step (ii) is carried out at a temperature in the range of 80 °C to 84 °C for 10 hours to 12 hours.
In step (iii), the separation of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde from the product mixture is carried out by the following steps:
a) cooling the product mixture comprising 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde to a temperature in the range of 25 °C to 30 °C and filtering to obtain a filtrate comprising 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde and at least one fluid medium,
b) distilling the filtrate at a temperature in the range of 55 °C to 60 °C to obtain a residue containing 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde,
c) mixing the residue with water to obtain an aqueous mixture of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde,
d) stirring the aqueous mixture of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde to obtain a homogenous mixture,
e) cooling the homogenous mixture to 10°C to 12 °C for a time period in the range of 1 hours to 2 hours to obtain a suspension containing 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde,
f) filtering the suspension to obtain a residue comprising 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde of purity in the range of 95.0 % to 99.5 % and yield in the range of 70% to 80%.
Stirring in step (d) is carried out at a temperature in the range of 30°C to 35°C for a time period in the range of 1 hour to 2 hours.
The fluid medium used in step (ii) is at least one selected from the group consisting of acetone, N, N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethylsulphoxide.
The distillation in step (b) is carried out under reduced pressure.
DETAILED DESCRIPTION
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.
As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed elements.
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.
Eliglustat is an active pharmaceutical ingredient (API), which is used for the treatment of type 1 Gaucher disease. Eliglustat is synthesized from Formula A. In the present disclosure Formula A is synthesized from 3,4-dihydroxybenzaldehyde (Formula II), which in turn is synthesized from 4-hydroxy-3-methoxybenzaldehyde (Formula I). The present disclosure envisages a simple and economical process for preparing 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (Formula A) with high purity.
The present disclosure provides a process for the preparation of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (Formula A).

A schematic description of the process of the present disclosure is provided below.
Step 1: Dealkylation of 4-hydroxy-3-methoxybenzaldehyde (Formula I)

Step 2: Etherification of 3, 4-dihydroxybenzaldehyde (Formula II)

Dealkylation of 4-hydroxy-3-methoxybenzaldehyde (Formula I) is carried out with aluminium chloride and pyridine using dichloromethane as a solvent to obtain a product mixture comprising 3,4-dihydroxybenzaldehyde (Formula II). The dealkylation is carried out in a stepwise manner. The first step involves, solubilizing 4-hydroxy-3-methoxybenzaldehyde in dichloromethane followed by adding pyridine and aluminium chloride at a temperature in the range of 30 °C to 40 °C. The reaction mixture is stirred at a temperature in the range of 35 °C to 45 °C for 22 hours to 26 hours to obtain a product mixture. Water and dilute hydrochloric acid are added to the product mixture, and stirred at a temperature in the range of 30 °C to 35 °C for 6-8 hours. The aqueous layer of the product mixture comprising Formula II is extracted with ethyl acetate followed by distillation under reduced pressure. Dichloromethane is added to the extracted Formula II and the mixture is filtered to obtain crude Formula II. Crude Formula II is washed by using dichloromethane to obtain Formula II having a yield in the range of 70.0% to 80.0% and purity in the range of 95.0% to 99.5 %.
In accordance with one embodiment of the present disclosure, Formula II is produced with a yield of 77.0% and purity of 99.0%.
Etherification of Formula II is carried out with 1,2-dichloroethane using potassium carbonate in a fluid medium to obtain a product mixture comprising 2, 3-dihydro-1, 4-benzodioxine-6-carbaldehyde (Formula A). The etherification is carried out in a stepwise manner. In the first step, Formula II, 1,2 –dichloroethane, potassium carbonate and a fluid medium are mixed at a temperature in the range of 75 °C to 80 °C for 4 hours to 5 hours, followed by refluxing the reaction mixture at a temperature in the range of 80 °C to 84 °C for 10 hours to 12 hours to obtain a product mixture containing Formula A. This is followed by the step of separating Formula A from the product mixture by filtration to obtain a residue and a filtrate comprising Formula A. The filtrate is subjected to distillation to distil out 1,2-dichloroethane under reduced pressure at 55 °C to 60 °C to obtain a residue containing Formula A. The residue comprising Formula A is cooled to a temperature in the range selected from 30 °C to 35 °C. Water is added to the cooled residue comprising Formula A and the resultant cooled residue comprising Formula A is stirred at a temperature in the range of 30 °C to 35 °C for 1 hour to 2 hours. The residue comprising Formula A is cooled further to a temperature in the range of 10 °C to 12 °C and stirred for 1 hour to 2 hours to obtain a cooled residue comprising Formula A, which is filtered to obtain crude Formula A. Crude Formula A is washed with water to obtain Formula A with an yield in the range of 70.0% to 80.0% and having purity in the range of 95.0% to 99.5 %.
The fluid medium used for etherification can be at least one selected from the group consisting of acetone, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethylsulphoxide.
In accordance with one embodiment of the present disclosure, the fluid medium used for etherification is N, N-dimethylformamide.
In accordance with another embodiment of the present disclosure the fluid medium used for etherification is N-methyl-2-pyrrolidone.
In accordance with one embodiment of the present disclosure, the etherifying step is carried out at 82 °C for 12 hours under continuous stirring.
Typically, the residue comprising Formula A is cooled further to temperature 11 °C and stirred for 1.5 hours to obtain a cooled residue comprising Formula A, which is filtered to obtain crude Formula A.
In accordance with one embodiment of the present disclosure, Formula A is produced with a yield of 77.0% and purity of 99.0% when N, N-dimethylformamide is used as a solvent in step (ii).
In accordance with another embodiment of the present disclosure a yield of 80.0% and purity of 99.0% when N-methyl-2-pyrrolidone is used as a solvent in step (ii).
The process of present disclosure provides Formula II with high purity by a simple process involving extraction with ethyl acetate and washing using dichloromethane. Formula II can be used for the next step without further purification. Further, the etherification of Formula II provides Formula A with high purity by a simple process involving cooling the product mixture, filtering and washing the product with water. Thus, the etherification provides Formula A with high purity and without the need for a purification step.
Thus, the process of the present disclosure is environmentally friendly as the process does not use hazardous chemicals such as petroleum ether for the extraction or purification as used in the known prior art methods. Further, the process of the present disclosure uses commonly available and inexpensive reagents and fluid media. Furthermore, the process of the present disclosure has mild reaction conditions, simple operations, easy purification, and low production costs.
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.
EXPERIMENT
Experiment 1:
Step 1: Dealkylation of 4-hydroxy-3-methoxybenzaldehyde (Formula I)
4-Hydroxy-3-methoxybenzaldehyde (500 g) was dissolved in dichloromethane (2500 ml) to obtain a solution. Pyridine (858 g) was mixed with the solution under stirring at 30 °C., Aluminium chloride (610 g) was added in portions to the solution at 38 °C, to obtain a reaction mass. The reaction mass was stirred at 40 °C for 24 hours to obtain a product mass.
The product mass was added to dilute hydrochloric acid (1500 g) and water (3500 ml) at 32°C and the product mass was stirred at 32°C for 6 hours. An aqueous layer was isolated from the product mass and extracted with ethyl acetate 3 times. The 3 extracts were combined and ethyl acetate was removed from the product mass by distillation under reduced pressure to obtain a residue. The residue obtained was suspended in dichloromethane (1000 ml) and stirred for 30 minutes. The product suspension was filtered to obtain a residue. The residue obtained was washed with dichloromethane and dried to obtain 350 g of 3,4-dihydroxybenzaldehyde (Formula II) with a yield of 77.0 % and purity of 99.0% by HPLC.

Step 2: Etherification of 3,4-dihydroxybenzaldehyde (Formula II)
A solution of 3,4-dihydroxybenzaldehyde (400 g) in N, N-dimethylformamide (600 ml) was added to a solution of 1,2-dichloroethane (2000 g) and potassium carbonate (1000 g) at 78 °C for 4 hours to obtain a reaction mass. The reaction mass was stirred at 82 °C for 12 hours to obtain a product mass. The product mass was cooled to 28 °C and filtered to obtain a filtrate containing Formula A. The filtrate containing 1,2-dichloroethane was distilled under reduced pressure at 58 °C to obtain the residue containing Formula A. The residue containing Formula A was further cooled to 33 °C and water (2400 ml) was added at 33 °C to obtain a solution containing Formula A. The solution containing Formula A was cooled to 11°C and stirred for 1 hour to obtain a suspension containing Formula A. The suspension containing Formula A was filtered to obtain a crude Formula A. The crude Formula A was washed with water (400 ml) and dried to obtain 360 g of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (Formula A) with a yield of 75.0% and purity of 99.0% by HPLC.
Experiment 2:
Step 1: Dealkylation of 4-hydroxy-3-methoxybenzaldehyde (Formula I)
4-Hydroxy-3-methoxybenzaldehyde (500 g) was dissolved in dichloromethane (2500 ml) to obtain a solution. Pyridine (858 g) was mixed with the solution under stirring at 30 °C., Aluminium chloride (610 g) was added in portions to the solution at 38 °C, to obtain a reaction mass. The reaction mass was stirred at 40 °C for 24 hours to obtain a product mass.
The product mass was added to dilute hydrochloric acid (1500 g) and water (3500 ml) at 32°C and the product mass was stirred at 32°C for 6 hours. An aqueous layer was isolated from the product mass and extracted with ethyl acetate 3 times. The 3 extracts were combined and ethyl acetate was removed from the product mass by distillation under reduced pressure to obtain a residue. The residue obtained was suspended in dichloromethane (1000 ml) and stirred for 30 minutes. The product suspension was filtered to obtain a residue. The residue obtained was washed with dichloromethane and dried to obtain 350 g of 3,4-dihydroxybenzaldehyde (Formula II) with a yield of 77.0 % and purity of 99.0% by HPLC.
Step 2: Etherification of 3,4-dihydroxybenzaldehyde (Formula II)
A solution of 3,4-dihydroxybenzaldehyde (400 g) in N-methyl-2-pyrrolidine (600 ml) was added to a solution of 1,2-dichloroethane (2000 g) and potassium carbonate (1000 g) at 78 °C for 4 hours to obtain a reaction mass. The reaction mass was stirred at 82 °C for 12 hours to obtain a product mass. The product mass was cooled to 28 °C and filtered to obtain a filtrate containing Formula A. The filtrate containing 1,2-dichloroethane was distilled under reduced pressure at 58 °C to obtain the residue containing Formula A. The residue containing Formula A was further cooled to 33 °C and water (2400 ml) was added at 33 °C to obtain a solution containing Formula A. The solution containing Formula A was cooled to 11°C and stirred for 1 hour to obtain a suspension containing Formula A. The suspension containing Formula A was filtered to obtain a crude Formula A. The crude Formula A was washed with water (400 ml) and dried to obtain 385 g of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (Formula A) with a yield of 80.0% and purity of 99.0% by HPLC.
TECHNICAL ADVANCES AND ECONOMICAL SIGNIFICANCE
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of a process for preparation of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (Formula A); that is
• simple,
• environment friendly,
• results in low production costs, and
• results in a pure product with high yield.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
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 disclosure to achieve one or more of the desired objects or results.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.
While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments 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 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde, said process comprising the following steps:
i) dealkylating 4-hydroxy-3-methoxybenzaldehyde with aluminium chloride and pyridine, using dichloromethane as a solvent, to obtain 3,4-dihydroxybenzaldehyde,
ii) etherifying 3,4-dihydroxybenzaldehyde with 1,2-dichloroethane and potassium carbonate using a fluid medium, to obtain a product mixture comprising 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde, and
iii) separating 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde from said product mixture to obtain 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde.
2. The process as claimed in claim 1, wherein said dealkylation in step (i) is carried out at a temperature in the range of 35 °C to 45 °C for 22 hours to 26 hours under continuous stirring.
3. The process as claimed in claim 1, wherein said etherification in step (ii) is carried out at a temperature in the range of 80 °C to 84 °C for 10 hours to 12 hours.
4. The process as claimed in claim 1, wherein in step (iii), separation of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde from the product mixture is carried out by the following steps:
a) cooling said product mixture comprising 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde to a temperature in the range of 25 °C to 30 °C and filtering to obtain a filtrate comprising 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde and at least one fluid medium,
b) distilling said filtrate at a temperature in the range of 55 °C to 60 °C to obtain a residue containing 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde, and
c) mixing said residue with water to obtain an aqueous mixture of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde,
d) stirring said aqueous mixture of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde to obtain a homogenous mixture,
e) cooling said homogenous mixture to 10°C to 12 °C for a time period in the range of 1 hours to 2 hours to obtain a suspension containing 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde,
f) filtering said suspension to obtain a residue comprising 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde of purity in the range of 95.0 % to 99.5 % and yield in the range of 70% to 80%.
5. The process as claimed in claim 4, wherein stirring in step (d) is carried out at a temperature in the range of 30°C to 35°C for a time period in the range of 1 hour to 2 hours.
6. The process as claimed in claim 1, wherein said fluid medium used in step (ii) is at least one selected from the group consisting of acetone, N, N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethylsulphoxide.
7. The process as claimed in claim 4, wherein said distillation is carried out under reduced pressure.