WO2023228083A1

WO2023228083A1 - A process for the preparation of pentoxifylline intermediate

Info

Publication number: WO2023228083A1
Application number: PCT/IB2023/055301
Authority: WO
Inventors: Ketan Chandubhai BUHA; Purushottamdas Ramdhani SONI; Hirendra Kiritkumar BHAGATWALA; Jignasu Thakorbhai DESAI; Sanjay Lakhabhai Vasoya
Original assignee: Ami Organics Ltd.
Priority date: 2022-05-23
Filing date: 2023-05-23
Publication date: 2023-11-30

Abstract

The present disclosure relates to a process for the preparation of pentoxifylline intermediate. Particularly, the present disclosure relates to a process for the preparation of 6-chloro-2- hexanone. The present disclosure provides an alternative process for the preparation of 6-chloro-2-hexanone by using non-hazardous and cheap reagents. Thus, the process of the present disclosure is cost efficient, economic and environmental friendly.

Description

A PROCESS FOR THE PREPARATION OF PENTOXIFYLLINE INTERMEDIATE

FIELD

The present disclosure relates to a process for the preparation of pentoxifylline intermediate. Particularly, the present disclosure relates to a process for the preparation of 6-chloro-2- hexanone.

BACKGROUND

The background information herein below relates to the present disclosure but is not necessarily prior art.

6-chloro-2-hexanone is a key intermediate used in the synthesis of pentoxifylline. Pentoxifylline, also known as oxpentifylline, is a xanthine derivative used for the treatment of muscle pain (in human) with peripheral artery disease. Pentoxifylline is sold under many brand names worldwide.

Various methods for the preparation of 6-chloro-2-hexanone are reported in the art. Conventionally, the preparation of 6-chloro-2-hexanone is carried out by using reagents which are expensive, hazardous to environment and difficult to recover. One of the reported methods discloses the synthesis of 6-chloro-2 -hexanone by using sodium methoxide powder, which is not feasible for commercial scale as sodium methoxide is fire hazard. Another reported method discloses the synthesis of 6-chloro-2 -hexanone by oxidation of 1- methylcyclopentanol in the presence of ozone and sodium hypochlorite. However, the oxidation reactions are avoided commercially due to the runaway reaction behaviour. Further, the reagents such as ozone and sodium hypochlorite are environmental hazards. Still another reported method discloses the use of chlorine gas for the synthesis of 6-chloro-2 -hexanone, wherein 1 -methylcyclopentyl hypochlorite intermediate is formed which is an unstable byproduct. The formation of by-product leads to lower yield of the desired product and subsequently, the by-product generation results in environmental hazard.

Moreover, the conventional processes of preparing 6-chloro-2 -hexanone result in obtaining the product with a low yield and a less purity and thus, not suitable for commercial scale-up. In addition, these conventional processes involve tedious purification stages, thereby making the process expensive. Therefore, there is felt a need to provide an alternative process for preparing 6-chloro-2- hexanone that mitigates the drawbacks mentioned hereinabove or at least provides a useful alternative.

OBJECTS

Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:

An object of the present disclosure is to ameliorate one or more problems of the background or to at least provide a useful alternative.

Another object of the present disclosure is to provide a process for the preparation of pentoxifylline intermediate, particularly, 6-chloro-2 -hexanone.

Still another object of the present disclosure is to provide a process for the preparation of 6- chloro-2 -hexanone with a comparatively high yield and high purity.

Yet another object of the present disclosure is to provide a simple, efficient, environmental friendly and economical process for the preparation of 6-chloro-2 -hexanone.

Still another object of the present disclosure is to provide a process for the preparation of 6- chloro-2 -hexanone that employs cheap, non-hazardous and easily available reagents.

Yet another object of the present disclosure is to provide a process for the preparation of 6- chloro-2 -hexanone that is feasible at industrial scale-up.

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 relates to a process for the preparation of pentoxifylline intermediate. Particularly, the present disclosure relates to a process for the preparation of 6-chloro-2- hexanone. The process comprises the step of reacting 1,3-dihalopropane with an alkyl acetoacetate by using a base in a fluid medium at first predetermined conditions to obtain an intermediate. The intermediate is treated with a halogenating agent at second predetermined conditions to obtain a product mixture comprising a crude pentoxifylline intermediate. The crude pentoxifylline intermediate is isolated and purified to obtain a pure pentoxifylline intermediate.

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, known processes or well-known apparatus or 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 are 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.

Moreover, the conventional processes of preparing 6-chloro-2-hexanone result in obtaining the product with a low yield and a less purity and thus, not suitable for commercial scale-up. In addition, these conventional processes involve tedious purification stages, thereby making the process expensive.

The present disclosure provides a simple, economic and environmental friendly process for the preparation of pentoxifylline intermediate, particularly, 6-chloro-2 -hexanone.

6-chloro-2 -hexanone

The schematic representation of the process for the preparation of 6-chloro-2-hexanone is given below as Scheme 1 :

Scheme 1 wherein,

Ris Ci to Cio alkyl; and Xi, X₂ and X₃ are independently selected from -Br, -Cl and -I.

The process for preparing pentoxifylline intermediate comprises the following steps:

(i) reacting 1,3-dihalopropane with an alkyl acetoacetate by using a base in a fluid medium at first predetermined conditions to obtain an intermediate;

(ii) treating the intermediate with a halogenating agent at second predetermined conditions to obtain a product mixture comprising a crude pentoxifylline intermediate; and

(iii)isolating and purifying the crude pentoxifylline intermediate to obtain a pure pentoxifylline intermediate.

The process for preparing pentoxifylline intermediate is described in detail herein below.

Step (i): Preparation of alkyl 6-methyl-3,4-dihydro-2H-pyran-5-carboxylate (intermediate of 6-chloro-2 -hexanone)

The process for preparing alkyl 6-methyl-3,4-dihydro-2H-pyran-5-carboxylate comprises the following sub-steps: a. mixing predetermined amounts of 1,3-dihalopropane and an alkyl acetoacetate in a predetermined amount of a first fluid medium under stirring at a temperature in the range of 25 °C to 40 °C to obtain a first mixture; b. adding a first predetermined amount of a first base in portions to the first mixture and heating at a first predetermined temperature for a first predetermined time period to obtain a reaction mixture; c. adjusting pH of the reaction mixture in the range of 6.5 to 7.5 by adding a weak acid and filtering to obtain a filtrate comprising alkyl 6-methyl-3,4-dihydro-2H-pyran-5- carboxylate followed by washing the filtrate to obtain a resultant filtrate; and d. distilling the resultant filtrate to obtain a residual mass comprising alkyl 6-methyl-3,4- dihydro-2H-pyran-5 -carboxylate .

In a first embodiment of the present disclosure, a second predetermined amount of the first base is added in portions to the reaction mixture so obtained in sub-step (b) and heating at a temperature in the range of 60 °C to 90 °C for a time period in the range of 15 hours to 35 hours to obtain a mass comprising alkyl 6-methyl-3,4-dihydro-2H-pyran-5-carboxylate and the first fluid medium; and distilling out the first fluid medium from the mass and cooling the resultant mass to a temperature in the range of 25 °C to 40 °C to obtain a cooled mass which is followed by sub-steps (c) and (d).

In accordance with the first embodiment, in the sub-step (c), the filtrate is washed with the first fluid medium.

In a second embodiment of the present disclosure, the reaction mixture so obtained in substep (b) is filtered and washed with methylene chloride to obtain a filtrate which is followed by sub-steps (c) and (d).

In accordance with the second embodiment, in the sub-step (c), the filtrate is washed with methylene chloride and water in a predetermined volume ratio to obtain a biphasic mixture comprising an organic layer and an aqueous layer. The organic layer was separated from the biphasic mixture and the organic layer is subjected to atmospheric distillation to remove methylene chloride to obtain the residual mass. The residual mass is vacuum distilled to obtain alkyl 6-methyl-3,4-dihydro-2H-pyran-5 -carboxylate.

The predetermined volume ratio is in the range of 1:2 to 1:4. In an exemplary embodiment of the present disclosure, the predetermined volume ratio is 1:2.5.

1,3-dihalopropane is selected from the group consisting of l-bromo-3-chloropropane, 1,3- dibromopropane and 1,3 -dichloropropane. In an exemplary embodiment of the present disclosure, 1,3-dihalopropane is l-bromo-3 -chloropropane. In another exemplary embodiment of the present disclosure, 1,3-dihalopropane is 1,3 -dibromopropane.

The alkyl acetoacetate is selected from the group consisting of methyl acetoacetate, ethyl acetoacetate, butylacetoacetate and t-butyl acetoacetate. In an exemplary embodiment of the present disclosure, the alkyl acetoacetate is methyl acetoacetate. In another exemplary embodiment of the present disclosure, the alkyl acetoacetate is ethyl acetoacetate.

The first fluid medium is selected from the group consisting of ethanol, methanol, propanol, isopropanol and butanol. In an exemplary embodiment of the present disclosure, the first fluid medium is ethanol. In another exemplary embodiment of the present disclosure, the first fluid medium is methanol.

In accordance with the present disclosure, the first base is selected from an inorganic base and an organic base.

The inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide and mixtures thereof.

The organic base is selected from the group consisting of triethylamine, diisopropylethylamine, trimethylamine, pyridine, 2-methyl pyridine, 3 -methylpyridine and 4- methylpyridine.

In an exemplary embodiment of the present disclosure, the first base is sodium hydroxide. In another exemplary embodiment of the present disclosure, the first base is potassium carbonate.

The first predetermined temperature is in the range of 60 °C to 90 °C. In an embodiment of the present disclosure, the first predetermined temperature is in the range of 70 °C to 80 °C. In an exemplery embodiment of the present disclosure, the first predetermined temperature is 80 °C. In another exemplery embodiment of the present disclosure, the first predetermined temperature is 70 °C.

The first predetermined time period is in the range of 15 hours to 35 hours. In an embodiment of the present disclosure, the first predetermined time period is in the range of 18 hours to 22 hours. In an exemplery embodiment of the present disclosure, the first predetermined time period is 20 hours.

The weak acid is selected from the group consisting of acetic acid, propionic acid, formic acid, butyric acid, isobutyric acid. In an exemplary embodiment of the present disclosure, the weak acid is acetic acid.

In an embodiment of the present disclosure, the first fluid medium is distilled out from the mass at a temperature in the range of 80 °C to 90 °C.

Step 2: Preparation of crude pentoxifylline intermediate The process for preparing crude pentoxifylline intermediate comprises the following substeps: a. treating the residual mass comprising alkyl 6-methyl-3,4-dihydro-2H-pyran-5- carboxylate obtained in step- 1 with a solution of halogenating agent at a temperature in the range of 20 °C to 40 °C to obtain a second mixture; and b. heating the second mixture to a second predetermined temperature followed by passing the halogenating agent in an anhydrous gas form for a second predetermined time period to obtain a product mixture comprising a crude pentoxifylline intermediate.

The halogenating agent is selected from the group consisting of hydrogen chloride and hydrogen bromide. In an embodiment, the halogenating agent is hydrogen chloride solution. In another embodiment, the halogenating agent is anhydrous hydrogen chloride gas. In still another embodiment, the halogenating agent is a combination of hydrogen chloride solution and anhydrous hydrogen chloride gas.

The second predetermined temperature is in the range of 50 °C to 70 °C. In an exemplary embodiment of the present disclosure, the second predetermined temperature is 55 °C.

The second predetermined time period is in the range of 1 hour to 4 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 2 hours.

Step 3: Isolation and purification of the crude pentoxifylline intermediate

The process for isolating and purifying the crude pentoxifylline intermediate comprises the following sub-steps: a. cooling the product mixture obtained in step-2 to a temperature in the range of 20 °C to 40 °C and adding predetermined amounts of water and a second fluid medium to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer; b. separating the first organic layer from the first biphasic mixture and adjusting the pH of the first organic layer in the range of 6 to 7 by adding a second base to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer; c. separating the second organic layer from the second biphasic mixture and distilling out the second fluid medium from the separated second organic layer to obtain a residue comprising pentoxifylline intermediate; and d. vacuum distilling the residue at a third predetermined temperature to obtain a pure pentoxifylline intermediate.

The second fluid medium is selected from the group consisting of methylene dichloride (MDC). In an exemplary embodiment of the present disclosure, the second fluid medium is methylene dichloride.

In accordance with the present disclosure, the second base is selected from an inorganic base and an organic base.

The inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and mixtures thereof. In an exemplary embodiment of the present disclosure, the second base is sodium bicarbonate.

The pure pentoxifylline intermediate is vacuum distilled at a temperature in the range of 90 °C to 110 °C. In an embodiment of the present disclosure, the vacuum distillation temperature is in the range of 95 °C to 105 °C. In an exemplery embodiment of the present disclosure, the vacuum distillation temperature is 100 °C.

In a first exemplary embodiment of the present disclosure, the schematic representation of the process for the preparation of 6-chloro-2 -hexanone is given below as Scheme la:

Scheme la In a second exemplary embodiment of the present disclosure, the schematic representation of the process for the preparation of 6-chloro-2 -hexanone is given below as Scheme lb:

Scheme lb In a third exemplary embodiment of the present disclosure, the schematic representation of the process for the preparation of 6-chloro-2 -hexanone is given below as Scheme 1c:

Scheme 1c

In a fourth exemplary embodiment of the present disclosure, the schematic representation of the process for the preparation of 6-chloro-2 -hexanone is given below as Scheme Id:

Scheme Id

In a fifth exemplary embodiment of the present disclosure, the schematic representation of the process for the preparation of 6-chloro-2 -hexanone is given below as Scheme le:

Scheme le

In a sixth exemplary embodiment of the present disclosure, the schematic representation of the process for the preparation of 6-chloro-2 -hexanone is given below as Scheme If:

Scheme If

In a seventh exemplary embodiment of the present disclosure, the schematic representation of the process for the preparation of 6-chloro-2 -hexanone is given below as Scheme 1g:

Scheme 1g

In an eighth exemplary embodiment of the present disclosure, the schematic representation of the process for the preparation of 6-chloro-2 -hexanone is given below as Scheme Ih:

Scheme Ih

In an embodiment of the present disclosure, the pentoxifylline intermediate has a purity in the range of 98.5% to 99.5% and a yield in the range of 60% to 70%. Particularly, the purity of pentoxifylline intermediate is in the range of 98.9% to 99.1% and the yield is in the range of 62% to 65%.

The present disclosure provides an alternative process for the preparation of 6-chloro-2- hexanone by using non-hazardous and cheap reagents. As a result of using non-hazardous, inexpensive and easily available reagents, the process of the present disclosure is cost efficient, economic and environmental friendly.

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 illustrated herein below with the help of the following experiments. The experiments used herein are intended merely to facilitate an understanding of the 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 experiments should not be construed as limiting the scope of embodiments herein. These laboratory scale experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial/commercial scale.

EXPERIMENTAL DETAILS

Experiment 1: Preparation of 6-chloro-2-hexanone (pentoxifylline intermediate) in accordance with the present disclosure

Example 1:

A first reactor was charged with 1250 ml of ethanol, 500 g of l-bromo-3 -chloropropane and 534 g of ethyl acetoacetate under stirring at 30 °C to obtain a first mixture. 255 g of sodium hydroxide was added in portions to the first mixture and the temperature was raised and maintained at 80 °C for 20 hours to obtain a reaction mixture. The reaction mixture was cooled to 75 °C to obtain a cooled reaction mixture. 100 g of sodium hydroxide was again added in portions to the cooled reaction mixture and the temperature was raised to 80 °C and further maintained at 86 °C to obtain a mass comprising ethyl-6-methyl-3,4-dihydro-2H- pyran-5 -carboxylate and ethanol. Ethanol was distilled out at atmospheric pressure and the resultant mass was cooled to 30 °C to obtain a cooled mass. pH of the cooled mass was adjusted to 7 by adding acetic acid and filtering to obtain a filtrate comprising ethyl-6- methyl-3,4-dihydro-2H-pyran-5 -carboxylate followed by washing the filtrate with 100 ml ethanol to obtain a resultant filtrate. Ethanol was distilled out from the resultant filtrate to obtain a residual mass comprising ethyl-6-methyl-3,4-dihydro-2H-pyran-5-carboxylate.

1610 ml of cone. HC1 was taken in a second reactor and the residual mass was charged in the second reactor at 30 °C to obtain a second mixture. The second mixture was heated to 55 °C and anhydrous hydrogen chloride gas was purged into the second reactor containing the second mixture for 2 hours to obtain a product mixture comprising a crude 6-chloro-2- hexanone. The product mixture was cooled to 30 °C followed by adding 1600 ml of water and 2015 ml of methylene dichloride to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer. The first organic layer was separated from the first biphasic mixture and the separated organic layer was washed with 403 ml of water to obtain a washed organic layer. pH of the washed organic layer was adjusted to 7 by adding sodium bicarbonate solution to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer was separated from the second biphasic mixture and methylene dichloride (organic layer) was distilled out from the separated second organic layer to obtain a residue comprising 6-chloro-2-hexanone. The residue was cooled to 30 °C followed by vacuum distilling the residue at 100 °C to obtain a pure 6-chloro-2 -hexanone having yield 62% and purity 99%.

Example 2:

A first reactor was charged with 1250 ml of methanol, 500 g of l-bromo-3 -chloropropane and 477 g of methyl acetoacetate under stirring at 30 °C to obtain a first mixture. 255 g of sodium hydroxide was added in portions to the first mixture and the temperature was raised and maintained at 70 °C for 20 hours to obtain a reaction mixture. The reaction mixture was cooled to 65 °C to obtain a cooled reaction mixture. 100 g of sodium hydroxide was again added in portions to the cooled reaction mixture and the temperature was raised to 70 °C and further maintained at 70 °C to obtain a mass comprising methyl-6-methyl-3,4-dihydro-2H- pyran-5 -carboxylate and methanol. Methanol was distilled out at atmospheric pressure and the resultant mass was cooled to 30 °C to obtain a cooled mass. pH of the cooled mass was adjusted to 7 by adding acetic acid and filtering to obtain a filtrate comprising methyl-6- methyl-3,4-dihydro-2H-pyran-5 -carboxylate followed by washing the filtrate with 100 ml methanol to obtain a resultant filtrate. Methanol was distilled out from the resultant filtrate to obtain a residual mass comprising methyl-6-methyl-3,4-dihydro-2H-pyran-5-carboxylate.

1610 ml of cone. HC1 was taken in a second reactor and the residual mass was charged in the second reactor at 30 °C to obtain a second mixture. The second mixture was heated to 55 °C and anhydrous hydrogen chloride gas was purged into the second reactor containing the second mixture for 2 hours to obtain a product mixture comprising crude 6-chloro-2- hexanone.

The product mixture was cooled to 30 °C followed by adding 1430 ml of water and 2015 ml of methylene dichloride to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer. The first organic layer was separated from the first biphasic mixture and the separated organic layer was washed with 403 ml of water to obtain a washed organic layer. pH of the washed organic layer was adjusted to 7 by adding sodium bicarbonate solution to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer was separated from the second biphasic mixture and methylene dichloride (organic layer) was distilled out from the separated second organic layer to obtain a residue comprising crude 6-chloro-2-hexanone. The residue was cooled to 30 °C followed by vacuum distilling the residue at 100 °C to obtain the pure 6-chloro-2- hexanone having yield 64 % and purity 99 %.

Example 3:

A first reactor was charged with 850 ml of ethanol, 532 g of 1,3-dibromopropane and 300 g of ethyl acetoacetate under stirring at 30 °C to obtain a first mixture. 728.5 g of potassium carbonate was added in portions to the first mixture and the temperature was raised and maintained at 75 °C for 20 hours to obtain a reaction mixture. The reaction mixture was filtered and washed with methylene chloride to obtain a filtrate. pH of the filtrate was adjusted to 7 by adding acetic acid. Ethanol was distilled out at atmospheric pressure to obtain a resultant mixture followed by cooling to 30 °C to obtain a cooled resultant mixture. Methylene chloride and water (in a volume ratio of 1:2.5) was added to the resultant mixture at 30°C to obtain a biphasic mixture comprising an organic layer (methylene chloride) and an aqueous layer. The organic layer was separated from the biphasic mixture and the organic layer is subjected to atmospheric distillation to remove methylene chloride to obtain the residual mass. The residual mass is vacuum distilled to obtain ethyl-6-methyl-3,4-dihydro- 2H-pyran-5 -carboxylate .

1710 ml of cone. HC1 was taken in a second reactor and the residual mass was charged in the second reactor at 30 °C to obtain a second mixture. The second mixture was heated to 55 °C and anhydrous hydrogen chloride gas was purged into the second reactor containing the second mixture for 2 hours to obtain a product mixture comprising crude 6-chloro-2- hexanone.

The product mixture was cooled to 30 °C followed by adding 1050 ml of water and 2145 ml of methylene dichloride to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer. The first organic layer was separated from the first biphasic mixture and the separated organic layer was washed with 403 ml of water to obtain a washed organic layer. pH of the washed organic layer was adjusted to 7 by adding sodium bicarbonate solution to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer was separated from the second biphasic mixture and methylene dichloride (organic layer) was distilled out from the separated second organic layer to obtain a residue comprising crude 6-chloro-2-hexanone. The residue was cooled to 30 °C followed by vacuum distilling the residue at 100 °C to obtain the pure 6-chloro-2- hexanone having yield 65 % and purity 99 %.

Example 4:

The same procedure of Example 3 was repeated except 850 ml of methanol and 300 g of methyl acetoacetate were used to obtain the pure 6-chloro-2-hexanone having yield 64 % and purity 99 %.

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 the preparation of 6-chloro-2-hexanone (pentoxifylline intermediate), wherein;

• the process provides 6-chloro-2 -hexanone with high purity and in greater yields;

• the process employs inexpensive, non-hazardous and easily available reagents;

• the process is simple, efficient, economic and environment friendly; and

• the process is feasible at industrial scale-up.

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

CLAIMS:

1. A process for preparing pentoxifylline intermediate, said process comprising the following steps:

(i) reacting 1,3-dihalopropane with an alkyl acetoacetate by using a base in a fluid medium at first predetermined conditions to obtain an intermediate, alkyl 6- methyl-3 ,4-dihydro-2H-pyran-5 -carboxylate ;

(ii) treating said intermediate with a halogenating agent at second predetermined conditions to obtain a product mixture comprising a crude pentoxifylline intermediate; and

(iii) isolating and purifying said crude pentoxifylline intermediate to obtain a pure pentoxifylline intermediate.

2. The process as claimed in claim 1, wherein said first predetermined conditions include a first predetermined temperature and a first predetermined time period; and said second predetermined conditions include a second predetermined temperature and a second predetermined time period.

3. The process as claimed in claim 1, wherein said alkyl 6-methyl-3,4-dihydro-2H- pyran-5 -carboxylate is prepared by the following sub-steps: a. mixing predetermined amounts of 1,3-dihalopropane and an alkyl acetoacetate in a first fluid medium under stirring at a temperature in the range of 25 °C to 40 °C to obtain a first mixture; b. adding a first base in portions to said first mixture and heating at a first predetermined temperature for a first predetermined time period to obtain a reaction mixture; c. adjusting pH of said reaction mixture in the range of 6.5 to 7.5 by adding a weak acid and filtering to obtain a filtrate comprising alkyl 6-methyl-3,4- dihydro-2H-pyran-5 -carboxylate followed by washing said filtrate to obtain a resultant filtrate; and d. distilling the resultant fdtrate to obtain a residual mass comprising alkyl 6- methyl-3 ,

4-dihydro-2H-pyran-5 -carboxylate . . The process as claimed in claim 3, wherein 1,3-dihalopropane is selected from the group consisting of l-bromo-3 -chloropropane, 1,3 -dibromopropane and 1,3- dichloropropane.

5. The process as claimed in claim 3, wherein said alkyl acetoacetate is selected from the group consisting of methyl acetoacetate, ethyl acetoacetate, butylacetoacetate and t- butyl acetoacetate.

6. The process as claimed in claim 3, wherein said first fluid medium is selected from the group consisting of ethanol, methanol, propanol, isopropanol and butanol.

7. The process as claimed in claim 3, wherein said first base is selected from an inorganic base and an organic base.

8. The process as claimed in claim 7, wherein said inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium tert- butoxide, potassium tert-butoxide and mixtures thereof; and said organic base is selected from the group consisting of triethylamine, diisopropylethylamine, trimethylamine, pyridine, 2-methyl pyridine, 3 -methylpyridine and 4-methylpyridine.

9. The process as claimed in claim 3, wherein said first predetermined temperature is in the range of 60 °C to 90 °C; and said first predetermined time period is in the range of 15 hours to 30 hours.

10. The process as claimed in claim 3, wherein said first predetermined temperature is in the range of 70 °C to 80 °C; and said first predetermined time period is in the range of 18 hours to 22 hours.

11. The process as claimed in claim 3, wherein said weak acid is selected from the group consisting of acetic acid, formic acid, butyric acid, isobutyric acid, propionic acid and pentanoic acid.

12. The process as claimed in claim 1, wherein said crude pentoxifylline intermediate is prepared by the following sub-steps: a. treating said residual mass comprising alkyl 6-methyl-3,4-dihydro-2H-pyran- 5 -carboxylate as claimed in claim 3 with a solution of a halogenating agent at a temperature in the range of 20 °C to 40 °C to obtain a second mixture; and b. heating said second mixture to a second predetermined temperature followed by passing said halogenating agent in an anhydrous gas form for a second predetermined time period to obtain a product mixture comprising said crude pentoxifylline intermediate.

13. The process as claimed in claim 12, wherein said halogenating agent is selected from the group consisting of hydrogen chloride and hydrogen bromide.

14. The process as claimed in claim 12, wherein said second predetermined temperature is in the range of 50 °C to 70 °C; and said second predetermined time period is in the range of 1 hour to 4 hours.

15. The process as claimed in claim 12, wherein said second predetermined temperature is 55 °C; and said second predetermined time period is 2 hours.

16. The process as claimed in claim 1, wherein said crude pentoxifylline intermediate is isolated and purified by the following sub-steps: a. cooling said product mixture as claimed in claim 11 to a temperature in the range of 20 °C to 40 °C and adding predetermined amounts of water and a second fluid medium to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer; b. separating said first organic layer from said first biphasic mixture and adjusting the pH of said separated first organic layer in the range of 6 to 7 by adding a second base to obtain a second biphasic mixture comprising a second organic layer and a second aqueous layer; c. separating said second organic layer from said second biphasic mixture and distilling out said second fluid medium from said separated second organic layer to obtain a residue comprising pentoxifylline intermediate; and d. vacuum distilling said residue at a third predetermined temperature to obtain a pure pentoxifylline intermediate.

17. The process as claimed in claim 16, wherein said second base is selected from an inorganic base and an organic base.

18. The process as claimed in claim 17, wherein said inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and mixtures thereof; and said organic base is selected from the group consisting of triethylamine, diisopropylethylamine, trimethylamine, pyridine, 2-methyl pyridine, 3 -methylpyridine and 4-methylpyridine.

19. The process as claimed in claim 16, wherein said third predetermined temperature is in the range of 90 °C to 110 °C.

20. The process as claimed in claim 16, wherein said third predetermined temperature is 100 °C.

21. The process as claimed in claim 1, wherein said pentoxifylline intermediate has a purity in the range of 98.5% to 99.5% and a yield in the range of 60% to 70%.

22. The process as claimed in claim 1, wherein said purity of pentoxifylline intermediate is in the range of 98.9% to 99. 1% and said yield is in the range of 62% to 65%.

23. The process as claimed in claim 1, wherein said pentoxifylline intermediate is 6- chloro-2 -hexanone .

24. A process for preparing 6-chloro-2 -hexanone, said process comprising the following steps:

(i) reacting 1,3-dihalopropane with an alkyl acetoacetate by using a base in a fluid medium at a temperature in the range of 60 °C to 90 °C for a time period in the range of 15 hours to 30 hours to obtain an intermediate, alkyl 6-methyl-3,4- dihydro-2H-pyran-5 -carboxylate ;

(ii) treating said intermediate with a halogenating agent at a temperature in the range of 50 °C to 70 °C for a time period in the range of 1 hour to 4 hours to obtain a product mixture comprising a crude 6-chloro-2 -hexanone; and

(iii) isolating and purifying said crude 6-chloro-2 -hexanone to obtain a pure 6- chloro-2 -hexanone . e process as claimed in claim 24, comprising the following steps:

(i) reacting l-bromo-3 -chloropropane with an ethyl acetoacetate by using sodium hydroxide in ethanol at a temperature in the range of 60 °C to 90 °C for a time period in the range of 15 hours to 30 hours to obtain an intermediate, ethyl 6- methyl-3 ,4-dihydro-2H-pyran-5 -carboxylate ;

(ii) treating said intermediate with hydrogen chloride at a temperature in the range of 50 °C to 70 °C for a time period in the range of 1 hour to 4 hours to obtain a product mixture comprising a crude 6-chloro-2 -hexanone; and

(i) reacting l-bromo-3 -chloropropane with an methyl acetoacetate by using sodium hydroxide in methanol at a temperature in the range of 60 °C to 90 °C for a time period in the range of 15 hours to 30 hours to obtain an intermediate, ethyl 6-methyl-3,4-dihydro-2H-pyran-5-carboxylate;

(iii) isolating and purifying said crude 6-chloro-2 -hexanone to obtain a pure 6- chloro-2 -hexanone . The process as claimed in claim 24, comprising the following steps:

(i) reacting 1,3 -dibromopropane with an ethyl acetoacetate by using potassium carbonate in ethanol at a temperature in the range of 60 °C to 90 °C for a time period in the range of 15 hours to 30 hours to obtain an intermediate, ethyl 6- methyl-3 ,4-dihydro-2H-pyran-5 -carboxylate ;

(iii) isolating and purifying said crude 6-chloro-2-hexanone to obtain a pure 6- chloro-2 -hexanone . The process as claimed in claim 24, comprising the following steps:

(i) reacting 1,3 -dibromopropane with an methyl acetoacetate by using potassium carbonate in methanol at a temperature in the range of 60 °C to 90 °C for a time period in the range of 15 hours to 30 hours to obtain an intermediate, ethyl 6-methyl-3,4-dihydro-2H-pyran-5-carboxylate;

(iii) isolating and purifying said crude 6-chloro-2 -hexanone to obtain a pure 6- chloro-2 -hexanone . The process as claimed in claim 24, wherein said pentoxifylline intermediate has a purity in the range of 98.5% to 99.5% and a yield in the range of 60% to 70%. The process as claimed in claim 24, wherein said purity of pentoxifylline intermediate is in the range of 98.9% to 99. 1% and said yield is in the range of 62% to 65%.