DESC:FIELD
The present disclosure relates to a process for the preparation of 4-Piperidone HCl hydrate.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
4-Piperidone HCl Hydrate represented as Formula (I) is used as an intermediate in the manufacture of chemicals and pharmaceutical drugs such as Lumateperone and Efinaconazole. It is a starting material for the synthesis of fentanyl (hydrochloride), which is a potent opioid agonist with analgesic and anaesthetic properties.

Formula (I)
The widespread use of 4-Piperidone HCl hydrate requires its production on a large scale. The conventional route for preparing 4-Piperidone HCl Hydrate includes multiple steps that uses expensive and toxic reagents and has low product yield and purity.
Therefore, there is felt a need to provide a process for the preparation of 4-Piperidone HCl Hydrate, that mitigates the drawbacks mentioned herein above.

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.
An object of the present disclosure is to provide a process for the preparation of 4-Piperidone HCl hydrate.
Another object of the present disclosure is to provide a process for the preparation of 4-Piperidone HCl hydrate in a comparatively high yields and in high purity.
Yet another object of the present disclosure is to provide a simple, economical, and eco-friendly process for the preparation of 4-Piperidone HCl hydrate.
Still another object of the present disclosure is to provide a process for the preparation of 4, 4-dimethoxypiperidine intermediate in a comparatively high yield and in 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:
The present disclosure relates to a process for the preparation of 4-Piperidone HCl Hydrate. The process comprises etherifying N-Carbethoxy-4-piperidone by using trimethyl orthoformate in the presence of an acid catalyst in a fluid medium at a first predetermined temperature for a first predetermined time period to obtain N-Carbethoxy-4,4-dimethoxypiperdine. N-Carbethoxy-4,4-dimethoxypiperdine is hydrolyzed by using a base at a second predetermined temperature for a second predetermined time period to obtain 4,4-dimethoxypiperdine. 4,4-dimethoxypiperdine is reacted with hydrochloric acid at a third predetermined temperature for a third predetermined time period to obtain 4-Piperidone HCl Hydrate.
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.
4-Piperidone HCl Hydrate represented as Formula (I) is used as an intermediate in the manufacture of a wide variety of chemicals and pharmaceutical drugs.

Formula (I)
CAS number: 40064-34-4

The conventional route of preparing 4-Piperidone HCl Hydrate uses expensive and toxic reagents and the product obtained has a low yield and a low purity.
The present disclosure provides a process for the preparation of 4-Piperidone HCl Hydrate. The process of the present disclosure is simple and environment friendly that provides 4-Piperidone HCl Hydrate in high yield and high purity.
The process for the preparation of 4-Piperidone HCl Hydrate comprises the following steps:
i. etherifying N-Carbethoxy-4-piperidone by using trimethyl orthoformate in the presence of an acid catalyst in a fluid medium at a first predetermined temperature for a first predetermined time period to obtain N-Carbethoxy-4,4-dimethoxypiperdine;
ii. hydrolyzing N-Carbethoxy-4,4-dimethoxypiperdine by using a base at a second predetermined temperature for a second predetermined time period to obtain 4,4-dimethoxypiperdine; and
iii. reacting 4,4-dimethoxypiperdine with hydrochloric acid at a third predetermined temperature for a third predetermined time period to obtain 4-Piperidone HCl Hydrate.
In an embodiment of the present disclosure, the schematic representation of the synthetic route for preparing 4-Piperidone HCl hydrate (I) is given below as scheme I.

Scheme I
The process for the preparation of 4-Piperidone HCl Hydrate in accordance with the present disclosure is described in detail herein below:
Step 1- Preparation of 4,4-dimethoxypiperdine from N-Carbethoxy-4-piperidone:
N-carbethoxy 4-piperidone, a fluid medium and trimethyl orthoformate are mixed under stirring at 25 °C to 30 °C to obtain a mixture. The temperature of the mixture is raised to 37 °C to 40 °C and an acid catalyst is added in portions to obtain a reaction mass. After complete addition of acid catalyst, the reaction mass is maintained at room temperature for 15 minutes followed by raising the temperature of the reaction mass to a first pre-determined temperature and maintaining the first pre-determined temperature for a first predetermined time period to obtain a mass comprising N-Carbethoxy-4, 4-dimethoxypiperdine.
In accordance with the present disclosure, the fluid medium is selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol. In an exemplary embodiment, the fluid medium is methanol.
In accordance with the present disclosure, the acid catalyst is selected from the group consisting of p-toluene sulphonic acid (PTSA), sulphuric acid, anhydrous hydrochloric acid and anhydrous hydrobromic acid. In an exemplary embodiment, the acid catalyst is p-toluene sulphonic acid (PTSA).
In accordance with the present disclosure, an amount of the acid catalyst is in the range of 0.2 mass% to 10 mass% with respect to total mass of the mixture. In an exemplary embodiment, the amount of the acid catalyst is 1.5 mass% with respect to total mass of the mixture.
In accordance with the present disclosure, the first predetermined temperature is in the range of 55 °C to 70 °C. In an exemplary embodiment, the first predetermined temperature is 64 °C.
In accordance with the present disclosure, the first predetermined time period is in the range of 30 minutes to 180 minutes. In an exemplary embodiment, the first predetermined time period is 60 minutes. In another exemplary embodiment, the first predetermined time period is 120 minutes.
In accordance with the present disclosure, a molar ratio of N-Carbethoxy-4-piperidone to trimethyl orthoformate is in the range of 1:0.5 to 1:4. In an exemplary embodiment, the molar ratio of N-Carbethoxy-4-piperidone to trimethyl orthoformate is 1.0:1.6.
The mass comprising N-Carbethoxy-4,4-dimethoxypiperdine is cooled to 50 °C followed by adding a solution of a base in portions over a time period in the range of 60 minutes to 90 minutes by maintaining a temperature below 60 °C to obtain a slurry. After complete addition of the base, the slurry is maintained at a temperature in the range of 55 °C to 65 °C for a time period in the range of 10 minutes to 15 minutes. The temperature of the mass is raised to a second predetermined temperature and maintained for a second predetermined time period to obtain 4,4-dimethoxypiperdine.
In accordance with the present disclosure, the base is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium carbonate, lithium hydroxide, potassium carbonate, sodium carbonate and cesium carbonate. In an exemplary embodiment, the base is potassium hydroxide.
In accordance with the present disclosure, the second predetermined temperature is in the range of 65°C to 85°C. In an exemplary embodiment, the second predetermined temperature is 77°C.
In accordance with the present disclosure, the second predetermined time period is in the range of 25 hours to 35 hours. In an exemplary embodiment, the second predetermined time period is 32 hours.
In an embodiment of the present disclosure, the process for the preparation of 4,4-dimethoxypiperdine is represented as scheme Ia.

Scheme Ia
Step 2 – Preparation of 4-Piperidone HCL hydrate from 4,4-dimethoxypiperdine:
4,4-dimethoxypiperdine obtained in step 1, is added in portions to concentrated HCl at a temperature in the range of 5 °C to 10 °C over a time period in the range of 90 minutes to 120 minutes to obtain a reaction mass. After complete addition of 4,4-dimethoxypiperdine, the reaction mass is maintained at the temperature in the range of 5 °C to 10 °C for 15 minutes to 30 minutes and the temperature of the reaction mass was further raised to a third predetermined temperature for a third predetermined time period to obtain Piperidone HCl hydrate.
In accordance with the present disclosure, the third predetermined temperature is in the range of 65 °C to 85 °C. In an exemplary embodiment, the third predetermined temperature is 75°C.
In accordance with the present disclosure, the third predetermined time period is in the range of 2 hours to 5 hours. In an exemplary embodiment, the third predetermined time period is 4 hours.
In accordance with the present disclosure, a molar ratio of 4,4 dimethoxypiperdine to hydrochloric acid is in the range of 1:1 to 1:10. In an exemplary embodiment, the molar ratio of 4,4 dimethoxypiperdine to hydrochloric acid is 1:3.6.
In accordance with the present disclosure, a concentration of HCl is in the range of 15% to 40%. In an exemplary embodiment, the concentration of HCl is 30%.
In an embodiment of the present disclosure, the process for the preparation of 4-Piperidone HCL hydrate is represented as scheme Ib.

Scheme Ib
The process of the present disclosure employs inexpensive and easily available reagents. Thus, the process of the present disclosure is economical.
The process of the present disclosure employs non-hazardous reagents. Thus, the process of the present disclosure is environment friendly.
The foregoing description of the embodiments has been provided for purposes of illustration and is 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 the industrial scale.
EXPERIMENTAL DETAILS:
Experiment-I: Preparation of Piperidone HCl Hydrate in accordance with the present disclosure
Step 1: Preparation of 4, 4-dimethoxypiperidine from N-Carbethoxy-4-piperidone
500 g N-Carbethoxy-4-piperidone, 2 liter methanol, 500 gm trimethyl orthoformate (TMOF) were charged in a reactor under stirring at 30 °C to obtain a mixture. Slowly, the temperature of the mixture in the reactor was raised up to 40 °C followed by a lot wise (minimum 4 equal lots) addition of 7.5 g p-toluene sulphonic acid (PTSA) to obtain a reaction mass. After completion of the addition of PTSA, the reaction mass was maintained at 25 °C for 15 minutes followed by raising the temperature of the reaction mass up to 64 °C and maintaining the temperature at 62 °C for 60 minutes to obtain a mass comprising N-Carbethoxy-4,4-dimethoxypiperdine. The completion of reaction was monitored by GC analysis (showing absence of the raw material).
Workup: The mass comprising N-Carbethoxy-4,4-dimethoxypiperdine was cooled to 50 °C to obtain a cooled mass. 1500 g of 50% KOH (750 gm KOH + 750 gm water) was added in portions to the cooled mass over a time period of 90 minutes by maintaining the temperature below 60 °C to obtain a slurry. After complete addition of KOH, the slurry was maintained at 60 °C for 15 minutes followed by slowly raising the temperature of the slurry up to 75 °C and maintaining the temperature for 32 hours to obtain a product mixture comprising 4,4-dimethoxypiperidine. The reaction was monitored by GC analysis. After completion of the reaction, methanol and trimethyl orthoformate were distilled out at an atmospheric pressure below 100 °C. After complete removal of methanol and trimethyl orthoformate, the product mixture was cooled to 40 °C and the cooled product mixture was settled for 60 minutes to separate out an organic layer followed by distilling out the remaining solvents and water by applying low vacuum and by increasing the temperature below 80°C using 1 feet column having structure packing. High vacuum was applied and approximately 15-20 gm (1st cut) of 4,4-dimethoxypiperidine was distilled out.
Further, changed the cut and distilled out 4,4-dimethoxypiperidine at high vacuum [Yield = 2nd cut: 350 gm (82.9 %); Purity (GC) = 99.05%]
Step 2: Preparation of 4-Piperidone HCl hydrate from 4,4-dimethoxypiperdine
1050 g conc. HCl (30%) was charged to a reactor at 25°C and the reactor was cooled to 10 °C followed by adding 350 g of 4,4-dimethoxypiperidine in portions over a time period of 120 minutes to obtain a reaction mass. The reaction mass was further maintained at 10 °C for 20 minutes and then the temperature of the reaction mass was slowly raised up to 75°C and the temperature was maintained for 4 hours to obtain a product mass comprising Piperidone HCl hydrate. The reaction was monitored by GC analysis. After completion of the reaction, vacuum was applied and HCl was distilled out below 80°C till color of the product mass became hazy or white slurry type viscous mass. After complete distillation of HCl, the hazy or white slurry type viscous mass was cooled up to 40 °C and vacuum was removed. 1750 ml isopropyl alcohol was added to the hazy or white slurry type viscous mass below 40°C and stirred for 20 minutes to obtain a product mixture. The product mixture was cooled to 5 °C and the temperature of the product mixture was maintained for 3 hours to obtain a cooled product mixture. The cooled product mixture was filtered and washed with 500 ml IPA (isopropyl alcohol) to obtain a wet cake. The wet cake was dried under vacuum at 55°C for 5 hours to obtain 4-Piperidone HCl hydrate [Yield= 320 gm (86.37%); Purity (Assay) = 98.08%].
Experiment-II: Comparative examples for Step-I
To study the effect of the quantity of PTSA on the yield and purity of the step-I product (4,4-dimethoxypiperdine)
Comparative example 1: Increasing the quantity of PTSA
500 g N-Carbethoxy-4-piperidone, 1.5 litre methanol, 500 g trimethyl orthoformate (TMOF) were charged in a reactor and flushed with 0.5 litre methanol under stirring at 30°C to obtain a mixture. Slowly, the temperature of the mixture in the reactor was raised up to 40 °C followed by a lot wise (minimum 4 equal lots) addition of 15 g p-toluene sulphonic acid (PTSA) to obtain a reaction mass. After addition of 1st lot of 2 g PTSA, the temperature of reaction mass was raised to 55 °C due to which exothermic reaction was observed and hence, the temperature of the reaction mass was controlled by external cooling. Remaining all lots were added below 55oC. After completion of addition of PTSA, the reaction mass was maintained at 25 °C for 15 minutes followed by raising the temperature of the reaction mass up to 64 °C and maintaining the temperature at 62 °C for 60 minutes to obtain a mass comprising N-Carbethoxy-4,4-dimethoxypiperdine. The completion of reaction was monitored by GC analysis (showing absence of raw material).
The same work up procedure was carried out as in step-1 of Experiment I to obtain 4,4-dimethoxypiperidine [Yield = 2nd cut: 298 g (70.65%); Purity (GC) = 97.23%].
Comparative example 2: Decreasing the quantity of PTSA
The same procedure was followed as in comparative example 1 except 3g of PTSA was used instead of 15g of PTSA to obtain 4,4-dimethoxypiperidine [Yield = 2nd cut: 250 g (59.28%); Purity (GC) = 98.25%]
To study the effect of PTSA solution in methanol on the yield and purity of the step-I product (4,4-dimethoxypiperdine)
Comparative example 3:
The same procedure was followed as in comparative example 1 except a methanolic solution of PTSA (7.5 gm PTSA in 50 ml methanol) was used instead of 15g of PTSA to obtain 4,4-dimethoxypiperidine [Yield = 2nd cut: 230 g (54.53%); Purity (GC) = 98.21%].
Experiment III: Comparative examples for Step-II
Comparative example 4:
Comparative example 4: To study the effect of the quantity of Conc.HCl on the yield and purity of 4-Piperidone HCl hydrate
50 g conc. HCl (30%) was charged to a reactor at 25°C and the reactor was cooled to 10 °C followed by adding 30 g 4,4-dimethoxypiperidine in portions over a time period of 120 minutes to obtain a reaction mass. The reaction mass was further maintained at 10 °C for 20 minutes and the temperature of the reaction mass was slowly raised up to 75 °C and the temperature was maintained for 4 hours to obtain a product mass comprising Piperidone HCl hydrate. The reaction was monitored by GC analysis. After completion of the reaction, vacuum was applied and HCl was distilled out below 80°C till colour of the product mass became hazy or white slurry type viscous mass. After complete distillation of HCl, the hazy or white slurry type viscous mass was cooled up to 40°C and vacuum was removed. 150 ml of isopropyl alcohol was added to the hazy or white slurry type viscous mass below 40 °C and stirred for 30 minutes to obtain a product mixture. The product mixture was cooled to 5 °C and the temperature of the product mixture was maintained for 3 hours to obtain a cooled product mixture. The cooled product mixture was filtered and washed with 30 ml IPA to obtain a wet cake. The wet cake was dried under vacuum at 55°C for 5 hours to obtain 4-Piperidone HCl hydrate [Yield= 17 gm (53.59%); Purity (Assay) = 93.55%].
Comparative example 5: To study the effect of using a mixture of IPA.HCl and aq.HCl instead of aq.HCl in step-II reaction on the yield and purity of 4-Piperidone HCl hydrate
The same procedure was followed as in comparative example 4 except a mixture of 150 g IPA.HCl and 15 g aqueous HCl (30%) was used instead of 50 g conc. HCl (30%) to obtain 4-Piperidone HCl hydrate [Yield= 21 gm (66.20%); Purity (Assay) = 102.0%].
Comparative example 6: To study the effect of using IPA.HCl instead of aq.HCl in step-II reaction on the yield and purity of the 4-Piperidone HCl hydrate
The same procedure was followed as in comparative example 4 except 80 ml IPA.HCl was used instead of 50 g conc. HCl (30%) and 20g of 4,4-dimethoxypiperidine was used instead of 30g 4,4-dimethoxypiperidine to obtain 4-Piperidone HCl hydrate [Yield= 15.5 gm (73.32%); Purity (Assay) = 98.60%].
From the Experiments 1 and 2, it was observed that when the quantity of the acid catalyst (PTSA) was increased (upto 15g) or decreased (upto 3g) beyond the optimum level (7.5g), the yield of 4,4-dimethoxypiperidine is decreased from 82% to a range of 54% - 70%. Thus, the quantity of the acid catalyst (PTSA) plays an important role in achieving high yield of 4,4-dimethoxypiperidine which in turn leads to high yield of 4-Piperidone HCl hydrate.
Further, from the Experiments 1 and 3, it was observed that if the concentration and quantity of HCL is altered, the yield of 4-Piperidone HCl hydrate is affected i.e. yield of 4-Piperidone HCl hydrate is decreased from 86% to a range of 53% - 73%.
Thus, the inventors of the present disclosure, have developed an optimized process to obtain 4-Piperidone HCl hydrate in comparatively high yield and high purity. Furthermore, the process of the present disclosure employs inexpensive, easily available and non-hazardous reagents. Thus, the process of the present disclosure is economical and environment friendly.
TECHNICAL ADVANCEMENTS
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of a process for the preparation of 4-Piperidone HCl hydrate:
- that provides 4,4-dimethoxypiperdine intermediate with a comparatively high purity and high yield;
- that avoids isolation and purification of N-Carbethoxy-4,4-dimethoxypiperdine (III) for further reaction;
- that results in high yield and purity of 4-Piperidone HCl hydrate; and
- employs inexpensive reagents and has industrial applicability.
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 the preparation of 4-Piperidone HCl Hydrate, said process comprising the following steps:
i. etherifying N-Carbethoxy-4-piperidone by using trimethyl orthoformate in the presence of an acid catalyst in a fluid medium at a first predetermined temperature for a first predetermined time period to obtain N-Carbethoxy-4,4-dimethoxypiperdine;
ii. hydrolyzing N-Carbethoxy-4, 4-dimethoxypiperdine by using a base at a second predetermined temperature for a second predetermined time period to obtain 4, 4-dimethoxypiperdine; and
iii. reacting 4, 4-dimethoxypiperdine with hydrochloric acid at a third predetermined temperature for a third predetermined time period to obtain 4-Piperidone HCl Hydrate.
2. The process as claimed in claim 1, wherein said acid catalyst is selected from the group consisting of p-toluene sulphonic acid (PTSA), sulphuric acid, anhydrous hydrochloric acid and anhydrous hydrobromic acid.
3. The process as claimed in claim 1, wherein an amount of said acid catalyst is in the range of 0.2 mass% to 10 mass% with respect to total mass of the mixture.
4. The process as claimed in claim 1, wherein said fluid medium is selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.
5. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 55 °C to 70 °C.
6. The process as claimed in claim 1, wherein said first predetermined time period is in the range of 30 minutes to 180 minutes.
7. The process as claimed in claim 1, wherein a molar ratio of N-Carbethoxy-4-piperidone to trimethyl orthoformate is in the range of 1: 0.5 to 1:4.
8. The process as claimed in claim 1, wherein said base is selected from the group consisting of potassium hydroxide, sodium hydroxide, Lithium carbonate, lithium hydroxide, potassium carbonate, sodium carbonate and cesuium carbonate.
9. The process as claimed in claim 1, wherein said second predetermined temperature is in the range of 65 °C to 85 °C.
10. The process as claimed in claim 1, wherein said second predetermined time period is in the range of 25 hours to 40 hours.
11. The process as claimed in claim 1, wherein said third predetermined temperature is in the range of 65°C to 85°C.
12. The process as claimed in claim 1, wherein said third predetermined time period is in the range of 2 hours 5 hours.
13. The process as claimed in claim 1, wherein a molar ratio of 4,4 dimethoxypiperdine to hydrochloric acid is in the range of 1:1 to 1:10.
14. The process as claimed in claim 1, wherein a concentration of said HCl is in the range of 15% to 40%.
Dated this 9th day of December, 2021

_______________________________
MOHAN RAJKUMAR DEWAN, IN/PA – 25
of R.K.DEWAN & CO.
Authorized Agent of Applicant