DESC:Field of the invention:
The present invention relates to a novel process for the preparation of Diphenoxylate Hydrochloride. Particularly, the invention relates to the preparation of Diphenoxylate Hydrochloride using novel intermediate, 4-Phenylpiperidine-4-carboxylic acid hydrobromide.

4-Phenylpiperidine-4-carboxylic acid hydrobromide.

Background of Invention:
Diphenoxylate Hydrochloride is a centrally active opioid drug of the phenylpiperidine series that is used for the treatment of diarrhea. Diphenoxylate is a controlled substance in USA, therefore, it is used in combination with atropine to prevent drug abuse and overdose.

Diphenoxylate Hydrochloride is chemically known as 4-Piperidinecarboxylic acid, 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-, ethyl ester, hydrochloride (1:1). It is having the following chemical formula.

Diphenoxylate Hydrochloride was first reported in US2898340. The patent reported preparation of Diphenoxylate Hydrochloride by reacting ethyl ester of 4-phenylisonipecotic acid (Normeperidine) and 2,2-diphenyl-4-bromobutyronitrile in xylene. However it did not mention the preparation details of the starting material, Normeperidine.

A journal, Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen, Volume74B, pages 1433-50, 1941, reported preparation of Normeperidine by hydrolysis of 4-phenyl-1-(p-tolylsulfonyl)-4-piperidinecarbonitrile with 75% H2SO4 followed by reaction with alcohol to obtain Normeperidine. In the Journal of Chemical Society, pages 559-61, 1947, and US4282325 also reported similar process for preparation of Normeperidine as mentioned in the Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen journal. The process includes reaction of 4-Cyano-1-p-tolylsulfonyl-4-phenylpiperidine with conc. H2SO4 in water to obtain 1-p-tolylsulfonyl-4-phenyl-4-piperidinecarboxylic acid, which was reacted with EtOH in presence of H2SO4 at reflux to obtain Normeperidine. Another patent, US5936089, also reported hydrolysis of 4-cyano-4-phenylpiperidine hydrochloride in presence of sulfuric acid in water followed by reaction with ethanol to form Normeperidine product. The product was extracted with ether and isolated as an oil. The obtained base was treated with HCl in ether solvent to obtain Normeperidine hydrochloride. The product was re-crystallized from EtOAc/hexanes.

Preparation of Normeperidine hydrochloride mentioned in all the above references involves hydrolysis of 4-Cyano-1-p-tolylsulfonyl-4-phenylpiperidine with conc. H2SO4 and esterification in presence of H2SO4 catalyst. This process is found to be giving less yield and more impurities.

US3847926 reported preparation of Diphenoxylate HCl by reaction of Normeperidine with 4-Bromo-2,2-diphenylbutanenitrile in the presence of sodium carbonate using water and N,N-dimethyl formamide as a mixture of solvents at reflux temperature for 12 hours. After completion of reaction the Diphenoxylate base is isolated by extraction with tetrahydrofuran and heptane followed by reaction with concentrated HCl in water. The crude Diphenoxylate Hydrochloride was crystallized from isopropyl alcohol. Later patents, US4086234 & CN107586275A, also reported same reaction in water using potassium iodide and potassium/sodium bi carbonate. Another patent application, IN5359CHE2012, reported same reaction using potassium iodide in catalytic amount. However, these patents did not disclose the preparation of the intermediate, Normeperidine.

CN108912041A discloses reaction of 4-bromo diphenyl acetonitrile with 4-phenyl-4-piperidine carboxylic acid ethyl ester in toluene as a solvent, an alkali catalyst, wherein, 4-bromo diphenyl acetonitrile and 4-bromoethyl-phenyl-4-piperidine carboxylic acid ethyl ester are added in a mass ratio of 1.2~1.4: 1, to obtain Diphenoxylate Hydrochloride in an overall yields of upto 90%.

Consequently, there is a need for an improved process to prepare Diphenoxylate Hydrochloride with reduced level of impurities. The present invention addresses this need by providing robust process as described herein below.

Summary of invention:
Accordingly, one aspect of the present invention provides a novel compound, 4-Phenylpiperidine-4-carboxylic acid hydrobromide of formula- II.

Formula-II
According to another aspect, the present invention provides high purity Diphenoxylate Hydrochloride wherein, 3-Cyano-3,3-diphenylpropyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride impurity (DPA ester of Difenoxin) is below 0.1%. The structure of this impurity is given below.

3-Cyano-3,3-diphenylpropyl
1-(3-cyano-3,3-diphenylpropyl)-
4-phenylpiperidine-4-carboxylate
Hydrochloride
(DPA ester impurity)
MF: C44H42ClN3O2
M Wt: 680.29
According to third aspect, the present invention provides 3-cyano-3,3-diphenylpropyl,1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride.

According to fourth aspect, the present invention provides a process for the preparation of Normeperidine hydrochloride, as shown in scheme 1, which comprises;
a) reacting 4-phenylpiperidine-4-carbonitrile of formula-I, wherein R is aromatic sulfonyl group, with phenol and hydrogen bromide to obtain 4-phenylpiperidine-4-carboxylic acid hydrobromide of formula II; and
b) reacting the 4-phenylpiperidine-4-carboxylic acid hydrobromide with a chlorinating agent followed by reacting with ethanol to obtain Normeperidine hydrochloride.

Scheme 1:

The aromatic sulfonyl group according to the invention is selected from benzene sulfonyl group or toluene sulfonyl group.

According to fifth aspect, the present invention provides a process preparation of Diphenoxylate hydrochloride, as shown in scheme II, which comprises;
a) reacting 4-phenylpiperidine-4-carbonitrile of formula-I, wherein R is aromatic sulfonyl group, with phenol and hydrogen bromide to obtain 4-phenylpiperidine-4-carboxylic acid hydrobromide of formula II;
b) reacting the 4-phenylpiperidine-4-carboxylic acid hydrobromide with chlorinating agent followed by reacting with ethanol to obtain Normeperidine Hydrochloride;
c) reacting the Normeperidine Hydrochloride with 4-bromo-2,2-diphenylbutanenitrile to obtain Diphenoxylate base; and
d) reacting the Diphenoxylate base with hydrochloric acid to obtain Diphenoxylate Hydrochloride.

Scheme II:

The aromatic sulfonyl group according to the invention is selected from benzene sulfonyl group or toluene sulfonyl group.

The chlorinating agent may be selected from the group consisting of thionyl chloride, phosphorus trichloride and phosphoryl chloride (phosphorus oxychloride), etc.

In a preferred embodiment, present invention provides a process for the preparation of Normeperidine hydrochloride, as shown in scheme III, which comprises;
a) reacting 4-phenyl-1-(p-tolylsulphonyl)piperidine-4-carbonitrile with phenol and hydrogen bromide to obtain 4-phenylpiperidine-4-carboxylic acid hydrobromide; and
b) reacting the 4-phenylpiperidine-4-carboxylic acid hydrobromide with thionyl chloride followed by reacting with ethanol to obtain Normeperidine hydrochloride.

Scheme III:

In another preferred embodiment, present invention provides a process for the preparation of Diphenoxylate Hydrochloride, as shown in Scheme IV, which comprises;
a) reacting 4-phenyl-1-(p-tolylsulphonyl)piperidine-4-carbonitrile with hydrogen bromide to obtain 4-phenylpiperidine-4-carboxylic acid hydrobromide of formula II;
b) reacting the 4-phenylpiperidine-4-carboxylic acid hydrobromide with thionyl chloride followed by reacting with ethanol to obtain Normeperidine hydrochloride;
c) reacting the Normeperidine hydrochloride with 4-bromo-2,2-diphenylbutanenitrile to obtain Diphenoxylate base; and
d) reacting the Diphenoxylate base with hydrochloric acid to obtain Diphenoxylate Hydrochloride.

Scheme IV:

According to a sixth aspect, the present invention provides Diphenoxylate HCl in crystalline form having XRPD characteristic peaks at 2? value: 4.24(±0.2), 8.45(±0.2), 15.97(±0.2), 17.02(±0.2), 19.08(±0.2), 19.58(±0.2), 21.31(±0.2) and 25.65 (±0.2) 2?.

According to seventh aspect, the present invention provides Diphenoxylate HCl in crystalline form characterized by Differential Scanning Calorimeter thermogram (DSC) of Diphenoxylate HCl having peaks at: 228.41°C (endotherm) and 232.80°C (endotherm).

Brief description of drawings:

Figure-1 represents Powder X-Ray diffraction pattern (XRPD) of Diphenoxylate HCl, prepared as per example 13.

Figure-2 represents Differential Scanning Calorimeter thermogram (DSC) of Diphenoxylate HCl, prepared as per example 13.

Description of Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.

The invention is directed to process for the preparation of Diphenoxylate Hydrochloride. Accordingly, in one aspect of the invention, the present invention provides a novel intermediate compound, 4-Phenylpiperidine-4-carboxylic acid hydrobromide of formula II.

Formula II
According to another aspect, present invention provides a process for preparation of 4-Phenylpiperidine-4-carboxylic acid hydrobromide of formula II. The compound of formula II can be prepared by hydrolyzing 4-phenylpiperidine-4-carbonitrile of formula-I, wherein R is aromatic sulfonyl group, with phenol and hydrogen bromide. The aromatic sulfonyl groups may be selected from benzene sulfonyl group or toluene sulfonyl group. The toluene sulfonyl group includes ortho and para toluene sulfonyl groups. However the preferred aromatic sulfonyl group is para toluene sulfonyl group. The reaction may be performed in suitable solvents. The hydrolysis of the nitrile group and deprotection of the sulphonyl group occurs simultaneously in this step which results in production of formula II.

Phenol or substituted phenols is used as a reagent / medium for hydrolysis of nitrile and aromatic sulfonyl group. However, in a particular embodiment, phenol reagent is preferred.

Hydrogen bromide may be used in gaseous form or in solution form (dissolved in water). However, in a specific embodiment, commercial hydrobromic acid having > 40% concentration is used. Usually this reaction occurs at elevated temperatures above 100°C. After completion of reaction, the product, 4-Phenylpiperidine-4-carboxylic acid hydrobromide of formula II is isolated by filtration.

The obtained 4-Phenylpiperidine-4-carboxylic acid hydrobromide is further subjected for a chlorination reaction with suitable chlorinating agents such as phosphorus trichloride, phosphoryl chloride (phosphorus oxychloride) and thionyl chloride. However, in one preferred embodiment, the chlorinating agent is thionyl chloride.

Typically the chlorination is conducted at higher temperatures in the range of 50 - 80°C. Once the acid chloride conversion took place, the product is reacted with ethanol at near to reflux temperature to obtain Normeperidine hydrochloride. After completion of reaction, the mass may be concentrated to remove excess ethanol and the byproducts of chlorinating agent followed by addition of suitable solvent such as hexane or heptane and then filtration to isolate the product, Normeperidine hydrochloride.

According to another aspect, present invention provides a process for preparation of Diphenoxylate Hydrochloride. Accordingly, the Normeperidine hydrochloride prepared as per the present invention is reacted with 4-bromo-2,2-diphenylbutanenitrile in water in presence of a base such as sodium carbonate at reflux temperature to obtain Diphenoxylate base. After completion of reaction, the product is extracted with suitable solvent such as ethyl acetate. The extract is concentrated to obtain Diphenoxylate base as an oil. Alternately, the crude may be subjected for purification to obtain the purified Diphenoxylate base.

The obtained Diphenoxylate base is dissolved in alcohol solvent such as iso-propanol or ethanol followed by addition of concentrated hydrochloric acid. Alternately, dry hydrochloric acid may also be passed for conversion of Diphenoxylate base into Diphenoxylate Hydrochloride. After addition of the hydrochloric acid, the reaction mass may be further heated to reflux and cooled to ambient temperature. Then the product obtained is filtered and washed with alcohol. The wet product is subjected for repeated purifications using an alcoholic solvent to obtain purified Diphenoxylate Hydrochloride. The obtained Diphenoxylate Hydrochloride is crystalline in nature. The crystalline Diphenoxylate Hydrochloride thus obtained is characterized by a powder X-ray diffraction pattern (XRPD) which exhibits peaks at about 4.24(±0.2), 8.45(±0.2), 15.97(±0.2), 17.02(±0.2), 19.08(±0.2), 19.58(±0.2), 21.31(±0.2) and 25.65 (±0.2) 2?. This novel form is further characterized using differential scanning calorimetric thermogram (DSC) which exhibits peaks at: 228.41°C (endotherm), 232.80°C (endotherm).

The starting material, 4-phenylpiperidine-4-carbonitrile of formula-I, wherein R is aromatic sulfonyl group, e.g. benzene sulfonyl or toluene sulfonyl may be prepared according to the process mentioned in the art. The preferred compound, 4-phenyl-1-(p-toluenesulphonyl)piperidine-4-carbonitrile, may be prepared by reacting bis(2-chloroethyl)amine hydrochloride with para-toluene sulphonyl chloride in methylene dichloride solvent in presence of triethyl amine base. Alternately, bis(2-chloroethyl)amine hydrochloride may be reacted with sodium hydroxide to obtain bis(2-chloroethyl)amine base and the obtained base may be reacted with para-toluene sulphonyl chloride in presence of triethyl amine to obtain N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide.

The N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide is further reacted with phenyl acetonitrile in dimethyl sulfoxide and in presence of a base such as cesium carbonate to obtain 4-phenyl-1-(p-toluenesulphonyl)piperidine-4-carbonitrile.

The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.

Example 1: Preparation of N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide
Charged para-toluene sulphonyl chloride (100.0 g) in dichloromethane (1000 mL) and stirred the mass for 10 -15 minutes at 25 ± 5°C. Then charged bis(2-chloroethyl)amine hydrochloride (112.0 g). Added triethyl amine (117.0 g) slowly over the period of 30 - 40 minutes. Raised temperature of mass to 42 ± 3°C and maintained for 3 ± 1 hours. The reaction was monitored by HPLC for consumption of para-toluene sulphonyl chloride. The reaction mass cooled to 25 - 30°C, quenched with water (500 mL), stirred and separated layers. Product from aqueous layer was extracted with dichloromethane (200 mL). Combined organic layer washed with a solution of concentrated hydrochloric acid (40 mL) in water (500 mL). Further, the organic layer was washed with water (500 mL). Solvents from organic layer were distilled out at atmospheric pressure at 42 ± 3°C. The residual solvents were removed under vacuum for 30 - 40 minutes at temperature, below 45°C. Charged n-hexane (600 mL), cooled the mass to 25 - 30°C and stirred for 12 hours. Filtered the product and washed with n-hexane (200 mL). Dried the product under vacuum at 25 - 30°C for 4 ± 1 hours to get off-white powder.
Results:
Yield: 88.24% (137.10 g)
Purity: 99.99% (by HPLC)
Characterization data of N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide:

d (PPM): CDCl3
1H NMR:
2.46(s, 3H, 1), 3.44-3.51(t, 4H, 8,10), 3.68-3.72(t, 4H, 9, 11), 7.34-7.37(d, 2H, 3,7), 7.72-7.75(d, 2H, 4,6)
13C NMR:
21.57(1C, 1), 42.19(2C, 9,11), 51.69(2C, 8,10), 127.23(2C, 4,6), 130.01(2C, 3,7), 135.63(1C, 2), 144.15(1C, 5)

M Wt: 295.02 (exact mass) Mass data:
M/Z = 296.10 [M+H]+, 318.07 [M+Na]+
IR data in wave number (cm-1):
1338 (S=O stretching vibration)
756 (-C-Cl stretching vibration)
Melting point : 48.94°C

Example 2: Preparation of N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide.
Dissolved N,N-bis(2-chloro ethyl)amine hydrochloride (100.0 g) in water (500 mL) at 25 - 30°C. Cooled the mass to 15 - 20°C and charged solution of sodium hydroxide (22.41 g) in water (200 mL). Charged dichloromethane (500 mL), stirred, settled and separated layers.

Charged organic layer (from above operation) followed by para-toluene sulphonyl chloride (96.11 g) and dichloromethane (500 mL) at 25 - 30°C. Charged triethyl amine (62.36 g) slowly over the period of 30 - 40 minutes. Raised temp of mass to 42 ± 3°C and maintained for 3 ± 1 hours. The reaction was monitored by HPLC for consumption of para-toluene sulphonyl chloride. Charged water (500 mL) and sodium hydroxide (2.24 g) and stirred the mass for 1 hour at 35 - 40°C. Cooled the mass to 25 - 30°C and separated layers. Washed the organic layer with solution of concentrated hydrochloric acid (40 mL) in water (500 mL) and then with water (500 mL). Distilled out the solvents from organic layer at atmospheric pressure at 42 ± 3°C. The residual solvents removed under vacuum for 30 - 40 minutes at < 45°C. Charged n-heptane (600 mL) , cooled the mass to 25 - 30°C and stirred for 3 ± 1 hours. Filtered the product and washed with n-heptane (100 mL). Dried product under vacuum at 25 - 30°C for 3 ± 1 hours to get white powder.
Results:
Yield: 83.70% (125.0 g)
Purity: 98.78% (by HPLC)

Example 3: Preparation of 4-phenyl-1-(p-tolylsulphonyl) piperidine-4-carbonitrile from N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide (in-situ).
A mixture of bis(2-chloroethyl)amine hydrochloride (98.30 g), triethyl amine (139.33 g) and para-toluene sulfonyl chloride (100.0 g) was stirred at 42 ± 3°C for 3 ± 1 hours. The reaction was monitored by HPLC for the consumption of para-toluene sulphonyl chloride. The reaction mass was cooled to 25 -30°C and quenched with water (500 mL). Stirred and separated layers. Product from aqueous layer was extracted with dichloromethane (200 mL). Combined organic layers washed with a solution of concentrated hydrochloric acid (40 mL) in water (500 mL). Further, the organic layer was washed with water (500 mL). Distilled out solvents from the organic layer at atmospheric pressure at 42 ± 3°C. The residual solvents were removed under vacuum for 30 to 40 minutes at temperature below 45°C. The residue containing N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide taken to next step.

To the above residue, charged dimethyl sulfoxide (700 mL) followed phenyl acetonitrile (61.45 g) and cesium carbonate (341.82 g). Raised temperature of mass to 115 ± 5°C and maintained for 5 ± 1 hours. The reaction was monitored by HPLC for the consumption of N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide. Cooled reaction mass to 25 - 30°C and charged dichloromethane (800 mL) followed by water (1100 mL). Stirred and separated layers. The product from aqueous layer was extracted with dichloromethane (200 mL). Combined organic layers washed with water (2 X 250 mL). The solvents from organic layer was distilled out atmospherically at 42 ± 3°C and the residual solvents removed under vacuum for 30 - 40 minutes at temperature below 45°C. Charged methanol (500 mL) and stirred at 25 - 30°C for 3 ± 1 hours. Filtered the product, washed with methanol (200 mL) and dried in oven under vacuum at 55 ± 5°C.
Results:
Yield: 45.92% (82.0 g)
Purity: 98.9% (by HPLC)

Characterization data of 4-phenyl-1-(p-tolylsulphonyl)piperidine-4-carbonitrile:
d (PPM): CDCl3
1H NMR:
2.12-2.27(m, 4H, 9,11), 2.48(s, 3H, 1), 2.70-2.79, 3.98-4.03(m, d, 2H 8, 10), 7.34-7.48(m, 7H, 3, 7, 14, 15, 16,17, 18), 7.67-7.72(m, 2H, 4,6)

13C NMR:
21.62(1C, 1), 35.89(2C, 9, 11), 42.33(1C, 12), 43.79(2C, 8,10), 120.86(1C, 13), 125.47(2C, 15,17), 127.59(2C, 4, 6), 128.60(1C, 16), 129.27(2C, 14, 18), 130.01(2C, 3,7), 132.81(1C, 2), 138.83(1C, 19), 144.16(1C, 5)

M Wt: 340.44 Mass data:
M/Z = 341.20 [M+H]+, 363.21 [M+Na]+
IR data in wave number (cm-1):
2234 (-C?N stretching vibration)
Melting point : 201.01°C

Example 4: Preparation of 4-phenyl-1-(p-tolylsulphonyl)piperidine-4-carbonitrile from isolated N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide.

Stirred the mixture of dimethyl sulfoxide (400 mL), N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide (80.0 g), benzyl cyanide (79.13 g), cesium carbonate (320.0 g) at 115 ± 5°C for 4 ± 1 hours. Cooled the mass to 25 - 30°C and then charged dichloromethane (800 mL), water (1100 mL), stirred, settled and separated layers. The product from aqueous layer was extracted with dichloromethane (200 mL). The combined organic layer was washed with water (800 mL). Distilled out solvents from organic layer under vacuum to obtain oily viscous liquid. Charged methanol (600 mL), cooled the mass to 25 - 30°C, filtered the product and washed the wet cake with methanol (200 mL). Dried the product in oven under vacuum at 65°C for 5 hours to get off-white solid.
Results:
Yield: 76.87% (70.65 g)
Purity: 97.64% (by HPLC)

Example 5: Preparation of 4-phenyl-1-(p-tolylsulphonyl)piperidine-4-carbonitrile from N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide (in-situ).
Dissolved N,N-bis(2-chloro ethyl)amine hydrochloride (100.0 g) in water (500 mL) at 25 - 30°C. Cooled the mass to 15 - 20°C and charged solution of sodium hydroxide (22.41 g) in water (200 mL). Charged dichloromethane (500 mL), stirred, settled and separated layers.
Charged organic layer containing N, N-bis(2-chloro ethyl)amine (from above operation) followed by para-toluene sulphonyl chloride (96.11 g) and dichloromethane (500 mL) at 25 - 30°C. Charged triethyl amine (62.36 g) slowly over the period of 30 - 40 minutes. Raised temperature of mass to 42 ± 3°C and maintained for 3 ± 1 hours. The reaction was monitored by HPLC for the consumption of para-toluene sulphonyl chloride. Charged water (500 mL) and sodium hydroxide (1.5 g) and stirred the mass for 2.5 hours at 35 - 40°C. Cooled the mass to 25 - 30°C and separated layers. Distilled out solvents from organic layer at atmospheric pressure at 42 ± 3°C. The residual solvents removed under vacuum for 30 - 40 minutes at temperature, below 45°C.

To the above residue containing N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide, charged dimethyl sulfoxide (1000.0 mL) followed by phenyl acetonitrile (68.88 g) and cesium carbonate (456.16 g). The temperature of mass was raised to 120 ± 10°C and maintained for 4 ± 1 hours. The reaction was monitored by HPLC for the consumption of N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide. The reaction mass cooled to 25 - 30°C and charged dichloromethane (1000 mL) followed by water (1500 mL). Stirred and separated layers. Organic layer was washed with water (500 mL). Distilled out solvents from organic layer atmospherically at 42 ± 3°C and the residual solvents were removed under vacuum for 30 - 40 minutes at < 45°C. Charged methanol (500 mL) and stirred at 25 - 30°C for 3 ± 1 hours. Filtered the product, washed with methanol (200 mL) and dried in oven under vacuum at 55 ± 5°C for 4 ± 1 hours to get off-white powder.
Results:
Yield: 61.33% (105.28 g)
Purity: 99.20% (by HPLC)

Example 6: Preparation of 4-phenyl-1-(p-tolylsulphonyl) piperidine-4-carbonitrile from in-situ N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide.
Dissolved N,N-bis(2-chloro ethyl)amine hydrochloride (100.0 g) in water (500 mL) at 25 - 30°C. Cooled the mass to 15 - 20°C and charged solution of sodium hydroxide (22.4 g) in water (200 mL). Charged dichloromethane (500 mL), stirred, settled and separated layers.

Charged organic layer containing N,N-bis(2-chloroethyl)amine (from above operation) followed by para-toluenesulphonyl chloride (89.03 g), dichloromethane (100 mL), triethyl amine (56.66 g) and stirred the reaction mass at 25 - 30°C for 3 hours. Monitored the reaction by HPLC for the consumption of para-toluenesulphonyl chloride. Charged water (500 mL) and sodium hydroxide (1.5 g), stirred the mass for 2.0 - 2.5 hours at 25 - 30°C and separated layers. Organic layer washed with solution of concentrated hydrochloric acid (5 mL) in water (500 mL) followed by water (250 mL). Distilled out solvents from organic layer at atmospheric pressure at 42 ± 3°C and removed residual solvents under vacuum for 30 - 40 minutes at temperature, below 45°C. Dissolved the residue in N,N-dimethylformamide (100 mL) and taken to next step.

Charged solution of N,N-bis(2-chloro ethyl)-4-methyl benzene sulfonamide in N,N-dimethylformamide (from above operation) to the mixture of N,N-dimethyl formamide (400 mL), sodium hydroxide (145.6 g), benzyl triethyl ammonium chloride (6.38 g) and benzyl cyanide (98.4 g). Stirred the mass for 1.0 - 1.5 hours at temperature, below 85°C and then at 60 ± 5°C for 1 hour. Monitored reaction by HPLC for the consumption of N,N-bis(2-chloro ethyl)-4-methylbenzene sulfonamide. Cooled the mass to 25 - 30°C and charged dichloromethane (1000 mL) and water (1000 mL). Separated layers and washed the organic layer with solution of concentrated hydrochloric acid (5 mL) in water (500 mL) followed by water (250 mL). Distilled out solvents from the organic layer at atmospheric pressure at 42 ± 3°C. Charged methanol (100 mL) and distilled out solvents under vacuum at temperature, below 45°C. Charged methanol (800 mL) and stirred for 3 hours at 25 - 30°C. Filtered the product and washed wet cake with methanol (400 mL). Dried the wet cake under vacuum at 55 ± 5°C for 5 hours to get off-white powder.
Results:
Yield: 69.97%
Purity: 99.77% (by HPLC)

Example 7: Preparation of 4-phenylpiperidine-4-carboxylic acid hydrobromide
A mixture of 48% aqueous hydrobromic acid (510 mL), 4-phenyl-1-(p-tolylsulphonyl)piperidine-4-carbonitrile (85.0 g) and phenol (46.99 g) stirred at 120 ± 5°C for 8 ± 1 hours. The reaction was monitored by HPLC for the consumption of 4-phenyl-1-(p-tolylsulphonyl)piperidine-4-carbonitrile. Cooled the reaction mass to 30 ± 5°C and charged toluene (170 mL) and stirred the mass for 5 ± 1 hours. Filtered product , washed with toluene (170 mL). The wet cake thus obtained was charged in ethyl acetate (425 mL) and stirred for 3 ± 1 hours at 25 - 30°C. Filtered the product, washed with ethyl acetate (170 mL). Dried the product at 55 ± 5°C under vacuum for 6 ± 1 hours to get off-white powder.
Results:
Yield: 91.36% (65.28 g)
Purity: 99.02% (by HPLC)

Characterization data of 4-phenylpiperidine-4-carboxylic acid hydrobromide:
d (PPM): DMSO-d6
1H NMR:
2.02-2.11, 2.50-2.56(m, 4H, 3, 5), 2.94-2.97, 3.26-3.30(m, 4H, 2, 6), 7.28-7.35(m, 1H, 10), 7.40-7.41(d, 4H, 8,9,11,12), 8.57(s, 2H, 1), 13.04(bs, 1H, 14)

13C NMR:
30.24(2C, 3, 5), 41.85(2C, 2, 6), 47.69(1C, 4), 126.09 (2C, 9,11), 127.88(1C, 10), 129.27(2C, 8, 12), 141.71(1C, 7), 174.88(1C, 13)

M Wt: 286.17
(Free base: 205.26) Mass data:
M/Z = 206.12 [Base + H]+
IR data in wave number (cm-1):
1711 (-C=O stretching vibration)
Melting point range: No melting observed till 250°C

Example 8: Preparation of 4-phenylpiperidine-4-carboxylic acid hydrobromide
A mixture of 48% aqueous hydrobromic acid (45 mL), 4-phenyl-1-(p-tolylsulphonyl)piperidine-4-carbonitrile (15.0 g) and phenol (8.29 g), stirred at 120 ± 5°C for 8 ± 1 hours. The reaction was monitored by HPLC for the consumption of 4-phenyl-1-(p-tolylsulphonyl)piperidine-4-carbonitrile. The reaction mass was cooled 30 ± 5°C and charged toluene (30 mL) and stirred the mass for 5 ± 1 hours. Filtered product , washed with toluene (30 mL). The wet cake thus obtained was charged in ethyl acetate (75 mL) and stirred for 3 ± 1 hours at 25 - 30°C. Filtered the product, washed with ethyl acetate (15 mL). Dried the product at 55 ± 5°C under vacuum for 6 ± 1 hours to get off-white powder.
Results:
Yield: 90.47% (11.40 g)
Purity: 99.54%

Example 9: Preparation of ethyl 4-phenylpiperidine-4-carboxylate hydrochloride (Normeperidine Hydrochloride)
Mixture of thionyl chloride (200.0 mL) and 4-phenylpiperidine-4-carboxylic acid hydrobromide (50.0 g) stirred at 70 ± 5°C for 3 ± 1 hours. The reaction mass cooled to 5 -10°C and charged ethanol (250 mL) slowly, maintaining temperature, below 35°C. Raised temperature of mass to 75 ± 5°C and stirred for 2.0 ± 0.5 hours. Distilled out solvents under vacuum at temperature, below 60°C. Charged ethyl acetate (50.0 mL), raised temperature of mass to 60 ± 5°C and stirred for 20 - 30 minutes. Charged n-hexane (400.0 mL) at 60 ± 5°C and stirred for 2 ± 1 hour. Cooled the precipitated mass to 25 - 30°C and stirred for 1.0 - 1.5 hour. Filtered the product, washed with n-hexane (100.0 mL) and dried the product in oven under vacuum at 55 ± 5°C for 8 ± 2 h to get off-white powder.
Results:
Yield: 92.29% (43.50 g)
Purity: 99.33% (by HPLC)

Characterization data of Normeperidine Hydrochloride:
d (PPM): DMSO-d6
1H NMR:
1.08 - 1.13(t, 3H, 15), 2.15 - 2.25, 2.50 - 2.57(m, 4H, 3,5), 2.89 - 2.92, 3.22 - 3.26(m, 4H, 2,6), 4.07 - 4.14(q, 2H, 14), 7.28 - 7.34(m, 1H, 10), 7.36 - 7.43(m, 4H, 8, 9, 11, 12), 9.23 - 9.35(d, 2H, 1)
13C NMR:
14.26(1C, 15), 30.21(2C, 3, 5), 41.45(2C, 2, 6), 48.05(1C, 4), 61.63(1C, 14), 126.02(2C, 8,12), 128.01(1C, 10), 129.34(2C, 9,11), 141.41(1C, 7), 173.18(1C, 13)

M Wt: 269.77
(free base: 233.31)

Mass data:
M/Z = 234.15 [Base + H]+
IR data in wave number (cm-1):
1718 (-C=O stretching vibration)
Melting point: 167.9°C

Example 10: Preparation of ethyl 4-phenylpiperidine-4-carboxylate hydrochloride (Normeperidine Hydrochloride)
Mixture of thionyl chloride (135 mL) and 4-phenylpiperidine-4-carboxylic acid hydrobromide (45.0 g) stirred at 70 ± 5°C for 4 ± 1 hours. The reaction mass cooled to 5 -10°C and charged ethanol (225 mL) slowly, maintaining temperature, below 35°C. Then, raised temperature of mass to 75 ± 5°C and stirred for 1 hour ± 15 minutes. Distilled out solvents under vacuum at temperature below 60°C. Charged n-heptane (225.0 mL), raised temperature of mass to 70 ± 5°C and stirred for 1 hour. Cooled the precipitated mass to 25 ± 5°C and stirred for 1.0 - 1.5 hour. Filtered the product, washed with n-heptane (90 mL) and dried the product in oven under vacuum at 50 ± 5°C for 5 ± 1 hour.
Results:
Yield: 91.93% (41.02 g)
Purity: 94.92% (by HPLC)

Example 11: Preparation of ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride (Diphenoxylate Hydrochloride)
Charged water (50 mL) followed by ethyl 4-phenylpiperidine-4-carboxylate hydrochloride (5.0 g) and sodium carbonate (1.96 g). Stirred the mass for 25 - 30 minutes at 25 - 30°C and then charged 4-bromo-2,2-diphenylbutanenitrile (5.56 g). Charged sodium carbonate (2.94 g), raised temperature mass to 100 ± 5°C and stirred for 10 hours. The reaction was monitored by HPLC for the consumption of ethyl 4-phenylpiperidine-4-carboxylate hydrochloride. Cooled the mass to 25 - 30°C and extracted product with ethyl acetate (50 mL). The product from aqueous layer extracted with ethyl acetate (40 mL). Washed the combined organic layer with water (50 mL). Distilled out solvents from organic layer under vacuum at temperature, below 45°C. Charged iso-propyl alcohol (150 mL) and stirred the mass to obtain clear solution at 25 - 30°C. Charged concentrated hydrochloric acid (10 mL), raised temperature of mass to 75 ± 5°C. Cooled the mass to 25 - 30°C, filtered the product and washed with iso-propyl alcohol (10 mL).
Charged wet cake of product (from above operation), iso-propyl alcohol (75 mL) and raised temperature of mass to 75 - 80°C. Cooled the mass to 25 - 30°C, filtered the product and washed with iso-propyl alcohol (10 mL). Dried the product in oven under vacuum at 50 ± 5°C for 5 ± 1 hour to get white powder.
Results:
Yield: 49.66% (4.50 g)
Purity: 99.66% (by HPLC)
DPA ester impurity: 0.03% (by HPLC)

Example 12: Preparation of 3-Cyano-3,3-diphenylpropyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride (DPA ester impurity)
Charged 1-(3-Cyano-3,3-Diphenylpropyl)-4-Phenylpiperidine-4-Carboxylic acid (7.5 g) followed by water (75 mL), sodium carbonate (5.61 g) and 4-Bromo-2,2-diphenylbutanenitrile (7.95 g). Raised temperature of the mass to 100 ± 5°C and stirred for 55 hours. The reaction was monitored by HPLC for the consumption of 1-(3-Cyano-3,3-Diphenylpropyl)-4-Phenylpiperidine-4-Carboxylic acid. Cooled the mass to 25 - 30°C and extracted product with ethyl acetate (75 mL). Distilled out solvents from organic layer under vacuum at temperature below 45°C. Charged iso-propyl alcohol (115 mL) and stirred the mass for 15 min at 25 - 30°C to obtain clear solution. Charged concentrated hydrochloric acid (2.41 g) and stirred the precipitated mass for 6 hours at 25 - 30°C. Filtered the product and washed with iso-propyl alcohol (15 mL). Dried the product under vacuum at 55 ± 5°C for 2 hours.

Charged dried product (from above operation) into iso-propyl alcohol (70 mL) and raised temperature of the mass to 55 ± 5°C. Cooled the mass to 15 - 20°C and stirred for 3 hours, filtered the product and washed with iso-propyl alcohol (10 mL). Dried the product in oven under vacuum at 50 ± 5°C for 5 ± 1 hour to get off-white powder.
Results:
? Yield: 21.94% (2.50 g)
? Purity: 97.39% (by HPLC)
Characterization data of DPA ester impurity:
d (PPM): CDCl3
1H NMR:
2.63-2.67(m, 4H, 18, 20), 2.71-2.73(m, 2H, 30) 2.78-2.90, 3.55-3.58(m, 4H, 17, 21), 3.08(m, 2H, 16), 3.19-3.22(m, 2H, 15), 4.21-4.25(t, 2H, 29), 7.29-7.53(m, 25H, 1, 2, 4, 5, 6, 9, 10, 11, 12, 13, 24, 25, 26, 27, 28, 33, 34, 35, 36, 37, 40, 41, 42, 43, 44), 12.87(bs, 1H, 45)
13C NMR:
30.49(2C, 18, 20), 33.09(1C, 15), 37.51(1C, 30), 48.25(1C, 31), 49.17(1C,19), 50.04(1C, 7), 51.31(2C, 17, 21), 54.34(1C, 16), 62.51(1C, 29), 121.25(1C, 38), 121.88(1C, 14), 125.42(2C, 25, 27), 126.57-126.65(4C, 33, 37, 40, 44), 128.07(1C, 26), 128.39(2C, 35, 42), 128.66(2C, 6, 11), 129.03(2C, 24, 28), 129.19(4C, 2, 4, 9, 13), 129.48(4C,1, 5, 10, 12), 137.88(2C, 32, 39), 139.16(2C, 3, 8), 139.80(1C, 23), 173.02(1C, 22)

M Wt: 680.29
(Free base: 643.83)
Mass data:
M/Z = 644.32 [Base + H]+
IR data in wave number (cm-1):
1737 (-C=O stretching vibration)

Example 13: Preparation of ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride (Diphenoxylate Hydrochloride) using in-situ normeperidine base
Stirred the mixture of 4-phenylpiperidine-4-carboxylic acid hydrobromide (30.0 g), ethanol (120 mL), concentrated sulfuric acid (41.2 g) at 80 - 85°C for 7 hours and monitored reaction by HPLC for the consumption of 4-phenylpiperidine-4-carboxylic acid hydrobromide. Cooled mass to 50 - 60°C and distilled solvents under vacuum. Cooled the mass to 25 - 30°C, charged water (210 mL), ethyl acetate (300 mL) and cooled the mass to 5 - 10°C. Adjusted pH of the mass to 10.0 ± 0.5 with solution of sodium hydroxide (37.8 g) in water (90 mL) maintaining temperature, below 30°C. Separated layers and took organic layer containing ethyl 4-phenylpiperidine-4-carboxylate to next step.

Distilled out solvents from organic layer under vacuum at temperature, below 45°C. Charged water (150 mL), 4-bromo-2,2-diphenylbutanenitrile (31.5 g), sodium carbonate (16.6 g) and stirred the reaction mass at 95 - 100°C for 10 hours. Monitored reaction by HPLC for the consumption of ethyl 4-phenylpiperidine-4-carboxylate and cooled the mass to 25 - 30°C. Charged ethyl acetate (300 mL), stirred , settled and separated layers. Washed organic layer with water (150 mL). Distilled out solvents from organic layer under vacuum at temperature below 50°C. Charged isopropyl alcohol (900 mL), cooled mass to 25 - 30°C and added concentrated hydrochloric acid (30 mL). Raised temperature of mass to 70 - 75°C and stirred for 50 - 60 minutes. Cooled the mass to 45 - 50°C and stirred for 1.0 - 1.5 hours. Further cooled the mass to 15 - 20°C, filtered the product and washed the wet cake with isopropyl alcohol (90 mL). Stirred a mixture of wet cake, with isopropyl alcohol (450 mL), water ( 15 mL) at 75 - 80°C for 40 - 50 minutes. Cooled the mass to 45 - 50°C and stirred for 1.0 - 1.5 hours. Further cooled the mass to 25 - 30°C, filtered the product and washed the wet cake with isopropyl alcohol (60 mL). Dried the wet cake under vacuum for 6 hours at 55 ± 5°C to obtain white crystalline powder.
Results:
Yield: 61.37%
Purity: 99.83% (by HPLC)
Characterization data of Diphenoxylate Hydrochloride
DSC, Endotherm / Exotherm peaks:
228.14°C (endotherm), 232.44°C (endotherm)
TGA, Weight loss:
0.1847% w/w.
XRD, Characteristic 2? value peaks:
4.24, 8.45, 15.97, 17.02, 19.08, 19.58, 21.31, 25.65

Example 14: Preparation of ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride (Diphenoxylate Hydrochloride) using in-situ normeperidine base and ethanol as a crystallization solvent
Stirred the mixture of 4-phenylpiperidine-4-carboxylic acid hydrobromide (20.0 g), ethanol (80 mL), concentrated sulfuric acid (27.42 g) at 80 - 85°C for 7 hours and monitored reaction by HPLC for the consumption of 4-phenylpiperidine-4-carboxylic acid hydrobromide. Cooled mass to 50 - 60°C and distilled solvents under vacuum. Cooled the mass to 25 - 30°C, charged water (140 mL), ethyl acetate (200 mL) and cooled mass to 5 - 10°C. Adjusted pH of the mass to 10.0 ± 0.5 with solution of sodium hydroxide (25.15 g) in water (60 mL) maintaining temperature, below 30°C. Separated layers and took organic layer containing ethyl 4-phenylpiperidine-4-carboxylate to next step.

Distilled out solvents from organic layer under vacuum at temperature below 45°C. Charged water (100 mL), 4-bromo-2,2-diphenylbutanenitrile (20.98 g), sodium carbonate (11.11 g) and stirred the reaction mass at 95 - 100°C for 10 hours. Monitored the reaction by HPLC for the consumption of ethyl 4-phenylpiperidine-4-carboxylate and cooled the mass to 25 - 30°C. Charged ethyl acetate (200 mL), stirred , settled and separated layers. Washed the organic layer with water (100 mL). Distilled out the solvents from the organic layer under vacuum at temperature, below 50°C. Charged ethanol (200 mL), cooled the mass to 25 - 30°C and added concentrated hydrochloric acid (10 mL). Raised temperature of the mass to 65 ± 5°C and stirred for 50 - 60 minutes. Cooled the mass to 45 - 50°C and stirred for 1.0 - 1.5 hours. Further cooled to 20 - 25°C, filtered the product and washed the wet cake with ethanol (40 mL). Stirred a mixture of wet cake and ethanol (160 mL) at 65 ± 5°C for 50 - 60 minutes. Cooled the mass to 45 - 50°C and stirred for 1.0 - 1.5 hours. Further cooled to 20 - 25°C, filtered the product and washed the wet cake with ethanol (40 mL). Dried the wet cake under vacuum for 6 hours at 55 ± 5°C to get white crystalline powder.

Results:
Yield: 58.82%
Purity: 99.88% (by HPLC)
DSC, Endotherm / Exotherm peaks:
228.41°C (endotherm), 232.80°C (endotherm)
TGA, weight loss:
0.1393% w/w.
XRD, Characteristic 2? value peaks:
4.28, 8.53, 15.98, 17.07, 19.12, 19.58, 21.35, 25.68

,CLAIMS:
1. A process for preparation of Diphenoxylate hydrochloride which comprises;
a) reacting 4-phenylpiperidine-4-carbonitrile of formula-I, wherein R is aromatic sulfonyl group, with phenol and hydrogen bromide to obtain 4-phenylpiperidine-4-carboxylic acid hydrobromide of formula II;
b) reacting the 4-phenylpiperidine-4-carboxylic acid hydrobromide of formula II with chlorinating agent followed by reacting with ethanol to obtain Normeperidine Hydrochloride;
c) reacting the Normeperidine Hydrochloride with 4-bromo-2,2-diphenylbutanenitrile to obtain Diphenoxylate base; and
d) reacting the Diphenoxylate base with hydrochloric acid to obtain Diphenoxylate Hydrochloride in crystalline form.

2. The process as claimed in claim 1, wherein, the aromatic sulfonyl group is selected from benzene sulfonyl group or toluene sulfonyl group.
3. The process as claimed in claim 1, wherein the chlorinating agent is selected from the group consisting of thionyl chloride, phosphorus trichloride and phosphoryl chloride (phosphorus oxychloride).
4. The process as claimed in claim 1, wherein, the Diphenoxylate Hydrochloride is obtained with an impurity, i.e., 3-Cyano-3,3-diphenylpropyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride impurity (DPA ester of Difenoxin) below 0.1%.

3-Cyano-3,3-diphenylpropyl
1-(3-cyano-3,3-diphenylpropyl)-
4-phenylpiperidine-4-carboxylate
Hydrochloride
(DPA ester impurity)

5. A crystalline form of Diphenoxylate HCl characterized by XRPD having characteristic 2? peaks at 4.24(±0.2), 8.45(±0.2), 15.97(±0.2), 17.02(±0.2), 19.08(±0.2), 19.58(±0.2), 21.31(±0.2) and 25.65 (±0.2) 2?.
6. A process for the preparation of Normeperidine hydrochloride as claimed in claim 1, which comprises;
a) reacting 4-phenylpiperidine-4-carbonitrile of formula-I, wherein R is aromatic sulfonyl group, with phenol and hydrogen bromide to obtain 4-phenylpiperidine-4-carboxylic acid hydrobromide of formula II; and
b) reacting the 4-phenylpiperidine-4-carboxylic acid hydrobromide of formula II with a chlorinating agent followed by reacting with ethanol to obtain Normeperidine hydrochloride.

7. The process as claimed in claim 6, wherein, the aromatic sulfonyl group is selected from benzene sulfonyl group or toluene sulfonyl group.
8. The process as claimed in claim 6, wherein, the chlorinating agent is selected from the group consisting of thionyl chloride, phosphorus trichloride and phosphoryl chloride (phosphorus oxychloride).
9. 4-Phenylpiperidine-4-carboxylic acid hydrobromide of formula- II.

Formula-II
10. A process for preparation of 4-Phenylpiperidine-4-carboxylic acid hydrobromide of formula- II, as claimed in claim 9, which process comprises reaction of 4-phenylpiperidine-4-carbonitrile of formula-I, wherein R is aromatic sulfonyl group, with phenol and hydrogen bromide to obtain 4-phenylpiperidine-4-carboxylic acid hydrobromide of formula II.

11. 3-cyano-3,3-diphenylpropyl,1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride.

(DPA ester impurity)