Title of Invention

METHOD OF SYNTHESIS OF STABLE FORMS OF LOPERAMIDE N-OXIDE: (4-[4-(4-CHLOROPHENYL)-4- HYDROXYPIPERIDIN-1-YL]-N,N-DIMETHYL-2,2-DI(PHENYL)BUTANAMIDE) N-OXIDE AND STABLE LOPERAMIDE N-OXIDE MADE THEREBY

Abstract A novel aqueous based method of synthesis A novel method of synthesis of (4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide) N-oxide (Loperamide N-Oxide is disclosed . The invention also provides the product by the method disclosed. The method to produce the compound is capable of being carried out at low temperatures not exceeding about 50°C.
Full Text The present invention provides novel method of synthesis of Stable forms of Loperamide N-Oxide: (4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide) N -Oxide.
Particularly the present invention provides the synthesis of 4-[4-(4-chlorophenyl)-
4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide) N-oxide
(Loperamide N-Oxide) comprising reacting 4-[4-(4-chlorophenyl)-4-
hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide (Loperamide
Base) with an organic anhydride in the presence of hydrogen peroxide.
.Loperamide N-oxide (4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide N-Oxide) dehydrate, is the metabolite of the original drug Loperamide. Loperamide N-oxide has lower toxicity and has faster action. Literature procedures are known for the synthesis of N-Oxides from the original drug, and these involve the use of hydrogen peroxide , with or with out catalysts like sodium tungstate/tungstic acid or sodium moiybdate in the presence of organic solvents like methanol.
Patent US4898873 assigned to Wals et a! discloses the synthesis of alpha., .alpha.-DiaryM-aryl-4-hydroxyl-1-piperidinebutanamide.N-oxides (Loperamide N-Oxide) .The procedure disclosed in the patent is tedious and involves a method to remove the organic solvents and inorganic catalysts to the required levels. The procedure requires multiple purification steps to get pharmaceutically acceptable pure compounds.
A convenient, high yielding method of preparing a form of stable Loperamide N-Oxide,(4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide is thus desired.
It is an object of the present invention to provide novel method of synthesis of Stable fonns of Loperamide N-Oxide: (4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide) N -Oxide..

Another object of the present invention is to provide synthesis of Stable fomris of
Loperamide N-Oxide comprising reaction with an organic anhydride in the
presence of hydrogen peroxide.
Still another object of the present invention is to provide a high purity N -oxide of
at least 99.5%.
In the drawing accompanying this specification Fig 1; represents the novel
alpha,alpha-diaryl-4-aryl-4-hydroxy-l-piperldinebutanamide,N-oxldes
(Loperamide N-Oxide. Fig 2 represents a general formula. Fig 3 represents the
formula of the starting material which is used to do N oxidation
Accordingly the present invention provides novel method of synthesis of Stable
forms of Loperamide N-Oxide: (4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-
N,N-dimethyl-2,2-di(phenyl)butanamide) N -Oxide comprising reacting (4-[4-(4-
chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide)
(Loperamide Base) with an organic anhydride in the presence of hydrogen
peroxide, thereby giving stable 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-
N,N-dimethyl-2,2-di(phenyl)butanamide)n-Oxide
In an embodiment of the present invention , the anhydride may be selected
from pthalic, acetic, maleic and succinic anhydride.
In another embodiment of the present invention hydrogen peroxide may be in a
concentration range between about 1% and about 90%.
In still another embodiment of the present invention the reaction may be carried
out for a time in a range between about 2 hours and 6 hours.
In yet another embodiment of the present invention reaction may be conducted at
temperatures in a range between about 40 °C and about 80 °C.
In still another embodiment of the present invention provided is a method of
formation of N-Oxides by reacting hydrogen peroxide with pharmaceutically
active tertiary amines and imines.
In yet another embodiment of the present invention said tertiary amines may
contain a residual solvent selected from ethyl acetate, or any ester ,
toluene/hydrocarbon or acetone or any ketone.

In still another embodiment of the present invention the said solvent may be present in an amount in the range between about 250ppm and about SOOppm in the finished product.
Accordingly the present invention provides stable fomris of Loperamide N-Oxide obtained by the method of the invention
The invention further discloses methods for oxidizing tertiary amines and imines to corresponding n-Oxide, the method exhibiting exemplary yields of the n-oxide.
The present invention is concerned with novel alpha,alpha-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, N-oxides (Loperamide N-Oxide) which may structurally be represented by the formula as given in Fig 1 and represented by a general formula as given in Fig 2(a). The exact mass of alpha,aipha-diaryl-4-aryl-4-hydroxy-l-piperidinebutanamide, N-oxIdes (Loperamide N-OxIde) is 492.22 and molecular weight is 493.04. and having a general fonnula shown in Fig 2(a) The pharmaaceutically acceptable acid addition salts and stereochemically isomeric forms thereof of Fomriula 2 as shown in Fig 2 (a), compounds, wherein R is hydrogen or methyl; Ar.^ and Ar. ^ are, each independently, phenyl or halophenyl; Alk is -CH.2 ~CH. 2~ or -CH. 2-CH(CH. 3)-; R.^ and R^ are, each independently, hydrogen, C.i^ alkyl, phenylmethyl or 2-propenyl or R.^ and R.^combined with the nitrogen atom bearing said R.^and R.^ may form a pyrrolidinyl, piperidinyl, C. .1-6 alkylpiperidinyl, 4-morpholinyl or 2,6-di(C. .1.6 alkyl)-4-morpholinyl radical;:
Ar.^ is phenyl being optionally substituted with up to 3 substituents selected from the group consisting of C. 1^ alkyl, C. 1^ alkyloxy, halo and trifiuoromethyl. As used in the foregoing definitions the tenn halo is generic to fluoro, chloro, bromo and iodo: "C. 1^ alkyl" is meant to include straight and branched saturated hydrocarbon radicals, having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, 1.1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like. Preferred compounds within the invention are those wherein R.^ and R. ^ are both methyl and Ar^. and Ar. ^ are both phenyl.

Preferred compounds are those compounds wherein Ar\ Ar^ and Ar^ are phenyl
where in Ar^ is optionally substituted with one or two substituents independently
selected from halo and trifluoromethyl
More particularly preferred compounds within the invention are selected from the
group consisting of 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-.alpha.,.alpha.-
diphenyl-1-piper idinebutanamide N-oxide (Loperamide N-Oxide) , the
pharmaceutically acceptable acid addition salts and stereoisomeric forms
thereof.
The most preferred compounds within the invention are selected from the group
consisting of trans-4-(4-chlorophenyl)-4-hydroxy-N,N-dlmethyl-.alpha.,.alpha.-
diphenyl-1 -piperidinebutanamide N-oxide (Loperamide N-Oxide) and the
pharmaaceutically acceptable acid addition salts thereof.
The compounds of formula 1 may generally be prepared by N-oxidating a
starting material with the formula as shown in Fig2 (b)
Where Ar\ Ar^, Ar^...and Alkyl and R= H as depicted in Fig 2.(a)
The above said N-oxidation reaction may generally be carried out by reacting
the starting material of formula 3 with an appropriate organic or inorganic
anhydride in hydrogen peroxide. Appropriate anhydrides include for example
pthalic anhydride, acetic anhydride, succinic anhydride, maleic anhydride, pivalic
anhydride having a general formula (RC0)20) where in R is alyl, aryl or cyclic
anhydride.
Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali
metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium
peroxide, barium peroxide and the like. Appropriate organic peroxides comprise
alkylhydroperoxides, e.g. t.butyl hydroperoxide and the like. Suitable solvents
are, for example, acetyl acetate.ethyl acetate, methyl acetate, butyl acetate,
amyl acetate and the like, water, lower alkanols, e.g. methanol, ethanol,
propanol, butanol and the like, hydrocarbons, e.g. benzene, methylbenzene,
dimethylbenzene and the like, ketones, e.g. 2-propanone, 2-butanone and the
like, halogenated hydrocarbons, e.g. dichloromethane, trichloromethane and the
like, and mixtures of such solvents. In order to enhance the reaction rate, it may

be appropriate to heat the reaction mixture. The reaction may be conducted at temperatures in the range of 25°C to 75°C. In particular the reaction may be conducted in the range of 40°C to 50°C. The reaction may be earned out for at least a period of 5 to about 10 hours. The reactants may be stirred, cooled and separated from water.
In all of the foregoing and in the following preparations, the reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art.
The compounds of formula (I) have basic properties and, consequently, they may
be converted to their therapeutically active non-toxic acid addition salt forms by
treatment with appropriate acids, such as, for example, inorganic acids, such as
hydrohalic acid, e.g. hydrochloric, hydrobromic and the like, and sulfuric acid,
nitric acid, phosphoric acid and the like; or organic acids, such as, for example,
acetic, propanoic, hydroxyacetic, 2-hydroxy-propanoic, 2-oxopropanoic,
ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-
hydroxybutanediolc, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-
propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, benzoic, 2-hydroxybenzoic, 3-phenyl-2-propenoic, .alpha.-hydroxybenzeneacetic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base fonn.
The n-Oxide of the invention shows exemplary purity and can high yields. The process of the invention can give great benefits as the number of reaction steps are lower compared to procedures disclosed earlier. The process will give extensive procedural and economic benefits to manufacturing entities as the technical complexities and costs are lower compared to earlier disclosed methods. The purity of the compounds of the disclosed method are significantly higher compared to earlier disclosed methods.
Following examples are given by way of illustration only and do not limit the scope of the invention

Procedure for synthesis of compounds of the type Formula 1as given in Fig 1:
Example-1
30% Hydrogen peroxide (278 mL pre stabilized with phosphoric acid, 0.001 to 2 %)
was added to a suspension of (4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-
dimethyl-2,2-di(phenyl)butanamide) Base (Loperamide base, 400 g, prepared by
bascifying (4-[4-(4-chlorophenyl)-4-hydroxyptpericKn-1 -yf]-N,N-dimethyl-2,2-
di(phenyl)butanamide) Hydrochloride with sodium carbonate in methanol), ethyl acetate (4000 mL) and pthalic anhydride (400 g ) at 45 to 50 °C over a period of 4 h keeping the temperature below 50°C. Stir the reaction mixture at the same temperature for 6 h. Cool and add to aqueous sodium carbonate solution (572 g in 4 Lt water). The solid thus separated was filtered and washed with water to get (4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamide) N-Oxide (Loperamide N-Oxide) 350 g . This can be crystalized with acetone: methanol (1:1) to get pure (4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dlmethyl-2,2-di(phenyl)butanamide ) N-Oxide which >99.5% pure by HPLC as per BP2009 HPLC method (about 275 g).
The main advantages of the present invention are:
1. The present invention gives pure (4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1 -yl]-N,N-dimethyl-2,2-di(phenyl)butanamide ) N-Oxide with a purity of at least 99.5%
2. The method is a low temperature process to prepare the compound.



We Claim:
1. A novel method of synthesis of (4-[4-(4-chlorophenyl)-4-
hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-di(phenyl)butanamicle) N-oxide
(Loperamide N-Oxide) comprising reacting (4-[4-(4-chlorophenyl)-4-
hydroxypiperidin-1-yl]-N,N-dlmethyl-2,2-dl(phenyl)butanamlde) base
(Loperamide base) with an organic anhydride In presence of hydrogen
peroxide
2. The method of claim 1 wherein said anhydride is an anhydride of organic or inorganic acids having the general formula (RC0)2 O with R being an alkyl or aryl group.
3. The method of claim 1 wherein said hydrogen peroxide Is in a concentration range between about 1% and about 90%.
4. The method of claim 1 wherein said reaction is carried out for a time In a range between about 2 hours and 6 hours.
5. The method of claim 1 wherein said reaction is conducted at temperatures in a range between about 40 °C and about 80 °C.
6. A method of formation of N-Oxides of claim 1 by reacting hydrogen peroxide with compounds selected from pharmaaceutically active tertiary amines and imines.
7. The method of claim 6, where said tertiary amines contain a residual solvent selected from ethyl acetate, or any ester, toluene/hydrocarbon or acetone or any ketone wherein said solvent Is present In an amount In the range between about 250ppm and about 500ppm In the finished product.
8. Stable forms of Loperamide N-Oxide obtained by the method of the invention as claimed In claims 1 to 7

9. A novel method of synthesis of (4-[4-(4-chlorophenyl)-4-
hyclroxypiperidin-1-yl]-N,N-dimethyl-2,2-cli(phenyl)butanamicle) N-oxide (Loperamide N-Oxide substantially herein as described and illustrated in the figures of accompanying drawings


Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=6XknEyhntWu+rvlFvc59KA==&loc=egcICQiyoj82NGgGrC5ChA==


Patent Number 272078
Indian Patent Application Number 3010/CHE/2009
PG Journal Number 12/2016
Publication Date 18-Mar-2016
Grant Date 16-Mar-2016
Date of Filing 07-Dec-2009
Name of Patentee R L FINE CHEM
Applicant Address HIG 2000, RAY HOUSE, YELAHANKA NEW TOWN, BANGALORE - 560 106.
Inventors:
# Inventor's Name Inventor's Address
1 ANDAGAR RAMAKRISHNA RAMESHA NO 15, R L FINE CHEM, KHB INDUSTRIAL AREA, YELAHANKA NEW TOWN, BANGALORE-560 106.
2 ROY. ANJAN KUMAR NO 15, R L FINE CHEM, KHB INDUSTRIAL AREA, YELAHANKA NEW TOWN, BANGALORE-560 106.
PCT International Classification Number C07D 211/52 ; A61K 31/445
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA