Claims: We claim
1. A solid form of Methyl-4{4-[4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate (compound I) having following structure

wherein solid form is a hydrate of compound I.
2. The compound as claimed in claim 1 having a melting point in range of 118-123°C.
3. The compound as claimed in claim 1 having water of crystallization in range of 2.7 – 3.7%.
4. The compound as claimed in claim 1 having ratio of para isomer to meta isomer is at least 95:5 or at least 98:2.
5. The compound as claimed in claim 1 which is storage stable compound when stored at room temperature at least for one year.
6. A process for preparation of solid form of Methyl-4{4-[4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate comprising
a) Reacting Azacyclonol (IV) and Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate (V) in a suitable solvent comprising an organic solvent and first portion of water in presence of a base, catalyst and heating to reflux;
b) Adding second portion of water to the reaction mixture after completion of reaction and draining aqueous layer;
c) Adding third portion of water and cooling to below 20°C, or below 10°C, or below 5° C optionally under stirring, precipitating solid form; and
d) Isolating solid form;
wherein solid form of Methyl-4{4- [4- (hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate is a hydrate form.
7. The process as claimed in claim 6 further comprising one or more of following
a) solvent in Step a is selected from toluene and xylene;
b) base in Step a is potassium bicarbonate;
c) catalyst in Step a is potassium iodide;
d) reaction mixture is refluxed in step a till such time when both the reactants are present in amounts less than 10 %, or less than 5 % or less than 2 %;
e) Isolation in step d is done by filtration and drying to constant weight.
8. The process as claimed in claim 6, wherein ratio of para and meta isomer of Methyl-4{4- [4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate mono hydrate is in the range of 95:5 to 99.9:0.1 or 98:2 to 99.9:0.1 respectively.
9. A process for preparation of fexofenadine base from solid form of Methyl-4{4- [4- (hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate (Compound-I) comprising.
a) Treating said solid form with suitable reducing agent in a suitable solvent to reduce to Methyl-4{4-[4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-hydroxy butyl]-a,a-dimethyl benzene acetate (hydroxyl derivative);
b) treating the hydroxyl derivative with a base in suitable solvent to obtain Fexofenadine base;
c) precipitating Fexofenadine base using suitable precipitating / neutralizing agent; and
d) optionally purifying Fexofenadine base in a suitable solvent;
wherein solid form of Methyl-4{4- [4- (hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate is a hydrate form.
10. A process as claimed in claim 9 further comprising one or more of following
a) reducing agent in step a is one or more of sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride;
b) Solvent in step a is methanol or ethanol.
c) base in step b is one or more of alkali metal hydroxide, amide, alkoxide, alkali metal, wherein alkali metal hydroxide comprises one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide;
d) Solvent in step b is one or more of water, lower alcohol and mixture of water and lower alcohol from 20: 80 to 80: 20 preferably 50:50 wherein lower alcohol is one or more of methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol.
11. A process for preparation of fexofenadine base comprising
a) Reacting Azacyclonol (IV) and Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate (V) in a suitable solvent comprising an organic solvent and first portion of water in presence of a base and a catalyst and heating to reflux;
b) Adding second portion of water to the reaction mixture after completion of reaction and draining aqueous layer;
c) Adding third portion of water and cooling to below 20°C, preferably below 10°C, more preferably below 5° C and most preferably in the range of 0-5°C under stirring and precipitating solid form of Methyl-4{4- [4- (hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate;
d) Isolating solid form;
e) Treating solid form with suitable reducing agent in a suitable solvent to reduce to Methyl-4{4- [4- (hydroxy diphenylmethyl)-l-piperidinyl}-l-hydroxy butyl]-a, a-dimethyl benzene acetate (hydroxyl derivative);
f) treating the hydroxyl derivative with a base in a suitable solvent to obtain Fexofenadine base;
g) precipitating Fexofenadine base using suitable precipitating / neutralizing agent; and
h) optionally purifying base in a suitable solvent;
wherein solid form of Methyl-4{4- [4- (hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate is a hydrate form.
12. The process as claimed in claim 11 further comprising one or more of following
a) solvent in Step a is selected from toluene and xylene;
b) base in Step a is potassium bicarbonate;
c) catalyst in Step a is potassium iodide;
d) reaction mixture is refluxed in step a till such time when both the reactants are present in amounts less than 10 %, or less than 5 % or less than 2 %;
e) Isolation in step d is done by filtration and drying to constant weight
f) reducing agent in step e is one or more of sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride;
g) Solvent in step e is methanol or ethanol
h) base in step f is one or more of alkali metal hydroxide, amide, alkoxide, alkali metal, wherein alkali metal hydroxide comprises one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide;
i) Solvent in step f is one or more of water, lower alcohol and mixture of water and lower alcohol from 20: 80 to 80: 20 preferably 50:50 wherein lower alcohol is one or more of methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol.
13. A process as claimed in claim 9 or 11, wherein precipitating / neutralizing agent is selected from one of alkyl formate and mineral acid, preferably selected from the group consisting of methyl formate, ethyl formate and hydrochloric acid.
14. A process as claimed in claim 9 or 11, wherein solvent for purifying Fexofenadine base is methanol.
15. A process as claimed in claim 9 or 11, wherein fexofenadine base is at least 95% pure; more preferably, at least 97 % pure and most preferably, at least 98 % pure without applying any purification method.
16. A process as claimed in claim 9 or 11, wherein fexofenadine base is at least 98% pure; more preferably, at least 99 % pure and most preferably, at least 99.5 % pure after purifying it in a suitable solvent.
17. Process to prepare highly purified Fexofenadine base employing solid form of Methyl-4{4-[4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate wherein highly purified Fexofenadine base is at least 99 % pure or at least 99.5 % pure containing no single impurity in amounts greater than 0.2 % or greater than 0.1 % or greater than 0.05 % and wherein solid form of Methyl-4{4-[4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate is a hydrate form.
18. Fexofenadine base which is at least 99.5 % or at least 99.8 % or at least 99.9 % pure and having less than 0.2 % or less than 0.1 % or less than 0.05 % any single impurity prepared by process employing hydrate of Methyl-4{4- [4- (hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate.

Dated this 05th day of April 2018

, Description:NOVEL HYDRATE INTERMEDIATE FOR FEXOFENADINE
Field of the invention
The invention relates to the field of chemical, pharmaceutical and life science. The invention covers a hydrate of Methyl-4{4- [4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate, hereinafter hydrate of compound-I which is an intermediate in the preparation of Fexofenadine. The invention further covers process to prepare hydrate of compound-I and process to prepare fexofenadine from hydrate of compound-I.
Background of the invention
Fexofenadine hydrochloride is a histamine H 1-receptor antagonist. Fexofenadine is indicated in adults and children 6 years of age and older for i) the relief of symptoms associated with seasonal allergic rhinitis and ii) for treatment of uncomplicated skin manifestations of chronic idiopathic urticaria. Compound-I is routinely employed as an intermediate for preparing Fexofenadine. Compound-I is reported as thick oily liquid. Some literature reports that it has a boiling point of around 657°C (Lookchem.com and Chembk.com). It is difficult to purify Compound-I.

The example 5 of US4254129 patent reports synthesis of Fexofenadine using Ethyl ester form of intermediate. A Hydrochloride salt of the intermediate is produced and is converted again to base in subsequent step. Formation of hydrochloride salt is done to separate intermediate in solid form from the reaction mixture and it unnecessary adds to one more synthetic step.
The example 8 of US20130237709 patent provides preparation of Intermediate Viz. Compound (I) and isolating the same by distilling off the solvents from the organic phase. This method cannot remove any impurities present in Compound (I)
and it affects both the purity of the intermediate and thereby the final product, Fexofenadine base.
In the patent WO2009136412A2, the synthesis of the intermediate viz. compound (I) is carried out in presence of acetonitrile in place of toluene. The Acetonitrile is removed from the reactant mixture under vacuum at 40-45°C to yield residue which is further used for production of Fexofenadine base. This again presents the same disadvantage of remnants of impurities in the residue, thereby affecting the final purity.
In the patent WO2007007347, the Methyl ester intermediate viz. Compound (I) is obtained in the form of thick oily mass. Further, Fexofenadine is synthesized from such oily mass which produces both the para as well as the undesired meta isomer. The disadvantage of this process is that the exclusive separation of para isomer from this isomeric mixture needs to be achieved with multiple suspensions in methanol: methylethylketone mixture having specific ratio of ingredients and finally refluxing the material in methanol: dimethylformamide.
The patent WO2007049303A2 reports highly purified Fexofenadine prepared from Compound (I) as intermediate. It does not however report purity of Compound (I) and meta isomer in Compound (I) when used as a starting material for making highly pure fexofenadine. The patent does not provide any chromatograms reflecting such highly pure Fexofenadine.
Object of the invention
The first object of the invention is to provide an intermediate for the preparation of Fexofenadine. This novel intermediate is a hydrate of Methyl-4{4- [4- (hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate and found to be highly pure than its anhydrous form obtained using the same reactants. This novel hydrate intermediate is simple to prepare, easy to handle, storage stable and highly pure. The object is to provide a storage stable intermediate which is a hydrate of compound-I which is stable for at least 6 months, preferably 9 months and most preferably for one year at room temperature.
Second object of the invention is to provide a process of preparation of hydrate of compound-I which yields pure hydrate as compared to its anhydrous form which is easy, scalable and economically efficient compared to conventional techniques like high vacuum distillation, chromatography or crystallizations which are commercially inefficient due to more energy, time and solvent consumption respectively.
Third object of the invention is to provide a process of preparation of Fexofenadine using novel compound which is a hydrate of compound I. The fexofenadine prepared by this method is at least 95 % pure without applying any purification method. More preferably, the fexofenadine is at least 97 % pure and most preferably it is at least 98 % pure.
Fourth object of the invention is to provide a process of preparation of Fexofenadine from reactants Azacyclonol (IV) and Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate (V) using novel intermediate compound which is a hydrate of compound I. The entire process is designed to restrict meta analog of intermediates and final products below 2 %, preferably below 1 %, more preferably below 0.5 % and most preferably below 0.2 %.
Summary of the invention
The first aspect of the invention covers a novel intermediate for the preparation of Fexofenadine. This novel intermediate is a hydrate of Methyl-4{4- [4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate (compound-I) and found to be highly pure than its anhydrous form obtained using the same reactants. This novel hydrate intermediate is simple to prepare, easy to handle, highly pure. storage stable for at least 6 months, preferably 9 months and most preferably for one year at ambient temperature.
Second aspect of the invention provides a process to prepare a novel intermediate for the preparation of Fexofenadine. This novel intermediate is a hydrate of compound-I and the process yields pure hydrate as compared to its anhydrous form when prepared using same reactants. The process to prepare hydrate of compound-I is a simple, single step and an economical process. First, Azacyclonol viz. compound (IV) and Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate viz. compound (V) are reacted in a suitable solvent comprising an organic solvent in presence of aqueous base and a catalyst such as potassium iodide. Preferably organic solvent is toluene or xylene. Preferably, the reaction mixture is refluxed till such time when both the reactants are present in amounts less than 10 %, preferably less than 5 % and more preferably less than 2 %. Preferably, more water is added at the end of the reaction and aqueous layer is drained. Further, more water is added to organic layer and cooled to below 20°C, preferably below 10°C, more preferably below 5° C and most preferably in the range of 0-5°C preferably under stirring. Followed by isolating solid hydrate form of compound-I by filtration and drying to constant weight.
The third aspect of the invention provides process of preparation of fexofenadine from novel hydrate form of compound-I which includes following steps
a) Treatment of hydrate form of compound-I with suitable reducing agent to reduce keto group to hydroxyl group followed by treating the hydroxyl derivative with a base to cause hydrolysis of an ester to acid which is a Fexofenadine base;
b) precipitating Fexofenadine base using suitable precipitating agent such as alkyl formate and mineral acid;
c) Optionally purifying base in suitable solvent as per purity requirement.
Fourth aspect of the invention provides a process of preparation of Fexofenadine from reactants Azacyclonol (IV) and Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate (V) employing first preparing a novel intermediate compound which is a hydrate of compound I. The entire process is designed to restrict meta analog of intermediates and final products below 2 %, preferably below 1 %, more preferably below 0.5 % and most preferably below 0.2 %.
The process involves following step
A) Reacting Azacyclonol (IV) & Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate (V) in a suitable solvent comprising an organic solvent and first portion of water in presence of a base and potassium iodide and heating to reflux;
B) Adding second portion of water to the reaction mixture after completion of reaction and draining aqueous layer;
C) Adding third portion of water and cooling to below 20°C, preferably below 10°C, more preferably below 5°C under stirring and precipitating hydrate form;
D) Isolating solid hydrate form by filtration and drying to constant weight;
E) Treating hydrate form with suitable reducing agent to reduce keto group to hydroxyl group followed by treating the hydroxyl derivative with a base to cause hydrolysis of an ester to acid which is a Fexofenadine base;
F) precipitating Fexofenadine base using suitable precipitating agent such as alkyl formate and mineral acid;
G) Optionally Purifying base in suitable solvent.
This process described under third and fourth aspects, yield at least 95 % pure fexofenadine without any purification. More preferably, the fexofenadine is at least 97 % pure and most preferably it is at least 98 % pure. The entire process is designed to restrict meta analog of intermediates and final products below 2 %, preferably below 1 %, more preferably below 0.5 % and most preferably below 0.2 %.
Brief description of the drawings:
Fig.1: Differential scanning calorimetry (DSC) of hydrate form of Methyl-4{4- [4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate
Fig.2: Thermal gravimetric analysis (TGA) of hydrate form of Methyl-4{4- [4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate
Fig.3: A representative chromatogram of reaction mixture after completion of reaction to prepare Methyl-4{4-[4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate
Fig.4: A representative chromatogram of isolated hydrate form of Methyl-4{4- [4-(hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate
Fig.5: A representative chromatogram of hydrate form of Methyl-4{4- [4- (hydroxy diphenylmethyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate showing stability of said hydrate intermediate after one year at room temperature
Fig.6 and 7: A representative chromatogram of isolated fexofenadine base neutralized by Hydrochloric acid and methyl formate respectively.
Fig.8: A representative chromatogram of isolated fexofenadine base which is neutralized by Hydrochloric acid and purified using methanol.
Fig.9: A representative chromatogram of isolated fexofenadine base which is neutralized by methyl formate and purified using methanol.
Detailed description of the Invention
Synthetic process of preparation of Fexofenadine has several challenges. Several process impurities and degradants are generated and added to final Fexofenadine compound during preparation.
Table 1-part A provides limits on various related substances / degradants specified in USP. Table 1 – part B provides other related substances not specified in USP.
Name of related compound / degradant Structure Limit
Related compound A
NMT 0.2 %
Related compound B
NMT 0.2 %
Decarboxylated degradant
NMT 0.15 %
Related compound reported in literature, hereinafter impurity C and D respectively but not in USP
and
Impurity C Impurity D

Impurity C hereinafter, Compound-I is routinely employed as an intermediate for preparing Fexofenadine. Compound-I is likely to remain in final Fexofenadine product and thereby reported as impurity C.
Use of Compound-I as an intermediate compound to prepare Fexofenadine has several disadvantages as follows:
a) Compound-I is an oily liquid compound and it is difficult to purify it.
b) Compound-I is a high boiling oily liquid and is not separable from reaction mass by conventional distillation techniques.
c) the reactant Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate (V) to obtain Compound-I is also a liquid compound and hence even reactant remaining in compound-I which is a liquid cannot be separated by crystallization.
d) Hydrochloride salt of Compound-I is a solid form and several attempts are made in art to prepare hydrochloride solid form. However, hydrochloride form also offers several disadvantages. First, in the subsequent reaction step hydrochloride salt form should be converted back into the base form. Second, if reactant Azacyclonol is not fully consumed while preparation of Compound-I, hydrochloride salt of Azacyclonol also precipitates out along with hydrochloride of compound-I. This requires further purification of Compound-I.
e) Any reaction which subjects Compound-I to acid hydrolysis should be avoided. Hydrochloride formation of Compound-I may cause partial hydrolysis of Compound-I which results in undesired impurity, a known related compound of Fexofenadine reported in United States Pharmacopoeia (USP) as Fexofenadine Related Compound A. The limit specified for Fexofenadine Related Compound A impurity by USP is not more than 0.2 %. Hence, any sample having large amount of Related Compound A will fail in quality control test.
f) Compound-I contains large amount of meta analog – hereinafter Compound (I-A). This meta analog comes from meta analog (compound (V-A)) of precursor Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate compound (V). Meta analog (V-A) in (V) may go up to 15 % or even more.
If Fexofenadine is prepared using compound-I containing large amount of meta analog (I-A), a known related compound of Fexofenadine reported in United States Pharmacopoeia (USP) as Fexofenadine Related Compound B / (III-A) is formed in large amounts. The limit specified for Fexofenadine Related Compound B / (III-A) impurity by USP is not more than 0.2 %. Hence, any sample having large amount of Related Compound B will fail in quality control test.
The prior arts such as WO2007/007347 that have employed compound-I with large amount of meta impurity for further reaction to obtain Fexofenadine emphasized on multiple purification of Fexofenadine to restrict Fexofenadine Related Compound B impurity within specified limits.
The inventors of the present invention have developed a method which solves all above problems by employing just a single solution viz. preparing a solid form of compound-I which is a novel hydrate form of compound-I. The isolated hydrate form has surprisingly much lesser meta analog, is a solid form and a stable intermediate. Hydrate form of compound-I is a solid form and thus can be easily separated from liquid reactants (compound V) and liquid products (compound-I). It dispenses with the need to form hydrochloride salt and avoids further complications such as formation of hydrochloride of Azacyclonol and conversion to base form in subsequent step.
Characterization and analysis of Hydrate of compound-I
The hydrate form of compound-I is characterized by following techniques, Melting point, Water content, Differential scanning calorimetry, Thermal gravimetric analysis, and Meta impurity content.
The melting point of hydrate of compound-I is from 118°C – 123°C.
The hydrate form is analyzed using Karl Fischer method and is found to contain around 3.3 % water corresponding to a monohydrate.
The DSC data in figure-1 shows two endotherms, the first at 101.23 indicating dehydration i.e. presence of hydrate and second at 121.69 indicating melting of the compound.
The TGA data in figure-2 shows loss of weight around 3.1 % when heated from 20° C to 100°C confirming presence of monohydrate.
Water present in the compound is water of crystallization as evident by endotherm at ~100°C in DSC and TGA prior to its melting temperature range of 118-123°C. Also, corresponding water loss matches to theoretical quantity of water to form monohydrate.
Meta impurity content of the hydrate of compound-I is below 10 %, preferably below 5 % and most preferably below 2 %.
The hydrate form of compound-I is simple to prepare, easy to handle, stable and highly pure as compared to compound-I in reaction mixture or a concentrated form of compound-I.
Table-2 below provides Analytical method to determine impurity profile including meta impurity of hydrate of compound-I Table 3 below provides Data of multiple batches performed for comparison of para isomer and meta isomer in compound-I in reaction mixture and compound-I in isolated hydrate form.
Table 2: HPLC Method to quantify Compound I, its hydrate, its meta form and hydrate of meta form.
Column: Zorbax SB Phenyl, 250 X 4.6 mm, 5µm
Buffer Buffer 6.64 g/L of NaH2PO4 & 0.84g/L of aq. NaClO4; pH 2 (H3PO4)
Mobile phase A Buffer: ACN (13:7). 0.3 mL/Lit TEA
Mobile phase B ACN
Flow rate, injection volume and wavelength 1.5 mL/min; 20 µl; 230 nm
Gradient Diluent: Buffer : ACN (1:1); A:B 100:0; 0-10 min; A:B 80:20; 15-20 min; A:B 100:0; 25-30 min

Table 3 Comparison of para isomer and meta isomer in Compound-I in reaction mixture and Compound-I in isolated hydrate form.
In process result Isolated product
% by area Ratio % by area Ratio
Meta isomer Para Isomer Meta isomer Para Isomer Meta isomer Para Isomer Meta isomer Para Isomer
16.46 66.83 19.76 80.24 1.51 92.3 1.61 98.39
16.94 66.33 20.34 79.66 1.93 91.91 2.06 97.94
18.66 56.65 24.78 75.22 1.6 92.03 1.71 98.29
16.97 71.74 19.13 80.87 1.02 95.05 1.06 98.94
17.15 70.06 19.67 80.33 1.46 93.59 1.54 98.46
17.74 70.69 20.06 79.94 1.47 93.75 1.54 98.46
17.76 70.91 20.03 79.97 1.47 93.92 1.54 98.54
19.02 70.34 21.28 78.72 1.26 95.24 1.31 98.69
Figures 3 and 4 provide representative chromatograms of reaction mixture and isolated hydrate respectively. Thus, preparation of novel hydrate form of compound-I relieves it from several disadvantages associated with it.
In this aspect, isolated hydrate form is storage stable and can be stored at temperatures from around 15 – 30°C, preferably 25-30°C.
Table 4 provides representative stability data of one of above batches of hydrate of compound-I when samples are stored at room temperature of around 15 – 30°C, preferably 25-30°C for one year.
Table 4 - Stability data on Hydrate of Compound-I
Initial analysis Analysis after 1 year
Purity Total impurities Purity Total impurities
95.05 % 4.95 % 95.65%* 4.35%
*Increase in purity is probably due to loss of trapped toluene during storage at ambient temperature reflected in the test of loss on drying
Second aspect of the invention provides a process to prepare a novel intermediate for the preparation of Fexofenadine. This novel intermediate is a hydrate of compound-I and the process yields pure hydrate as compared to its anhydrous form when prepared using same reactants.
The process to prepare hydrate of compound-I is a simple, single step and an economical process. First, the reaction is carried out to prepare compound-I as reported in literature. After reaction is completed, water is added to the reaction mixture preferably in lots or portions. The detailed reaction is as follows. First, Azacyclonol viz. compound (IV) and Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate viz. compound (V) are reacted in a suitable solvent comprising an organic solvent and first portion of water in presence of a base and a catalyst such as potassium iodide. Preferably, volume ratio of the organic solvent to first portion of water is from 95:5 to 50:50. Preferably, the reaction mixture is refluxed till such time when both the reactants are present in amounts less than 10 %, preferably less than 5 % and more preferably less than 2 %. Second portion of water is added at the end of the reaction and aqueous layer is drained. Further, third portion of water is added to organic layer and cooled to below 20°C, preferably below 10°C, more preferably below 5° C and most preferably in the range of 0-5°C preferably under stirring. The hydrate of compound-I is precipitated.
The ratio of different portions of water preferably are as follows:
Third portion: first portion: second portion = 1: 1–10: 1-25
Preferably the ratio of different portions of water are as follows:
Third portion: first portion: second portion = 1: 2– 8: 5-25
Most Preferably the ratio of different portions of water are as follows:
Third portion: first portion: second portion = 1: 4-6: 15-20
The product Methyl-4{4- [4-(hydroxy diphenyl methyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate hydrate is separated by filtration and dried at around 45°C till constant weight. The product is characterized by melting point, DSC and TGA analysis and water content. Thus, process of preparation of hydrate is not a separate process but a continuation or extension of preparation of compound-I without requiring separation and purification of compound-I. Hydrate viz. compound (VI) is formed quickly without investing additional resources, equipment and time. Isolated hydrate offers several advantages mentioned previously. It is highly pure particularly with respect to meta isomer viz. compound (I-A). The ratio of para and meta isomer in the isolated hydrate form prepared by this process is at least 95:5 or at least 98:2 or in the range of 95:5 to 99.9:0.1 or 98:2 to 99.9:0.1.
Fexofenadine, the final product it produces is also pure with respect to its meta isomer viz. Fexofenadine Related Compound B/ (III-A). Thus, use of hydrate (compound VI) helps in restricting Fexofenadine Related compound B in final product.
Third aspect of the invention provides process of preparation of Fexofenadine using novel hydrate compound viz. compound VI which is a hydrate of compound-I.
Hydrate / Compound VI has around or less than 2 % of meta isomer viz. compound (I-A). Use of hydrate as starting material almost eliminates meta analog of Fexofenadine which is Fexofenadine Related Compound B/ (III-A). The limit specified in USP for Fexofenadine Related compound B/ (III-A) is 0.2 %.
Use of reactants and intermediates having high amounts of meta analog cannot restrict Fexofenadine Related Compound B/ (III-A) in final fexofenadine product. Fexofenadine prepared from hydrate of compound (I) as described above has Fexofenadine Related compound B below 0.2 %, preferably below 0.1 % and most preferably below 0.05 %.
Further, Fexofenadine prepared from hydrate of compound (I) as described above has Fexofenadine Related compound A below 0.2 %, preferably below 0.1 % and most preferably below 0.05 %.
Under this aspect, hydrate intermediate viz. compound (VI) is subjected to following treatments:
A) reduction using suitable reducing agent
B) hydrolysis of an ester using suitable base
C) precipitation using suitable precipitating / neutralizing agent
Suitable reducing agent is selected from sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride preferably sodium borohydride in presence of a suitable solvent such as methanol or ethanol to reduce keto group to hydroxyl group and then subjecting it to alkaline hydrolysis using suitable base or alkali such as metal hydroxide, amide, alkoxide, alkali metal, wherein alkali metal hydroxide comprises one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide in presence of a suitable solvent such as one or more of water, lower alcohol and mixture of water and lower alcohol from 20: 80 to 80: 20 preferably 50:50 wherein lower alcohol is one or more of methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol.to cause hydrolysis of an ester group to acid group. The last step involves precipitating the Fexofenadine base using suitable precipitating / neutralizing agent. Various precipitating / neutralizing agents were tried such as mineral and organic acids and alkyl formates. The most preferred precipitating / neutralizing agents were methyl and ethyl formate which consistently yields relatively pure fexofenadine with better yield and purity compared to use of mineral acids like hydrochloric acid.
Fourth aspect of the invention provides a process of preparation of Fexofenadine from reactants Azacyclonol (IV) and Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate (V) using novel intermediate compound which is a hydrate of compound I. The entire process is designed to restrict meta analog of intermediates and final products below 2 %, preferably below 1 %, more preferably below 0.5 % and most preferably below 0.2 %.
The process involves following step
A) Reacting Azacyclonol (IV) & Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate (V) in a suitable solvent comprising an organic solvent such as toluene or xylene and first portion of water in presence of a base such as potassium bicarbonate and a catalyst such as potassium iodide and heating to reflux;
B) Adding second portion of water to the reaction mixture after completion of reaction and draining aqueous layer;
C) Adding third portion of water and cooling to below 20°C, preferably below 10°C, more preferably below 5°C under stirring and precipitating hydrate form;
D) Isolating solid hydrate form by filtration and drying to constant weight preferably at 40- 45°C;
E) Treating hydrate form with suitable reducing agent in a suitable solvent to reduce keto group to hydroxyl group followed by treating the hydroxyl derivative with a base in a suitable solvent to cause hydrolysis of an ester to acid which is a Fexofenadine base wherein i) reducing agent is one or more of sodium borohydride, potassium borohydride, tetralkyl ammonium borohydride, and zinc borohydride; wherein suitable solvent for reduction is methanol or ethanol and wherein ii) base is one or more of alkali metal hydroxide, amide, alkoxide, alkali metal, wherein alkali metal hydroxide comprises one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide and suitable Solvent for hydrolysis is one or more of water, lower alcohol and mixture of water and lower alcohol from 20: 80 to 80: 20 preferably 50:50 wherein lower alcohol is one or more of methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol.
F) precipitating Fexofenadine base using suitable precipitating/neutralizing agent such as alkyl formate and mineral acid;
G) Optionally Purifying base in suitable solvent such as methanol.
The ratio of different portions of water for hydrate in above preparation preferably are as follows:
Third portion: first portion: second portion = 1: 1–10: 1-25
Preferably the ratio of different portions of water are as follows:
Third portion: first portion: second portion = 1: 2– 8: 5-25
Most Preferably the ratio of different portions of water are as follows:
Third portion: first portion: second portion = 1: 4-6: 15-20.

Under third and fourth aspects, purity of Fexofenadine base prepared by using two different precipitating / neutralizing agents viz. alkyl formate and mineral acid are provided in table 5 below. The fexofenadine prepared by this method is at least 95 %, more preferably, the fexofenadine is at least 97 % pure and most preferably it is at least 98 % pure without applying any further purification method.
Table 5 - % Purity of Fexofenadine from hydrate of Compound-I using different precipitating / neutralizing agents
Precipitation/ Neutralization using Methyl formate (% Purity) Precipitation / Neutralization using Hydrochloric acid (% Purity)
98.74% 97.27%
98.56% 98.36%
98.10% 96.64%
98.05% 98.53%

Further, few batches from above are purified using methanol as solvent and are tested for purity. The purified Fexofenadine base is at least 99 % pure and preferably at least 99.5 % pure and most preferably at least 99.8 or at least 99.9 % pure. The analytical method used to analyze purity of fexofenadine base of table 5 and purity of purified Fexofenadine base is USP Analytical method for Related compounds reported in Fexofenadine monograph in USP 35 on page 3186.
Figures 6, 7, 8 and 9 provide representative chromatograms of the crude Fexofenadine base and the purified fexofenadine base analyzed by the USP Analytical method mentioned above. The RRT of keto analog of Fexofenadine i.e. Related Compound A by this method is about 1.7. The RRT of meta impurity of Fexofenadine i.e. Related Compound B by this method is about 1.09. The meta impurity / Related Compound B in the representative chromatograms were below detectable limits. Related compound A is below detectable limits in purified Fexofenadine base.
Following schemes represent reactions involved in preparation of Fexofenadine base. The schemes do not limit the scope of the invention in any way.
Scheme 1 provides preparation of compound-I by reacting Azacyclonol (IV) & Methyl 2-[4-(4-chlorobutanoyl) phenyl]-2-methylpropanoate (V).
Scheme 2 provides preparation of hydrate of compound-I
Scheme 3 provides preparation of Fexofenadine base from hydrate of compound-I

Scheme 1

Scheme 2

Scheme 3

Scheme 4 provides how meta impurities are generated in the entire sequence

Following embodiments without limitation illustrate hydrate preparation of compound-I and process of preparation of Fexofenadine base using the said hydrate.
Example-1: Synthesis of Methyl-4{4- [4- (hydroxy diphenyl methyl)-l-piperidinyl}-l-oxobutyl]-a, a-dimethyl benzene acetate Hydrate
To 8.25 Lit Toluene, 1.188 Kg Methyl2-[4-(4-chlorobutanoyl)phenyl]-2-methyl propanoate, 0.75 Kg Azacyclonol, 1.188 Kg potassium bicarbonate 40 g Potassium iodide and 0.9 Lit water were added and reaction mas was heated to reflux for ~72 hrs when both the reactants were found to be <5% by in HPLC analysis of reaction mass. Reaction mass was then diluted with 2.7 Lit water and cooled to 65-70°C. Lower aqueous layer was drained and 150 mL water was charged to upper organic layer and reaction mass was cooled to 0-5°C for 4 hrs under stirring during which Methyl-4{4-[4-(hydroxy diphenyl methyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate Hydrate precipitates out which was separated by filtration and air dried at 40-45°C till constant weight was observed.
Yield around 1.2 Kg. Water Content = 3.3 %
Example-2: Synthesis of fexofenadine
Synthesis is done in two steps as follows:
A) Reduction using sodium borohydride and,
B) Hydrolysis using sodium hydroxide.
1.2 Kg of Methyl-4{4- [4-(hydroxy diphenyl methyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate Hydrate is dissolved in 15.6 lit methanol and 85.38 g sodium borohydride is added to this solution at 10-15°C . After completion of addition, the reaction mass stirred at ambient temperature for 2 hrs. Completion of reaction was confirmed by In-process HPLC analysis. Reaction mass was neutralized with acetic acid and methanol was distilled out completely.
To the reaction mixture was added 3.6 Lit methanol and 3.6 Lit 1.88 M sodium hydroxide. Reaction mass was further heated to reflux overnight until unreacted ester intermediate (II) was found to be absent in the reaction mass. Reaction mass was cooled to ambient temperature and 0.9 Lit methyl formate was added and stirring was continued till pH of reaction mass was neutral. Precipitated solid is filtered and dried to get ~ 1.1 Kg fexofenadine base having purity > 98%.

Example-3: Comparative study of Isolation of fexofenadine base, by precipitation using hydrochloric acid and methyl formate
General procedure
100 g of Methyl-4{4- [4-(hydroxy diphenyl methyl)-l-piperidinyl}-l-oxobutyl]-a,a-dimethyl benzene acetate Hydrate was dissolved in 1.3 lit methanol and was reduced by addition of 7.11 g sodium borohydride at 10-15°C. After completion of addition, the reaction mass was stirred at ambient temperature for 2 hrs when In-process HPLC analysis indicated reaction completion. Reaction mass was then neutralized with acetic acid and methanol was distilled out completely, followed by addition of 300 mL methanol, and 300 mL 1.88 M sodium hydroxide. Reaction mass was heated to reflux till clear solution was obtained. Reaction mass was then cooled to ambient temperature and neutralized by adding ~75 mL methyl formate / 50 mL 30% hydrochloric acid and stirring was continued till pH of reaction mass was neutral. Precipitated solid was filtered dried to get ~ 92 g fexofenadine base. Purity of isolated fexofenadine base was in the range of 96-99% depending on the reagent used for work-up i.e. mineral acid / hydrochloric acid or methyl formate. Fexofenadine base could be optionally purified to meet the purity requirement as per pharmacopeia by refluxing with methanol.
Table 6 & 7 below provides comparison of use of two precipitating agents

Table 6: Purity and % yield of Fexofenadine base by two different precipitating / neutralizing agents
Precipitation/ Neutralization using Methyl formate Precipitation/ Neutralization using Hydrochloric acid
Yield % 75-79% 70-75%
Purity % 98-99% 96-99%
Total impurities % 1-2% 1-4 %

Table 7: Purity and % yield of Fexofenadine base before and after purification
Initial crude Fexofenadine base prepared from same source of hydrate of compound-I Corresponding pure Fexofenadine Base upon purification from methanol
Yield
w/w of input of hydrate of compound-I Purity Isolation method Purity
0.98 98.05% Neutralization by Methyl formate 99.86%
0.90
96.64% Neutralization by Hydrochloric acid 99.93%