Claims:
1. A process for racemization of undesired enantiomer of intermediate of cetirizine viz. 1-(4-Chlorophenyl)-1-phenylmethamine, comprising;
a) reacting undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine with an acid anhydride in presence of suitable organic solvent to form an intermediate of the said enantiomer and
b) hydrolysing the said intermediate of step a) in glycolic solvents in presence of an inorganic base to obtain racemic mixture of the 1-(4-Chlorophenyl)-1-phenylmethamine.

2. A process for the racemization of undesired enantiomer of intermediate of cetirizine viz. 1-(4-Chlorophenyl)-1-phenylmethamine is carried out in-situ by; reacting undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine with an acid anhydride in presence of suitable organic solvent to form an intermediate of the said enantiomer and in-situ hydrolysing the said intermediate in glycolic solvents in presence of an inorganic base to obtain racemic mixture of the 1-(4-Chlorophenyl)-1-phenylmethamine.

3. The process as claimed in claim 1 and 2, wherein the acid anhydride is selected from acetic anhydride and phthalic anhydride.

4. The process as claimed in claim 1 and 2, wherein the undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine is preferably (S)-enatiomer of 1-(4-Chlorophenyl)-1-phenylmethamine with a contamination of (R)-enatiomer.

5. The process as claimed in claim 4, wherein the undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine has R:S Isomeric ratio from about 10:90 to about 40:60 in approx. proportion.
6. The process as claimed in claim 1 and 2, wherein the suitable organic solvent of step a) is selected from hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride or chloroform, ethers such as THF, diethylether, nitriles such as acetonitrile, alcohols such as C1 toC6 alcohols or acetates such as ethylacetate and polar aprotic solvent such as Dimethyl sulfoxide (DMSO).

7. The process as claimed in claim 1 and 2, wherein the reaction of step a) is carried out at a temperature range of 50°C to reflux temperature of the solvent used.

8. The process as claimed in claim 1 and 2, wherein the glycolic solvents are selected from the group consisting of monoethylene glycol, diethylene glycol and polyethylene glycol.

9. The process as claimed in claim 1 and 2 , wherein the inorganic base is alkali metal hydroxide or carbonate selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate and caesium carbonate.

10. The process as claimed in claim 1 and 2, wherein the hydrolysis of the said intermediate in step b) is carried out at a temperature range of 100°C to 150°C for 10-30 hrs.

11. A novel phthalate intermediate of cetirizine, the compound of formula II.

Formula II
12. A novel acetate intermediate of cetirizine, the compound of formula III.

Formula III
, Description:Technical filed:
The present invention relates to novel and commercially viable process for racemization of intermediates of active pharmaceutical ingredients. More particularly, the present invention relates to a novel process for racemization of key chemical intermediate of cetirizine and novel intermediates thereof.

Background and prior art:
A large fraction of active pharmaceutical ingredients (APIs) currently in use are enantiomers and the desired biological activity is provided only by one of the enantiomers. Strict regulatory requirements and fierce competition have forced the pharmaceutical industry to develop new methods to produce pharmaceuticals consisting of APIs of the desired enantiomer. During the resolution process of a racemic mixture to produce desired optical enantiomer, the undesired enantiomer is to be thrown out as waste product in the earlier days. However, later on methods have been developed for effective utilization of an undesirable antipode remained after isolating the desired active substance by converting the same into racemic mixture. Therefore, reutilization of the undesired antipode by racemization becomes an important industrial subject matter.

Optically active 1-(4-Chlorophenyl)-1-phenylmethamines are important intermediates in the production of Cetirizine. In such a process of producing an optically active substance due to optical resolution, undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine are also obtained. Thus the recyclization methods are reported for the racemization of the undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine.

1-(4-Chlorophenyl)-1-phenylmethamine is an important intermediate in the preparation of cetirizine. Certain methods are reported on resolution of racemic 1-(4-Chlorophenyl)-1-phenylmethamine wherein after isolation of the desired (R)-enantiomer, the undesired enantiomer enriched with (R)-enantiomer is recovered and recycled by racemizing the undesired enantiomer.
There is ample literature available on such racemization process of the undesired enantiomer enriched with (S)-1-(4-Chlorophenyl)-1-phenylmethamine.

US5723672A discloses a method of racemization of (S)-(4-Chlorophenyl)-1-phenylmethamine, wherein, optically enriched (S)-(4-Chlorophenyl)-1-phenylmethamine is treated with an aldehyde such as pivalaldehyde, isobutylaldehyde to obtain an optically active imine, which is reacted with an alkaline metal tert-alkoxide in an aprotic polar solvent or a mixture of the aprotic polar solvent and an aprotic nonpolar solvent, and then hydrolyzing the resultant racemic imine.

The racemization of optically active 1-(4-chlorophenyl) ethylamine by reacting the amine with potassium tert-butoxide in dimethyl sulfoxide has been described in Japanese Patent JPH04275258. However, according to the teachings of US5723672A, this method did not result in racemization.

The process of dehydration-condensation of optically active 1-(4-chlorophenyl) ethylamine with acetophenone, followed by reacting with potassium tert-butoxide has been described in Japanese Patent JPH07188120. This process results in large amount of an undesirable amine as a by-product after hydrolysis because isomerization (migration of double bond) of the imine proceeds simultaneously as the racemization reaction.

CN101928223A reports another process for racemization of 1-(4-Chlorophenyl)-1-phenylmethamine, wherein, after isolating the desired enantiomer, the mother liquor containing unwanted enantiomer is treated with a strong acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid at a temperature of 60-130°C to obtain racemic mixture.

US20130345475 reports a process for the racemization of an optically active 1-(4-Chlorophenyl)-1-phenylmethamine which comprises reaction of optically active amine of formula I, in the presence of hydrogen and a hydrogenation/dehydrogenation catalyst at an elevated temperature of from 100 to 300° C., to form a racemization product, wherein the hydrogenation/dehydrogenation catalyst comprises as active components nickel, cobalt and copper, and a hydrogen partial pressure of from 0.1 to 10 bar is maintained during the reacting.

As is evident from the above, it is difficult to provide a reliable racemization process for optically active 1-(4-Chlorophenyl)-1-phenylmethamine.

In view of there being no satisfactory racemization process for optically active 1-(4-Chlorophenyl)-1-phenylmethamine; the present invention provides an improved racemization process which will eliminate the prior art problems such as formation of by-products, incomplete reactions etc.

Summary of the invention
Accordingly, the present invention provides novel and commercially viable process for racemization of intermediates of active pharmaceutical ingredients. More particularly, the present invention provides a novel process for racemization of undesired enantiomer of key chemical intermediate of cetirizine and novel intermediates thereof.

Accordingly in an aspect, the invention provides an efficient process for the racemization of the undesired enantiomer of key chemical intermediate of cetirizine viz. 1-(4-Chlorophenyl)-1-phenylmethamine by treating with an acid anhydride followed by hydrolysis to obtain racemic mixture.

The invention further encompasses novel chemical intermediates of cetirizine.

Detailed description of the 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.

The present invention provides novel and commercially viable process for racemization of undesired enantiomer of intermediate of cetirizine and novel intermediates thereof.

Accordingly in an embodiment, the invention provides an efficient process for the racemization of the undesired enantiomer of key chemical intermediate of cetirizine viz. 1-(4-Chlorophenyl)-1-phenylmethamine by treating with an acid anhydride followed by hydrolysis to obtain racemic mixture.

According to preferred embodiment, the invention provides process for racemization of undesired enantiomer of intermediate of cetirizine, 1-(4-Chlorophenyl)-1-phenylmethamine wherein the process comprises;
a) reacting undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine with an acid anhydride in presence of suitable organic solvent to form an intermediate of the said enantiomer and
b) hydrolysing the said intermediate of step a) in glycolic solvents in presence of an inorganic base to obtain racemic mixture of the 1-(4-Chlorophenyl)-1-phenylmethamine.

The racemic mixture thus obtained is extracted using suitable solvent such as methylene dichloride, toluene, ethyl acetate etc.

The undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine is preferably (S)-enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine with a contamination of (R)-enantiomer.

In one preferred embodiment, undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine has R:S Isomeric ratio from about 10:90 to about 40:60 in approx. proportion.

The acid anhydride according to the invention is selected from acetic anhydride and phthalic anhydride.

The suitable organic solvent is selected from hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride or chloroform, ethers such as THF, diethyl ether, nitriles such as acetonitrile, alcohols such as C1 to C6 alcohols or acetates such as ethylacetate, and polar aprotic solvent such as Dimethyl sulfoxide (DMSO).

The reaction of the undesired enantiomer with acid anhydride may be conveniently conducted at a temperature range of 50°C to reflux temperature of the solvent used.

The glycolic solvents in the hydrolysis are selected from the group consisting of monoethylene glycol(MEG), diethylene glycol(DEG) and polyethylene glycol(PEG).

The inorganic base is alkali metal hydroxide or carbonate selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate and caesium carbonate.

The hydrolysis of the said intermediate may be conveniently conducted at a temperature range of 100°C to 150°C for about 10-30 hrs to obtain racemic mixture.

The invention further encompasses novel intermediates of cetirizine viz., N-[(4-Chloro-phenyl)-phenyl-methyl]-phthalamic acid and N-[(4-Chloro-phenyl)-phenyl-methyl]-acetamide.

Accordingly, in one embodiment, 1-(4-Chlorophenyl)-1-phenylmethamine having R:S Isomeric ratio of from about 10:90 to about 40:60 in approx. proportion, is reacted with phthalic anhydride at a temperature range of 50 to 60°C in toluene to obtain a novel intermediate compound of formula II. After the distillation of toluene completely under vacuum, the compound of formula II is further subjected to basic hydrolysis in glycolic solvent at a temperature of 100-150 °C for about 10-30 hrs. The reaction mass is cooled to room temperature, adding water followed by extraction with toluene or DCM and further distillation of the solvent to obtain 1-(4-Chlorophenyl)-1-phenylmethamine having R:S Isomer of ratio of about 45:55 to about 50:50 in approx. proportion, as an oil.

Accordingly, in a further embodiment, the invention provides novel phthalate intermediate of cetirizine, viz., N-[(4-Chloro-phenyl)-phenyl-methyl]-phthalamic acid compound of formula II.

Formula II
According to another embodiment, 1-(4-Chlorophenyl)-1-phenylmethamine having R:S Isomeric ratio of from about 10:90 to about 40:60 in approx. proportion, reacts with acetic anhydride at a temperature range of 50 to 60°C in toluene to obtain a novel intermediate compound of formula III. After the distillation of toluene completely under vacuum, the compound of formula III is further subjected to basic hydrolysis in glycolic solvent at a temperature of 100-150 °C for about 10-30 hrs. The reaction mass is cooled to room temperature, added water followed by extraction with toluene or DCM and further distillation of the solvent to obtain 1-(4-Chlorophenyl)-1-phenylmethamine having R:S Isomer ratio of about 45:55 to about 50:50 in approx. proportion, as an oil.

Accordingly, in another preferred embodiment, the invention provides novel acetate intermediate of cetirizine, N-[(4-Chloro-phenyl)-phenyl-methyl]-acetamide compound of formula III.

Formula III
In yet another embodiment, the racemisation process is optionally carried out in-situ. Accordingly, the invention provides in-situ process for racemization of undesired enantiomer of intermediate of cetirizine, 1-(4-Chlorophenyl)-1-phenylmethamine wherein the process comprises; reacting undesired enantiomer of 1-(4-Chlorophenyl)-1-phenylmethamine with an acid anhydride in presence of suitable organic solvent to form an intermediate of the said enantiomer and in-situ hydrolysing the said intermediate in glycolic solvents in presence of an inorganic base to obtain racemic mixture of the 1-(4-Chlorophenyl)-1-phenylmethamine.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Example 1

Preparation of N-[(4-Chlorophenyl)-phenylmethyl]-phthalamic acid (Formula II)
100 gm (0.46 mol) of 1-(4-Chlorophenyl)-1-phenylmethamine of Formula I of about 10:90 to about 40:60 proportion was dissolved in 500 ml Toluene, to this 61.5 gm (0.41 mol) of phthalic anhydride was added. The reaction mass was heated at 50°-60°C and maintained for 1 hr to form intermediate, N-[(4-Chlorophenyl)-phenylmethyl]-phthalamic acid of Formula II. The reaction mass was cooled and digested at 10°-15°C for 1 hrs. The product thus obtained was filtered and washed with 50 ml chilled toluene. Then the product is dried to get 155 gm of the intermediate of Formula II with a purity of 98 %.

The intermediate, N-[(4-Chlorophenyl)-phenylmethyl]-phthalamic acid thus obtained was subjected to Mass, IR and NMR and the results of which are deposed as below:
Molecular Formula: C21H16ClNO3
Weight: 365.08
Mass: [M+H]+ = 366.17
1H NMR: (400 MHz, CDCl3): d=7.82(1H(d), 7.2-7.8(13H(m), 6.31H(s).
FTIR (KBr, Cm-1): 800-860, 1190, 1600, 1640, 1685, 3028-3063, 3281
Preparation of racemate of 1-(4-Chlorophenyl)-1-phenylmethamine by Hydrolysis of N-[(4-Chlorophenyl)-phenylmethyl]-phthalamic acid (Formula – II):
200 ml Polyethylene glycol was charged in to glass assembly, followed by charged 155 gm of N-[(4-Chlorophenyl)-phenylmethyl]-phthalamic acid i.e. Formula-II obtained in example -2. To this mass charged 400 ml 48% Caustic lye. Reaction mass was heated at 115°-125°C and maintained for 10-15 hrs to convert intermediate of Formula II in to compound of Formula I. Reaction mass was cooled at RT, to this 200 ml water was added followed by 200 ml Toluene and further the organic layer was separated to extract the product in toluene. Toluene was distilled out and 95 gm compound of Formula I having R: S Isomer in proportion of about 45: 55 to about 50:50 in oil form was obtained.

Example 2:
Racemisation of 1-(4-Chlorophenyl)-1-phenylmethamine using Phthalic anhydride:
100 gm (0.46 mol) of 1-(4-Chlorophenyl)-1-phenylmethamine of Formula I of about 10:90 to about 40:60 proportion was dissolved in 500 ml Toluene, to this 61.5 gm (0.41 mol) of phthalic anhydride was added. The reaction mass was heated at 50°-60°C and maintained for 1 hr to form intermediate, N-[(4-Chloro-phenyl)-phenyl-methyl]-phthalamic acid of Formula II. Toluene was distilled completely from the reaction mass. 200 ml Polyethylene glycol was charged to the residue obtained; to this charge 400 ml 48% Caustic lye. Reaction mass was heated at 115°-125°C and maintained for 10-15 hrs to convert intermediate of Formula II in to compound of Formula I. Reaction mass was cooled at RT, to this 200 ml water was added followed by 200 ml Toluene and further the organic layer was separated to extract the product in toluene. Toluene was distilled out and 98 gm compound of Formula I having R: S Isomer in proportion of about 45: 55 to about 50:50 in oil form was obtained.

Example 3:
Preparation of N-[(4-Chlorophenyl)-phenylmethyl]-acetamide(Formula III)
100 gm (0.46 mol) of 1-(4-Chlorophenyl)-1-phenylmethamine of Formula I of about 10:90 to about 40:60 in approximate Proportion was dissolved in 500 ml Toluene, to this 70.30 gm (0.70 mol) of acetic anhydride was added. The reaction mass was heated at 50°-60°C and maintained for 2-3 hrs to form intermediate, N-[(4-Chlorophenyl)-phenylmethyl]-acetamide compound of Formula III. The reaction mass was cooled and digested at 10°-15°C for 1 hr. The product thus obtained was filtered and washed with 50 ml chilled toluene. Then the product is dried to get 110 gm of the intermediate of Formula III with a purity of 95 % and Formula I (approx. 3-4%) remaining unreacted.

The intermediate, N-[(4-Chlorophenyl)-phenylmethyl]-acetamide thus obtained was subjected to Mass, IR and NMR and the results of which are deposed as below:
Molecular Formula: C15H14ClNO
Weight: 259.08
Mass: [M+H]+ = [M+H]+ = 260.2
1H NMR: (400 MHz, DMSO): d=8.9 (1H(d), 7.2-7.4 (9H(m), 6.1(1H(s), 1.9(3H(s)
FTIR (KBr, Cm-1): 800-860, 1089, 1600, 1644, 3028-3063, 3294.
Preparation of racemate 1-(4-Chlorophenyl)-1-phenylmethamine by Hydrolysis of N-[(4-Chlorophenyl)-phenylmethyl]-acetamide (Formula – III):
Charged 200 ml Monoethylene glycol in glass assembly, followed by charged 110 gm of N-[(4-Chlorophenyl)-phenylmethyl]-acetamide i.e. Formula-III obtained in example-4. To this charged 300 ml 48% Caustic lye. Reaction mass was heated at 115°-125°C and maintained for 10-15 hrs to convert intermediate of Formula III in to compound of Formula I. Reaction mass was cooled at RT, to this 200 ml water was added followed by 200 ml DCM and further the organic layer was separated to extract the product in DCM. DCM was distilled out and 85 gm compound of Formula I having R: S Isomer in proportion of about 45: 55 to about 50:50 in oil form was obtained.

Example 4:
Racemisation of 1-(4-Chlorophenyl)-1-phenylmethamine using acetic anhydride:
100 gm (0.46 mol) of 1-(4-Chlorophenyl)-1-phenylmethamine of Formula I of about 10:90 to about 40:60 in approximate Proportion was dissolved in 500 ml Toluene ,to this 70.30 gm (0.70 mol) of acetic anhydride was added. The reaction mass was heated at 50°-60°C and maintained for 2-3 hrs to form intermediate, N-[(4-Chloro-phenyl)-phenyl-methyl]-acetamide compound of Formula III.

Toluene was distilled completely from the reaction mass. 200 ml Monoethylene glycol was charged to the residue obtained. To this charge 300 ml 48% Caustic lye. Reaction mass was heated at 115°-125°C and maintained for 10-15 hrs to convert intermediate of Formula III in to compound of Formula I. Reaction mass was cooled at RT, to this 200 ml water was added followed by 200 ml DCM and further the organic layer was separated to extract the product in DCM. DCM was distilled out and 92 gm compound of Formula I having R: S Isomer in proportion of about 45: 55 to about 50:50 in oil form was obtained.