PHENOXYPHENYL ACETIC ACID ESTERS AND PROCESS FOR THE PREPARATION THEREOF
The present invention relates to novel esters of phenoxyphenyl acetic acid compound and process for preparation thereof. More particularly, the invention is related to (5-chloro-2-phenoxyphenyl) acetic acid esters and preparation thereof. These esters can be hydrolyzed to achieve corresponding acids. The esters of the present invention and their corresponding acids are represented by general formula II and III, respectively.

(Formula Removed)
wherein,
X is selected from hydrogen or halogen and
R is selected from the group comprising alkyl, aryl or heteroaryl.
The compounds of formula II and III can be used as pharmaceutical intermediates for the preparation of the asenapine or pharmaceutically acceptable salts thereof, which is known to have CNS-depressant, antihistamine and antiserotonin activities.
Asenapine, which is disclosed in US patent 4,145,434 (hereinafter referred to as US '434 patent), is chemically designated as ^ram--5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole as represented by formula (I) and is known to have CNS-depressant, antihistamine and antiserotonin activities.
(Formula Removed)
Maleate salt of Asenapine, known as ORG 5222, is a broad spectrum, high potency serotonin, noradrenaline and dopamine antagonist. Asenapine and its maleate salt are cairrently undergoing clinical trials.
A general methodology for the preparation of asenapine is described in the US '434 patent, the disclosure of which is incorporated herein for reference. Following the generalized method given in US -434 patent, asenapine can be prepared by the method depicted in scheme-1, given below.
(Formula Removed)

[SCHEME-1]
Additional synthetic methods for the preparation of asenapine or salts thereof are known from WO 2006/106136, WO 1998/54186 and EP 0,569,096 patent applications. Vader et al. (./. Labelled Comp. Radiopharm., 34(9), 845-869, 1994) discloses synthetic methods for the preparation of radiolabelled ORG 5222 and derivatives thereof. Orthorhombic crystal form of asenapine maleate is disclosed in WO 2006/106135.
A method of preparation of (5-chloro-2-phenoxyphenyl) acetic acid has been disclosed by J. Med. Chem. 25, 855 (1982). The method employed is Willegerodt-Kindler reaction whose synthetic utility is seriously limited by the necessity of elevated reaction temperature and use of frequently high pressure. The yield of the acid obtained by the method is less (46%) that is not commercially viable for pharmaceutical industries.
A generalized method for one step synthesis of methyl (monosubstituted)arylacetates from acetophenones is disclosed in Synthesis 126-127 (1981). According to this disclosure, tor example, when a mixture of acetophenone, methanol and boron trifluoride etherate is added in one lot to a stirred suspension of lead(IV) acetate in benzene at room temperature, it leads to the formation of methyl phenyl acetate in good yields. This article does not disclose preparatory methods for the phenoxyphenyl acetic acid compounds of the present invention, particularly (disubstituted)phenylacetates, more particularly (5-chloro-2-phenoxyphenyl)acetic acid or esters thereof and their further conversion to asenapine or salts thereof.
The present invention provides novel esters of compound of formula II. These novel esters are easy to synthesize in high yields and can be conveniently converted into their corresponding acids (formula III) upon hydrolysis. Thus, the high yielding process of the present invention to obtain compounds of formula II and III overcomes the disadvantages associated with the prior art.
Accordingly, the present invention is directed towards esters of compounds of formula II, process for preparation thereof and their conversion to the corresponding acids of tormula III. These compounds can be used to make asenapine or salts thereof, for example, asenapine maleate.
The term 'alky!' as used herein is referred to any straight or branched, open or closed chain alkyl commonly known to a person who is skilled in the art. Preferably, the alkyl as used herein comprises 1 -6 carbon atoms, for example, but not limiting to methyl, ethyl, propyl, t-butyl, cyclobutyl, pentyl, etc. The closed chain alkyl can be oxiryl, morpholyl, piperidinyl, pipera/inyl, pyrrolidinyl, or the like. The alkyl can be substituted with aryl or heteroaryl.
The term 'aryl' as used herein is referred to any substituted or unsubstituted aryl commonly known to a person who is skilled in the art. The 'aryl' can be monocyclic or fused ring, for example, phenyl, toluyl, naphthyl or the like. The 'aryl' can be substituted with heteroaryl or alkyl groups.
The term 'heteroaryl' as used herein is referred to any substituted or unsubstituted heteroaryl commonly known to a person who is skilled in the art. The 'heteroaryl' can be monocyclic or fused ring containing at least one hetero atom selected from N, P, S or 0. The non-limiting examples of heteroaryls are furyl, pyranyl, chromenyl, benzofuranyl, thiophenyl,
imidazolyl, oxazolyl, thiazolyl, or the like. The 'heteroaryl' can be substituted with aryl or alkyl groups.
The term 'halogen' as used herein is referred to Cl, Br, I or F. The preferred halogen is Cl or Br. The most preferred is Cl.
A first aspect of the present invention provides phenoxyphenyl acetic acid esters of general formula II

(Formula Removed)
wherein,
X is hydrogen or halogen and
R is selected from the group comprising alkyl, aryl and heteroaryl.
In an embodiment of this aspect, the preferred esters are compound of formula II in which X is halogen.
In another embodiment of this aspect, the preferred esters are (5-chloro-2-phenoxyphenyl) acetic acid esters.
In another embodiment of this aspect, alkyl esters of (5-chloro-2-phenoxyphenyl) acetic acid are preferred. Most preferred is methyl ester of (5-chloro-2-phenoxyphenyl) acetic acid of formula V.
(Formula Removed)
The esters represented by formula II and V, above, in this aspect can be used to prepare asenapine or pharmaceutically acceptable salts.
A second aspect of the present invention provides a process for the preparation of phenoxyphenyl acetic acid esters of general formula II

which comprises
reacting compound of following formula VI

(Formula Removed)

with R-OH wherein,
X is hydrogen or halogen and
R is selected from the group comprising alkyl, aryl and heteroaryl.
The preparation of compound of formula II comprising reacting compound of formula VI with R-OH can be carried out in presence of lewis acid and lead(IV)acetate.

The lewis acid can be selected from the group comprising

In an embodiment of this aspect, esters of general formula II can be hydrolyzed to achieve corresponding acids of general formula III.
In another embodiment of this aspect, esters of general formula II and their corresponding acids of general formula III, as depicted herein, can be converted to asenapine or pharmaceutical ly acceptable salts thereof. The acids of general formula III can be subjected to halogenation to produce corresponding acid halides that are then converted to asenapine or salt thereof following the generalized procedure described in the US '434 patent.
A third aspect of the present invention provides a process for the preparation of methyl (5-chloro-2-phenoxyphenyl) acetate of formula V
(Formula Removed)

which comprises
reacting compound of formula VII
(Formula Removed)
(VII) with methanol.
The preparation of compound of formula V comprising reacting compound of formula VII with methanol can be carried out in presence of lewis acid and lead(IV)acetate.
The term Tewis acid' as used herein implies the same meaning as described in the second aspect of the invention.
In an embodiment of this aspect, the methyl ester of formula V, as depicted above, can be hydrolyzed to achieve its corresponding acid.
In another embodiment of this aspect, methyl ester of formula V, as depicted above, and its corresponding acid can be converted to asenapine or pharmaceutically acceptable salts thereof. The hydroly/ed product, i.e. acid, can be subjected to halogenation to produce corresponding acid halide of formula IV that is then converted to asenapine or salt thereof Ibllowing the synthetic scheme-1, as shown hereinabove.
While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
In the following section aspects are described by way of examples to illustrate the processes of the invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
Example 1 Preparation of methyl (5-chloro-2-phenoxyphenyl)acetate
To a BFaOEta (2.1 ml, 0.017 mol) solution in flask, dipped in water bath at room temperature, methanol (1.1 ml, 0.034 mol) was added drop wise. The solution was stirred for 15 min at room temperature and 5-chloro-2-phenoxy acetophenone (1.0 g, 0.004 mol) was added to it. The reaction mixture was then stirred for 10 min at room temperature and lead (IV) acetate (2.2 g, 0.0049 mol) was added to it. After stirring for 3 h, lead (IV) acetate (0.45 g. 0.001 mol) was added again. The mixture was stirred for 2h and subsequently a third lot of lead (IV) acetate(0.2 g, 0.00045 mol) was added. After 2 h of stirring, methanol (5 ml) was added to the reaction mixture and stirring continued for few minutes. After the reaction was over, water (70 ml) was added to the reaction mixture and the product was extracted in toluene (50 ml). The organic layer was filtered using hyflo bed. The bed was washed with toluene. The toluene layer thus obtained, was finally washed with water (50 ml) and dried over anhydrous Ts^SO/j. Toluene was recovered on rotavapour to obtain pale yellow oily compound (1.02 g), yield = 83.6 %
H'NMR (CDCi,): 3.62(s,3H), 3.66(s,2H), 6.77-6.8(d,lH, J=8.6 Hz), 6.93-6.95(d, 2H, J 7.84), 7.06-7.40(m, 5H)
Example 2 Preparation of (5-chloro-2-phenoxyphenyl)acetic acid
To a solution of methyl (5-chloro-2 -phenoxyphenyl)acetate (12.22 g, 0.0442 mol) in methanol (62 ml), aqueous NaOH solution (25%, 10 ml) was added. The reaction mixture was stirred for 2 h at room temperature. After the reaction was over, methanol (45 ml) was recovered in rotavapour at 50 °C. Water (150 ml) was added to the crude residue and the aqueous layer washed with toluene thrice (70 ml x 3). The aqueous layer was separated and acidified with cone. HC1 to a pH=l. The oil, which separated out was vigorously stirred and it slowly converted to solid. The suspension was stirred for 1.5 h and then filtered. The filtrate was washed with water and dried in buchner funnel under suction for 2 h and further in vacuum dessicator for 15 h at room temperature to obtain (5-chloro-2-phenoxyphenyl)acetic acid (9.9 g) % yield - 85 %
Example 3
Methanol (13.75 ml, 0.429 mol) was added drop wise to BF3OEt2 (26.25ml, 0.212 mol) in the flask, which was dipped in ice water bath. The solution, so formed, was stirred for 15 min at 5°C. 5-chloro-2-phenoxy acetophenone (12.5 g, 0.050 mol) was added to this solution. The reaction mixture was stirred for 10 min at 20-25°C and lead (IV) acetate (35.62 g, 0.08 mol) was added to it in three lots. After stirring the reaction mixture for 4 hr at room temperature, it was left standing overnight at room temperature. Then, methanol (20 ml) was added to the reaction mixture and stirred for 10 min at room temperature. Water (250 ml) was added to the reaction mixture and then reaction product was extracted with toluene (200 ml). The obtained toluene emulsion was filtered using hyflo bed. The bed was washed with toluene. The obtained toluene layer was washed with water (150 ml x 2) and dried over NaiSCU (anhydrous). Toluene was recovered on rotavapour to obtain light brown oily compound (13.1 g).
The, so obtained, oily compound (13.1 g) was dissolved in methanol (65.5 ml) and 25% NaOH solution (10.56 ml) was added to it. The reaction mixture was stirred for 2 h at room temperature. Methanol was distilled out at 45°C under vacuum and the crude was dissolved in water (78 ml) by heating to 50°C and cooled to room temperature. The aqueous layer was washed with toluene (50 ml x 3). Then, the aqueous layer was acidified with cone. 1IC1 (pH=2). The oil thus separated was stirred vigorously for 2 hr at 5°C. The product solidified, was filtered and washed with water (50 ml). It was then dried in air at room temperature for 24 hr to obtain 10.1 g (5-chloro-2-phenoxyphenyl)acetic acid. %Yield= 76%
Example 4
Methanol was added slowly to precooled BF3OEt2 (319.6 ml, 45-50% in THF) at 3-4°C and stirred for 15 min. To this solution, 5-chloro-2-phenoxy acetophenone (188g, 0.76 mol) was added maintaining temperature at 3°C and stirred for 15min. Lead (IV) acetate (395.8g, 0.893 mol) was added to the solution in five lots over a period of 55 min. at 3-18°C. The reaction mixture was stirred for 1 h at 10-25°C and further stirred at room temperature tor 15 h. After 24 h, lead (IV)acetate (140g, 0.316 mol) was again added to the reaction mixture and stirred for 5 h at room temperature. This was kept at room temperature for 40 h and again Lead(IV)acetate (25g, 0.056 mol) was added. The mixture was further stirred for 5 h and then, toluene (1.5 L) was added to it. This was stirred for 5 min and then reaction mixture was filtered through hyflo bed. Toluene layer thus separated was washed with water
(500ml x 2) and the toluene distilled off on rotavapour at 55°C to obtain (5-chloro-2-phenoxyphenyl)acetate as brown oily product (21 Ig)
Example 5
196.5g of the product obtained in example 4 (mentioned above) was dissolved in methanol (982.5 ml) and 25% NaOH solution (158ml) was added to it in 5 min. The reaction mixture was stirred for 2 h. After the reaction was over, methanol was distilled off at 45°C on rotavapour. The crude thus obtained was dissolved in water (1L) at 50°C and this was then washed with toluene three times (200ml x 3). Aqueous layer was separated. It was cooled to 5-10°C and slowly acidified to pH=l with cone. HCI at 5-15°C. It was further stirred for 1.5 h vigorously. The powdered solid, so obtained, was filtered and washed with water (200 ml x 2). The product was then dried in air oven at 55°C for 15 h and 60°C for 3h. Yield= 167g (89.5%)

WE CLAIM:
1. Phenoxyphenyl acetic acid esters of general formula II
(Formula Removed)
wherein, X is hydrogen or halogen and R is selected from the group comprising alkyl, aryl and heteroaryl.
2. The esters of claim 1, wherein X is halogen and R is alkyl.
3. Use of the esters of claim 1 for the preparation of asenapine or pharmaceutically
acceptable salts thereof.
4. Methyl ester of (5-chloro-2-phenoxyphenyl)acetic acid of formula V
(Formula Removed)
5. Use of methyl (5-chloro-2-phenoxyphenyl) acetate for the preparation of asenapine or
pharmaceutically acceptable salts thereof.
6. A process for the preparation of phenoxyphenyl acetic acid esters of general formula II
(Formula Removed)
which comprises reacting compound of following formula VI

(Formula Removed)
with R-OH
wherein, X is hydrogen or halogen and R is selected from the group comprising alkyl, aryl and heteroaryl.
7. The process of claim 6, wherein compound of formula VI is reacted with R-OH in
presence of lewis acid and lead(IV)acetate.
8. The process of claim 7, wherein lewis acid is selected from the group comprising
BF3OEt2, A1C13, SnCl4, FeCl3 and ZnCl2.
9. The process of claim 6, wherein esters of formula II are further hydrolyzed to obtain
corresponding acids.
10. The process of claim 9, wherein the esters or acids are further used to prepare
asenapine or pharmaceutically acceptable salt thereof.
11. A process for the preparation of methyl (5-chloro-2-phenoxyphenyl)acetate of
formula V
(Formula Removed)
which comprises reacting compound of formula VII

(Formula Removed)
with methanol.
12. The process of claim 11, wherein compound of formula VII is reacted with methanol
in presence of lewis acid and lead(IV)acetate.
13. The process of claim 12, wherein lewis acid is selected from the group comprising
BF3OEt2, A1C1.1, SnCl4, FeCl3 and ZnCl2.
14. The process of claim 11, wherein compound of formula V is further hydrolyzed to get corresponding acid.
15. The process of claim 14, wherein formula V or its corresponding acid is converted to asenapine or pharmaceutically acceptable salt thereof.