FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A NOVEL PROCESS FOR CONVERTING UNDESIRED ISOMER OF PROSTAGLANDIN AND THEIR DERIVATIVES TO THE DESIRED
ACTIVE ISOMER"
2. APPLICANT (S):
(a) NAME: FDC Limited
(b) NATIONALITY: Indian company incorporated under the Companies
Act, 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai- 400 102,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

Technical field:
The present invention relates to a novel process of converting undesired 15-epimer of prostaglandins and their derivatives into the desired active isomers of formula 1. Prostaglandin derivatives of formula I are used for the treatment of ocular hypertension and glaucoma. They also have clinical uses which include regulation of gastric secretion. blood platelet aggregation, blood pressure, lipolysis. gastric ulceration, inflammation, carbohydrate metabolism and corticosteroid genesis which is effective on platelet congregation.

formula 1
Wherein
R1 is selected from branched or linear chain alkoxy and alkylamino preferably C1 to C6
alkoxy groups and C1 to C6 alkylamino, R2 is selected from benzyl or phenoxy group
optionally substituted with alkyl, halo or haloalkyl, and represents a single or
double bond.
Background and prior art:
Prostaglandin analogues such as latanoprost, bimatoprost and travoprost have been used in the management of open-angle glaucoma. They reduce intra-ocular pressure by enhancing uveoscleral outflow and may also have some effect on the trabecular meshwork as well. Several literature articles disclose preparation of prostaglandin derivatives.
US Patent no. 5422368 discloses preparation of latanoprost and its usefulness as an ophthalmic agent. The patent discloses a process to prepare latanoprost and related derivatives.

US Patent No. 5352708 discloses preparation of Bimatoprost and methods of treating cardiovascular, pulmonary-respiratory, gastrointestinal, reproductive and allergic diseases, shock and ocular hypertension.
US Patent No. 7109371 describes process for synthesizing prostaglandins specifically the preparation of Latanoprost and Travoprost by the following processes as shown in Scheme 1.

Scheme 1
Wherein A is alkyl, aralkyl or aryl portion is substituted or unsubstituted, P is protecting group, and B is alkoxide and alkylamine.

J. Med. Chemistry 1993, 36, 243 discloses the synthesis and biological activity of phenyl-substituted analogues of prostaglandin F2n (PGF2a) and their 15-epimers. The preparation of analogues of prostaglandin and their 15-epimers is illustrated by two synthetic routes as shown below in Schemes 2 and 3.



Scheme 3
(15S)-13,14-dihydro-17-phenyl-l8,19-20-trinor-PGF2aisopropyl ester was prepared in similar way.
Eur. J. Org. chem. 2007, 689-703 describes synthesis of latanoprost in eight synthetic steps. The a chain of (-)- "Corey Lactone'' was elongated first, followed by the attachment of an enantiomerically pure "ω chain" synthon, which ensures the absence of the undesired 15(S)-Latanoprost in the synthesized prostaglandin.
According to the prior art, 15-epimer is an impurity that is present in the prostaglandin which would alter the therapeutic efficacy of the drug. Further, the prior art processes fail to recognize the effective recycle of the undesired epimer to useful isomer.

Since none of the aforementioned prior art discloses synthesis of prostaglandin derivatives using undesired isomer, the present invention provides a novel way of transforming the undesired 15-epimer of prostaglandin derivative into the desired isomer. This novel transformation not only reduces the cost but also increases the efficiency of production of prostaglandin derivatives. In a way, the present invention relates to a novel process for the synthesis of prostaglandin derivatives of formula 1.
Object of the invention:
The primary objective of the present invention is to provide a process for the synthesis of prostaglandin derivatives of formula 1 by a novel way of transforming the undesired 15-epimer of prostaglandin or its derivatives into the desired isomers.
Another objective of the present invention is to provide a process for the synthesis of prostaglandin derivatives using inexpensive reagents which will not only make it a cost effective process but will also increase the efficiency of production.
Summary of the invention:
formula 1
In accordance with the above objectives, the present invention discloses a novel process of transforming the undesired 15-epimer of prostaglandin derivatives and intermediates thereof to the desired active isomer of formula 1. The prostaglandin derivatives of formula 1 are used for the treatment of ocular hypertension and glaucoma. They also have clinical uses which include regulation of gastric secretion, blood platelet aggregation, blood pressure, lipolysis, gastric ulceration, inflammation, carbohydrate metabolism and corticosteroid genesis which is effective on platelet congregation.


wherein R1 is selected from branched or linear chain alkoxy and alkylamino preferably C| to Cealkoxy groups and C1 to C6 alkylamino, R2 is selected from benzyl or phenoxy group
optionally substituted with alkyl, halo or haloalkyl, and represents a single or
double bond.
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.
Accordingly, the present invention provides a novel process for the synthesis of prostaglandin derivatives of formula 1 and intermediates thereof.

Wherein R1 is selected from branched or linear chain alkoxy and alkylamino preferably C1to C6 alkoxy groups and C1 to C6 alkylamino, R2 is selected from benzyl or phenoxy
group optionally substituted with alkyl, halo or haloalkyl, and represents a single
or double bond.
The prostaglandin derivatives of the present invention can be prepared by a number of different synthetic routes as disclosed in prior art. However, the process of converting undesired isomer (epimer) to desired isomer is not reported anywhere in the prior art. To illustrate the process of the invention, the detailed description is provided herein below as depicted in Scheme 4.


Scheme 4
Wherein P is a protecting group selected from p-nitrobenzoyl or benzoyl, and R1, R2and
are same as defined above,
The starting material is the undesired 15-epimer of the prostaglandin derivative of formula 2 (Scheme 4), which is isolated during the preparation of prostaglandin derivatives, or is selectively produced by general processes known in the art. The process of the present invention comprises reacting the undesired 15-epimer of prostaglandin derivative of formula 2 with n-butylboronic acid in a chlorinated solvent, to yield corresponding 9,11-boronate ester of formula 3. Mitsuiioubo reaction is carried out in order to invert the center at 15-hydroxyl group of 9,1 l-boronate ester by treating the boronate ester with p-nitrobenzoic acid or benzoic acid in presence of triphenylphosphine and diethylazodicarboxylate to yield protected boronate ester of formula 4. Deprotection of the protected boronate ester using an alcoholic solvent and an alkali carbonate, leads to formation of the desired 15-epimer of prostaglandin derivatives of formula I.

The desired !5-epimer of prostaglandin derivatives of formula I prepared by the present invention, are selected from Latanoprost, Travoprost and Bimatoprost as structurally illustrated below:

General process
Preparation of compound of formula 3


Wherein R1 is selected from branched or linear chain alkoxy and alky tarn ino preferably C1 to C6 alkoxy groups and C1 to C6alkylamino, R2 is selected from benzyl or phenoxy
group optionally substituted with alkyl, halo or haloalkyl, and represents a single
or double bond.
To a stirred solution of compound of formula 2 (10 mmol) in a chlorinated solvent (10-20ml) was added n-butyl boronic acid. The reaction mixture was heated under gentle reflux until the disappearance of starting material. The solvent was evaporated to yield the crude boronate ester of formula 3. This was used as such for the next step.
The chlorinated solvent is selected from chloroform, carbon tetrachloride, tetrachloro ethylene or methylene chloride.
The amount of n-butyl boronic acid in the reaction ranges from lOmmol to 15 mmol.
Preparation of compound of formula 4

wherein R1, R2 and are same as defined above, and. P is protecting group selected
from p-nitrobenzoy! or benzoyl.
To a stirred solution of compound of formula 3 (10 mmol), triphenylphosphine, and p-nitrobenzoic acid or benzoic acid in an organic solvent at room temperature, was added

diethylazodicarboxylate dropwise. The reaction mixture was stirred for 4-8 hrs at room
temperature. All the volatiles were removed to afford crude residue of the compound of
formula 4.
The concentration of triphenylphosphine in the reaction mixture ranges from 45 mmol to
55 mmol.
The concentration of p-nitrobenzoic acid or benzoic acid in the reaction mixture ranges
from 40 mmol to 46 mmol.
The organic solvent is selected from a group consisting of dry benzene, toluene and
tetrahydrofuran.
The concentration of diethylazodicarboxylate in the reaction mixture ranges from 45
mmol to 55 mmol.
Preparation of compound of formula 1

wherein R1, R2 and are same as defined above.
To a stirred solution of the compound of formula 4 (5 mmol) in alcohol was added alkali carbonate, and the reaction mixture was stirred at ambient temperature for 2-3 hrs. The reaction mixture was then quenched by the addition of acetic acid and stirred for about 30 min at room temperature. The volatiles were evaporated and to that ethyl acetate was added followed by water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and dried over sodium sulfate. Removal of solvent followed by purification of the crude product on a silica column gave the desired compound of formula 1.
The alcohol is selected from methanol, ethanol, propanol or isopropanol preferably methanol

The alkali carbonate is selected from sodium carbonate or potassium carbonate, and is in the range of 8 mmol to 15 mmol.
Lantanoprost, travoprost and bimatoprost can be prepared employing the process described above.
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.
Examples:
Example 1
Preparation of Latanoprost
A) Preparation of (Z)-isopropyl 7-((lR, 5S, 6R, 7R)-3-buryl-7-((S)-3-hydroxy-5-
pheny]penryi)-2,4-dioxa-3-borabicyclo[3.2.1]octan-6-yl)hept-5-enoate

To a stirred solution of 15-epi latanoprost (4.32 g, 10 mmol) in methylene chloride (15 ml) was added n-butyl boronic acid (1.313 g, 13 mmol). The reaction mixture was heated under gentle reflux until the disappearance of starting material (2-4 hr). Once, the reaction was adjudged complete, the solvent was evaporated to yield the crude boronate ester, which was used as such for the next step.
B) Preparation of (R)-1-((1S, 5R, 6R, 7R)-3-buryl-7-((Z)-7-isopropoxy-7-oxohept-2-enyl)-2,4-dioxa-3-borabicyclo[3,2.1]octan-6-yl)-5-pheny!pentan-3-yl-4-nitrobenzoate


To a stirred solution of the above alcohol (4.98 g, 10 mmol). triphenylphosphine (12.9 g, 49.2 mmol) and p-nitrobenzoic acid (7.3 g, 43.8 mmol) in dry benzene (190 mL) at room temperature, was added diethylazodicarboxylate dropwise (7.7 mL, 49.2 mmol). The reaction mixture was stirred for 4-8 hrs at room temperature. All the volatiles were removed to afford crude residue of the inverted boronate ester.
C) Preparation of Latanoprost

To a stirred solution of the resulting boronate ester (3 g, 5 mmo!) in MeOH (25 mL) was added potassium carbonate (1.4 g. 10 mmol), and the reaction mixture was stirred at ambient temperature for 2-3 hrs. The reaction mixture was quenched by the addition of acetic acid (2 mL) and stirred for about 30 min at room temperature. The volatiles were evaporated, and to that ethyl acetate (50 mL) was added, followed by water (15 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (2 x 25 mL). The combined organic phases were washed with water and dried over sodium sulfate. Removal of solvent followed by purification of the crude product on a silica column using ethyl acetate /hexane (7:3) mixture gave the desired pure latanoprost (Igm).

Example 2
Preparation of (Z)-isopropyl 7-((lR, 5S, 6R, 7R)-3-buryl-7-((S)-3-hydroxy-5-
phenylpentyl)-2,4-dioxa-3-borabicyclo[3.2.1]octan-6-yl)hept-5-enoate
To a stirred solution of 15-epi latanoprost (4.32 g, 10 mmol) in methylene chloride (15 ml) was added n-butyl boronic acid (1.515 g, 15 mmol). The reaction mixture was heated under gentle reflux until the disappearance of starting material (2-4 hr). Once, the reaction was adjudged complete, the solvent was evaporated to yield the crude boronate ester, which was used as such for the next step.
Preparation of (R)-1-((1S, 5R, 6R, 7R)-3-butyI-7-((Z)-7-isopropoxy-7-oxohept-2-enyl)-2,4-dioxa-3-borabicyclo[3.2.l]octan-6-yl)-5-pheny]pentan-3-yl-4-nitrobenzoate
To a stirred solution of the above alcohol (4.98 g, 10 mmol), triphenylphosphine (14.42 g, 55 mmol) and p-nitrobenzoic acid (7.67 g, 46 mmol) in dry benzene (190 mL) at room temperature, was added diethylazodicarboxylate dropwise (8.6 mL, 55 mmol). The reaction mixture was stirred for 4-8 hrs at room temperature. All the volatiles were removed to afford crude residue of the inverted boronate ester.
Preparation of Latanoprost
To a stirred solution of the resulting boronate ester (3 g, 5 mmol) in MeOH (25 mL) was added potassium carbonate (2.1 g, 15 mmol), and the reaction mixture was stirred at ambient temperature for 2-3 hrs. The reaction mixture was quenched by the addition of acetic acid (3 mL) and stirred for about 30 min at room temperature. The volatiles were evaporated, and to that ethyl acetate (50 mL) was added, followed by water (15 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (2 x 25 mL). The combined organic phases were washed with water and dried over sodium sulfate. Removal of solvent followed by purification of the crude product on a silica column using ethyl acetate /hexane (7:3) mixture gave the desired pure latanoprost (Igm).

We claim:
I. A process for synthesis of prostaglandin derivatives of formula I and intermediates thereof,

formula 1
wherein R1 is selected from branched or linear-chain C1-C6 alkoxy and CI to C6 alkylamino, R2 is selected from benzyl or phenoxy group optionally substituted
with alkyl, halo or haloalkyl, and represents a single or double bond;
comprising the steps of:

wherein R1, R2 and are same as defined above,
(a) reacting undesired 15-epimer of prostaglandin derivative of formula 2 with n-butylboronic acid in a chlorinated solvent, to form corresponding 9,11-boronate ester of formula 3,

(b) performing Mitsunoubo reaction on 9,11 -boronate ester of formula 3 in order to invert its stereogenic center at 15-hydroxyl group, by treating the 9,11 -boronate ester with p-nitrobenzoic acid or benzoic acid in presence of triphenylphosphine and diethyiazodicarboxylate in an organic solvent, to yield protected boronate ester of formula 4

wherein R1, R2 and are same as defined above, and Pisa protecting group
selected from p-nitrobenzoyl or benzoyl group, and
(c) deprotecting the protected boronate ester of formula 4 using an alcohol and an alkali carbonate to yield desired 15-epimer of prostaglandin derivatives of formula
I.
2. The process according to claim 1, wherein the chlorinated solvent used in step (a) is selected from chloroform, carbon tetrachloride, tetrachloroethylene or methylene chloride.
3. The process according to claim 1, wherein the organic solvent used in step (b) is selected from dry benzene, toluene or tetrahydrofuran.
4. The process according to claim 1, wherein the alcohol used in step (c) is selected from methanol, ethanol, propanol or isopropanol preferably methanol.
5. The process according to claim 1, wherein the alkali carbonate used in step (c) is selected from sodium carbonate or potassium carbonate.

6. The prostaglandin derivative of formula I according to ciaim I is Latanoprost.
7. The prostaglandin derivative of formula 1 according to claim I is Travoprost
8. The prostaglandin derivative of formula 1 according to claim I is Bimatoprost.