FORM 2
THE PATENTS ACT 1970
(39 of l970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and ru!e l3)
1. TITLE OF THE INVENTION:
"A PROCESS FOR PREPARATION OF OXALIPLATIN"
2. APPLICANT


(a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, Town Centre, Andheri-Kurla Road, Andheri (East),
Mumbai-400059, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed
346 MUM 2009
1 7 FEB 2009

TECHNICAL F1ELD OF THE INVENTION:
The present invention relates to a process for preparation of Oxaliplatin in higher yield with low content of impurities. It also deals with a process for recovery of Oxaliplatin from its mother liquor to improve overall yield.
BACKGROUND AND PRIOR ART:
Oxaliplatin is an international non-proprietary name for (SP-4-2)[(1R,2R)-],2-
cyclohexanediamine-N,N'](oxalato-0,0']p!atinum(ll) of formula (1)

(1) used in chemotherapy specially to treat large bowel cancer. It interrupts cancer cell growth and slows the spread of cancer cells in the body. Oxaliplatin is marketed as ELOXATIN(TM)
There are several processes reported in the prior art like US4169846, US5290961, WO2005/035544, WO03/004505, US7351846 etc. The closest prior art to the present invention is disclosed in US Patent No. 7351846 and International Patent Publication No. WO03/004505. According to process disclosed in US 7351846, a suspension of (SP-4-2)-dichloro-[(1 R,2R)-l,2~cyclohexanediamine-N,N']platinurn(II) compound of formula (2)

(2) in water is treated with silver nitrate, then, after removal of the solid phase, the obtained solution is treated with quaternary ammonium iodide of the formula (R)4NI.
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The separated solid phase is removed and the obtained solution is treated with oxalic acid. Oxaliplatin thus formed is isolated, washed with water and a polar organic solvent or their mixture and dried. The crude product after recrystallising from water, is washed with water and polar organic solvent or their mixture, and dried to yield Oxaliplatin with low content of impurities. Further, International Patent Publication No. WO03/004505, describes a similar process starting from potassium chloroplatinate.
The major drawback of the said prior art is it requires the purification of crude solid to yield Oxaliplatin with low content of impurities and also purification consists of recrystallization from water, isolation of solid, washing with water and/or polar organic solvent or their mixture, and drying. In spite of the fact that Oxaliplatin is poorly soluble in water and requires large volume of water for recrystallization, the subsequent recovery of pure Oxaliplatin from such large volume of water is low,
In view of the above drawbacks there still remains a need to develop a process for the preparation of Oxaliplatin, which produce Oxaliplatin in higher yield with low content of impurities in simpler operations, saving time and large volume of solvents along with the recovery of Oxaliplatin from its mother liquor to increase overall yield, thereby making large scale production economical.
OBJECT OF THE INVENTION:
The first object of the present invention is to develop a process which provides a high yield of Oxaliplatin with low content of impurities without resorting to any extra purification step.
Another object is to provide a process for the recovery of Oxaliplatin from its mother liquor to increase overall yield.
SUMMARY OF THE INVENTION:
According to present invention there is provided a high yielding process for the preparation of Oxaliplatin comprising;
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a) reacting (SP-4-2)-dichloro-[(lR.2R)-l,2-cyclohexanediamine-N,N'] platinum (II) of formula (2) with silver sulfate in water;
b) filtering the reaction mass of step (a) containing stable diaqua sulfate salt of Platinum (II) and reacting filtrate with Tetraethyl ammonium iodide;
c) filtering the reaction mass of step (b) to obtain corresponding diaqua complex of platinum and reacting the filtrate with oxalic acid;
d) isolating the solid from reaction mass of step (c);
e) recovering the second crop of Oxaliplatin from the mother liquor by neutralizing with sodium bicarbonate; and
f) concentrating the solution followed by recrystallization of raw Oxaliplatin of step (e).
DETAILED DESCRIPTION OF THE INVENTION:
Unless defined otherwise, all the technical and scientific terms used herein have same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
According to present invention there is provided a high yielding process for the preparation of Oxaliplatin. As defined in the summary of the invention, the process for the preparation of Oxaliplatin comprises of following steps:
In step (a), (SP-4-2)-dichloro-[(lR,2R)-l,2-cyclohexanediamine-N,N']platinum (II) of formula (2)

is treated with silver sulfate in water for 70 hrs at room temperature with exclusion of light to form the corresponding diaqua sulfate salt of platinum (II). Silver sulfate being sparingly soluble in water as compared to silver nitrate, the removal of excess silver
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sulfate is easily affected by simple process of filtration. Moreover, the resulting diaqua sulfate salt of Platinum (II) is more stable than diaqua nitrate salt of platinum (II). Therefore, the use of silver sulfate over silver nitrate is preferable. Silver sulfate is used in stoichometric amount or slightly more to compound (2), preferably 1.015 mole per mole of compound (2). The amount of reaction medium i. e. water is extremely important and it is used in ratio of 17 volumes with respect of compound (2). This large volume of water helps in completion of reaction and helps retain the impurity of reaction in the filtrate, thereby reducing the total impurities in the isolated product. This therefore does away with the need to purify the product further.
In step (b). the reaction mass obtained in step (b) is filtered and filtrate is treated with Tetraethy] ammonium iodide (TEAI) to produce Silver iodide salt which is insoluble in water. TEAI is added in the molar ratio 0.65 with respect to compound of formula (2). The reaction is carried out for 16 hrs under dark at room temperature. Then activated charcoal is added to reaction mass, stirred for 20 minutes.
In step (c), the reaction mass obtained in step (a) is filtered and to the clear filtrate, oxalic acid is added. The reaction mixture is stirred for 4 hours at room temperature and cooled to l0°C.
in step (d), the reaction mass obtained in step (c) is filtered and the filtrate is kept aside for the recovery of Oxaliplatin. The solid obtained is first washed with Dimethyl formamide and then chilled water, methanol and acetone respectively. Without purifying, the solid is then dried under vacuum at 70° C for 6 - 8 hrs to yield Oxaliplatin in higher yield with total impurity level below 0.01% and content of silver is less then 0.0002%.
The advantage of the present invention is higher yield of the product with respect to said closest prior art. Another advantage is it gives Oxaliplatin with total impurity level below 0.01%) and content of silver is less then 0.0002% without purification of the solid obtained in step (d). This invention also provides a method for the recovery of the Oxaliplatin from the mother liquor, so that the overall yield of Oxaliplatin increases.
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In step (e), for the recovery of product from mother liquor, the filtrate of step (d) is treated with sodium bicarbonate and concentrated to minimum volume. Then, the reaction mixture is cooled to 10°C and filtered. The solid obtained is washed in the same manner as described instep (d).
In step (f), the solid is recrystallized from hot water to yield Oxaliplatin with total impurity level below 0.01% and content of silver is less then 0.0002%.
The following examples have been described in order to further illustration and not intended to limit the invention in any way.
EXAMPLES:
EXAMPLE 1:
To a suspension of 25 g of compound of formula (2) in 375 ml of distilled water, 20.807 g of Silver sulfate is added and the obtained mixture is stirred for 70 hours at room temperature, in the dark. The reaction mixture is filtered off and washed with 25 ml of distilled water. To the clear filtrate, 0.65 g of Tetraethylammonium iodide is added and stirred for 16 hours at room temperature. 0.2 g of activated charcoal is added to the reaction mixture and stirred for 20 minutes. Then the mixture is filtered and washed with 12.5 ml of distilled water. To the filtrate, 9.125 g of Oxalic acid dihydrate is added and stirred for 4 hours. The crystals of the desired product (I) is collected by filtration, washed with 12.5 ml of chilled water and further with 12.5 ml of Dimethyl Formamide, 12.5 ml of chilled water, 125 ml of methanol in five portions and finally with 25 ml of acetone in that order. The crystalline Oxaliplatin is dried under vacuum at 70° C for 6-8 hrs to yield 18 g (69 %) which meets the B. P. specification.
EXAMPLE 2:
Isolation of Oxaliplatin from mother liquor:
Filtrate kept for isolation of Oxaliplatin in example (1) is treated with 6 g of sodium bicarbonate and concentrated under vacuum to minimum volume. The reaction mixture is cooled to 10 ° C and filtered. The solid obtained is washed in the same manner as
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described in example (1). Then the solid is recrystalhsed from hot water to yield 1.5 g of Oxalipiatin. (B. P. specification)
EXAMPLE 3:
Comparative example of US Patent No. 7351846
Silver nitrate (22.66 gm) is added to a suspension of 25 gm of compound of formula (2) in 253 ml of water and the obtained mixture is stirred for 70 hrs. at room temperature in the dark. The insoluble portion is stirred off of the reaction mixture and this portion is washed with 25 ml of water. Tetraethylammonium iodide (0.703gm) is added to the filtrate and the obtained mixture is stirred for 16 hrs. Activated charcoal (0.17 gm) is added to the reaction mixture and the mixture is filtered. Oxalic acid dihydrate (8.3 gm) is added to the obtained filtrate, and 4 hours later the precipitated Oxalipiatin is filtered off. The product is washed with 8.3 ml of water and 140 ml of ethanol divided into five portions and the crude Oxalipiatin is dried at 70° under vacuum. After recrystallisation from water, the pure Oxalipiatin obtained is washed with 8.3 ml water and subsequently with 140 ml of ethanol (in five lots) and dried under vacuum at 70° C. Oxalipiatin is obtained in a yield of 14.11 gm (54% of the theoretical yield) based on (2).
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ABSTRACT:
The present invention provides a high yielding process for the preparation of Oxaliplatin by reacting (SP-4-2)-dichloro-[(lR,2R)-l,2-cyclohexanediamine-N,N']platinum (II) with silver sulfate in water to form more stable diaqua sulfate salt of platinum (II), followed by treating with oxalic acid. Further, the present invention provides a process for the recovery of second crop Oxaliplatin from its mother liquor to increase overall yield.
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