FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF OCTREOTIDE OR SALT OR INTERMEDIATES THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an efficient process for the preparation of octreotide or salt or intermediates thereof.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention relates to an efficient process for the preparation of octreotide or salt or intermediates thereof.
Octreotide is a octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is indicated to reduce blood levels of growth hormone and IGF-I in acromegaly patients. It is also indicated for the symptomatic treatment of patients with metastatic carcinoid tumors and Vasoactive Intestinal Peptide Tumors (VIPomas)
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FORMULA 1
US Patent No 4,395,403 (the '403 Patent) and European Patent EP 029,579 (the '579 Patent) discloses solution synthesis for the preparation of octreotide.
Several solid phase synthesis procedures have been subsequently described viz. European Patent No EP 953,577 and U.S. Pat. No 5,889,146 and in various research publications. Mergler et al (Proceedings of the 12.sup.th American Peptide Symposium) have used aminomethyl resin and Fmoc-butyl protection scheme for synthesis of octreotide. Alsina et al. Tetrahedron Letters, 38, 883, 1997) have used an active carbonate resin and Boc-Bzl protection scheme, necessitating the use of hydrogen fluoride/anisole for final deprotection. Edwards et al (J. Med. Chem., 37, 3749, 1994)) have described another synthesis using Fmoc-butyl protection and HMP resin, and Berta et al (European Patent EP 953,577) described a synthesis using 2-chlorotrityl-type resin and Fmoc-butyl protection scheme.
All the solid phase synthesis procedures described are not suitable for commercial manufacture of octreotide because they use costly resins and costly Fmoc-butyl protected amino acids in 2 to 4 times excess at every step. Some synthesis procedures use destructive and hazardous reagents for final deprotection.
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The present inventors now found out an efficient process for the preparation of octreotide or intermediates thereof. The present invention has the advantages of reduced process time, low ratio of reactants, lowered cost, enhanced yield and purity, easy purification and applicability for large-scale production.
In one of the aspects of the invention there is provided a process for preparation of Cys(Acm)-Phe-OMe or salt thereof wherein the said process comprises of
a) treating t-BOC-Cys(Acm)-Phe-OMe or salt thereof with less than 10 moles of trifluoroacetic acid,
b) removing excess trifluoroacetic acid,
c) isolating Cys(Acm)-Phe-OMe or salt thereof from the reaction mass thereof.
t-BOC-Cys(Acm)-Phe-OMe was prepared by the procedure which is well known to those skilled in the art of peptide chemistry. Prior art mentions that for the preparation of Cys(Acm)-Phe-OMe almost 25 to 32 moles of trifluoroacetic acid was required but the present inventors now found that when less than 10 moles of trifluoroacetic acid is employed impurities in the reaction mixture have been reduced which further helps to remove the product from reaction mixture with greater ease. The excess trifluoroacetic acid is removed after completion of reaction by vacuum distillation and the residue is triturated with mixture of ether and hexane to get the product.
In another aspect of the invention there is provided a process for preparation of Cys(Acm)-Thr-OL or salt thereof wherein the said process comprises of
a) treating t-BOC-Cys(Acm)-Thr-OL or salt thereof with less than 15 moles of trifluoroacetic acid,
b) removing excess trifluoroacetic acid,
c) isolating Cys(Acm)-Thr-OL or salt thereof from the reaction mass thereof.
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t-BOC-Cys(Acm)-Thr-OL was prepared by the procedure which is well known to those skilled in the art of peptide chemistry. After the deprotection, the mass is concentrated under vacuum and the product is triturated with non-polar hydrocarbon solvent to get the desired product.
The intermediates thus obtained as part of this invention can be converted to octreotide or salt thereof by processes known in the art.
While the present invention has been described in terms of its specific embodiments, 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.
Example 1
Preparation of H-Cys(Acm)-Phe-OMe trifluroacetate salt
t-BOC-Cys(Acm)-Phe-OMe (181 g) was suspended in dichloromethane (271 ml) and stirred at 5°C and to it was added trifluoroacetic acid (245 ml). The resultant mass after completion of reaction was distilled under vacuum to remove trifluoroacetic acid and dichloromethane. To the residue was added ether (180 ml x 3) and hexane (360 ml x 3), the mixture was triturated and allowed to settle under ice cooling. The ether-hexane layer was discarded and the residue was further concentrated under vacuum to get the title product as syrupy oil. Yield= 186 g on anhydrous and dry basis. Calculated mass = 353 Obtained mass= 354.1
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WE CLAIM:
1. A process for preparation of Cys(Acm)-Phe-OMe or salt thereof wherein the
said process comprises of
a) treating t-BOC-Cys(Acm)-Phe-OMe or salt thereof with less than 10 moles of trifluoroacetic acid,
b) removing excess trifluoroacetic acid,
c) isolating Cys(Acm)-Phe-OMe or salt thereof from the reaction mass thereof.
2. A process for preparation of Cys(Acm)-Thr-OL or salt thereof wherein the said
process comprises of
a) treating t-BOC-Cys(Acm)-Thr-OL or salt thereof with less than 15 moles of trifluoroacetic acid,
b) removing excess trifluoroacetic acid,
c) isolating Cys(Acm)-Thr-OL or salt thereof from the reaction mass thereof.

3. A process according to claims 1 or 2, wherein the amount of TFA required is less than 8 moles.
4. A process for preparation of octreotide or salt thereof comprising process of claim 1.
5. A process for preparation of octreotide or salt thereof comprising process of claim 2.

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Dated this 28th day of March, 2006

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