FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)


1. TITLE OF THE INVENTION:
"PROCESSES FOR THE SYNTHESIS OF BORTEZOMIB AND INTERMEDIATES FOR USE THEREIN"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies Act, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.


Technical Field of the Invention:
The present invention relates to process for the synthesis of Bortezomib. The present invention further relates to process for preparation of the key intermediate (A) and various other intermediates useful in the synthesis of Bortezomib.
Background and Prior Art:
Bortezomib is an antineoplastic agent, acting as an inhibitor of dipeptide boronic acid protease.

Bortezomib US5780454 discloses a class of potent and highly selective boronic acid and ester compounds including Bortezomib. The synthesis of Bortezomib comprises a coupling reaction of (lR)-(S)-pinanediol-l-ammonium trifluoroacetate-3-methylbutane-l-boronate with N-(pyrazine-2-yl-carbonyl)-L-phenyl alanine in presence of 0-(lH-benzotriazole-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) as the peptide coupling agent.
US20050240047 describes a process for preparation of Bortezomib comprising
rearrangement of an intermediate (lS)-(S)-pinanedioI-l-chloro-3-methyIbutane-l-
boronate complex, in presence of a Lewis acid catalyst. (lS)-(S)-pinanediol-l-chloro-
3-methylbutane-l-boronate further reacts with lithium bis(trimethylsilyl) amide to
obtain (lR)-(S)-pinanediol-l-bis(trimethylsiIyl)amino-3-methylbutane-]-boronate,
which reacts with trifluoroacetic acid to obtain (lR)-(S)-pinanediol-l-ammonium
trifluoroacetate-3-methylbutane-l-boronate, which further couples with protected L-
phenyl alanine in presence of TBTU and a tertiary amine in dichloromethane to obtain
corresponding protected (lS,2S,3R,5S)-pinanediol-L-phenylalanine-L-leucine
boronate, which is first deprotected and then coupled with 2-pyrazine carboxylic acid in presence of TBTU as coupling agent to obtain (lS,2S,3R,5S)-pinanediol-N-(2-
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pyrazinecarbonyl)-L-phenylalanine-L-Ieucine boronate, which is trans-esterified to obtain Bortezomib.
WO2009004350 and WO2009036281 disclose synthesis of Bortezomib in which (1R)-(S)-pinanediol-1 -ammonium trifluoroacetate-3-methylbutane-1 -boronate is coupled with N-(pyrazine-2-yl-carbonyl)-L-phenyl alanine or its sodium salt in presence of a coupling agent to obtain (lR)-(S)-pinanediol-N-(pyrazine-2-yl-carbonyl)-L-phenyl alanine-L-Leucine boronate, which is subjected to trans-esterification using 2-methylpropyl boronic acid to obtain Bortezomib.
With the advancements of research and development, there are continuous attempts to design more simple and convenient,processes for preparation of Bortezomib. The present invention describes new processes for the preparation of Bortezomib and the key intermediates therein.
Objects of the Invention:
It is an object of the present invention to provide simple and convenient process for the preparation of Bortezomib.
It is another object of the present invention to provide process for the preparation of the key intermediate (A) and other intermediates useful in synthesis of Bortezomib.
Detailed description of the invention:

(A)
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The present invention provides process for preparation of Bortezomib that is simple and can be applied to an Industrial scale very conveniently. Compound (A) represented by the following structure is the key intermediate useful in synthesis of Bortezomib. The present invention provides new method for synthesis of compound (A).

According to one embodiment of the present invention, there is provided a process for preparing compound of formula (A) as described in scheme I below:


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Scheme-!

The process for preparation of compound of formula (A) comprises treating L-phenyl alanine with triphosgene or imidazole sulphonyl chloride to obtain corresponding N-carboxy or N-sulfoxy anhydride, whioh is further reacted with compound (6) to obtain a compound of formula (7). The compound of formula (7) is reacted with a compound of formula (2) in presence of a base and a solvent to obtain compound (A).
In another embodiment, there is provided another process for preparation of compound (A) as represented in scheme II below:
(A)
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Scheme-II



The process comprises reaction of the compound of formula (7) with an active ester of compound (1) in presence of a base.
An active ester of compound (1) represented by following structure, is obtained by reacting compound (1) with a suitable reagent such as, but not limiting to, N,N-carbonyl diimidazole (CDI), chlorodimethoxy triazene (CDMT), Dicyclohexylcarbodiimide (DCC) /N-hydroxysuccinimide (HOSu), DCC/N-hydroxybenzotriazole. (HOBT) DCC/N-hydroxy phthalimide or peatafluorophenol.

R" group is derived from the corresponding reagents used for formation of the active ester.
The solvent used for the reaction is selected from toluene, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, ethyl acetate, dichloromethane, most preferably tetrahydrofuran.
In another embodiment, there is provided another process for preparation of compound of formula (A) as described in scheme III.
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The process comprises;
i) hydrolyzing a compound of formula (4) in presence of a base to obtain corresponding carboxylic acid or its metal salt of formula (5a);
ii) treating compound of formula (5a) with a suitable reagent to convert the
hydroxyl (-OH) group or (-OM) group (wherein M+ may be Na+, K+, Ca+2, Li+ ) into a suitable leaving group to obtain compound (5b);
iii) acylating compound (5b) by reacting with compound of formula (6) in presence of a base to obtain compound (A) or;
coupling compound of formula (5a) with compound of formula (6) in presence of a coupling agent to obtain compound of formula (A).
The base used for the hydrolysis reaction in step (i) is an inorganic base selected from potassium hydroxide, sodium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate and calcium carbonate.
The suitable reagent in step (ii) may be selected from thionyl chloride or propane phosphonic acid anhydride (T3P) or pivaloyl chloride to generate the suitable leaving group such as chloride (-C1), phosphonate (-n-Pr-PO3H), an ester (-OCOR) respectively.
A suitable coupling agent in step (iii) is selected from Benzotriazole-1-yl-oxy-tris-
(dimethylamino)-phosphonium hexafluorophosphate(BOP), N -(3
dimethylaminopropyl)-N'-ethyl carbodiimide (EDC)/N-hydroxysuccinimide (HOSu),
N,N'-dicyclohexyl carbodiimide DCC/HOBT, DCC/HOSu, 2 -(6 -chloro-lH-
benzotriazole-1- yl)-l,l,3,3 - tetramethylaminium hexafluorophosphate (HCTU), 2-
(7-Aza-1H-benzotriazole-l-yl) - 1,4,3,3-tetramethyluronium hexafluorophosphate
(HATU), 0-(6-Chloro-l -hydrocibenzotriazol-1 -yl)-l, 1,3,3-tetramethyluronium
tetrafluoroborate (TCTU), Benzotriazol-1 -yl-oxy-tris-(pyrrolidino)-phosphonium Hexafluorophosphate (PyBOP), N,N'-diisopropylcarbodiimide (DIC).
The compound of formula (4) is prepared by a process comprising converting 2-pyrazine carboxylic acid (1) to obtain a compound of formula (2), which is further
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treated with the L-phenyl alanine ester (3) in presence of a suitable base to obtain compound of formula (4).
The conversion of 2-pyrazinecarboxylic acid (1) to obtain a compound of formula (2) is carried out by its reaction with a suitable reagent that converts the (-OH) group of carboxylic acid or (-OM) group of its metal salt into a suitable leaving group, as described hereinbefore, to obtain compound (2).
The compound of formula (2) is further treated with the L-phenyl alanine ester (3) to obtain a compound of formula (4).
Optionally, a nucleophilic acylating catalyst can be used in the reaction such as N,N-dimethylpyridine-4 amine.
Alternatively, the compound of formula (4) is prepared by coupling of compound of formula (1) with the compound of formula (3) in presence of a suitable coupling agent, as described hereinbefore.
In the processes of the present invention as described in schemes I, II and III, unless and otherwise specified, the following reaction conditions apply;
i) the base used is an organic base. The organic base may be selected from pyridine, triethylamine or N,N-diisopropylethyl amine. Most preferably, the base used is triethylamine.
ii) the solvent used may be selected from toluene, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, ethyl acetate, N-methyl pyrrolidine, dichloromethane, dioxane or a mixture of solvents, most preferably dichloromethane.
iii) the processes are carried out at a temperature below 25°C.
iv) the compound (6) is in the form of its trifluoroacetate salt.


The compound (A) prepared by any of the processes described herein can be converted to Bortezomib by treating with isobutyl boronic acid in presence of aqueous HC1 and methanol to obtain Bortezomib.
Optionally, the processes as described hereinabove for preparation of Bortezomib and the key intermediate (A) may be carried out in a single reaction vessel without isolating any of the intermediates. This eventually results in good yield of the final product. The processes of the present invention are advantageous as they are simple and can be effectively applied on an industrial scale.

Dr. P. Aruna Sree Agent for the Applicant
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