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THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENS RULES, 2003 PROVISIONAL SPECIFICATION
[See section 10, Rule 13]
ACID MEDIATED DEACYLATION OF 6-0-TRICHLOROGALACTOSUCROSE TO TRICH-LOROGALACTOSUCROSE;
PHARMED MEDICARE PVT. LTD., A COMPANY INCOPORATED UNDER THE COMPANIES ACT, 1956, WHOSE ADDRESS IS 141 WALCHAND HIRACHAND MARG, MUMBAI -400 001, MAHARASHTRA, INDIA.
THE FOLLOWING SPECIFICATION
DESCRIBES THE INVENTION.
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TECHNICAL FIELD
The present invention relates to acid mediated deacylation of 6-0-trichlorogalactosucrose (TGS) to TGS during the process of production of TGS (1-6-Dichloro-1-6-DIDEOXY-p-Fructofuranasyl-4-chloro-4-deoxy-galactopyranoside).
DESCRIPTION
Strategies of prior art methods of production of 4,1', 6' trichlorogalactosucrose (TGS) predominantly involve chlorination of sucrose-6-ester by use of Vilsmeier Haack reagent derived from various chlorinating agents such as phosphorus oxychloride, oxalyl chloride, phosphorus pentachloride etc, and a tertiary amide such as dimethyl formamide (DMF) or dimethyl acetamide to chlorinate Sucrose-6-ester, to form 6 acetyl 4,1', 6'trichlorogalactosucrose. After the said chlorination reaction, the reaction mass is neutralized to pH 7.0 -7.5 using appropriate alkali hydroxides of calcium, sodium, etc. to deesterify / deacetylate the 6 acetyl 4,1', 6'trichlorogalactosucrose to form 4,1', 6' trichlorogalactosucrose (TGS).
Process of this invention describes a novel method of deacylation of 6-0-protected TGS to TGS. This method employs an acid hydrolysis of the 6-O-protected TGS without addition of any base for the deacylation.
TGS is prepared from sucrose by first protecting the primary hydroxyl group of the pyranose ring of sucrose and then subjecting the 6-0-protected sucrose to chlorination using the vilsmeier reagent.
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The chlorinated reaction mass is then neutralized with a suitable base. TGS in 6-O-protected form in the chlorinated mass is easier to extract using solvents such as ethyl acetate, chloroform, methyl ethyl ketone, etc. The de-protection is avoided at the neutralization step by control of pH to the acidic side. Also the removal of DMF further down during the processing also favours the TGS presence in 6-O-acyl form.
Various processes have been described in prior art, to deacylate the 6-O-protected TGS under solvent and aqueous conditions before and after isolation of the said compound. In all these cases, the use of the deacylating agent is a base and the pH condition is maintained in the alkaline range. The pH is usually maintained above 9.5 to 11.5 as described in prior art. During the process of this deacylation, it has been noticed that TGS formed is not very stable at the said pH and starts to decompose. So it is mandatory to neutralize the mass immediately after deacylation in any of the said processes. Also if the tertiary amide is present during the deacylation, its exposure to alkaline pH also is vulnerable to hydrolysis to dialkyl amine and carboxylic acid. In the industrial process, this results in reduced recovery of the tertiary amide and affects the economics of the process.
This invention describes a process to deacylate the 6-O-TGS under acidic and anhydrous condition with or without the presence of the tertiary amide. This deacylation is highly efficient, achieved with reduced consumption of the deacylating acid compound, and without decomposition of the tertiary amide and TGS formed.
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The acid mediated deacylation of 6-O-TGS can be performed during any part of the extraction and purification process of TGS from the chlorinated mass. It can be used
a) After neutralization of the chlorinated mass.
b) As a crude compound along with other chlorinated sucrose derivatives at intermediate stage of TGS isolation.
c) After complete isolation of 6-O-TGS.
The results given below are an account of interim results, which shall be improved upon by further work and fine tuned until complete specification is submitted. The details of work done so far disclosed below serve as illustrations and do not limit the scope of actual techniques used or scope of reaction conditions or process conditions claimed. The techniques and reaction conditions or process conditions disclosed below are subject matter of ongoing trials and fine tuning or trials in alternative or better conditions in method for acid mediated deacylation of 6-O-protected TGS.
In one experiment , the chlorinated reaction mass was neutralized using ammonia gas and the deacylation of the TGS is well controlled under these conditions. The 6-O-TGS is then extracted into water immiscible or partially immiscible solvents such as ethyl acetate, methyl ethyl ketone, etc. After the extraction, the organic layer is concentrated completely and the deacylation was carried out.
The concentrate was diluted with 1:0.5 to 1:5 times w/v of methanol and stirred well. Acetyl chloride was added slowly dropwise to the mixture and
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the temperature was maintained below 40°C. The quantity of acetyl chloride varies from 10% to 30% of the reaction mixture. After the addition of the acetyl chloride, the pH of the reaction mass was controlled to 4.0 by addition of an appropriate buffer solution. The reaction was stirred continuously and the deacylation was monitored by TLC. The deacylation time varied from 3.0 hr to 16 hrs.
After the deacylation, the methanol was stripped off by distillation and the reaction mass was neutralized and taken for TGS isolation.
Thus, 250g of organic layer concentrate containing 70g of 6-O-protected TGS was mixed with 250 ml of methanol. 75 ml of acetyl chloride was added dropwise to the reaction flask kept under stirring. The temperature was controlled below 35°C. After the addition of the acetyl chloride, the pH was adjusted to 4.0 using acetate buffer prepared in methanolic solution. The reaction was kept stirring and TLC was checked every one hour to monitor deacylation.
At the end of 5 hours, the TLC showed absence of 6-O-TGS and the coversion to TGS. Complete deacylation was confirmed by HPLC. The overall yield loss during deacylation was less than 0.5%.

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