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A Process To Prepare Pure Sodium 2 Mercaptoethanesulfonate

Abstract: The present invention relates to the process for the preparation of sodium 2-mercaptoethanesulfonate of formula (I). More particularly the present invention relates to a process for the preparation of pure sodium 2-mercaptoethanesulfonate salt from 2-thiouronium ethanesulfonate of formula (e) using aqueous ammonia and gaseous ammonia at below room temperature. The pure sodium 2-mercapotethanesulfonate is obtained by purification with alcohol or the mixture of alcohol: water. The HPLC purity of the final product of formula (I) obtained after the purification is more than 99.0% along with less than 1% of impurity-D in the final product of formula (I).

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
19 January 2009
Publication Number
42/2010
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2014-08-06
Renewal Date

Applicants

AARTI HEALTHCARE LIMITED
71, UDHYOG KSHETRA, 2ND FLOOR, MULUND-GOREGAON LINK ROAD, MULUND(WEST), MUMBAI-400080, MAHARASHTRA, INDIA.

Inventors

1. DESAI PARIMAL HASMUKHLAL
71, UDHYOG KSHETRA, 2ND FLOOR, MULUND-GOREGAON LINK ROAD, MULUND(WEST), MAHARASHTRA, INDIA.
2. SALVI NARENDRA JAGANNATH
71, UDHYOG KSHETRA, 2ND FLOOR, MULUND-GOREGAON LINK ROAD, MULUND (WEST), MUMBAI-400080, MAHARASHTRA, INDIA.
3. PATRAVALE BHARATKUMAR SURENDRA
71, UDHYOG KSHETRA, 2ND FLOOR, MULUND-GOREGAON LINK ROAD, MULUND (WEST), MUMBAI-400080, MAHARASHTRA, INDIA.
4. SUBRAMANIAN SEETHARAMAN
71, UDHYOG KSHETRA, 2ND FLOOR, MULUND-GOREGAON LINK ROAD, MULUND (WEST), MUMBAI-400080, MAHARASHTRA, INDIA.
5. KAJALE NITIN BABURAO
71, UDHYOG KSHETRA, 2ND FLOOR, MULUND-GOREGAON LINK ROAD, MULUND (WEST), MUMBAI-400080, MAHARASHTRA, INDIA.
6. SALUNKE SAMBHAJI VISHRAM
71, UDHYOG KSHETRA, 2ND FLOOR, MULUND-GOREGAON LINK ROAD, MULUND (WEST), MUMBAI-400080, MAHARASHTRA, INDIA.
7. BARVE PRASAD DINKAR
71, UDHYOG KSHETRA, 2ND FLOOR, MULUND-GOREGAON LINK ROAD, MULUND (WEST), MUMBAI-400080, MAHARASHTRA, INDIA.

Specification

FORM - 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See section 10; rule 13) "A PROCESS TO PREPARE PURE SODIUM 2-MERCAPTOETHANESULFONATE AND THE PRODUCT OBTAINED THEREFROM" AARTI HEALTHCARE LIMITED An Indian Company Registered under The Companies Act 1956 Having its registered Office at 71, Udhyog Kshetra, 2nd Floor, Mulund-Goregaon link Road, Mulund (West), Mumbai- 400080, Maharashtra, India. The following specification particularly describes the invention and the manner in which it is to be performed: FIELD OF THE PRESENT INVENTION: The present invention relates to a process for the preparation of pure sodium 2-mercaptoethanesulfonate [of formula (I) as described herein] and the product obtained therefrom. BACKGROUND OF THE PRESENT INVENTION: Sodium 2-mercaptoethanesulfonate of the formula (I) below is a mucolytic agent or a detoxifying agent. Sodium 2-mercaptoethanesulfonate of the formula (I) is known from the therapeutic point of view as a mucolytic drug for the upper respiratory tract and as an antidote in the case of haemorrhagic cystitis induced by anti-tumoral drugs. (I) Research studies show marked activity of mercaptoethanesulfonic acid and its salt thereof capable of releasing it into the organism, as an anti-tumoral drug in the treatment of the bladder carcinoma as well as in the treatment and in the prevention of cistinic kidney calculi. A process for the preparation of sodium 2-mercaptoethanesulfonate of formula (I) is known in the prior art: The prior art references can be described as follows: II US 2694723 dated September 27.1952 This patent document discloses a process for the preparation of sodium 2-mercaptoethanesulfonate of formula (I). Schematic diagram as scheme-1 of the process is provided as follows: According to the disclosure [Scheme-I], ethylene dibromide of formula (a) is reacted with sodium sulfite (b) at a reflux temperature in a mixture of ethanol:water to obtain Sodium 2-bromoethanesulfonate of formula (c) which is further reacted with potassium ethytxanthate (p) in water to give sodium salt of ethyl 2-xanthogenatoethanesulfonic acid of formula (q). Sodium salt of ethyl 2-xanthogenatoethanesulfonic acid of formula (q) is further taken for ammonolysis in ethanol solvent, evaporating the reaction mass to dryness which involves the distillation of water and ethanol at higher temperature. The reaction mass is starried with ethanol: ethyl ether to remove the ethylxanthamidate from the mass followed by processing through ion-exchange resin to obtain 2- mercaptoethanesutfonic acid of formula (g). Which is further on neutralization with NaOH gives sodium 2-mercaptoethanesulfonate of the formula (I). The above process has following disadvantages: i. In the preparation of sodium 2-bromoethanesulfonate of fonnula (c), the sodium bromide content is 32.6% which can not be removed till the final stage due to higher solubility of product in water. The sodium bromide content is hazardous to the health and thus it is preferred to have low content of sodium bromide while carrying the reaction, ii. Due to presence of higher sodium bromide content, poor yield and less purity is observed in the preparation at all stages. iii. In the ammonolysis reaction higher temperature i.e. 65°C to 75°C is required for the reaction that results in the formation of higher percentage of impurity, iv. The ammonolysis reaction is completed within 48 hrs and after the completion of the reaction, the evaporation of solvents is also required at higher temperature which makes the process very lengthy, tedious and commercially not viable. II] US-2695310 dated December 12, 1951 discloses a process for the preparation of sodium 2-mercaptoethanesulfonate of formula (I) using guanidinium mercaptoethanesulforcate of fonnula (f). The route of synthesis is depicted in scheme-2 as follows: According to the scheme-2, ethyjene dibromide (a) is reacted with sodium sulfite (b) in a mixture of ethanot water at a reflux temperature to give sodium 2- bromoetahnesulfonate of formula (c).Sodium 2-bromoetahnesulfonate of formula (c) is then reacted with thiourea of formula (d) in water at a reflux temperature (90°C-100°C) followed by crystallization in water to give 2-S-thiuronium ethanesulfonate of formula (e). 2-S-thiuroniumethanesulfonate of formula (e) is further reacted with aqueous ammonia at higher temperature (105°F-150°F). After completion of the reaction, water is removed under vacuum which is recrystallized with absolute alcohol to give guanidinium 2-mercaptoethanesulfonate of formula (f). Scheme-2: The above patent has provided two different methods for the preparation of sodium 2-mercaptoethanesulfonate (I) from guanidinium 2-mercaptoethanesulfonate of formula (f) (scheme-2 & 3). According to the scheme-2, guanidinium 2-mercaptoethanesulfonate of formula (f) is processed through cation exchange resins i.e. Amberlite-120 or Dowex-50 to give sodium 2-mercaptoethanesulfonate of formula (g). Sodium 2-mercaptoethanesulfonate (g) is further neutralized with sodium hydroxide followed by removal of water from the mass completely at higher temperature and recrystallization with ethanol to give sodium 2-mercaptoethanesulfonate of formula (I). According to the scheme-3, guanidinium 2-mercaptoethanesulfonate of formula (f) is converted to the sodium salt by means of double decomposition with a nitrate salt such as sodium nitrate which generates guanidine nitrate which is having lower solubility in water can be removed from the mass by filtration to give sodium 2-mercaptoethanesulfonate of formula (I). The above processes He. the prior artl have following disadvantages: 1. The reaction with the aqueous ammonia takes place at higher temperature which results in the formation of the impurities. 2. At the time of heating with aqueous ammonia, ammonia escapes from the reaction mass which results in lower reaction rate and thus higher quantity of ammonia is required to complete the reaction which in turn generates impurities in the higher percentage. 3. The use of resin involves the use of large volume of solvent/water. Thus to remove the solvent or water from the reaction mass becomes very lengthy procedure which makes the process industrially not viable. The European Pharmacopoeia-monograph 1674 has listed out 5 impurities i.e. A, B, C, D, and E in the final sodium 2-mercaptoefoanesulfonate of formula (I). Impurities can be shown as follows: According to the European Pharmacopoeia-monograph 1674, the impurity level analyzed by High Performance Liquid Chromatography [HPLC] is fixed as follows. Impurity-A, B, E (HPLC): 0.3% Impurity-C (HPLC): 0.2% Impurity-D (HPLC): 3% Any other impurity (HPLC): 0.1%. Sum of other impurities (HPLC): 0.3% The impurity-D is in higher amount (3% by HPLC) in the final product of formula (I). It is thus very much essential to obtain a pure produce of formula (I) that does not contain higher amount of impurity-D. Therefore, it is important that those salts be prepared h an industrially advantageous manner and in the form of suitable purity for the therapeutic use. The .main object of ine present inyenlion is therefore j© provide 3 process for the preparation of pure sodium 2-mercaptoethanesulfonate 0f formula (I) and the product obtained therefrom that result in optimum purity. OBJECTS OF THE PRESENT INVENTION The main object of the present invention is to provide an environmental friendly, non-polluting, simple and convenient method for the preparation of sodium 2-mercaptoethanesutfonate of formula (I). It is yet another object of the invention to provide a firocess that does not require elaborate work up or purification processes like chromatography for the isolation of products or recrystallization in solvent which leads to a lengthy reaction process and minimizing the yield of the product. It is another object of the invention to provide a process which is simple, easy to handle, inexpensive, non-hazardous so that large scale production is possible. It is also an object of the invention to provide a process for the preparation of pure sodium 2-mercaptoethanesulfonate which contains less than 1% of impurity-D. It is yet another object of the invention to provide a process for the preparation of sodium 2-mercaptoethanesulfonate of formula (I) in high yield along with HPLC purity of more than 99.0%. SUMMARY OF THE PRESENT INVENTION: Therefore according to the present invention, there is provided a process to prepare sodium 2-mercaptoethanesulfonate of formula (I) ^-"^ S03Na (I) at a temperature below room temperature comprising: i. Reacting 2-thiouroniumethanesulfonate of formula (e) with aqueous ammonia and gaseous ammonia to form a reaction mass; NH2 2-S-Thiouronium ethanesulfonate

Documents

Application Documents

# Name Date
1 116-MUM-2009-FORM 3(29-11-2010).pdf 2010-11-29
1 116-MUM-2009-RELEVANT DOCUMENTS [30-09-2021(online)].pdf 2021-09-30
2 116-mum-2009-abstract.doc 2018-08-10
2 116-MUM-2009-FORM 18(29-11-2010).pdf 2010-11-29
3 116-MUM-2009-CORRESPONDENCE(29-11-2010).pdf 2010-11-29
3 116-mum-2009-abstract.pdf 2018-08-10
4 116-MUM-2009_EXAMREPORT.pdf 2018-08-10
4 116-mum-2009-assignment.pdf 2018-08-10
5 116-MUM-2009-REPLY TO EXAMINATION REPORT(2-7-2013).pdf 2018-08-10
5 116-MUM-2009-CLAIMS(AMENDED)-(2-7-2013).pdf 2018-08-10
6 116-MUM-2009-POWER OF ATTORNEY(2-7-2013).pdf 2018-08-10
6 116-MUM-2009-CLAIMS(GRANTED)-(6-8-2014).pdf 2018-08-10
7 116-MUM-2009-POWER OF ATTORNEY (2-7-2013).pdf 2018-08-10
8 116-MUM-2009-MARKED COPY(2-7-2013).pdf 2018-08-10
8 116-mum-2009-claims.pdf 2018-08-10
9 116-MUM-2009-CORRESPONDENCE (2-7-2013).pdf 2018-08-10
9 116-mum-2009-form 26.pdf 2018-08-10
10 116-MUM-2009-CORRESPONDENCE(2-7-2013).pdf 2018-08-10
10 116-mum-2009-form 2.pdf 2018-08-10
11 116-MUM-2009-CORRESPONDENCE(IPO)-(6-8-2014).pdf 2018-08-10
12 116-mum-2009-correspondence.pdf 2018-08-10
12 116-mum-2009-form 2(title page).pdf 2018-08-10
13 116-MUM-2009-FORM 2(TITLE PAGE)-(GRANTED)-(6-8-2014).pdf 2018-08-10
14 116-mum-2009-description(complete).pdf 2018-08-10
14 116-MUM-2009-FORM 2(GRANTED)-(6-8-2014).pdf 2018-08-10
15 116-MUM-2009-DESCRIPTION(GRANTED)-(6-8-2014).pdf 2018-08-10
15 116-MUM-2009-FORM 13(2-7-2013).pdf 2018-08-10
16 116-MUM-2009-FORM 1 (2-7-2013).pdf 2018-08-10
16 116-MUM-2009-FORM 13 (2-7-2013).pdf 2018-08-10
17 116-MUM-2009-FORM 1(2-7-2013).pdf 2018-08-10
17 116-mum-2009-form 1.pdf 2018-08-10
18 116-mum-2009-form 1.pdf 2018-08-10
18 116-MUM-2009-FORM 1(2-7-2013).pdf 2018-08-10
19 116-MUM-2009-FORM 1 (2-7-2013).pdf 2018-08-10
19 116-MUM-2009-FORM 13 (2-7-2013).pdf 2018-08-10
20 116-MUM-2009-DESCRIPTION(GRANTED)-(6-8-2014).pdf 2018-08-10
20 116-MUM-2009-FORM 13(2-7-2013).pdf 2018-08-10
21 116-mum-2009-description(complete).pdf 2018-08-10
21 116-MUM-2009-FORM 2(GRANTED)-(6-8-2014).pdf 2018-08-10
22 116-MUM-2009-FORM 2(TITLE PAGE)-(GRANTED)-(6-8-2014).pdf 2018-08-10
23 116-mum-2009-form 2(title page).pdf 2018-08-10
23 116-mum-2009-correspondence.pdf 2018-08-10
24 116-MUM-2009-CORRESPONDENCE(IPO)-(6-8-2014).pdf 2018-08-10
25 116-MUM-2009-CORRESPONDENCE(2-7-2013).pdf 2018-08-10
25 116-mum-2009-form 2.pdf 2018-08-10
26 116-MUM-2009-CORRESPONDENCE (2-7-2013).pdf 2018-08-10
26 116-mum-2009-form 26.pdf 2018-08-10
27 116-mum-2009-claims.pdf 2018-08-10
27 116-MUM-2009-MARKED COPY(2-7-2013).pdf 2018-08-10
28 116-MUM-2009-POWER OF ATTORNEY (2-7-2013).pdf 2018-08-10
29 116-MUM-2009-CLAIMS(GRANTED)-(6-8-2014).pdf 2018-08-10
29 116-MUM-2009-POWER OF ATTORNEY(2-7-2013).pdf 2018-08-10
30 116-MUM-2009-CLAIMS(AMENDED)-(2-7-2013).pdf 2018-08-10
30 116-MUM-2009-REPLY TO EXAMINATION REPORT(2-7-2013).pdf 2018-08-10
31 116-MUM-2009_EXAMREPORT.pdf 2018-08-10
31 116-mum-2009-assignment.pdf 2018-08-10
32 116-MUM-2009-CORRESPONDENCE(29-11-2010).pdf 2010-11-29
32 116-mum-2009-abstract.pdf 2018-08-10
33 116-MUM-2009-FORM 18(29-11-2010).pdf 2010-11-29
34 116-MUM-2009-RELEVANT DOCUMENTS [30-09-2021(online)].pdf 2021-09-30
34 116-MUM-2009-FORM 3(29-11-2010).pdf 2010-11-29

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