Claims:We claim:
1. A process for preparation of compound (I) or pharmaceutically acceptable salts thereof.

comprising the steps of
i) reacting the N-protected bis-(2-chloroethyl)amine hydrochloride (2) with sodium sulfide monohydrate in suitable solvents, to afford the N-protected thiomorpholine(3)

ii) Oxidising the N-protected thiomorpholine(3)with suitable oxidizing agent in appropriate solvents to provide the N-protected thiomorpholine-1,1-dioxide of formula (4).

iii) Deprotectionof protecting group in compound (4) with suitable deprotecting agents in suitable solvents to provide the thiomorpholine-1,1-dioxide of formula (1)

iv) Optionally, removing the TFA salt or converting it to other suitable salts through salt exchange.
2. The process as claimed in claim 1, step (i) wherein the suitable solvents are selected from acetone, methanol, ethanol, DMSO, DMF and their suitable mixtures.
3. The process as claimed in claim 1, step (ii) wherein the suitable oxidizing agents are selected from mCPBA, oxone, hydrogen peroxide, Urea.H2O2, KMNO4.MnO2,NaBrO3.
4. The process as claimed in claim 1, step (ii) wherein the suitable solvents are selected from DCM, EDC, CHCl3, ACN, acetone or their suitable mixtures.
5. The process as claimed in claim 1, step (iii) wherein the suitable deprotecting agents are selected from TFA, H2/Pd, H2SO4, HCl, NaOH, DBU, Piperidine or their suitable mixtures.
6. The process as claimed in claim 1, step (iii) wherein the suitable solvents are selected from DCM, EDC, Methanol, Ethanol, ACN, dioxane or their suitable mixtures.
7. The process as claimed in claim 1 step (iv) wherein the suitable salts of formula (1) are selected from hydrochloride, trifluoro acetate, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5-dinapsylate, lysinate, and arginate salts.

Dated this 12th day of October 2016.

(ASHISH K SHARMA)
ofSUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS

, Description:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION

“NOVEL PROCESS FOR THE PREPARATION OF THIOMORPHOLINE-1, 1-DIOXIDE”

We, CADILA HEALTHCARE LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad – 380015, Gujarat, India,

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The field of the invention relates to a novel process for the preparation of thiomorpholine-1,1-dioxide compound and intermediates thereof. Inparticular, the present invention relates to a new process for preparing the thiomorpholine-1,1-dioxidecompounds of the formula (1) .

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Several heterocycles containing nitrogen and sulphur have potential pharmacological properties. Thiomorpholine (henceforth referred to as TM) and thiomorpholine 1,1-dioxide(henceforth referred to as TMD) are important building blocks in drug discoveryresearch. Numerous biologically active analogues containinga TM or TMD ring have been described in the medicinalchemistry literature. Of these, Artemisone, Filgotinib andSutezolid are currently undergoing human clinical trialsfor the treatment of malaria, rheumatoid arthritis and tuberculosis, respectively.

Artemisone
Filgotinib
Sutezolid
Following scheme – A known in the literature references shows that thiomorpholine-1,1-dioxide is synthesised from thiomorpholine. Thiomorpholine was protected with protecting groups like BOC anhydride followed by oxidation of sulfide to sulfone with oxidizing agent like m-CPBA or Oxone afforded N protected thiomorpholine-1,1-dioxide.Removal of protecting group with varousdeprotecting agents like TFA, HCl, Pd/C, H2(g)and like afforded thiomorpholine1,1-dioxide.

Scheme-A

Such scheme is described in Jpn. KokaiTokkyoKoho, 2010229096, 2010, WO2009041559, WO2006094063, WO20060100426, WO20060135764, WO2005089770, WO2005089771, WO2005080389, WO2004063197, WO200206646.

There are mainly three methods reported in literature for the preparation of Thiomorpholine.
AngewandteChemie, International Edition, 47(20), 3784-3786; 2008discloses synthesis of morpholine, thiomorpholine and piperazine from B-heteroatom amino compounds and vinyl sulfonium salts. Jpn. KokaiTokkyoKoho, 2000256337, 2000 discloses two step synthesis of thiomorpholine. 2,2-bis-methanesulfonyl ethyl-methanesulfonyl amide on reaction with sodium sulfide gave 4-(methylsulfonyl)thiomorpholine. Removal of ethane sulfonyl group by heating it in conc. sulfuric acid followed by water workup and purification by fraction distillation afforded thiomorpholine.

Synthesis 2(4), 183, 1970 discloses synthesis of thiomorpholinestarting from diethanol amine which was then converted to bis-2(chloroethyl)aminehydrochloride by using thionyl chloride. Bis-2(chloroethyl)aminehydrochloride was treated with Na2S .H2O afforded thiomorpholine in 51 % yield.

The above literature methods for this synthesis of thipmorpholine required multistep synthesis with expensive starting material like vinyl triflate salt,2-aminoethane-1-thiol and labourious purification methods like fractional distillation and multiple crystallisation. Also there are some issues like long reactions hours and low yields with reported procedure.
There is still a need for an improved process for the large scale preparation of thiomorpholine-1,1-dioxide of formula (1) and intermediates thereof
In view of the above, it is therefore, desirable to provide anovel and efficient process for the preparation of thiomorpholine-1,1-dioxidecompounds of formula (1).
List of Abbreviation
DMF: Dimethyl formamide
DCM: Dichloromethane
EDC :Dichloro ethane
TFA: Trifluoro acetic acid
DIPEA: Disopropyl ethyl amine
EtOAc: Ethyl acetate
DMSO : Dimethyl sulfoxide
THF :Tetrahydrofurane
ACN : Acetonitrile
DBU :1,8-Diazabicyclo[5.4.0]undec-7-ene
KMnO4 : Potassium permanganate
MnO2 : Manganese dioxide
h: Hour(s)
min: Minute(s)
tRet: Retention time
HCl : Hydrochloric acid
RT: Room temperature [25-30 0C]
Instrument details
NMR spectrum: Bruker Avanc 400 mHz

SUMMARY OF THE INVENTION
In one general aspect, there is provided a novel process for the preparation of compound of formula (1) or pharmaceutically acceptable salts thereof,

DETAILED DESCRIPTION OF THE INVENTION
The above and other objects of the present invention are achieved by the process of the present invention, which leads a novel and improved process for preparation of thiomorpholine-1,1-dioxide compounds and intermediates thereof.
Optionally, the solution, prior to any solids formation, can be filtered to remove any un-dissolved solids, solid impurities and the like prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
In one general aspect, there is provided a novel process for the preparation of compound of formula (1) or pharmaceutically acceptable salts thereof.
(1)
In general, the pharmaceutically acceptable salt comprises one or more of hydrochloride,trifluoro acetate, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5-dinapsylate, lysinate, and arginate.
In another general aspect, there is provided the process for the preparation of thiomorpholine-1,1-dioxide compounds as per scheme 1.
Scheme 1
N-protected bis-(2-chloroethyl)amine hydrochloride (2) on treatment with sodium sulfide monohydrate in solvents like acetone, methanol, ethanol, DMSO, DMF and mixture thereof afforded N-protected thiomorpholine(3).The N-protected thiomorpholine(3) on treatment with oxidising agent like mCPBA, oxone, hydrogen peroxide,Urea.H2O2, KMNO4.MnO2, NaBrO3, and like in presence of solvents like DCM, EDC, chloroform, ACN, Acetone and like afforded N-protected thiomorpholine-1,1-dioxide (4).Deprotection of protecting group in compound (4) with suitable deprotecting agents like TFA, H(2)Pd, H2SO4, HCl, NaOH, DBU, Piperidine in solvents like DCM, EDC, Methanol, Ethanol, CAN, dioxaneor their suitable mixturesafforded thiomorpholine-1,1-dioxide of formula (1).
In general, the protecting agent ‘Pg’ comprises one or more of Boc anhydride, acetyl chloride, mesyl chloride, tosyl chloride, benzyl chloride, CBZ chloride. In particular, Boc anhydride may be used.
In another general aspect, the compound of formula (1), or pharmaceutically acceptable salts thereof are converted into pharmaceutically active agents or pharmaceutically acceptable salts thereof.
The examples are provided as one of the possible ways to practice the invention and should not be considered as a limitation of the scope of the invention.
Step I :Tert-butyl bis(2-chloroethyl)carbamate (4)

In a 5 L four necked round bottom flask equipped with mechanical stirrer, thermometer and and addition funnel, bis(2-chloroethyl)amine hydrochloride [100g, 560 mmol], 1.5 ltrof dichloromethaneand triethyl amine [124.7 g, 1233 mmol] was added. The reaction mixture was cooled to 100C. To this, BOC anhydride [134.5 g, 616 mmol] was added drop wise to the reaction mixture. The reaction mixture was stirred for 16 hr at 250C. After completion of reaction, mixture was quenched in water [1 L]. Compound was extracted with dichloro methane [500 mL*2]. Combined organic layers were washed with water [1 L], removed under reduced pressure to get title compound as colorless oil [130 g, 96%].1H NMR : (CDCl3) : 3.77-3.60 (8H, m), 1.47 (9H, s).
Step II :Tert-butyl thiomorpholine-4-carboxylate

In a 5 L four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, tert-butyl bis(2-chloroethyl)carbamate[130 gm, 537 mmol] was added followed by dimethyl sulfoxide [250 ml]. To this sodium sulfide [126 gm, 1611 mmol] was added and reaction mixture was stirred for 5 hr at 800C. After completion of reaction, mixture was quenched in ice cooled water [500 ml]. Off white solid obtained was filtered, washed with water and dried in air oven. [80 gm, Yield :73%].1H NMR : (CDCl3) : 3.70-3.68 (4H, m), 2.58-2.56 (4H, m), 1.45 (9H, s).
Step III :Tert-butyl thiomorpholine-4-carboxylate 1,1-dioxide

In a 100 L glass line reactor added tert-butyl thiomorpholine-4-carboxylate [4.5 kg, 2.13 mol] and dichloromethane [65 L]. The reaction mixture was cooled to -5 to 0°C. m-CPBA [12.73 kg, 55.3] was added in portionwise in the reaction mixture by maintaining -5 to 00C. After completion of reaction, water[10 L] was added and the mixture was stirred for 15 minutes at 25-35°C. The organic layer was separated and washedwith NaOH solution [20 L*3 ] [6 kg NaOH dissolved in 60 L of water]. Organic layer was removed under reduced pressure to get title compound as off white solid. [5.1 kg, Yield 98%] .1H NMR : (DMSO) : 3.74-3.72 (4H, m), 3.12-3.09 (4H, m), 1.39 (9H, s).

Step IV: Thiomorpholine-1,1-dioxide TFA salt.

In a 100 L glass line reactoradded tert-butyl thiomorpholine-4-carboxylate 1,1-dioxide [5.1 kg, 21.67 mol] followed bydichloro methane [60 L]. To this, trifluoroacetic acid [9.96 L, 130 mol] was added at 15-200C. The reaction mixture was stirred for 16 hrat 250C. After completion of reaction, organic volatiles were removed under reduced pressure. Diisopropyl ether [35L] was added to the stirred mass. Solid obtained was filtered, washed with diisopropyl ether [10 L], dried in air oven. The title compound was obtained as off white solid [5 kg, yield 93%].
1H NMR : (DMSO) : 9.54 (2H, bs), 3.55-3.49 (4H, m), 3.47-3.44 (4H, m).
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.