DESC:FIELD OF THE INVENTION
Present invention provides an improved process for the preparation of 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbaldehyde. The present invention also provides novel intermediate and its use for the preparation of 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbaldehyde.

BACKGROUND OF THE INVENTION
3-Oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbaldehyde is an important intermediate for preparation of some important bacterial topoisomerase inhibitor (BTI) disclosed in WO2019145919.
The patent application discloses the use of 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbaldehyde as an intermediate (6) for certain antibacterial compounds that are considered as BTI as explained below scheme 1 and scheme 2:
Process for preparation of BTI modulators:

Scheme – 1

Scheme – 2
Antibacterial drug resistance is a worldwide issue and the growing rates of antimicrobial resistance in clinical and non-clinical setting possess significant threat to human health globally. Multidrug resistance has become common among some pathogens, Eg. Staphylococcus aureus, Streptococcus pneumonia, Clostridium difficile and Pseudomonas aeruginosa. Of these, Staphylococcus aureus, a Gram +ve bacterium, is a major concern due to its potency and its capacity to adapt to environment condition. Methicillin resistant Staphylococcus aureus (MRSA) is the well-known group of resistant strain and has reached pandemic proportions.
Novel broad spectrum antibacterial (NBTI) compounds which are active against various Gram +ve and Gram –ve strains and are useful in the treatment of diseases or the condition developed due to infection cause by Gram +ve or Gram –ve bacteria.
Compound of formula (1) is a useful intermediate for the preparation of various antibacterial compounds. WIPO Patent Application no. WO2006021448 disclosed synthesis of compound of formula (I).

In this process sodium hydride is used as a base for the synthesis of (II) (ethyl 2-((4-formyl-2-nitrophenyl)thio)acetate). Sodium hydride is pyrophoric in nature and not suitable for large scale manufacturing of Active Pharmaceutical Ingredient. The formation of major impurity that is (ethyl 3-(4-((2-ethoxy-2-oxoethyl)thio)-3-nitrophenyl)-2-((4-formyl-2-nitrophenyl)thio)-3-hydroxypropanoate) and other unknown impurities are also observed which is very difficult to remove by crystallization and carry forward to final product. The process is inconsistent, low yielding and having low purity.
Aldehyde using existing reported procedure is low yielding, low purity (33% to 85%) and contains some known and unknown impurities. Overall yield of (I) from (III) is 9.6%.
The present invention provides improved process for the preparation of formula (I) with high yield and high purity.

SUMARY OF THE INVENTION
The present invention relates to an improved process for preparation of -Oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbaldehyde compound of formula (I)). Further the present invention provides a novel intermediate and its use for the preparation of compound of formula (I) with high yield and high purity.

EMBODIMENTS OF THE INVENTION
In one embodiment of the present invention, there is provided an improved process of compound of formula (I) with high yield and high purity. The process comprises:

In another embodiment, there is provided a novel intermediate of compound of formula (VI).
In another embodiment, there is provided a process for the preparation of compound of formula (VI) from compound of formula (V).
In a further embodiment, there is provided a process for the preparation of compound of formula I by using novel intermediate.

Following is the list of abbreviations used in description:
CDCl3: Deuterated chloroform
DCM: Dichloromethane
NMR: Nuclear Magnetic Resonance
GC: Gas chromatography
h: Hour
Kg: Kilogram
L: Liter
MeOD: Deuterated methanol
MS: Mass Spectrometry
MTBE: Methyl tert-butyl ether
NMR: Nuclear Magnetic Resonance
SOR: Specific Rotation
SSR: Stainless Steel Reactor
ESI-MS: Electrospray Ionization Mass Spectrometry
HPLC chromatograms were recorded on Agilent 1260 series.
Mass spectra were recorded with Waters, XevoG2a-ToF LCMS instrument.
NMR was recorded with Bruker 400 MHZ instrument
DSC : Model : Q20, Make : TA instruments
IR : Model : IRAffinity-1S, Make : Shimazdu

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention is provided a process of compound of formula (I) with high yield and purity.
In an embodiment there is provided an improved process of compound of formula (I) with high yield and high purity. The process comprises:

Stage 1 relates to the process for preparation of 4-chloro-3-nitrobenzaldehyde (III) by nitration of starting material 4-chlorobenzaldehyde (IV); nitrating mixture consisting conc. nitric acid and conc. Sulfuric acid in appropriate amount. Resulting compound (III) further used as starting material of stage 2.

Stage 2 relates to the process for preparation of compound of formula (V) from compound of formula (III) using reagent trimethyl orthoformate; p-toluenesulfonic acid and using appropriate solvent. Stage 2 reaction yield compound of formula (V) namely 1-Chloro-4-(dimethoxymethyl)-2-nitrobenzene. In an embodiment, solvent used for stage 2 is methanol.

Stage 3 relates to the novel process for preparation of compound of formula (VI) namely Ethyl 2-((4-(dimethoxymethyl)-2-nitrophenyl)thio)acetate from compound of formula (V) wherein ethyl-2-mercaptoacetate reacts to compound of formula (V) in presence of appropriate base and solvent at appropriate temperature and after proper work up of reaction mass, compound of formula (VI) obtained used further without any purification.

The suitable solvent used in stage 3 is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl ketone, cyclohexanone, diisobutyl ketone, diacetone alcohol or mixtures thereof. Most preferred solvent is acetone.
The suitable base used in stage 3 is selected from lithium hydroxide, Sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, sodium carbonate and potassium carbonate or mixtures thereof. Most preferred is potassium carbonate.
Stage 4 relates to process for the preparation of compound of formula (I) namely 3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbaldehyde from compound of formula (VI). Compound of formula (VI) heated at appropriate temperature in presence of iron powder and acetic acid to obtain compound of formula (I).

In an embodiment there is provided a novel compound of formula (VI) namely Ethyl 2-((4-(dimethoxymethyl)-2-nitrophenyl)thio)acetate and process for the preparation of compound of formula (VI).

Formula (VI)
The process comprises:
(i) reacting ethyl-2-mercaptoacetate with compound of formula (V) in presence of base and appropriate solvent at appropriate temperature and after proper work up of reaction mass, compound of formula (VI) obtained used further without any purification. In general solvent is acetone.

Formula (V) Formula (VI)
The suitable solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl ketone, cyclohexanone, diisobutyl ketone, diacetone alcohol or mixtures thereof. Most preferred solvent is acetone.
The suitable base is selected from lithium hydroxide, Sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, sodium carbonate and potassium carbonate or mixtures thereof. Most preferred base is potassium carbonate.

In a preferred embodiment, present invention provides an improved process for the preparation of compound of Formula (I) as disclosed herein:

Following are non-limiting examples of present invention; representing the preferred modes of carrying out the invention. The scope of invention is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge that are within the general understanding of a person skilled in the art.
Examples:
Example – 1: Process for the preparation of 4-Chloro-3-nitrobenzaldehyde (III)
The freshly prepared nitrating reagent {prepared from concentrated sulfuric acid (2.2 L) and concentrated nitric acid (1.68 L) at 0 oC} was added to a cold solution of 4-chlorobenzaldehyde (3.07 Kg, 21.84 mol) in sulphuric acid (11 L) at 0 to 10 °C over 45 minutes. The reaction mass was stirred for 1 h at room temperature. After completion of reaction, reaction mass was dumped into ice cold water (110 L) and stirred for 1 h at this temperature. The mixture was filtered and solid was washed with water (20 L), dried to get 4-chloro-3-nitrobenzaldehyde (III) as off white colored solid (3.6 Kg), Yield 88%, HPLC Purity 94.98% .
1H NMR (400 MHz, DMSO-d6): 10.065 (s, 1H), 8.58 (d, J = 2 Hz, 1H), 8.20 (dd, J1 = 2 Hz, J2 = 8.4 Hz 1H), 8.03 (d, J= 8 Hz, 1H),
13C NMR (400 MHz, DMSO-d6): 191.0, 148.3, 136.0, 133.9, 133.2, 131.1, 126.6
ESI MS m/z 201.99 [M+H]
Example – 2: Synthesis of 1-Chloro-4-(dimethoxymethyl)-2-nitrobenzene (V)
To a solution of 4-Chloro-3-nitrobenzaldehyde (3.414 Kg, 18.39 mol) in methanol (13.65 L) was added trimethyl orthoformate (2.92 Kg, 27.81 mol) and p-toluenesulfonic acid (15.8 g, 0.09 mol) at 15 to 25 °C. The reaction mass was heated to 55 to 65 °C for 2.5 h. After completion of reaction, it was cooled to room temperature and quenched with aqueous (10 %) sodium bicarbonate solution (0.66 L), concentrated under reduced pressure at 55 to 60 °C. The residual mass was dumped into cold water (6.8 L) at 15 to 20 °C and extracted with ethyl acetate (34.16 L). The organic layer was washed with water (6.8 L) and concentrated under reduced pressure to get 1-chloro-4-(dimethoxymethyl)-2-nitrobenzene as light brown colored oil (4.138 Kg), Yield (97 %), HPLC Purity; (95.41 %).
1H NMR (400 MHz, CDCl3): 7.96 (d, J = 1.6 Hz, 1H), 7.58 – 7.61 (dd, J1 = 1.6 Hz, J2 = 8 Hz 1H), 7.52 (d, J= 8.4 Hz, 1H), 5.42 (s, 1H), 3.31 (s, 6H)
13C NMR (400 MHz, CDCl3): 147.7, 139.0, 131.59, 131.51, 126.49, 123.97, 100.69, 52.57
Example – 3: Synthesis of Ethyl 2-((4-(dimethoxymethyl)-2-nitrophenyl)thio)acetate (VI)
To a solution of 1-Chloro-4-(dimethoxymethyl)-2-nitrobenzene (2.4 Kg, 10.36 mol) in acetone (12L) added ethyl 2-mercaptoacetate (1.494 Kg ,12.43 mol) at room temperature followed by added potassium carbonate (2.87 Kg, 20.76 mol) at 10 to 20 °C and it was stirred for 5.5 h at 20 to 40 °C. After completion of reaction, reaction mixture was concentrated under reduced pressure at 50 to 55 °C. The residual mass was dumped into cold water (19.2 L) at room temperature and extracted with ethyl acetate (39.6 L). The organic layer was washed with brine solution (17.45 L) and concentrated under reduced pressure to get ethyl 2-((4-(dimethoxymethyl)-2-nitrophenyl)thio)acetate as brown colored thick oil (3.53 Kg), yield (Quantitative) which used in next step without purification.
1H NMR (400 MHz, CDCl3): 8.25 (d, J = 1.6 Hz, 1H), 7.60 – 7.63 (dd, J1 = 1.6 Hz, J2 = 8.8 Hz, 1H), 7.45 (d, J= 8.4 Hz, 1H), 5.39 (s, 1H), 4.14 - 4.19 (q, 2H), 3.73 (s, 2H), 3.28 (s, 6H), 1.18 - 1.26 (m, 3H)
13C NMR (400 MHz, CDCl3): 168.7, 145.7, 136.4, 136.2, 132.0, 126.7, 124.5, 101.0, 61.6, 52.6, 35.09, 14.1
Example – 4: Synthesis of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbaldehyde (I)
To a solution of Ethyl 2-((4-(dimethoxymethyl)-2-nitrophenyl)thio)acetate (3.53 Kg, 10.36 mol) in acetic acid (29.4 L) added iron powder (2.327 Kg, 41.66 mol) at room temperature and the reaction mixture was heated to 80 to 90 °C for 1h. After completion of reaction, filtered through celite at 80 to 90 °C, washed with acetic acid (13 L). The filtrate was dumped into ice cold water (300 L) at 15 to 20 °C and further stirred for 1 h at 15 to 25 °C. Filtered the product and washed with water (26 L), dried to get crude product as light yellow colored solid (1.465 Kg), Purity (90.32 %), water content by KFR (1.69%). The crude product purified by a mixture of ethyl acetate (7.3 L), hexane (7.3 L) and methanol (0.73L) at 55 to 60 °C for 1 h and further stirred to 20 to 30 °C for 1 h. Filtered solid product and washed with mixture of ethyl acetate and hexane (1.465 L), dried to get 3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbaldehyde as light yellow colored solid (1.2 Kg), Yield (60%); Purity (93.2% HPLC ).
1H NMR (400 MHz, DMSO-d6): 10.84 (s, 1H), 9.9 (s, 1H), 7.55 (d, J = 8 Hz, 1H), 7.50 – 7.52 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H), 7.43 (d, J= 1.2 Hz, 1H), 3.57 (s, 2H),
13C NMR (400 MHz, DMSO-d6): 192.3, 165.2, 138.3, 135.2, 128.3, 127.8, 124.92, 116.64, 28.85
ESI MS m/z 194.04 [M+H]
Melting Point = 178 – 182 oC, DSC: 190.69 oC,
TGA = 0.3942 %,
IR = 1666.5 cm-1, 1595 cm-1
PXRD = Crystalline Pattern

,CLAIMS:We claim:
1. Process for the preparation of compound of formula (I) comprising:

i) reacting compound of formula (IV) with nitrating mixture consisting conc. nitric acid and conc. Sulfuric acid in appropriate amount to obtain compound of formula (III);

ii) reacting compound of formula (III) with trimethyl orthoformate and p-toluene sulphonic acid in presence of methanol to obtain compound of formula (V);

iii) reacting compound of formula (V) with ethyl-2-mercaptoacetate in presence of one or more solvent and base at suitable temperature to obtain compound of formula (VI);

iv) heating compound of formula (VI) in presence of iron powder and acetic acid to obtain compound of formula (I);
.

2. The process as claimed in claim 1, wherein one or more solvent used in step (iii) is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl ketone, cyclohexanone, diisobutyl ketone, diacetone alcohol or mixtures thereof.

3. The process as claimed in claim 1, wherein suitable base used in step (iii) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, sodium carbonate and potassium carbonate or mixtures thereof.

4. A novel intermediate of compound of formula (VI)
.
5. The process for the preparation of compound of formula (VI) as claimed in claim 4 comprising:
(a) reacting ethyl-2-mercaptoacetate with compound of formula (V) in presence of base and appropriate solvent at appropriate temperature and after proper work up of reaction mass, compound of formula (VI) obtained used further without any purification.
.

6. The suitable solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl ketone, cyclohexanone, diisobutyl ketone, diacetone alcohol or mixtures thereof.

7. The suitable base is selected from lithium hydroxide, Sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, sodium carbonate and potassium carbonate or mixtures thereof.

Dated this the 28th day of April 2023.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
of SUBRAMANIAM & ASSOCIATES
Attorneys for the applicants