Field of the invention
The present invention relates to one pot synthesis of acetylated amino phenols from aryl nitro compounds.More particularly, the present invention relates to one pot synthesis of Paracetamol from nitro benzene in the presence of metal catalyst, aqueous acid and or anhydride.

Background of the invention
Aspirin (acetylsalicylic acid), N-acetyl p-amino phenol (APAP), commonly known as Acetaminophen or paracetamol belongs to analgesic and anti-inflammatory class of drugs that are produced in huge amounts every year.
Paracetamol is known for a wide variety of uses. Its medicinal use is very well known, notably as a non-prescription analgesic and anti-pyretic agent with properties similar to aspirin. It is also a major component in over 200 other drug formulations and is in the market over few decades.
Considering the importance of these products, there have been several literature references for the preparation of the same. For example, US. Pat. Nos. 3,042,719; 3,113,150; 3,748,358; 3,781,354; 4,264,526; 4,524,217; 5,648,535; 5,856,575; 6,215,024 describe process for the preparation of Paracetamol; most of them involves the multi-step and P-Amino phenol is prepared from either Nitrobenzene or P-Nitro Chlorobenzene conventionally.
The aforementioned prior art processes have several limitations associated which are enumerated as follows:
1) No. of unit operations (Extractions, neutralizations, filtrations and drying.)
2) Higher reaction times and large inventory buildup.
3) High energy consuming steps.
4) High carbon foot print.
Mallinckrodt patented their technology for acetyl aminophenol synthesis from nitrobenzene without isolating the P-Amino phenol in US 5,155,269. They described their process as catalytic reduction of nitrobenzene to P- Amino phenol includes purification of P- Amino phenol solution is acetylated to obtain P-Acetyl amino phenol(Paracetamol).
The industrial preparation for Paracetamol is Hydroxylation of P-Nitro Chloro Benzene followed by iron /catalytic reduction of P- Nitro phenol to obtain P- Amino Phenol which is acetylated to Paracetamol. Above two processes have more no.of unit operations.
Similarly, various techniques are known for acetyl amino phenol preparation from phenol.Alexander et al from Stavropol University, published Nitro ethane in Poly phosphoric acid reagent for Acetamidation of phenol in “SYNLETT2010, No.17, 2628-2630”
Considering the requirement for Paracetamol as bulk drug, with an estimated global requirement of having more than hundred thousandtons globally, there is still need to have a simple, elegant and high yielding process for the preparation of these drugs with less carbon foot print. The present applicant diligently worked and identified a one pot synthesis, which is economical and sustainable for the production of acetylated aromatic aminophenol.

Objectives of the invention
The main objective of the present invention is to provide one pot synthesis of acetyl amino phenols from Aromatic nitro compounds.
Another objective of the present invention is to provide one pot synthesis of P-Acetyl amino phenol (Paracetamol) from Nitrobenzene
Another objective of the present invention is to prepare paracetamol from nitrobenzene in the presence of noble metal catalyst and aqueous sulfuric acidand organic acid and or its anhydride.
Yet another objective of the present invention is to prepare Paracetamol from nitrobenzene at 80-120°C, more preferably 100-110°C
Yet another objective is to prepare paracetamol from nitrobenzene in the presence of solvents selected from Cyclic ethers like 1, 4-Dioxane, THF, Methyl THF.
Yet another objective is to prepare paracetamol from nitrobenzene in the presence of hydrogen pressure 1-5 kg/cm2, more preferably 3-5 kg/Cm2.

Summary of the invention
Accordingly, there is provided a one pot synthesis for the production N-acetylated amino phenols from aromatic nitro compound, comprising the steps of:
i. Removing oxygen from the solution of aqueous acid, noble metal catalyst in glass autoclave with nitrogen purging followed by hydrogen,
ii. Making uniform mixture of aromatic nitro compound and acetic acid or it’s anhydride in the presence of solvent,
iii. Feeding uniform solution from step (ii) to glass autoclave having catalyst and aqueous acid from step (i) for few hours.

According to another embodiment there is provided a one pot synthesis for the production N-acetylated amino phenols from aromatic nitro compound, comprising the steps of:
i. Reducing the Nitrobenzene in the presence of metal catalyst and rearranged in aqueous acid followed by acetylation with acetic acid or acetic anhydride,
ii. Distilling out the solvent, water and acetic acid under reduced pressure from step (i) reaction mass
iii. Adding water to slurry obtained from step (ii) and separate the nitrobenzene layer at 90°C and cool the mass to 10-15°C and filter the crude product.
iv. Dissolving the crude product obtained from step (iii) in water at 90°C and charcollized and crystalized to get pure Paracetamol.

The process is shown in the Scheme -1 given below :

Detailed description of the invention
In an embodiment of the invention, the aromatic nitro compound is selected from nitrobenzene or a derivative or an analogous compound where a nitro group is present
In another embodiment, the reduction is carried out using noble metal catalyst in presence of hydrogen. Noble metal catalyst is selected from platinum, rhodium, ruthenium, palladium, molybdenum and like thereof.
In an embodiment, the rearrangement is carried out in aqueous acid. Aqueous acid consists of sulfuric acid, hydrochloric acid, phosphoric acid, methane sulfonic acid, triflouroaceticacid, perchloric acid, phosphotungstic acid and like thereof.
In an embodiment, the acetylation is carried out using acetic acid and or acetic anhydride.
In an embodiment, conversion is 80-100% and selectivity is 40-80% towards p-acetyl amino phenol.
In another embodiment the solvent is Cyclic ethers selected from 1, 4-Dioxane, THF, Methyl THF and like or mixture thereof.
In another preferred embodiment, the present invention provides a process for the preparation of Paracetamol which comprises reduction of nitrobenzenewith hydrogen in the presence of nobel metal catalyst to result in phenyl hydroxyl amine which undergoes rearrangement in the presence of aqueous sulfuric acid, followed by acetylation usingacetic acid and or its anhydride in a hydrogenation reactor. The reaction is shown in scheme -2 given below :

In another preferred embodiment charcollization is carried out with activated or granulated carbon in a batch reactor or in a adsorption column.
Thus the present invention provides a process for the preparation of Paracetamol wherein Reduction, Rearrangement and acetylation can be carried out in single reactor.
The one pot synthesis of the present invention offers less number of unit operations, less steps, increased throughput, and less carbon footprint.
The process of the present invention can be used for different scale of operations.

Glass autoclave equipped with jacket for heating or cooling, PTFE turbine type agitator with variable RPM controller, pressure regulator, temperature regulator etc. was cleaned & dried. The reactor was flushed with nitrogen gas and then to this reactor 1, 4-Dioxane, aqueous sulfuric acid (10% by wt), Pt/C catalyst paste (containing 66% moisture) was charged. Then the autoclave was again flushed with nitrogen & was closed. Then the reaction mixture was heated under stirring (360 RPM) to 109 to 110o C with the help of hot oil circulation using Julabo type thermic fluid circulator. Once the reaction temperature was attained; the reactor was pressurized with hydrogen gas to 4 to 4.5 kg-g/cm2 pressure. The reactor pressure was adjusted with hydrogen pressure regulator & hydrogen valve was kept open throughout the run so that any consumption in hydrogen was managed through the regulated hydrogen supply at constant pressure automatically.
Meantime in a feed vessel placed on the balance and connected to all glass autoclave through a SSI type laboratory high pressure metering pump Nitrobenzene, acetic anhydride, 1, 4Dioxane. This mixture was made uniform & the feed was continuously pumped into glass autoclave at 1.6 ml/min. The feed was charged into the reactor within 5 hours at the steady temperature and steady pressure. Then the reaction mixture was further digested for 30 more minutes
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention.

EXAMPLE-1:
5-L capacity all glass autoclave equipped with jacket for heating or cooling, PTFE turbine type agitator with variable RPM controller, pressure regulator, temperature regulator etc. was cleaned & dried. The reactor was flushed with nitrogen gas and then to this reactor 794gm of 1,4-Dioxane was charged, followed by 100 gm aqueous sulfuric acid (10% by wt), followed by 9gm of Pt/C catalyst paste (containing 66% moisture) was charged. Then the autoclave was again flushed with nitrogen & was closed. Then the reaction mixture was heated under stirring (360 RPM) to 109 to 110o C with the help of hot oil circulation using Julabo type thermic fluid circulator. Once the reaction temperature was attained; the reactor was pressurized with hydrogen gas to 4 kg-g/cm2 pressure. The reactor pressure was adjusted with hydrogen pressure regulator & hydrogen valve was kept open throughout the run so that any consumption in hydrogen was managed through the regulated hydrogen supply at constant pressure automatically.
Meantime in a feed vessel placed on the balance and connected to all glass autoclave through a SSI type laboratory high pressure metering pump, 125 gm of nitrobenzene (NB) was charge followed by 250 gm of acetic anhydride followed by 125 gm of 1,4 Dioxane. This mixture was made uniform & the feed was continuously pumped into glass autoclave @ 1.6 mL/min. The feed was charged into the reactor within 5 hours at the steady temperature and steady pressure. Then the reaction mixture was further digested for 30 more minutes, it was cooled, pressure was released & the catalyst was filtered. The clear filtrate was given for HPLC analysis which showed 45% conversion of nitrobenezene with the formation of paracetamol, 4-acetoxy-acetanilide and acetanilide with the selectivity of more than 80% towards paracetamol and 17.9% towards 4-acetoxy-acetanilide; rest i.e. 2.1% was acetanilide.
After completion of the reaction, catalyst was filtered washed with water & recycled in next batch. The filtrate i.e. the reaction mass was distilled under reduced pressure to remove water, acetic acid and 1, 4-Dioxane, and the bottom product was in the form of slurry. Then added water and heated to 90oC to separate Nitrobenzene from aqueous mother liquor. The mother liquor is cooled to 10-15oC and filtered. The filtered cake was taken in water which was heated to 90o C and treated with charcoal, followed by filtration of charcoal at same temperature and cooled the mass 10-15o C and filtered the reaction mass to obtain between 30 and 35 g of pure Paracetamol.
EXAMPLE-2:
5-L capacity all glass autoclave equipped with jacket for heating or cooling, PTFE turbine type agitator with variable RPM controller, pressure regulator, temperature regulator etc. was cleaned & dried. The reactor was flushed with nitrogen gas and then to this reactor 794gm of 1,4-Dioxane was charged, followed by 100 gm aqueous sulfuric acid (10% by wt), followed by 9gm of Pt/C catalyst paste (containing 66% moisture) was charged. Then the autoclave was again flushed with nitrogen & was closed. Then the reaction mixture was heated under stirring (360 RPM) to 109 to 110o C with the help of hot oil circulation using Julabo type thermic fluid circulator. Once the reaction temperature was attained; the reactor was pressurized with hydrogen gas to 3 kg-g/cm2 pressure. The reactor pressure was adjusted with hydrogen pressure regulator & hydrogen valve was kept open throughout the run so that any consumption in hydrogen was managed through the regulated hydrogen supply at constant pressure automatically.
Meantime in a feed vessel placed on the balance and connected to all glass autoclave through a SSI type laboratory high pressure metering pump, 125 gm of NB was charge followed by 250 gm of acetic anhydride followed by 125 gm of 1,4 Dioxane. This mixture was made uniform & the feed was continuously pumped into glass autoclave @1.6 mL/min. The feed was charged into the reactor within 5 hours at the steady temperature and steady pressure. Then the reaction mixture was further digested for 30 more minutes, it was cooled, pressure was released & the catalyst was filtered. The clear filtrate was given for HPLC analysis which showed 45% conversion of nitrobenezene with the formation of paracetamol, 4-acetoxy-acetanilide and acetanilide with the selectivity of more than 80% towards paracetamol and 17.9% towards 4-acetoxy-acetanilide; rest i.e. 2.1% was acetanilide.
After completion of the reaction, catalyst was filtered washed with water & recycled in next batch. The filtratei.e. the reaction mass was distilled under reduced pressure to remove water, acetic acid and 1, 4-Dioxane, and the bottom product was in the form of slurry. Then added water and heated to 90oC to separate Nitrobenzene from aqueous mother liquor. The mother liquor is cooled to 10-15oC and filtered. The filtered cake was taken in water which was heated to 90o C and treated with charcoal, followed by filtration of charcoal at same temperature and cooled the mass 10-15o C and filtered the reaction mass to obtain between 30 and 35 g of pure Paracetamol.
EXAMPLE-3:
5-L capacity all glass autoclave equipped with jacket for heating or cooling, PTFE turbine type agitator with variable RPM controller, pressure regulator, temperature regulator etc. was cleaned & dried. The reactor was flushed with nitrogen gas and then to this reactor 800 gm of 1,4-Dioxane was charged, followed by 100 gm aqueous sulfuric acid (10% by wt), followed by 9 gm of Pt/C catalyst paste (containing 66% moisture) was charged. Then the autoclave was again flushed with nitrogen & was closed. Then the reaction mixture was heated under stirring (250 RPM) to 104 to 105o C with the help of hot oil circulation using Julabo type thermic fluid circulator. Once the reaction temperature was attained; the reactor was pressurized with hydrogen gas to 3 kg-g/cm2 pressure. The reactor pressure was adjusted with hydrogen pressure regulator & hydrogen valve was kept open throughout the run so that any consumption in hydrogen was managed through the regulated hydrogen supply at constant pressure automatically.
Meantime in a feed vessel placed on the balance and connected to all glass autoclave through a SSI type laboratory high pressure metering pump, 125 gm of NB was charge followed by 250 gm of acetic anhydride followed by 125 gm of 1,4 Dioxane. This mixture was made uniform & the feed was continuously pumped into glass autoclave at 2 mL/min. The feed was charged into the reactor within 4 hours at the steady temperature and steady pressure. Then the reaction mixture was further digested for 30 more minutes, it was cooled, pressure was released & the catalyst was filtered. The clear filtrate was given for HPLC analysis which showed 75% conversion of nitrobenzene with the formation of paracetamol, 4-acetoxy-acetanilide and acetanilide with the selectivity of more than 60% towards paracetamol and 22% towards 4-acetoxy-acetanilide; rest i.e. 18% was acetanilide.
EXAMPLE-4:
5-L capacity all glass autoclave equipped with jacket for heating or cooling, PTFE turbine type agitator with variable RPM controller, pressure regulator, temperature regulator etc. was cleaned & dried. The reactor was flushed with nitrogen gas and then to this reactor 800 gm of recovered 1,4-Dioxane (from Example-2) was charged, followed by 750 gm aqueous sulfuric acid (10% by wt), followed by 9 gm of Pt/C catalyst paste (containing 66% moisture) was charged. Then the autoclave was again flushed with nitrogen & was closed. Then the reaction mixture was heated under stirring (450 RPM) to 108 to 110o C with the help of hot oil circulation using Julabo type thermic fluid circulator. Once the reaction temperature was attained; the reactor was pressurized with hydrogen gas to 2.8 to 3.5 kg-g/cm2 pressure. The reactor pressure was adjusted with hydrogen pressure regulator & hydrogen valve was kept open throughout the run so that any consumption in hydrogen was managed through the regulated hydrogen supply at constant pressure automatically.
Meantime in a feed vessel placed on the balance and connected to all glass autoclave through a SSI type laboratory high pressure metering pump, 130 gm of NB was charge followed by 250 gm of acetic anhydride followed by 125 gm of recovered 1,4 Dioxane (from Example-2). This mixture was made uniform & the feed was continuously pumped into glass autoclave at 3 mL/min. The feed was charged into the reactor within 2 hours & 45 minutes at the steady temperature and steady pressure. Then the reaction mixture was further digested for 30 more minutes, it was cooled, pressure was released & the catalyst was filtered. The clear filtrate was given for HPLC analysis which showed 97.4% conversion of nitrobenzene with the formation of paracetamol, 4-acetoxy-acetanilide and acetanilide with the selectivity of more than 78% towards paracetamol and 16.4% towards4-acetoxy-acetanilide; rest i.e. 5.6% was acetanilide.
EXAMPLE-5:
5-L capacity all glass autoclave equipped with jacket for heating or cooling, PTFE turbine type agitator with variable RPM controller, pressure regulator, temperature regulator etc. was cleaned & dried. The reactor was flushed with nitrogen gas and then to this reactor 800 gm of 1,4-Dioxane was charged, followed by 160 gm aqueous sulfuric acid (25% by wt), followed by 9 gm of Pt/C catalyst paste (containing 66% moisture) was charged. Then the autoclave was again flushed with nitrogen & was closed. Then the reaction mixture was heated under stirring (400 RPM) to 113 to 115o C with the help of hot oil circulation using Julabo type thermic fluid circulator. Once the reaction temperature was attained; the reactor was pressurized with hydrogen gas to 4.0 to 4.5 kg-g/cm2 pressure. The reactor pressure was adjusted with hydrogen pressure regulator & hydrogen valve was kept open throughout the run so that any consumption in hydrogen was managed through the regulated hydrogen supply at constant pressure automatically.
Meantime in a feed vessel placed on the balance and connected to all glass autoclave through a SSI type laboratory high pressure metering pump, 125 gm of NB was charge followed by 250 gm of acetic anhydride followed by 125 gm of 1,4 Dioxane . This mixture was made uniform & the feed was continuously pumped into glass autoclave at 2 mL/min. The feed was charged into the reactor within 4 hours & 15 minutes at the steady temperature and steady pressure. Then the reaction mixture was further digested for 30 more minutes, it was cooled, pressure was released & the catalyst was filtered. The clear filtrate was given for HPLC analysis which showed 24% conversion of nitrobenzene with the formation of paracetamol and acetanilide with the selectivity of more than 97% towards paracetamol; rest i.e. 3% was acetanilide.
,CLAIMS:We claim:
1. An one pot synthesis for the production N-acetylated amino phenols from aromatic nitro compound, comprising the steps of:
i. Removing oxygen from the solution of aqueous acid, noble metal catalyst in glass autoclave with nitrogen purging followed by hydrogen,
ii. Making uniform mixture of aromatic nitro compound and acetic acid or it’s anhydride in the presence of solvent,
iii. Feeding uniform solution from step (ii) to glass autoclave having catalyst and aqueous acid from step (i) for few hours.
2. The process as claimed in claim 1 wherein the noble metal catalyst for reduction is selected from platinum, rhodium, ruthenium, palladium and molybdenum thereof.

3. The process as claimed in claim 1 wherein the aqueous acid used for rearrangement is selected from sulfuric acid, hydrochloric acid, phosphoric acid, methane sulfonic acid, triflouro acetic acid, per chloric acid and phosphotungstic acid.

4. The process as claimed in claim 1 wherein the solvent used is selected from cyclic ethers such as 1, 4-Dioxane, THF and methyl THF.

5. The process as claimed in claim 1 wherein the acetylating agent is selected from either acetic acid or acetic anhydride.

6. The process as claimed in claim 1 wherein reaction temperature is from 80-120°C, more preferably 100-110°C

7. The process as claimed in claim 1 wherein Hydrogen pressure for reduction i is in the range of 1-5 kg-g/cm2, more preferably 3-4 kg-g/cm2..

8. An one pot synthesis for the production N-acetylated amino phenols from aromatic nitro compound, comprising the steps of:
i. Reducing the Nitrobenzene in the presence of metal catalyst and rearranged in aqueous acid followed by acetylation with acetic acid or acetic anhydride,
ii. Distilling out the solvent, water and acetic acid under reduced pressure from step (i) reaction mass
iii. Adding water to slurry obtained from step (ii) and separate the nitrobenzene layer at 90°C and cool the mass to 10-15°C and filter the crude product.
iv. Dissolving the crude product obtained from step (iii) in water at 90°C and charcollized and crystalized to get pure Paracetamol.