WO2017154024A1

WO2017154024A1 - A process for synthesis of paracetamol

Info

Publication number: WO2017154024A1
Application number: PCT/IN2017/050084
Authority: WO
Inventors: G. Pratap REDDY; Nithun REDDY
Original assignee: Reddy G Pratap
Priority date: 2016-03-08
Filing date: 2017-03-08
Publication date: 2017-09-14
Also published as: WO2017154024A4

Abstract

Provided herein are processes for manufacture of acetylated amines including paracetamol.

Description

A P R OC E SS F O R SY NT H E SIS OF PARAC E TA M O L

FIE L D OF THE INV E NTION

The present disclosure relates to a process for the preparation of paracetamol and more particularly, to an improved process for preparation of paracetamol that avoids isolation of intermediates at each stage.

BACKGROUND

Paracetamol (acetaminophen), chemically described

hydroxyphenyl)ethanamide or N-(4-hydroxyphenyl)acetamide belongs to a group of medicines known as analgesics or painkillers. It is used to relieve mi Id- to- moderate pain. It is also useful for lowering a raised temperature (fever) such as after childhood immunisation. Paracetamol is a common painkiller and is available to buy from many retail outlets as tablets/capsules and as liquid medicine. Many brands of 'over- the-counter' combination painkillers contain paracetamol, as do many cold and flu remedies. The exact mechanism by which acetaminophen produces its analgesic and antipyretic effects remains undefined. The primary mechanism of action is believed to be inhibition of cyclooxygenase (COX ), with a predominant effect on COX -2.

Many known processes of synthesis of paracetamol involve the use of expensive and controlled substances like acetic anhydride which are regulated under policies related to narcotics. Also control of iron-iron oxide sludge impurities on commercial scale is very difficult Further, conventionally available methods involve multiple steps, viz, use p-nitrochlorobenzene as starting material, which is further converted to p-nitrophenol and this in turn is converted to p-aminophenol and then finally to paracetamol thereby involving a number of steps.

Thus, there is a need for a novel and effective process for preparation of paracetamol which avoids use of costly and harmful chemicals and provides paracetamol with higher purity and better yield on industrial scale.

Also, there is a need for an improved process for the synthesis of paracetamol which is less time consuming. SU MMARY OF THE INV E NTION

Accordingly provided herein is a process for synthesis of acetylated amines, including, for example, paracetamol, that avoids the use of expensive or controlled reagents, thereby rendering the process industrially advantageous and suitable for preparation of paracetamol on a commercial scale.

In one aspect, provi ded herei n i s a process for manufacture of acetyl ated ami nes comprising

i ) pi aci ng aceti c aci d i n a reacti on vessel ; i i ) addi ng a compound of F ormul a I and a metal catalyst to the reacti on vessel and heating the reaction mixture; R-N0₂ I wherein R is an optionally substituted aromatic ring or an alkyl group, to obtain a reaction mixture comprising a compound of Formula II: R-NH-C(=0)CH₃ II; iii) (a) cooling the reaction mixture of step (ii) and filtering the cooled reaction mixture to obtain a filtrate;

OR

( b) cool i ng the reacti on mi xture of step (ii) and diluting the reacti on mixture of step (ii) with a solvent

(c) heating the mixture of step (iii)(b) at a temperature of about the boi I i ng poi nt of sai d solvent

(d) cooling the mixture of step (iii)(c) and filtering the cooled mixture to obtain a filtrate and a residue; (e) optionally, suspending the residue of step (iii)(d) in said solvent and repeating steps (iii)(c) ^" (iii)(d) 1-2 times, and combining the filtrates; iv) removing the solvent from the filtrate of step (iii)(a) or from the combined filtrates of step (iii)(e) to obtain a crude product cake comprising a compound of Formula II.

In an embodiment, the process described herein is a single pot/vessel/reactor process. In an embodiment the process described above is a single pot/vessel/reactor process for manufacture of paracetamol. In certain instances, in step (iii)(a) above, the residue from the filtration is optionally washed with a solvent described herein such that the solvent wash is combined with the filtrate. In other instances, in step (iii)(d) above, after filtration, the filtrate may itself comprise two layers which may be separated by phase separation and the layer comprising the compound of Formula II is taken to step (iv) described above. In some embodiments of the process, the reaction vessel is a pressure reactor, a bus loop reactor, a flow reactor, a continuous column, a gas induction pressure reactor, or a round bottom flask.

In one group of embodiments of the process, the metal catalyst of step (ii) is palladium, palladium on charcoal (Pd-C), silica gel, platinum (IV) oxide (Pt0₂), chromium (II) chloride (CrCI₂), Tin (II) chloride, Titanium (III) chloride, aluminum, nickel, iron, zinc, stannous chloride (SnCI₂), samarium or rhodium, or a combination thereof.

In another group of embodiments of the process, the metal catalyst of step (ii) is palladium on charcoal (Pd-C), or iron.

In yet another group of embodiments of the process, the metal catalyst of step (ii) is palladium on charcoal (Pd-C) and the process further comprises passage of hydrogen in the reaction vessel.

In additional embodiments of the process, the metal catalyst of step (ii) is iron (e.g., iron powder), and the metal catalyst and the compound of Formula I are added to the reaction vessel in portions such that the reaction temperature in step (ii) is at least 110 °C (does not fall below 110 °C).

In some embodiments of the process, the solvent of step (iii) is acetic acid, acetic anhydride, a C_rC₆ aliphatic primary alcohol, a C₃-C₆ aliphatic secondary alcohol, a C₄-C₆ aliphatic tertiary alcohol, a C₅-C₈ aliphatic cyclic alcohol, tetrahydrofuran, 1,4-dioxane, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, morpholine, toluene, xylenes, ethyl acetate, propyl acetate, butyl acetate, pyridine, or water, or a combination thereof.

In certain embodiments of the process, the solvent of step (iii) is methanol, ethanol, or ethyl acetate, or a combination thereof. In a specific embodiment of the process, the solvent of step (iii) is ethyl acetate. In some embodiments of the process, R is phenyl substituted with a hydroxy group, preferably a para-hydroxy group. In an embodiment the product comprising the compound of Formula II is paracetamol (acetaminophen).

In some embodiments, the process described above and herein further comprises purification of the crude product cake of step (iv) comprising the steps of: v) dissolvi ng the crude product i n water, opti onal ly by heati ng, and adding activated charcoal to the mixture; vi) filtering the mixture of step (v) and cooling the filtrate; vii) filtering the cooled filtrate of step (vi) to obtain a solid comprising the compound of F ormul a II; and viii) optionally repeating steps (v) to (vii) 1 -2 times with the solid of step (vii) to obtain a purified compound of Formula II.

In some embodiments of the process, the yield of the purified compound of Formula II is at least 90%. In some embodiments of the process, R is phenyl substituted with a para-hydroxy group and the yield of the purified compound of Formula II is at least 90%, or 92% or 94%. In some of such embodiments, the final yield may be a combination of an initial crop and additional crops from mother liquors obtained during the process described herein.

In certain embodiments of the process described above, the compound of Formula I is added as a solid or as a solution in acetic acid. In some embodiments, a process of manufacture of paracetamol comprises the use of purified para-nitrophenol where the para-nitrophenol is purified prior to addition to the reaction vessel. The purification of para-nitrophenol is carried out as follows: para-nitrophenol is dissolved in acetic acid, followed by addition of activated carbon and Hypo supercell,.followed by filtration to obtain a solution of purified para-nitrophenol in acetic acid, which is then added to the reaction vessel as a solution. In some of such embodiments, said solution is added at such a rate that the reaction temperature does not drop below 110 °C, as described in the Examples section.

In another aspect, provided herein is a process for manufacture of paracetamol comprising

i ) pi aci ng aceti c aci d i n a reacti on vessel ; i i ) addi ng para-ami nophenol , a solvent, and a metal catalyst to the reaction vessel; i i i ) heati ng the reacti on mi xture under pressure to obtai n a reacti on mixture comprising paracetamol; iv) cooling the reaction mixture of step (iii) and filtering the cooled reaction mixture to obtain a filtrate; v) removi ng the solvent and aceti c aci d from the f i Itrate of step ( iv) to obtain a crude product comprising paracetamol.

The reaction mixture is heated at a temperature ranging from about 110 °C to about 160 °C, or about 120 °C to about 150 °C, and the pressure in the reaction vessel is in a range from about 1 to about 6 kg cm². In some embodiments, the process for manufacture of paracetamol further comprises purification of the crude product comprising paracetamol of step (v) by recrystallization or precipitation from water.

In some embodiments of the process for manufacture of paracetamol the solvent of step (ii) is acetic acid, acetic anhydride, a C C₆ aliphatic primary alcohol, a C₃-C₆ aliphatic secondary alcohol, a C₄-C₆ aliphatic tertiary alcohol, a C₅-C₈ aliphatic cyclic alcohol, tetrahydrofuran, 1, -dioxane, di butyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, morpholine, toluene, xylenes, ethyl acetate, propyl acetate, butyl acetate, pyridine, or water, or a combination thereof. In a specific embodi ment, the solvent for the process is 1 Adioxane. BRIE F DESCRIPTION OF ACCOMPA NY ING DRAWINGS

Figure 1 shows an embodiment for the process described herein wherein the process is a continuous flow reaction.

DETAIL E D DESCRIPTION OF THE INV E NTION

The invention described herein is explained using specific exemplary details for better understanding. However, the invention disclosed can be worked on by a person skilled in the art without the use of these specific details.

References in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, characteristic, or function described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase Ίη one embodiment_, in various places in the specif i cati on are not necessari ly al I referri ng to the same embodi ment.

Provided herein is a process for synthesis of paracetamol. The process described herein is a single pot/vessel /reactor process for preparation of paracetamol that avoids isolation of intermediates at each stage, reduces the use of solvents, simplifies work up and provides paracetamol with higher yield and purity. The process described herein reduces the time required for manufacture of a batch of paracetamol. The process described herein for the synthesis of paracetamol avoids effluent problems caused due to the formation of iron-iron oxide sludge, and also reduces manufacturing costs by about 30% when compared to other methods. Further, the process described herein utilizes acetic acid for acetyl ati on instead of acetic anhydride, thereby avoiding the use of reagents such as acetic anhydride which are regulated under narcotics policies.

In an aspect, provided herein is a single pot process for synthesis of paracetamol. The single pot process for synthesis of paracetamol comprises a reaction mixture comprising a predefined quantity of p-nitrophenol, a metal catalyst, acetic acid, methanol/ethanol/ethyl acetate, water and activated carbon. The process of synthesis of paracetamol comprises the steps of:

a. charging a predefined quantity of acetic acid to a reaction vessel and heating said acetic acid to a predefined temperature;

b. adding an initial first lot of a predefined quantity of a starting material and metal catalyst at a predefined temperature to form a mixture;

c. repeati ng the step ( b) for at I east 4 ti mes;

d. stirring the aforesaid mixture for a predefined period of time at a predefined temperature;

e. checki ng the reacti on mass by T L C method;

f. addi ng a predef i ned quantity of solvent to af oresai d mixture; g. refluxing aforesaid mixture for a predefined period of time; h. al I owi ng the mixture of step (g) to settl e;

i. filtering the settled mixture of step (h);

j. repeati ng steps (f)-(i)

k. distilling the solvents from the aforesaid mixture of step (j) at a predef i ned temperature for a predef i ned peri od of ti me;

I. adding a predefined quantity of water, followed by heating at a predefined temperature to dissolve the aforesaid mixture of step (k); m adjusting pH to neutral;

n. adding a predefined quantity of activated carbon, followed by filtering of aforesaid mixture of step (I); o. cooling the mixture of step (n) at a predefined temperature for a predef i ned peri od of ti me;

p. f ormi ng of a net end product

q. purifying the aforesaid end product by adding a predefined quantity of water on the end product

r. dissolving the aforesaid end product by heating at a predefined temperature;

s. adj usti ng pH between 4-6;

t adding of activated carbon to the product of step (r) and stirring for a predef i ned peri od of ti me;

u. filtering and cooling the aforesaid product of step (t) for a predefined peri od of ti me at a predef i ned temperature;

v. repeati ng the f i Itrati on step f ol I owed by washi ng the af oresai d product with a predefined quantity of chilled water; and

w. spi n dryi ng the aforesai d end product of step (v).

The reaction occurring in the single pot process is an exothermic reaction and the temperature rises up to 130 eC e 5 eC in the reaction pot. The metal catalyst and the para-nitrophenol are added in portions as described in the Examples section and the temperature is monitored to ensure that the reaction temperature does not fall below 110 °C during the addition of the metal catalyst and para-nitrophenol to the acetic acid.

As used herein, a ^'single pot_ or ^'single vessel _, or ^'single reactor_, process refers to a process wherein the chemical reactions occur in the same pot or vessel or reactor; although additional potsA essels/reactors may optionally be used for isolation/purification steps. The starting material in step (b) may be para-nitrophenol (PNP), or, in the alternative, para-nitrosophenol, or a sodium salt of p-nitrophenol (sodium- - nitrophenolate) as described in the Examples section.

1) Accordingly, in other embodiments, provided herein is a process for manufacture of acetylated amines comprising

placing acetic acid in a reaction vessel;

2) adding a compound of Formula IA or IB and a metal catalyst to the reaction vessel and heating the reaction mixture;

R-N=0 IA (NaO)-R-N0₂ IB

wherein R is an optionally substituted aromatic ring or an alkyl group, to obtain a reaction mixture comprising a compound of Formula II: R-NH-C(=0)CH₃ Il^¬

3) ia) cooling the reaction mixture of step (2) and filtering the cooled reaction mixture to obtain a filtrate;

OR

(b) cooling the reaction mixture of step (2) and diluting the reaction mixture of step (2) with a solvent

(c) heati ng the mixture of step (3)(b) at a temperature of about the boi I i ng poi nt of sai d solvent

(d) cooling the mixture of step (3)(c) and filtering the cooled mixture to obtain a filtrate and a residue; (e) optionally, suspending the residue of step (3)(d) i n said solvent and repeating steps (3)(c) ^" (3)(d) 1-2 times, and combining the filtrates;

4) removing the solvent from the filtrate of step (3)(a) or from the combined filtrates of step (3)(e) to obtain a crude product cake comprisi ng a compound of Formula II.

As used herein, Yoom temperature_, is ambient temperature and may vary but is typically in a range of 20 °C to 30 °C. However it will be understood that Yoom temperature_, may vary by geographic regions.

As used herein, Optionally substituted aryl _ refers to an unsubstituted phenyl or unsubstituted naphthyl, or a phenyl or naphthyl substituted with 1-5 groups selected from the group consisting of nitro, hydroxy, cyano, halo, alky I or alkoxy.

As used herein, ^'alky I _ refers to a straight chain or branched hydrocarbon chain having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which also may be structurally depicted by the symbol, "Me"), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the f oregoi ng exampl es.. Ά I koxy _ refers to an al kyl group as def i ned herei n attached to an oxygen atom.

In an embodiment, the yield of a product of Formula II (e.g., paracetamol) is at least about 85% on a dry basis of p-nitrophenol, at least about 90% on a dry basis of p-nitrophenol, or about 85% ^" 95% on a dry basis of p-nitrophenol. By way of example only, in some embodiments, about 1.39 kg of p-nitrophenol starting material yields about 1.5 kg of paracetamol, thereby providing a yield of about 92 % on a dry basis of p-nitrophenol. In some of such embodiments, the mother liquors from purification steps are combined and/or reused to obtain additional yield of paracetamol.

Also contemplated within the scope of embodiments presented herein are processes comprising additional starting materials including and not limited to, p- nitrosophenol, sodium salt of p-nitrophenol (sodium- ~nitrophenolate) and the like, as shown in the Examples section. In a further embodiment, it was found that when para-ami nophenol is heated in acetic acid and a solvent under presure, paracetamol product is obtained, as described in the examples section.

The metal catalyst in the processes comprising starting materials of Formula IA or Formula IB is palladium, palladium on charcoal (Pd-C), silica gel, platinum (IV) oxide (Pt0₂), chromium (II) chloride (CrCI₂), Tin (II) chloride, Titanium (III) chloride, aluminum, nickel, iron, zinc, stannous chloride (SnCI₂), samarium or rhodium, or a combination thereof. In some embodiments, the metal catalyst is iron, palladium on carbon (Pd-C), or aluminum- nickel (Al-Ni), or any other preferred metal catalyst The metal catalyst in the processes comprising starting materials of Formula IA or Formula IB is any solvent described herein.

The present invention is further illustrated by some examples, which should not be construed as I i miti ng the scope of the i nventi on. EXAM PL ES

Material for the preparation of paracetamol

10g of p-nitrophenol, 10g of iron powder, 75 ml of acetic acid, 75 ml of methanol/ethyl acetate, 75 ml of water and 0.08 g of activated carbon.

Abbreviations used: PNP = para-nitrophenol; Pd-C or Pd/C = palladium on charcoal; Al-Ni = raney nickel; EtOAc = ethyl acetate; TLC = Thin Layer Chromatography. EXAM PL E 1

One pot process of synthesis of Paracetamol from p-nitro phenol

7.5 ml of acetic acid was charged to a reaction vessel and heated to about 80 °C to 90 °C. About 2.5g of p-nitrophenol as a starting material and 2.5g of iron powder as catalyst (or Pd-C or any other suitable catalyst) was added at about 90 °C to form a mixture. During the addition, the reaction was exothermic and led to a reaction temperature of about 130 °C. After the reaction cooled slightly, a second lot of 2.5g of p-nitrophenol and 2.5g of iron powder catalyst (or Pd-C or any other suitable catalyst) were added to the aforesaid mixture. The addition of 2.5g of p-nitrophenol and 2.5g of iron powder catalyst (or Pd-C or any other suitable catalyst) was repeated a total of about 4 times, thereby requiring a total 10g of each, p-nitrophenol and iron powder split in four lots. The reaction temperature was monitored during the addition of lots of p-nitrophenol and catalyst so that the temperature did not drop below 110 °C. The mixture was then refluxed (b.p. of acetic acid is ~ 118 °C). The reaction was completed in a time of about 2-6 hrs. Completion of reaction was then checked by TLC. The reaction mixture was then cooled to 60°C and 75 ml of any suitable solvent (methanol/ethanol/ethyl acetate) was added and the mixture was refluxed at 65-75 °C for 1 hr to extract paracetamol. The mixture was allowed to settle and then filtered. This extraction procedure was carried out twice. The filtrate was then concentrated under vacuum to obtain a cake; 75 ml of water was added to the cake and the mixture was heated to dissolve the cake. The pH was adjusted to neutral and then 0.08g of activated carbon was added, followed by filtration. The cake was then cooled at 0- 5 °C for 1 hour to form 16g of wet cake of paracetamol.

T he wet cake thus obtai ned was di ssol ved i n water by heati ng. pH was adj usted to about 4-6. Activated carbon was added and the mixture was stirred for about 30 minutes. The mixture was then filtered through 0.3micron filter, cooled at 5 °C and stirred for 1 hour. The filtration step was repeated followed by washing of the cake with chilled water which was then spin dried to obtain purified paracetamol in a yield of 98%.

EXAM PL E 2

One pot process of synthesis of Paracetamol from p-nitroso phenol

7.5 ml of acetic acid was charged to a reaction vessel and heated to about 80 °C to 90 °C. About 2.5g of p-nitrosophenol as a starting material and 2.5g of iron powder as catalyst (or Pd-C or any other suitable catalyst) were added at about 90°C to form a mixture. The exothermic reaction led to a reaction temperature of about 130 °C. After the reaction cools slightly, a second lot of 2.5g of p-nitrosophenol and 2.5g of iron powder catalyst (or Pd-C or any other suitable catalyst) were added to the aforesaid mixture. The addition of 2.5g of p-nitrosophenol and 2.5g of iron powder catalyst (or Pd-C or any other suitable catalyst) was repeated a total of about 4 times, thereby requiring a total 10g of each, p-nitrosophenol and iron powder split in four lots. The starting material was added in lots since the reaction is highly exothermic and addition in lots I helped in controlling the reaction temperature so that the reaction temperature does not f al I bel ow 110 °C . T he mi xture was then ref I ux ed ( b. p. of aceti c acid is ~ 118 °C). The reaction was completed in a time of 2-6 hrs. Completion of reaction was then checked by TLC. The reaction mixture was then cooled to 60 °C and 75 ml of any suitable solvent (methanol/ethanol/ethyl acetate) was added and the mixture was refluxed for 1 hr to extract paracetamol. The mixture was allowed to settle and then filtered. This extraction procedure was carried out twice. The filtrate was then concentrated under reduced pressure to obtain a cake, 75 ml of water was added to the cake and heated to dissolve the cake. The pH was adjusted to neutral and then 0.08g of activated carbon was added followed by filtration. The cake was then cooled at 0- 5 °C for 1 hour to form the end product of around 16g of wet cake of paracetamol.

The cake thus obtained was dissolved in water by heating. pH was adjusted to 4-6. Activated carbon was further added and the mixture was stirred for about 30 minutes. The mixture was then filtered through 0.3micron filter, cooled at 5°C and stirred for 1 hour. The filtration step was repeated followed by washing of the cake with chilled water which was then spin dried to obtain purified paracetamol in a yield of 96-98%.

EXAM PL E 3

One pot process of synthesis of Paracetamol from sodium salt of p-nitro phenol, sodi um-4-nitrophenol ate

75 ml of acetic acid was charged to a reaction vessel and heated to about 80 °C to 90 °C. About 2.5g of sodi um-4-nitrophenol ate as a starting material and 2.5g of iron powder as catalyst (or Pd-C or any other suitable catalyst) was added at about 90 °C to form a mixture The exothermic reaction led to a reaction temperature of about 130 °C. After the reaction cools slightly, a second lot of 2.5g of sodium-4- nitrophenolate and 2.5g of iron powder catalyst (or Pd-C or any other suitable catalyst) were added to the aforesaid mixture. The addition of 2.5g of sodium-4- nitrophenolate and 2.5g of iron powder catalyst (or Pd-C or any other suitable catalyst) was repeated a total of about 4 times, thereby requiring a total 10g of each, sodi um-4-nitrophenol ate and iron powder split in four lots. The starting material was added in lots since the reaction was highly exothermic and addition in lots allows for controlling the reaction temperature so that it does not fall below 110 °C. The mixture was then ref I uxed. T he reacti on was compl eted i n ati me of about 2-6 hrs. C ompl eti on of reaction was then checked by TLC. The reaction mixture was then cooled to 60 deg C and 75 ml of any suitable solvent (methanol/ethanol/ethyl acetate) was added and the mixture was refluxed for 1 hr to extract paracetamol. The mixture was allowed to settle and then filtered. This extraction procedure was carried out twice. The filtrate was then concentrated under reduced pressure to dryness, 75 ml of water was added to the cake and the mixture was heated to dissolve the cake. pH was adjusted to neutral and then 0.08g of activated carbon was added followed by filtration. The cake was then cooled at 0- 5 °C for 1 hour to form the end product of around 16g of wet cake of paracetamol.

The cake thus obtained was dissolved in water by heating. The pH was adjusted to 4-6. Activated carbon was further added and the mixture was stirred for about 30 minutes. The mixture was then filtered through 0.3micron filter, cooled at 5 °C and stirred for 1 hour. The filtration step was repeated followed by washing of the cake with chilled water which was then spin dried to obtain purified paracetamol in a yield of 95%..

EXAM PL E 4

Scale up of one pot process of synthesis of Paracetamol from sodium salt of p-nitro phenol, or sodium-4-nitrophenolate

Purification of p-Nitrophenol

Charges 200ml of acetic acid and 100gm of p-Nitrophenol to a round bottom flask. Stirred to dissolve at 40-50eC, added activated carbon 5gm and 5gm Hypo supercell. Stirred for 20min then filtered through 3 micron filter and collected the clear solution of purified p-nitrophenol.

Experiment No. 4 (a):

The reaction of p-nitrophenol (PNP) + Iron Powder + Acetic Acid was conducted as described above in Example 1.

Experiment No. 4 (b):

Acetic acid (200ml) and para Nitrophenol (lOOgms) were charged to a pressure reactor or Bus loop reactor over about 10-15 min. and Pd-C (5% by weight palladium on charcoal) 2-5 g was added. The mixture was then heated to 30-50eC. The reactor was purged with the nitrogen. The H₂ gas was passed into the reactor at a pressure of 2-4 kg/cm². The reaction was exothermic, the temperature rose to 70-100eC. The reaction was allowed to continue for 3-4 hours, then the mixture was heated to 110- 120eC over 30 minutes to 1 hour. The reaction was allowed to continue for a further 6-8 hours at 2 kg/cm² pressure, and monitored by TLC for completion of the reaction. The reaction mixture was cooled to 50-60eC, the pressure was released and the reaction mixture was filtered. The filtrate was further cooled to 15-30eC, stirred for 1 hour, and filtered to obtain a cake comprising Tech grade paracetamol.

Charcoalization of tech paracetamol was done by addition of 300-600ml water, then addition of activated carbon in an amount which was 2-4 % by weight of the weight of Tech grade paracetamol and the mixture was heated to 80-95eC and maintained for 30 minutes, the carbon was filtered and the filtrate was cooled to 5- 15eC over 5-6 hours. The solid was filtered and dried under suction, the loss on drying was about 5-10% by weight, then further dried in a fluid bed drier at 100 ^" 120 °C, and pulverized to get pharma grade paracetamol (meeting purity requirements in accord with United States Pharmacopeia (USP)).

The tech grade product mother liquor (acetic acid), and pharma-grade product mother liquor were concentrated under reduced pressure to get a solid. The solid was purified by dissolving and precipitating from water to get pharma grade paracetamol. About 1.39 kg of p-nitrophenol yields about 1.5 kg of pharma grade paracetamol, i.e., a yield of about 92%.

Experiment No. 4 (c):

In a flow reactor comprising 5% or 10% palladium on alumina catalyst as a bed was passed a mixture of p-Nitrophenol 100 gm + acetic acid 200 mL) via a metering pump. Hydrogen gas (controlled flow) was passed simultaneously at 10-25ml/min flow rate, the temperature was increased from room temperature to 120eC and the pressure was maintained at 2-5 kg/cm². The column temperature was maintained at 115eC-120eC, the mixture was cooled to 15-25eC, filtered and purified as described i n ex peri ment N o. 4 ( b).

About 1.39 kg of p-nitrophenol yields about 1.5 kg of pharma grade paracetamol, i.e., a yield of about 92%. Experiment No. 4 (d):

A continuous column is filled to form a catalyst bed comprising a 5% or 10% Palladium on Alumina. The mixture (PNP + acetic acid) is passed through the metering pump simultaneously. Hydrogen gas is also passed through the column at 2- 25 ml /minute flow rate, pressure 4-20 kg/cm², Temperature in the column is from 80- 200eC, the mixture is collected and cooled to 15-25 e C and filtered. Tech grade paracetamol was purified as described in Experiment No. 4 (b). The hydrogen and water are collected through a catch pot and reused

About 1.39 kg of p-nitrophenol yields about 1.5 kg of pharma grade paracetamol, i.e., a yield of about 92%. Experiment No. 4(e)

A gas induction pressure reactor was charged with 100g paranitrophenol (PNP) + Iron powder ( 2 moles) + acetic acid ( 60ml) + Ethyl acetate ( 200ml) at room temperature. The initial reaction was initiated with steam; the reaction was exothermic. Maintained the reaction at 115 - 140 °C, pressure 1 -6 kg cm². Stirred for 4-8 hours. Monitored the reaction by TLC. Transferred the mixture into another reactor. Removed the solvent by distillation, added 3-6 volumes of water and heated to 60-70 °C, Adjusted pH to 7, then heated to 80-95 °C. and let the mixture settle for 30 mins to l hr.

Filtered the mixture to obtain a filtrate, leached the residue with hot water. Cooled the filtrate to 2-5 °C and stirred for 2-4 hours, then filtered and washed the obtained cake with chilled water. Purified the tech paracetamol cake as described in experiment no 4. (b)

Y ield was 90-100 gms of paracetamol (including the second crop).

Experiment No. 4(f) In a gas induction pressure reactor was charged 100g paranitrophenol (PNP) +

4 volumes of ethyl acetate + raney nickel (5 gms) at room temperature. Passed the hydrogen gas at 2-6 kg cm² pressure, temp 30-90 °C, stirred for 2-4 hrs. Monitored the reaction by TLC. Removed the raney nickel by filtration. Recharged the filtrate into the same reactor. Added 55ml of acetic acid and heated the reaction mixture to 120 - 145 °C. Maintained the pressure at 2-6 kg/cm². Stirred for 2-4 hrs. Monitored the reaction by T LC.

Removed the solvent under reduced pressure, then added 3-6 volumes of water. Heated to dissolve the solid. Adjust the pH to 5.5 - 6.5. Added activated carbon, stirred for 30 mins. Filtered the reaction mixture, cooled the filtrate to 2-5 °C. Stirred for 2 hrs.

Filtered the crystal ine pure paracetamol. Washed with chilled water. Then dried and pulverised the pure paracetamol.

Output was: 98 - 105 gms. (including second crop) Experiment No. 4(g) A gas induction pressure reactor was charged with 100g paranitrophenol (PNP)

+ acetic acid (55ml) + ethyl aetate (200ml) + Pd/C ( 10% - 2.5gms). Passed hydrogen gas at 2-5 kg/cm² pressure, temp: 35 - 125 °C. When the hydrogen gas consumption tapers off, hydrogen feed to the reactor was stopped. Raised the temperature to 120 - 145 °C. Pressure raised to 6 kg cm². Stirred for 3-5 hrs. Monitored the reaction by TLC. Removed Pd-C by filtration. Removed solvent from the filtrate under reduced pressure. Added water 3-6 volumes. Heated to dissolve the solid. Adjusted the pH to 5.5 - 6.5. Added activated carbon, stirred for 30 mins. Removed the activated carbon by filtration, cooled the filtrate to 2-5 °C; stirred for 2 hrs. Filtered the mixture to obtain crystal ine purified paracetamol. Washed with chilled water. Dried and pulverised the pure paracetamol.

Output was: 98 - 105 gms. (including second crop) Experiment 4(h)

A gas induction pressure reactor was charged with lOOgms of nitrophenol with o-acetylated group + ethyl acetate (500 ml) + raney nickel (5 gms).

Passed hydrogen gas at 2-10 kg/cm² pressure, temperature: 100-160 °C for 6-10 hrs, monitored reaction by TLC.

Cooled the mixture to 50-60 °C. Filtered the mixture and removed solvent from the filtrate under reduced pressure. Added water 3-6 volumes. Heated to dissolve the solid. Adjusted the pH to 5.5 - 6.5. Added activated carbon, stirred for 30 mins. Removed the charcoal by filtration, cooled the filtrate to 2-5 °C; stirred for 2 hrs.

Filtered the mixture to obtaine the crystaline pure paracetamol. Washed with chilled water. Dried and pulverised the pure paracetamol.

Output was: 98 - 105 gms. (including second crop) EXAM PL E 5

A gas induction reactor was charged with 100gms of para amino phenol + 55ml of acetic acid + 1,4 dioxane at room temperature. Heated the reaction at 120- 150 °C under a pressure of 1-6 kg/cm², stirred for 2-4 hours. Monitored the reaction by T LC. The acetic acid was removed under reduced pressure or by distillation to obtain a dry mass to which was added 3-6 volumes of water, the mixture was heated at 80-95 °C to dissolve the dry mass. Activated charcoal was added and the mixture was stirred for 30 minutes. Removed the charcoal by filtration, cooled the filtrate to 2-5 °C, stirred for 2 hours. Washed the cake with chilled water. The resulting cake was dried at 80-100 °C to a moisture content of less than 0.5% and pulverized to obtain paracetamol. 1 mole of para-ami no phenol yields about 1.3 moles of paracetamol.

The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated. It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.

Claims

C laims :

A process for manufacture of acetyl ated amines comprising

i ) pi aci ng aceti c aci d i n a reacti on vessel ;

i i ) addi ng a compound of F ormul a I and a metal catalyst to the reacti on vessel and heating the reaction mixture;

R-NO2 I

wherein R is an optionally substituted aromatic ring or an alkyl group, to obtain a reaction mixture comprising a compound of Formula II:

R-NH-C(=0)CH₃ II;

iii) (a) cooling the reaction mixture of step (ii) and filtering the cooled reaction mixture to obtain a filtrate;

OR

(f) cool i ng the reacti on mi xture of step (ii) and diluting the reacti on mixture of step (ii) with a solvent

(g) heating the mixture of step (iii)(b) at a temperature of about the boi I i ng poi nt of sai d solvent

(h) cooling the mixture of step (iii)(c) and filtering the cooled mixture to obtain a filtrate and a residue; (i) optionally, suspending the residue of step (iii)(d) in said solvent and repeating steps (iii)(c) ^" (iii)(d) 1-2 times, and combining the filtrates;

iv) removing the solvent from the filtrate of step (iii)(a) or from the combined filtrates of step (iii)(e) to obtain a crude product cake comprising a compound of Formula II.

2. The process of clai m 1 , wherein the reaction vessel is a pressure reactor, a bus loop reactor, a flow reactor, a continuous column, a gas induction pressure reactor, or a round bottom flask.

3. The process of claim 1, wherein the metal catalyst of step (ii) is palladium, palladium on charcoal (Pd-C), silica gel, platinum (IV) oxide (Pt0₂), chromium (II) chloride (CrCI₂), Tin (II) chloride, Titanium (III) chloride, aluminum, nickel, iron, zinc, stannous chloride (SnCI₂), samarium or rhodium, or a combination thereof.

4. The process of claim 1, wherein the metal catalyst of step (ii) is palladium on charcoal (Pd-C), or iron.

5. The process of claim 1, wherein the metal catalyst of step (ii) is palladium on charcoal (Pd-C) and the process further comprises passage of hydrogen in the reaction vessel.

6. The process of claim 1, wherein the metal catalyst of step (ii) is iron, and the metal catalyst and the compound of F ormul a I are added to the reacti on vessel i n portions such that the reaction temperature in step (ii) is at least 110 °C.

7. T he process of cl ai m 1 , wherei n the solvent of step ( i i i ) i s aceti c aci d, aceti c anhydride, a C C₆ aliphatic primary alcohol, a C₃-C₆ ali phatic secondary alcohol, a C₄-C₆ al iphatic tertiary alcohol, a C₅-C₈ ali phatic cycl ic alcohol, tetrahydrofuran, 1 ,4- dioxane, dibutyl ether, ethylene glycol di methyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, morphol ine, toluene, xylenes, ethyl acetate, propyl acetate, butyl acetate, pyridine, or water, or a combination thereof.

8. The process of clai m 1 , wherein the solvent of step (i ii) is methanol, ethanol, or ethyl acetate, or a combination thereof.

9. T he process of cl ai m 1 , wherei n the solvent of step ( i i i ) i s ethyl acetate.

10. The process of clai m 1 , wherein R is phenyl substituted with a hydroxy group.

11. T he process of cl ai m 1 , further compri si ng purif i cati on of the crude product cake of step (iv) compri si ng the steps of:

v) dissolvi ng the crude product i n water, opti onal ly by heati ng, and addi ng activated charcoal to the mixture;

vi) filtering the mixture of step (v) and cooli ng the fi ltrate;

vi i) filtering the cooled fi ltrate of step (vi) to obtai n a solid comprisi ng the compound of Formula II; and

vi ii) optionally repeati ng steps (v) to (vii) 1 -2 ti mes with the solid of step (vii) to obtain a purified compound of Formula II.

12. The process of clai m 1 1, wherein R is phenyl substituted with a para-hydroxy group and the yield of the purified compound of Formula II is at least 90%.

13. The process of claim 1, wherein the compound of Formula I is added to the reaction vessel as a solid or as a solution in acetic acid.

14. A process for manufacture of paracetamol comprising

i ) pi aci ng aceti c aci d i n a reacti on vessel ;

ii) adding para-ami nophenol, a solvent, and a metal catalyst to the reaction vessel;

i i i ) heati ng the reacti on mi xture under pressure to obtai n a reacti on mixture comprising paracetamol;

iv) cooling the reaction mixture of step (iii) and filtering the cooled reacti on mixture to obtai n a f i Itrate;

v) removi ng the solvent and aceti c aci d from the f i Itrate of step ( iv) to obtain a crude product comprising paracetamol.

15. The process of claim 14, further comprising purification of the crude product comprising paracetamol of step (v) by recrystallization or precipitation from water.

16. The process of claim 14, wherein the solvent of step (ii) is acetic acid, acetic anhydride, a C C₆ aliphatic primary alcohol, a C₃-C₆ aliphatic secondary alcohol, a C₄-C₆ aliphatic tertiary alcohol, a C₅-C₈ aliphatic cyclic alcohol, tetrahydrofuran, 1,4- dioxane, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, morpholine, toluene, xylenes, ethyl acetate, propyl acetate, butyl acetate, pyridine, or water, or a combination thereof.

17. The process of claim 14, wherein the solvent is 1,4-dioxane.