The present invention relates to a novel process for the preparation of insecticidal agent belonging to class of anthranilamide compounds i.e. Chlorantraniliprole of formula I. The present invention further relates to novel intermediates of Formula V (Intermediate I), Formula XII (intermediate II) and process of preparation thereof. These intermediates are essential in the preparation of Chlorantraniliprole of formula I.
BACKGROUND OF THE INVENTION
Anthranilamide derivatives are insecticides with high efficacy and safety. Anthranilamide compounds are nitrogen-containing aromatic compounds that are selective targets of the ryanodine receptor in insects. Ryanodine receptors are calcium ion channels used in muscle function. When Anthranilamides bind to insect ryanodine receptors, the insect's muscles contract, leading to paralysis and ultimately death for pests. The control of invertebrate pests is extremely important in achieving high crop efficiency. Damage by invertebrate pests to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to consumer. Amongst the Anthranilamide derivatives, one of such compound i.e. 3-Bromo-N-(4-chloro-2-methyl-6-(methyl carbamoyl) phenyl)-l-(3-chloro-2-pyridyl)-lH-pyrazole-5-carboxamide is highly effective against insects, which is generically known as Chlorantraniliprole. Chlorantraniliprole; 3-bromo-N-(4-chloro-2-methyl-6-((methyl amino) carbonyl) phenyl)-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxamide is the first of the anthranilic diamide insecticides, it is a ryanodine receptor activator and is used to protect a wide variety of crops, including corn, cotton, grapes, rice and potatoes. It has a role as a ryanodine receptor agonist. It is an organ bromine compound, a pyrazole insecticide, a member of mono chlorobenzenes and a secondary carboxamide. It binds and activates ryanodine receptors (RyRs) located in the sarcoplasmic reticulum, to release stored intracellular calcium into 20 cytoplasm. It stimulates the release and depletion of intracellular calcium stores from the sarcoplasmic reticulum of muscle cells, causing impaired muscle regulation, paralysis and ultimately death of sensitive species. This novel and unique calcium-
induced muscle-contraction mode of action has been shown to be highly specific to insect ryanodine receptors.
Chlorantraniliprole (Formula I)
Chlorantramliprole is an example of such anthranilimides which when prepared as per prior art processes results in lower yield for use on commercial scale and has ample impurities. There are various literatures and publications, disclosing the preparation of Chlorantraniliprole, but, none of them teaches a cost-effective or green process (environmentally friendly), that yields high quality Chlorantraniliprole with a good commercial yield and is economically viable.
WO 2006/062978 Al discloses a process for the preparation of 2-amino-5-chloro-3,N-dimethylbenzamide of Formula-I by chlorinating the 2-amino-3-methylbenzoic acid of Formula-II in the presence of N-chloro succinimide in DMF solvent to produce 2-amino-5-chloro-3-methylbenzoic acid of Formula-Ill, which undergoes further esterification in the presence of dimethyl sulfate and DBU in acetonitrile solvent to obtain methyl 2-amino-5-chloro-3-methylbenzoate of Formula-IV. Further, compound of Formula-V is reacted with methylamine in acetonitrile solvent to obtain 2-amino-5-chloro-3 N-dimethyl benzamide of Formula-I. The synthetic scheme mentioned in this patent application is depicted in below Scheme-I.
COOH Dimcthylsulfiite/CIfcCN,' CI DBU
OCH,
Step-D
aijNIb/CHjCN/ Ethylene glycol y
.CHj
CH,
a
CH3
N-chlorosuccintniide/ DMF/ Ether solvent
Step-I
XX
VNlH2
CH3
III
Schenie-I
WO 2006/062978 Al further discloses coupling of carboxylic acid of Formula 2 with an aniline compound of Formula 3 using a sulfonyl chloride in the presence of base and a solvent. This is shown in the scheme depicted below:
2 3 1
The process disclosed in this patent application is expensive and non-eco-friendly.
WO 2003/015519A1 discloses a process for the preparation of Chlorantraniliprole, wherein 3-bromo-l-(3-chloro-2-pyridyl)-lH-pyrazole-5-carboxylic acid reacts with substituted anthranilic acid in the presence of methane sulfonyl chloride and pyridine to give the benzoxazinone in 85-92% yield. Then the product reacts with the methylamine to yield the Chlorantraniliprole. Calculated by 3-bromo-l-(3-chloro-2-pyridyl)-lH-pyrazole-5-carboxylic acid, the overall yield of the two steps process for Chlorantraniliprole compound is 58-65% only. The synthetic scheme is depicted below as Scheme-I:
Methanesulfonyl chloride/ pyridine
CH5
j-Bronm-Ki-chloro-Z-pyridyl)-IH- Substituted anthranilic acid pyraH)le-J-carto.\ylic acid
BeriiBHianoncs
Methylammc/THF/ Tmuraicd with Eihcr
CM)
Br
N-
Formula-I
Scheme-I
Thus, to overcome the drawbacks of the existing technology, a high yielding, high quality approach for the preparation of chlorantraniliprole that is both environmentally friendly and economically viable is required.
Thus, the motive of the present invention is to develop a cost-effective and green process for the synthesis of Chlorantraniliprole, which also provides high purity and good commercial yield of Chlorantraniliprole.
OBJECTIVES OF THE INVENTION
The main objective of the invention is to provide anovel process for the preparation of Chlorantraniliprole of formula I and novel intermediates and their process used in preparation of Chlorantraniliprole.
Another objective of the present invention is to provide novel intermediate of formula V i.e. 2,4,6-trichlorophenyl-2-amino-5-chloro-3-methylbenzoate for the preparation of Chlorantraniliprole of formula I.
Another objective of the present invention is to provide novel process to synthesize the intermediate I of formula V.
Another objective of the present invention is to provide novel intermediate II of Formula XII i.e. 2,4,6-trichlorophenyl-2-{[3-bromo-l-(3-chloropyridin-2-yl)-lH-pyrazol-5-carbonyl] amino}-5-chloro-3-methylbenzoate.
Another objective of the present invention is to provide novel process to synthesize the intermediate II of Formula XII.
Another objective of the present invention is to provide an economically viable process for preparation of Chlorantraniliprole of Formula I using a recyclable solvents.
Another objective of the present invention, is to provide novel process to synthesize Chlorantraniliprole of formula I in the purest and active state with high commercial yield.
Another objective of the present invention is to provide a process with reduced effluents, for preparation of Chlorantraniliprole.
Yet another objective of the present invention is to provide an improved process for preparation of Chlorantraniliprole which utilises locally available raw materials.
Another objective of the present invention is to provide an improved process for preparation of Chlorantraniliprole, which is environmental friendly and has high yield of Chlorantraniliprole.
Another objective of the present invention is to provide an improved process for preparation of Chlorantraniliprole and its intermediates, which have lesser impurities.
Further, objective of the present invention is to provide an improved process which yields more product per unit of raw materials consumed.
Yet another objective of the present invention is to provide cost effective process for preparation of Chlorantraniliprole on account of lower consumption norms of raw materials coupled with lower wastage due to various purification and isolations steps etc.
Yet another objective of the present invention is to provide an improved process that is both environmentally friendly and economically & commercially viable for preparation of Chlorantraniliprole.
ADVANTAGES OF THE INVENTION
a) High yield;
b) High purity;
c) Economically viable; and
d) Environmentally friendly.
e) The process of the present invention yields more product i.e. Chlorantraniliprole per unit of raw material consumed due to improved consumption norms of raw materials etc.
f) Chlorinating agents used are less expensive and readily available.
g) Lower consumption norms of raw materials coupled with lower wastage due to various purification and isolations steps etc. and cost of the process for manufacturing the Chlorantraniliprole technical will be substantially reduced
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a novel process for the preparation of Chlorantraniliprole i.e. 3-Bromo-N-[4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide, Formula I copound.
The process for preparation of 3-Bromo-N-[4-chloro-2-methyl-6-(methyl
carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide
(Formula I) compound comprises the steps of-
""iMvmli .IT
a) reacting of 2-amino-3-methylbenzoic acid, a compound of Formula - II
Formula -III
in presence of a suitable catalyst in a solvent (Toluene) to provide a 2,4,6-trichlorphenyl-2-amino-3-methylbenzoate, a compound of Formula IV
\M2 o C.
""Yi"^
CI'
Foimula -IV
b) chlorinating 2,4,6-trichlorphenyl-2-amino-3-methylbenzoate-compound of Formula IV in the presence of Potassium Chloride (KCl), Sulphuric acid (H2S04) and Hydrogen Peroxide (H202) or with Dimethyl Sulfoxide (DMSO), o-Xylene and Hydrocholoric acd (HCl)to obtain 2,4,6-trichloro-phenyl-2-amino-5-chloro-3-methylbenzoate, novel intermediate I com¬pound of Formula V
Fonnula-V
c) reacting 3-oxobutanoyl bromide compound of formula VI
o o
BT^-^CHj
Fonnula-VI
with 2-hydrazinyl-3-nitropyridine, compound of Formula VII
I IN
&'
Fomiiila-VII
in presence of a catalyst in a solvent (Toluene) to provide 2-(3-bromo-5-methyl-lH-pyrazol-l-yl)-3-nitropyridine, a compound of formula VIII
Fonnula VIII
d) Hydrogenation of 2-(3-bromo-5-methyl-lH-pyrazol-l-yl)-3-nitropyridine of Formula - VIII in presence of a catalyst to provide 2-(3-bromo-5-me-thyl-lH-pyrazol-l-yl)pyridine-3-amine, a compound of formula IX
Fonnula-IX
e) Diazotizing/reacting 2-(3-bromo-5-methyl-lH-pyrazol-l-yl)pyridine-3-amine, compound of formula IX in presence of NaN02, CuCl, an acid, and a base to provide 2-(3-bromo-5-methyl-lH-pyrazol-l-yl)-3-chloropyridine, a compound of Formula X
Bl
Fonnula-X
f) oxidizing 2-(3-bromo-5-methyl-lH-pyrazol-l-yl)-3-chloropyridine, com-pound of formula X with Ru04 or RuC>2, NaOCl in presence of Cetyl Tri-methylammonium Chloride, followed by a solution of Toluene Triphosgene to obtain 3-bromo-l-(3-chloropyridin-2-yl)-lH-pyrazol-5-carbonyl chlo¬ride, a compound of formula XI
Br
Formula-XI
g) reaction of the intermediate I of Formula - V and 3-bromo-l-(3-chloro-pyridin-2-yl)-lH-pyrazol-5-carbonyl chloride, the compound of formula XI in presence of a base to provide 2,4,6-trichlorophenyl-2-{[3-bromo-l-(3-chloropyridin-2-yl)-l-H-pyrazole-5-carbonyl]amino}-5-chloro-3-methylbenzoate, novel intermediate II of formula XII;
Formula-XII
h) reacting 2,4,6-trichlorophenyl-2-{[3-bromo-l-(3-chloropyridin-2-yl)-l-H-pyrazole-5-carbonyl]amino}-5-chloro-3-methylbenzoate of Formula - XII, intermediate II with a primary amine in a solvent to obtain 3-bromo-N-[4-chloro-2-methyl]-6-[(methylamino)carbonyl]phenyl]-l-(3-chloro-2-pyridi-nyl)-l-H-pyrazole-5-carboxamide of Formula-1 i.e. Chlorantraniliprole.
The present invention further relates to process for preparation of novel intermediates I (compound of Formula V) and intermediate II (compound of Formula XII), as described herein above.
In an embodiment of the present invention, the compound of formula V and formula XII can either be isolated or further reacted in next step without isolation.
In an embodiment of the present invention the catalyst used in step (a) is selected from the group consisting of p-toluenesulfonic acid (PTSA), Methane sulfonic acid or Ambarlyst-15.
In an embodiment of the present invention, the solvent used in step a) and step c) is toluene.
In yet another embodiment of the present invention, the chlorination process of step (b) is carried out in the presence of agents selected from sulfuric acid, hydrogen peroxide or hydrochloric acid, o-Xylene and dimethyl sulfoxide.
In yet another embodiment of the present invention the chlorination process of step (b) comprises reacting an activated aromatic compound with HC1 and a sulfoxide, while removing water from the reaction mixture, so as to ring chlorination said activated aromatic compound
In yet another embodiment of the present invention the chlorination process of step (b) is carried out in an inert organic solvent and the reaction conditions of temperature and pressure cause the water to be vaporized from the reaction mixture.
In yet another embodiment of the present invention the said sulfoxide and HC1 are each present in no greater than about a 15% excess over a molar amount which is stoichiometrically equivalent to said activated aromatic compound.
In another embodiment of the present invention, the catalyst used in step c) is p-toluene sulfonic acid (PTSA).
In another embodiment of the present invention, the catalyst of step d) is selected from palladium, Nickel or phase transfer catalyst like Tetra butyl ammonium bromide, Tetra butyl ammonium chloride.
In an embodiment of the present invention, the acid in step e) is selected from Hydrochloric acid or sulphuric acid in presence of water as solvent, and Hydrochloric acid or sulphuric acid in presence of water as solvent; and base is selected from sodium hydroxide or potassium hydroxide.
In yet another embodiment of the present invention the reagent used in step (f) is toluene triphosgene.
In yet another embodiment of the present invention the oxidizing agent used in step (f) is selected from Ru(0)2 or Ru(0)4.
In yet another embodiment of the present invention the base used in step (g) for the synthesis of formula XII is sodium bicarbonate.
In another embodiment of the present invention, the primary amine used in step h) is methyl amine, and solvent used is selected from acetone, N, N-Dimethyl formamide, acetonitrile, Dimethyl Sulfoxide, Isopropyl alcohol, methanol and or mixtures thereof.
In yet another embodiment of the present invention, the phase transfer catalyst used in step (h) is selected from Tetrabutyl ammonium bromide or Tetrabutylammonium chloride.
In yet another embodiment of the present invention, the base used in step (h) is selected from the group consisting of potassium carbonate, B-Picoline,3,5-Lutidine, sodium carbonate, sodium hydroxide, potassium hydroxide triethylamine, dimethylamine or mixtures thereof.
In another embodiment of the present invention, the yield of 3-Bromo-N-[4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide is atleast 92 % to atleast 98%.
In a preferred embodiment of the present invention, process for preparation of preparation of 3-Bromo-N-[4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide comprising the steps of-
a. reacting the compound of formula V
Foimula-V
and the compound of formula XI
Fonnula-XI
in presence of a base to provide a compound of formula XII; and
Fomiula-XII
b. reacting the compound of formula XII with a primary amine to provide 3-Bromo-N- [4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-1-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide.
In another embodiment, the primary amine is methyl amine and base is sodium
bicarbonate.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: Illustrates the preparation of Intermediate-I of Formula V and alternative process of Formula V
Figure 2: Illustrates the preparation of Intermediate-II of Formula XII
Figure 3: Illustrates the preparation of Chlorantraniliprole of Formula I
DETAILED DESCRIPTION OF THE INVENTION
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps of the process, features of the system, referred to or indicated in this specification, individually or collectively,
and any and all combinations of any or more of such steps or features.
The present disclosure is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent tp those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
The articles "a", "an" and "the" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms "comprise" and "comprising" are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as "consists of only".
The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.
In an embodiment, the term "impurities" refers to unreacted synthetic intermediates, reagents, solvents, organic and/or inorganic products of side reactions, organic and/or inorganic salts and/or undesired materials.
The present invention provides Chlorantraniliprole substantially free of impurities.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and methods are clearly within the scope of the
disclosure, as described herein.
The present invention discloses a novel process for the preparation of 3-bromo-N-(4-chloro-2-methyl-6-(methyl carbamoyl) phenyl)-1-(3-chloro-2-pyridyl) 1H-pyrazole-5-carboxamide (Chlorantranihprole) of formula (I)
CH3
Formula (I)
The process is described in the following schemes:
SCHEME-1
Preparation of Intermediate-I
"C
-CH3
PTSA
Toluene
2-amino-3-methylbenzoic acid M.W.=151.16
Formula -IT
2,4,6-Trichlorophenol
Mol.Wt =197.45 Formula -III
2,4,6-trichlorophenyl 2-amino—3-methylbenzoate
Mol.Wt.=330.59 Formula -TV
2,4,6-trichlorophenyl 2-amino-3-methylbenzoate M.W.=330.59 Formula -TV
KCI
H2S04 H202
2,4,6-trichlorophenyl 2-amino-5-chloro-3-methylbenzoate
M.W.=365.038
Formula -V
Or Alternate Process
2,4,6-trichlorophenyl2-amino-3-methylbenzoate
M.W.=330.59
Formula -IV
DMSO
*■
O-Xylene HCI
2,4,6-trichlorophenyl2-amino-5-chloro-3-methylbenzoate
M.W-365.038
Fonmila -V
SCHEME-2 Preparation of Intermediate-II
UN
CH3
3-oxobutanoyl bromide Mol.Wt=164.98 Formula -VI
2-liydrazinyl-3-nitropyridine
Mol.Wt.=154.13
Formula -VTI
2-(3-bromo-5-methyl-lff-pyrazol-l-yl)-3-nitropyridine
Mol.Wt.=283.08
Formula -VTII
Pd/Cat. *■ or Raney Nickel
2-(3-bromo-5-methyl-li/-pyrazDl-l-yl)-3-nitropyridine Mol.Wt= 283.08 Formula -VTTT
2-(3-bromo-5-methyl-li7-pyrazol-l-yl)pyridin-3-amine Mol.Wt =253.09 Formula -TX
J «
2-(3-bromo-5-methyl-1 ff-pyrazol-1 -yl)pyridin-3-amine
Mol.Wt-253.09 Formula -IX
36% HCI
NaN02
Copper(T)Chloride
!5%NaOH
MDC
2-(3-bromo-5-methyl-lff-pyrazol-l-yl)-3-chloropyriditie
Mol.Wt=272.53
Formula -X
'/ 1
N'
RU04 NaOCl
2-(3-bromo-5-methyl-1 H-pyrazol-1 -yl)-3-cbloropyridirie Mol.Wt-272.53 Formula -X
Cetyltrimethylammoriium chloride
Toluene Triphosgene
3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chlorid
Mol.Wt=320.% Formula -XI
NaCl
C02
H20
NaHCCB
w Carbon Dio*
3-bromo-l-(3
r'^/°H3
O NH2
Toluene
a
„ ., . . , - . , „ . ,, , , 2,4,6-trichlorophenyl 2-amino--3-methylbenzoate
2-amino-3-methylbenzoic acid 2,4,6-Tnchlorophenol v ' !
M.W-151.16 Mol.Wt-197.45 Mol.Wt.=330.59
Procedure:
1) Ensured that the assembly should be clean and free from any external impurity.
2) Charged 200 ml of Toluene in a reactor at room temperature.
3) Charged 1 gm of P-Toluene Sulphonic acid as a catalyst.
4) Charged 15.16 (0.1 Mole) gm of 2-Amino-3-methylbenzoic acid (Formula
II) and 19.74 gm (0.1 mole) of 2,4,6-trichlorophenol (Formula-Ill) at room
temperature.
5) Heating the reaction mixture and water removed completely by azeotropic distillation.
6) After completion of reaction, amount of 2-amino-3-methyl benzoic acid checked and it should below 0.3%, and toluene recovered under vacuum below 80°C.
Weight of Formula-IV= 32 gm Yield =97% Purity >97.00 %
STEP- :02
Preparation of 2,4,6-trichlorophenyl-2-amino-5-chloro-3-methylbenzoate (Formula-V) Intermediate-I
KCI
H2S04
H202
2,4,6-trichlorophenyl 2-amino-3-methylbenzoate 2,4,6-trichlorophenyl 2-amino-5-chloro-3-methylbenzoate
M.W.=330.59 M.W-365.038
Procedure: -A
1) Assembled 1 litre 4 Neck RBF having water bath, condenser and addition funnel arrangement.
2) Charged 300 ml of EDC, 180 gm of 2,4,6-trichlorophenyl-2-amino-3-methylbenzoate (Formula IV) and 43 % KCI 120 gm in 4 necked flask at 25°C temperature.
3) Charged 2.0 gm of Tetrabutyl ammonium bromide at 25°C and followed by addition of 68 gm sulphuric acid in reaction mass within 30 minutes at 25°C to 30°C. (formation of brown color precipitate ).
4) Charged Hydrogen peroxide in reaction mass at 25°C to 30°C, within 2.0 to 2.5 hours.
5) Maintaining reaction mass at 30°C for about 4 to 5 hours.
6) Amount of unreacted 2,4,6-trichlorophenyl-2-amino-3-methylbenzoate checked and should be below 1%.
7) Charged 80 gm 50% NaOH solution in reaction mass at 25 to 30°C and adjusted pH of the reaction mass 7.0 to 7.2.
8) Stirring the mass for half an hour, and left undisturbed for settling.
9) Separating aqueous layer and organic layer. Organic layer taken for solvent recovery by atmospheric distillation at 70°C and traces of EDC removed under vacuum at 745 to 750 mm/Hg.
Weight of Formula V = 228 gm.
Purity = 93 to 95%.
Yield =95.50% Example 2 Alternate Process for the preparation formula V
DMSO
O-Xylene HCI
2,4,6-trichlorophenyl 2-amino-3-methylbenzoate 2,4,6-trichlorophenyl 2-amino-5-chloro-3-methylbenzoate
M.W.=330.59 M.W-365.038
Procedure:
1) Ensured that the assembly should be clean and free from any external impurity.
2) Charged 33 gm of 2,4,6-trichlorophenyl-2-amino-3-methylbenzoate in DMSO.
3) Charge 20 gm of 35% con. HCI slowly within 3 to 4 hours at 30 to 110°C.
4) Reaction was stirred at 30°c to 120°c in presence of o-xylene.
5) After completion of reaction, o-xylene recovered and mass quenched in saturated sodium bicarbonate.
6) The solid washed with four times water.
7) Resultant solid washed with ether to give white solid product.
Weight of Formula V =31.00 gm
Purity = 95.00 %
Yield = 85.00%. Example 3: Preparation of Intermediate -II Step-01
Preparation of 2-(3-bromo-5-methyl-lH-pyrazol-l-yl)-3-nitropyridine (Formula-VIII)
Br
„NH2 Jj~i
Br v CH.
0 0
1 bromobutane 2,4 dione 2-hydrazinyl-3-mtropyndine 2-(3-bromo-5-methyl-lff-pyrazol-l-yl)-3-nitropyridine
Mol.Wt= 164.98 Mo1.Wt.= l54.l3
Mol.Wt-283.08
Procedure:
1) Ensured that the assembly should be clean and free from any extraneous matter.
2) Solution of 17.90 gm of l-bromobutane-2,4-dione (Formula-VI) in 60 ml glacial acetic acid was cooled to 7°C using ice/water bath.
3) 2-Hydrazinyl-3-nitropyridine (Formula-VII) 16.00 gm was added dropwise over a period of 60 minutes.
4) The reaction mass temperature increased to 15°C during the addition.
5) The resulting orange solution was held under ambient conditions for 60 minutes.
6) The bulk of the acetic acid was removed by stripping on a rotary evaporator at a bath temperature of 65°C.
7) The residue was dissolved in methylene chloride 150 ml. The solution was washed with aqueous sodium bicarbonate (3 gm in 50 ml water).
8) The purple-red organic layer was separated, treated with activated charcoal 2 gm and MgS04 and then filtered. Volatiles were removed on a rotary evaporator.
9) The crude product consisted of 23 gm of the desired product having purity >95.00%.
Step 2: Preparation of 2(3-bromo-5-methyl-lH-Pyrazole-l-yl-) pyridine-3-amine (Formula-IX)
J ^ H3C-\--N
HSC-V^N Pd/Cat. I
+ or *■ N-\-NH2
N/^/N°2 Raney Nickel l| I
^-^ 2 -(3 -bromo-5 -methyl- 1-ff-pyrazol-1 -yl)pyridrn-
2-(3-bromo-5-methyl-l-tf-pyrazol-l-yl)-3-nitropyridine M lWt=?^09
Mol.Wt- 283.08
Procedure: -
1) Ensured that the assembly should be clean and free from any external impurity.
2) 2-(3-bromo-5-methyl-lH-Pyrazol-l-yl)-3-nitropyridine (Formula-VIII) 2.830 gm was hydrogenated over 5% Pd/C in 40 ml ethanol at 50 psi.
3) When the uptake of hydrogen ceased the reaction was filtered through celite and the celite was washed with ether.
4) The filtrate was evaporated under reduced pressure to afford 2.40 gm of the 2(3-bromo-5-methyl-lH-Pyrazole-1-yl-) pyridine-3-amine as a solid.
Step 3: Preparation of 2(3-bromo-5-methyl-lH-Pyrazole-l-yl-)3-chloropyridine (Formula-X)
jn J «
»*-\.s 36o/oHC1 H*-V-
NH2 _, NaN02
^ ^T Copper(T)C1i1oride
15%NaOH
2-(3-bromo-5-methyl-lff-pyrazol-l-yl)pyridin-3-amine M00 2-(3-bromo-5-methy1-l//-pyrazo1-l-y1>3-ch1oropyridine
Mol.Wt=253.09 Mol.Wt=272.53
Procedure: -
1) Ensured that the assembly should be clean and free from any external impurity.
2) 44 gm of 2-(3-bromo-5-methyl-lH-Pyrazol-l-yl) pyridine-3-amine (Formula-IX), 80 ml of 36% HC1 and 30 ml of water was placed at -5°C in reaction flask.
3) To the mixture, 14 gm of sodium nitrite dissolved in 30 ml of water gradually added dropwise at 0°C.
4) In another flask 17.3 gm of copper (I) chloride and 80 ml of 36% hydrochloric acid were placed and cooled to -5°C.
5) In the resultant aqueous solution, the diazonium base solution was gradually added at 0°c.
6) Finally heated to 80°C.for 3.0 hour.
7) After the reaction, the reaction mixture was made alkaline by addition of 15% sodium hydroxide aqueous solution and the precipitated copper salt removed by filtration.
8) The clear, colourless alkaline solution was acidified by adding concentrated hydrochloric acid dropwise
until the pH reached -1.3 (28 g, 0.28 mole). Gas evolution was vigorous during the first two-thirds of the addition.
9) The product was collected via filtration, washed with water (3 x 40 mL), then dried overnight at 55°c.
10) The product consisted of 33 gm of a white, crystalline powder, which was essentially pure.
Step 4: Preparation 3-bromo-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carbonyl chloride (Formula-XI)
J ft
H3C-
RU04 NaOCl
Toluene Triphosgene
Cetyltmnethylaininonhim chloride
2-(3-bromo-5-methyl- lH-pyrazol-1 -yl)-3-cliloropyridiiie
3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonylchlorid
Mol.Wt=272.53 Mol.Wt=320.96
Procedure:
1) Ensured that the assembly should be clean and free from any external impurity.
2) Crude 2-(3-bromo-5-methyl-lH-pyrazol-l-yl)-3-chloropyridine (Formula-X) (-89%, 67 g, 0.22 mole) was mixed with water (100 mL) and cetyltrimethylammonium chloride (4.00 g, 0.011 mole).
3) The mixture was heated to 95°C. Ruthenium Tetroxide was added in 10 equal portions, spaced at -8-minute intervals (30 gm).
4) Charge Sodium hypochlorite at 30°C to 50°C within 2.0 hours in four parts.
5) The reaction mass was filtered while hot (75 °C) through a 1 cm thick bed of celite on a 150 d, coarse, glass frit.
6) The clear, colourless alkaline solution was acidified by adding concentrated hydrochloric acid dropwise until the pH reached -1.3 (28 g, 0.28 mole).
7) Gas evolution was vigorous during the first two-thirds of the addition.
8) Charged 300 ml Toluene in Reaction mass and remove water azeotropically by using dean and stark apparatus.
9) To the reaction mass was added 50.073 gm DMF, followed by addition of a solution of triphosgene by using dropping funnel (14 gm triphosgene having purity 98.00% in Toluene 28 mL).
10) The resulting reaction mass was heated to 50 to 55°C and monitored for the end of the reaction (Complete after 5 hours).
11) After completion of reaction the reaction mass, the solvent was removed under vacuum.
12) To the resulting concentrate fresh Toluene was added. Analysis of Toluene layer revealed that a 65.00 gm 93.2% yield of, acid chloride, having a purity of 97.00%.
13) Toluene layer was directly taken for next reaction.
Step-5 : Preparation of 2,4,6-trichlorophenyl-2-{[3-bromo-l-(3-chloropyridin-2-yl)-lH-pyrazol-5-carbonyl] amino }-5-chloro-3-methylbenzoate (Formula XII) Intermediate-II
NaHC03 i ^ j x NaC1 + mo + CQ2
Carbon Diox
3-bromo-l-(3-chloroPyndin-2-yl)- 2,4,6-tnchJorophenyl 2,4,6-tnchlorophenyl2-{[3-bromo-l-(3^hl Sodium Chloride Water
ltf-pyrazole^arbonyl chloride 2-amino-5^hloro-3-methylbenzoate oropyridin-2-yl)-1ff-pyrazole-596.00%
From the foregoing it will be observed that numerous modifications and variations can be effectuated without departing from the true spirit and scope of the novel concepts of the present invention. It is to be understood that no limitations with respect to the specific embodiments illustrated is intended or should be inferred. It should be understood that all such modifications and improvements have been
deleted herein for the sake of conciseness and readability but are properly within the scope of the following claims.
WE CLAIM:
1. A process for the preparation of 3-Bromo-N-[4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide, comprising the steps of-
a. reacting a compound of formula II
Foir.iula -11
with a compound of formula III
Formula -ill
in presence of a catalyst in a solvent to provide a compound of formula IV:
K>. J^V
FoimuU -IV
b. chlorinating the compound of formula IV with an agent in a solvent to provide a compound of formula V;
Y>tjr
Fonnula-Y
c. reacting compound of formula VI
0 0
Foimula-VI with compound of formula VII
&'
Formula-VEI
in presence of a catalyst in a solvent to provide a compound of formula VIII:
d. treating the compound of formula VIII in presence of a catalyst to
provide a compound of formula IX;
M &'
Formula-IX
e. treating the compound of formula IX in presence of NaN02, CuCl,
an acid, and a base to provide a compound of formula X;
;■
MJ;
Foimula-X
f reacting a compound of formula X with Ru04 or Ru02, NaOCl in presence of cetyl trimethyl ammonium chloride, in a solution of toluene tri phosgene to provide a compound formula XI;
vcf
Foimula-XI
g. reacting the compound of formula V and compound of formula XI in presence of a base to provide a compound of formula XII;
Foimula-Xn
h. reacting the compound of formula XII with a primary amine in a
solvent to provide 3-Bromo-N-[4-chloro-2-methyl-6-(methyl
carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-
carboxamide.
2. The process as claimed in claim 1, wherein the compound of formula V and formula XII can either be isolated or further reacted in next step without isolation.
3. The process as claimed in claim 1, wherein the catalyst used in step (a) is selected from the group consisting of p-toluenesulfonic acid (PTSA), Methane sulfonic acid or Ambarlyst-15.
4. The process as claimed in claim 1, wherein the solvent used in step a) and step c) is toluene.
5. The process as claimed in claim 1, wherein the agent used in step b) is selected from sulfuric acid, hydrogen peroxide or hydrochloric acid, o-Xylene and dimethyl sulfoxide.
6. The process as claimed in claim 1, wherein the solvent used in step b) is
selected from acetone, N, N-Dimethyl formamide, acetonitrile, dimethyl
Sulfoxide, chloro-solvents like Potassium Chloride, methylene chloride,
chloroform, mono-chlorobenzene and ethylene chloride; or hydrocarbon
solvents like toluene, xylene, heptane, cyclohexane, 2-methyl Cyclohexane
and 2-Ethyl cyclohexane and hexane, methylene chloride, ethylene chloride,
chloroform, dimethyl formamide or mixtures thereof.
7. The process as claimed in claim 1, wherein the catalyst used in step c) is p-toluene sulfonic acid (PTSA).
8. The process as claimed in claim 1, wherein the catalyst of step d) is selected from palladium, Nickel or phase transfer catalyst like Tetra butyl ammonium bromide, Tetra butyl ammonium chloride.
9. The process as claimed in claim 1, wherein the acid in step e) is selected from Hydrochloric acid or sulphuric acid in presence of water as solvent, and Hydrochloric acid or sulphuric acid in presence of water as solvent; and base is selected from sodium hydroxide or potassium hydroxide.
10. The process as claimed in claimed in claim 1, wherein the base used in step g) and h) is sodium bicarbonate.
11. The process as claimed in claim 1, wherein the primary amine used in step
h) is methyl amine.
12. The process as claimed in claim 1, wherein the solvent used in step h) is
selected from acetone, N, N-Dimethyl formamide, acetonitrile, Dimethyl
Sulfoxide, Isopropyl alcohol, methanol and or mixtures thereof.
13. The process as claimed in claim 1, wherein the yield of 3-Bromo-N-[4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide is atleast about 92 % to atleast about 98%.
14. A process for preparation of 3-Bromo-N-[4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide, comprising the steps of-
a. reacting the compound of formula V
Y^T
Fonnula-V
in presence of a base to provide a compound of formula XII; and
and the compound of formula XI
Foimula-Xn
b. reacting the compound of formula XII with a primary amine to provide 3-Bromo-N- [4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide.
15. The process as claimed in claim 14, wherein the primary amine is methyl amine and base is sodium bicarbonate.
16. The process as claimed in claim 14, wherein the compound of formula V, is prepared by
chlorinating the compound of formula IV,
with an agent in a solvent to provide a compound of formula V.
17. The process as claimed in claim 16, wherein the wherein the agent used is selected from sulfuric acid, hydrogen peroxide or hydrochloric acid, o-Xylene and dimethyl sulfoxide; and solvent is selected from acetone, N, N-Dimethyl formamide, acetonitrile, dimethyl Sulfoxide, chloro-solvents like Potassium Chloride, methylene chloride, chloroform, mono-chlorobenzene and ethylene chloride; or hydrocarbon solvents like toluene, xylene, heptane, cyclohexane, 2-methyl Cyclohexane and 2-Ethyl cyclohexane and hexane, methylene chloride, ethylene chloride, chloroform, dimethyl
18. The process as claimed in claim 16, wherein the compound of formula IV is prepared by reacting compound of formula II
Formula -II
with a compound of formula III
= NM2
Formula -III
in a solvent to provide a compound of formula IV.
19. The process as claimed in claim 18, wherein the solvent is toluene.
20. The process as claimed in claim 14, wherein the compound of formula XI is prepared by treating a compound of formula X
&
Fomiula-X
with Ru04 or Ru02, NaOCl in presence of cetyl trimethyl ammonium chloride, in a solution of toluene tri phosgene to provide a compound formula XI.
21. The process as claimed in claim 20, wherein the compound of formula X
is prepared by treating the compound of formula IX
&
Foimula-IX
in presence of NaN02, CuCl, an acid, and a base to provide a compound of formula X.
22. The process as claimed in claim 21, wherein the acid is selected from Hydrochloric acid or sulphuric acid in presence of water as solvent, and Hydrochloric acid or sulphuric acid in presence of water as solvent; and base is selected from sodium hydroxide or potassium hydroxide.
23. The process as claimed in claim 21, wherein the compound of formula IX is prepared by treating the compound of formula VIII
&"■
Formula VIE
in presence of a catalyst to provide a compound of formula IX.
24. The process as claimed in claim 23, wherein the catalyst is selected from palladium, Nickel or phase transfer catalyst like Tetra butyl ammonium bromide, Tetra butyl ammonium chloride.
25. The process as claimed in claim 23, wherein the compound of formula VIII is prepared by reacting compound of formula VI
o o Foimula-VI
with compound of formula VII
^Hi
I
Formula-VII
in presence of a catalyst in a solvent to provide a compound of formula VIII.
26. The process as claimed in claim 25, wherein the solvent is toluene and catalyst is p-toluene sulfonic acid (PTSA).
27. A novel compound represented by formula XII
Fomiula-Xn
28. The compound as claimed in claim 27, wherein the compound of formula XII is obtained by reacting the compound of formula V
Foimula-V
and compound of formula XI
" &'
Foimula-XI
in presence of a base to provide a compound of formula XII; and wherein the base is sodium bicarbonate.
Fonnula-Xn
29. The compound as claimed in claim 28, wherein the compound of formula XII can either be isolated or further reacted in next step without isolation.
30. A novel compound represented by formula V:
Fonnula-Y
31. The compound as claimed in claim 30, wherein the compound of formula V is prepared by
chlorinating the compound of formula IV,
FoimuU JV
with an agent in a solvent to provide a compound of formula V;
wherein the agent used is selected from sulfuric acid, hydrogen peroxide or
hydrochloric acid, o-Xylene and dimethyl sulfoxide; and wherein the
,1„„+„J f ™ „„„+ „ "NT "NT T"\:™„+U»»l f„
chloride, chloroform, mono-chlorobenzene and ethylene chloride; or hydrocarbon solvents like toluene, xylene, heptane, cyclohexane, 2-methyl Cyclohexane and 2-Ethyl cyclohexane and hexane, methylene chloride, ethylene chloride, chloroform, dimethyl formamide or mixtures thereof.
32. The process as claimed in claim 1, wherein the purity of obtained 3-Bromo-N-[4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-l-(3-chloropyridin-2-yl)-lH-pyrazole-5-carboxamide, is at least about 94.0% to at least about 96.0%.