Sign In to Follow Application
View All Documents & Correspondence

"New Process Of Preparation For Anacetrapib And Intermediates Thereof"

Abstract: The present invention relates to an economic and industrially advantageous process for preparation of compound of Formula II in high yields and purity. Formula II The present invention further relates to the preparation of Anacetrapib by utilizing compound of Formula II as an intermediate.

Get Free WhatsApp Updates!
Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
13 February 2017
Publication Number
33/2018
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2022-02-22
Renewal Date

Applicants

MANKIND PHARMA LTD
208 OKHLA INDUSTRIAL STATE PHASE 3, NEW DELHI-110020 INDIA

Inventors

1. SHARMA KAMAL
191-E SECTOR 4-II IMT MANESAR, GURUGRAM HARYANA-122050 INDIA
2. CHATURVEDI VIVEK
191-E SECTOR 4-II IMT, MANESAR, GURUGRAM HARYANA-122050 INDIA
3. BHASHKAR BHUWAN
191-E SECTOR 4-II IMT MANESAR, GURUGRAM HARYANA-122050 INDIA
4. KUMAR, ANIL
191-E SECTOR 4-II IMT MANESAR, GURUGRAM HARYANA-122050 INDIA

Specification

FIELD OF THE INVENTION The present invention provides an economic and industrially advantageous process for preparation of .compound of Formula II in high yields and purity and use of said compound of Formula II as an intermediate for synthesis of Anacetrapib. Formula II BACKGROUND OF THE INVENTION Anacetrapib is chemically known as 5(R)-[3, 5-Bis (trifluoromethyl) phenyl]-3-[4'-fluoro-5-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-ylmethyl]-4(S)-methyloxazolidin-2-one, and has the following structural Formula I: F CF3 Formula I The Anacetrapib raises HDL-cholesterol and lowers LDL-cholesterol in human patients, and may have utility in treating, preventing, or delaying the onset of atherosclerosis or slowing its progression. Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed to treat arteriosclerosis and hyperlipidaemia. There are numerous patent/ patent applications and non-patent literature available, which discloses the process of preparation of Anacetrapib and its intermediates thereof. United States Patent No. 7,652,049 discloses anacetrapib and a process for its preparation. United States Patent No. 7,863,307 discloses a process for producing Anacetrapib, wherein the process comprising the coupling of an oxazolidinone derivative with a biphenyl moiety. In a specific embodiment of this synthesis, a crystalline product is produced which is characterized as a non-solvated crystalline polymorph. United States Patent No. 7,863,307 discloses a crystalline non-solvate, crystalline heptane solvate and amorphous form of Anacetrapib. European Publication No. EP 2468735 and PCT Publication WO 2012/085133 also discloses processes for the preparation of Anacetrapib. United States Patent No. 9,212,118 discloses a process of synthesis of intermediate compounds of Anacetrapib by treating l-(2-fluoro-4-methoxyphenyl)ethanone with Grignard reagent in presence of two solvent system which was then hydrogenated and reacted with NBS to give 2-bromo-2-fluoro-4-methoxy isopropyl benzene. It was then reacted with 2-chloro-5-trifluoromethyl benzyl alcohol in presence of palladium catalyst followed by chlorination to give an intermediate, 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-l,r-biphenyl which can be used in the synthesis of Anacetrapib or derivatives thereof. United States Patent No. 9,145,348 discloses a process for synthesizing Anacetrapib and key chemical intermediates in the process. US'348 discloses preparation of 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-l,r-biphenyl by brominating of 2-(2-Fluoro-4-methoxyphenyl)propan-2-ol in presence of HBr and hydrogen peroxide followed by treatment with tri-isopropoxy borane to give 4-Fluoro-5-isopropyl-2-methoxyphenylboronic acid which is on reaction with 2-chloro-5-trifluoromethyl benzaldehyde and chlorination gives an intermediate, 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-1,1 '-biphenyl which can be used in the synthesis of Anacetrapib or derivatives thereof. PCT Patent Publication WO 2006/014413 discloses CETP inhibitors used for the prevention and treatment of atherosclerosis, comprising Anacetrapib and pharmaceutically acceptable salts thereof and discloses the process for its preparation. Although there are several processes known in the literature for preparation of Anacetrapib and its intermediate(s) and use of said intermediate(s) for preparation of Anacetrapib, there is a need to develop a process that is reproducible and economical at large scale production. Based on aforesaid, the present invention provides a novel process for the preparation of Anacetrapib which is simple, reproducible and well suited on commercial scale. Also, the instant application presents synthesis of compounds, which are useful intermediates in this novel process. OBJECT OF THE INVENTION The main aspect of the present invention is to provide a novel process for the preparation of Anacetrapib intermediate of Formula-II wherein said process is simple and cost effective at large scale production. Another object of the present invention is to develop a process for the preparation of important Anacetrapib intermediate wherein said process includes conversion of the undesired side products into desired compounds resulting into decrease in the loss of the yield of the compounds that are used for preparation of Anacetrapib intermediates. One another object of the present invention is to isolate Anacetrapib intermediate of Formula II with high yields and purity. Formula II SUMMARY OF THE INVENTION In the first aspect, the present invention relates to a process for preparation of a compound of Formula II Formula II comprising the steps of: i) reacting 2-bromo-5-fluoroaniline of Formula III with sodium nitrite in presence of acid to produce 2-bromo-5-fluorophenol of Formula IV; Formula III Formula IV. md ii) converting 2-bromo-5-fluorophenol of Formula IV to 2'-(chloromethyl)- 4- fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-l5r-biphenyl of Formula II. In further aspect, the present invention provides a process of preparation of 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4,-(trifluoromethyl)-1,1 '-biphenyl of Formula II, comprising the steps of: i) dehydrating 2-(5-bromo-2-fluoro-4-methoxyphenyl)propan-2-ol of Formula VII in presence of dehydrating agent to give l-bromo-4-fluoro-2-methoxy-5-(prop-l-en-2-yl)benzene of Formula VIII; OH 5!xx" 0' Formula VII Formula VIII ii) hydrogenating l-bromo-4-fluoro-2-methoxy-5-(prop-l-en-2-yl)benzene of Formula VIII in presence of palladium catalyst to give crude mixture comprising of desired compound, 1 -bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX and undesired side compound, 2-fluoro-l-isopropyl-4-methoxybenzene of Formula X; -Sx 0' Formula VIII Formula IX Formula X iii) reacting crude mixture of step ii) with brominating agent to convert undesired compound to desired compound, l-bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX; Formula X Formula IX CD G) Q. CD CN E o o m o m o o o CN ^, Formula IX . and iv) converting compound of Formula IX to compound of Formula II. DETAILED DESCRIPTION The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the -t^r^rt X 131 - r© i '§• *i*S - S ? CM CM contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims. The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein. Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples. In one embodiment, the present invention provides a process for preparation of a compound of Formula II F3C Formula II comprising the steps of: i) reacting 2-bromo-5-fluoroaniline of Formula III with sodium nitrite in presence of acid to produce 2-bromo-5-fluorophenol of Formula IV, Formula III Formula IV. ^ ii) converting 2-bromo-5-fluorophenol of Formula IV to 2'-(chloromethyl)- 4- fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-1,1 '-biphenyl of Formula II. In another embodiment, the preparation of compound of Formula IV is performed in absence of organic solvent. In a preferred embodiment, the preparation of compound of Formula IV is performed in presence of acid such as aqueous solution of sulphuric acid. In further embodiment, 2-bromo-5-fluorophenol of Formula IV can be converted to 2,-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4,-(trifluoromethyl)-l,r-biphenyl of Formula II by any of the conventional methods, wherein said compound of Formula II can be used as an intermediate for the preparation of Anacetrapib. In other embodiment, the present invention provides a process for preparation of 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4,-(trifluoromethyl)-1,1 '-biphenyl of Formula II comprising the steps of: i) reacting 2-bromo-5-fluoroaniline of Formula III with sodium nitrite in presence of acid to produce 2-bromo-5~fluorophenol of Formula IV; Br ^^ .Br Formula III Formula IV ii) treating 2-bromo-5-fluorophenol of Formula IV with alkylating agent to give l-bromo-4-fluoro-2-methoxybenzene of Formula V; Br ^. .Br Formula IV Formula V iii) acylating l-bromo-4-fluoro-2-methoxybenzene of Formula V in presence of catalyst to give 1 -(5-bromo-2-fluoro-4-methoxyphenyl)ethan-1 -one of Formula VI; •L^i £ £ -^i - TOVg; 2sfe :.ofe£ 8 FAA0/ Formula V Formula VI iv) treating l-(5-bromo-2-fluoro-4-methoxyphenyl)ethan-l-one of Formula VI with methyl magnesium halide to give 2-(5-bromo-2-fluoro-4- methoxyphenyl)propan-2-ol of Formula VII; O OH Formula VI Formula VII v) dehydrating 2-(5-bromo-2-fluoro-4-methoxyphenyl)propan-2-ol of Formula VII in presence of dehydrating agent to give l-bromo-4-fluoro-2-methoxy-5-(prop-l-en-2-yl)benzene of Formula VIII; OH Br FJUl0. Formula VII Formula VIII vi) hydro genating l-bromo-4-fluoro-2-methoxy-5-(prop-l-en-2-yl)benzene of Formula VIII in presence' of palladium catalyst to give crude mixture comprising of desired compound, l-bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX and undesired side compound, 2-fluoro-l-isopropyl-4-methoxybenzene of Formula X; 6x O' Formula VIII Formula IX Formula X vii) reacting crude mixture of step vi) with brominating agent to convert undesired compound to desired compound, 1 -bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX; Ijr. > —. A|j jig, fcjj, 2*©i*S _Ei %-T Formula IX Formula X Formula IX d viii) converting compound of Formula IX to compound of 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4!-(trifluoromethyl)-l,r-biphenyl of Formula II. In another embodiment, the alkylating agent used for alkylating hydroxyl group of Formula IV to give compound of Formula V, is selected from the group comprising of dimethyl sulphate, methyl iodide, methyl bromide and the like. Preferably, the alkylating agent used is dimethyl sulphate. In further embodiment, the preparation of compound of Formula V is performed in presence of solvent selected from ketonic solvent such as acetone, methyl isobutyl ketone, methyl ethyl ketone; ethers such as tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane; esters such as ethyl acetate, isopropyl acetate, butyl acetate; hydrocarbons such as toluene, xylene; halogenated solvents such as dichloromethane, chloroform and the like. Preferably the solvent used is ketonic solvent like acetone. In another embodiment, the acylation of compound of Formula V is performed in presence of catalyst such as aluminium trichloride. Moreover, said reaction is performed in presence of small amount of acetic anhydride. In further embodiment, the preparation of compound of Formula VII followed by dehydration of said compound of Formula VII to give Formula VIII is carried out in presence of aprotic solvents selected from the group comprising of tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene and the like. Preferably the solvent is selected from tetrahydrofuran and dichloromethane. In another embodiment, the hydrogenation reaction is performed in presence of protic solvent selected from alcohols such as ethanol, methanol, isopropanol and in presence of base selected from the group comprising of sodium bicarbonate, cesium carbonate, potassium carbonate, potassium bicarbonate, and sodium carbonate. The hydrogenation of l-bromo-4-fluoro-2-methoxy-5-(prop-l-en-2-yl)benzene of Formula VIII provides a desired compound, l-bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX. However, the process of hydrogenating double bond in presence of palladium catalyst also results into debromination resulting into production of de-brominated side compound i.e. 2-fluoro-1 -isopropyl-4-methoxybenzene of Formula X. In a preferred embodiment, the mixture of compound of Formula IX and X is treated with brominating agent without separating compounds of Formula IX and X. The step of bromination converts the undesired compound of Formula X back to compound of Formula IX wherein the whole step of isolation of undesired compound of Formula X from the crude mixture of IX and X, is omitted in toto. Hence, the overall process of brominating crude mixture of compound of Formula IX and X increases the overall yield of compound of Formula IX. In further embodiment, the brominating agent is selected from the group comprsing of N-bromo succinamide, phosphorus tribromide, hydrogen bromide and the like, Preferably, the brominating agent used is N-bromo succinamide. In still another embodiment, the compound of Formula IX can be converted to 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-1,1 '-biphenyl of Formula II by any of the convention methods, wherein said compound of Formula II can be used as an intermediate for the preparation of anacetrapib. In one another embodiment, the present invention provides a process of preparation of 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4,-(trifluoromethyl)-l,l,-biphenyl of Formula II, comprising the steps of: .JW i) dehydrating 2-(5-bromo-2-fluoro-4-methoxyphenyl)propan-2-ol of Formula VII in presence of dehydrating agent to give l-bromo-4-fluoro-2-methoxy-5-(prop-l-en-2-yl)benzene of Formula VIII; OH Br F^' F-^O' Formula VII Formula VIII ii) hydrogenating l-bromo-4-fluoro-2-methoxy-5-(prop-l-en-2-yl)benzene of Formula VIII in presence of palladium catalyst to give crude mixture comprising of desired compound, l-bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX and undesired side compound, 2-fluoro-l-isopropyl-4-methoxybenzene of Formula X; -Ixx" o* Formula VIII Formula IX Formula X iii) reacting crude mixture of step ii) with brominating agent to convert undesired compound, to desired compound, l-bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX; *^GC ; and Formula IX Formula X Formula IX . iv) converting compound of Formula IX to compound of Formula II. In still another embodiment, the dehydrating agent is an acid selected from the group comprising of mesyl chloride, sulphuric acid, phosphoric acid, hot aluminium X ££ -^1 ~ £*©£•£ S-fa 12 oxide, aluminium phosphate and the like. Preferably the dehydrating agent used is mesyl chloride. In still another embodiment, the compound of Formula IX can be converted to 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4,-(trifluoromethyl)«l,r-biphenyl of Formula II by any of the convention methods, or by the process comprising the steps of: i) treating l-bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX with triisopropyl borate in presence of base to give (4-fluoro-5-isopropyl-2- methoxyphenyl)boronic acid of Formula XI; Formula IX ii) reacting (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid of Formula XI with (2-chloro-5-(trifluoromethyl)phenyl)methanol of Formula XII in presence of base to give (4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-[l,r-biphenyl]-2-yl)methanol of Formula XIII; HO. F ^ O' Formula XI cr F^C Formula XII r ^ o' Formula XIII iii) chlorinating (4'"fluoro-5,-isopropyl-2,-methoxy-4-(trifluoromethyl)-[l>r-biphenyl]-2-yl)methanol of Formula XIII with thionyl chloride to give 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4,-(trifluoromethyl)-lsr-biphenyl of Formula II; -a. £& ~ ?5 X £>&■%% 13 Formula XIII F >^ O* Formula II ; and iv) optionally crystallizing 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-l,r-biphenyl of Formula II to give pure compound of Formula II. In preferred embodiment, the base used in step i) and ii) is selected from the group comprising of butyl lithium, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, dimethyl amino pyridine, triethyl amine, diisopropyl ethyl amine and the like. In another preferred embodiment, 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-l,r-biphenyl of Formula II prepared as per the process of the present invention can be used for the synthesis of Anacetrapib of Formula I by any of the conventional methods. F In another embodiment, the present invention provides a process of conversion of compound of Formula II to Anacetrapib of Formula I, wherein said process comprises the steps of: Z 1 —*!>S - £>mi% ~ »> iT 14 a) condensation of (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4- methyloxazolidin-2-one of Formula H with 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-l,r-biphenyl of Formula II in presence of base to give compound of Formula I; Formula H Formula I In further embodiment, the compound of Formula H can be procured from commercial source or can be prepared by any of the conventional methods. In one another embodiment, the Anacetrapib is characterized by purity above 97.0% and preferably above 99.0% and more preferably above 99.5%. In one another embodiment, the Anacetrapib is characterized by particle size distribution wherein, dgo is 0.1 (am to 200(^m. r In a preferred embodiment, the Anacetrapib is characterized by particle size distribution wherein, d9o is 2.0 ^m to 150^im. In further embodiment, the present invention provides a pharmaceutical composition comprising Anacetrapib and at least one pharmaceutical acceptable excipients, wherein said Anacetrapib is prepared by utilizing compound of Formula II which is prepared as per the process of the present invention. 15 The present invention is explained below by way of examples. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention. EXAMPLES: Preparation of 2'-(chloromethyI)-4-fluoro-5-isopropyI-2-methoxy-4'- (trifluoromethyl)-l,r-biphenyl of Formula II: EXAMPLE 1.0 Preparation of 2-bromo-5-fluorophenol of Formula IV: To 50% H2SO4 solution (2250.0 ml) added 300.0g of 2-bromo-5-fluoroaniline of Formula III. Heated the reaction mass to 70°C for 3h, and then cooled to 0°C to -5°C. Added NaNCh (1.2 mole equivalent) solution slowly at temperature between -5°C to 0°C. Stirred at 0°C for 2.0 h. Quenched the reaction mass by 50.0 % H2SO4 solution at temperature 120°C. Stirred at 120°C for 6.0 h and cooled the reaction mass to 20°C to 25°C. Extracted the material with methylene dichloride (MDC) followed by washing of MDC layer with DM water. Distilled out MDC Layer under vacuum to get the compound of Formula IV. Yield= 96.0 % ^ EXAMPLE 2.0 Preparation of l-bromo-4-fluoro-2-metboxybenzene of Formula V: To the acetone (5.3 V) was added compound of Formula IV (285.0 g) & K2CO3 (2.5 mole eq). Added Dimethyl Sulphate (1.2 mole eq.) slowly within 1.5 hrs. Stirred the reaction mass at 40°C for 12.0 h. Filtered the reaction mass and distilled the acetone under vacuum. Charged MDC and water to the compound so obtained. Separated the layer and washed the organic layer with sodium hydroxide solution. Washed the organic layer with DM water twice. Distilled out the organic layer under vacuum to get the compound V. Yield= 322.4 g EXAMPLE 3.0 K-S <£ *£ -en - £*@i*s i*S : S F 16 Preparation of l-(5-bromo-2-fluoro-4-methoxyphenyl)ethan-l-one of Formula VI: To the MDC (5V) added A1C13 (3.0 mole equivalent) at 0°C. Charged compound of Formula V (320.0 g) followed by slow solution of acetic anhydride (1.2 mole equivalent) at 0°C. Stirred the reaction at 0°C for 2h. Quenched the reaction mass with cold water and separated the layers and washed the organic layer with NaHCCb solution. Distilled out the MDC layer to get the compound VI. Crystallized the compound VI thus obtained by using Hexane. Yield= 67.0 % EXAMPLE 4.0 Preparation of 2-(5-bromo-2-fluoro-4-methoxyphenyl)propan-2-ol of Formula VII: Added methyl magnesium chloride (2.0 mole equivalent) and Compound VI (256.0 g) in tetrahydrofuran (THF) at 0°C. Stirred the reaction mass at 0°C for 2.0 h. Adjusted the pH to 2-3 by using 2N HC1 at temperature of 0-15°C. Charged ethyl acetate and separated the layers. Washed the organic layer with NaHC03 solution. Distilled out the organic layer to get the compound of Formula VII. Crystallized the Compound VII with Hexane. Yield= 84.0 % EXAMPLE 5.0 Preparation of l-bromo-4-fluoro-2-methoxy-5-(prop-l-en-2-yl)benzene of Formula VIII: To the MDC (10.V) added Compound VII (228 g) at -5°C to 0°C. Added triethylamine (4.38 mole eq.) drop wise at -5°C to 0°C. Added mesyl chloride (2.4 eq) drop wise at -5°C to 0°C. Stirred the reaction mass at 25°C for 12.0 h. Charged DM water to the reaction mass. Separated the layers and distilled out the MDC under vacuum. Charged DM water and IPE (Isopropyl ether) to the compound and separated the layers. Distilled out IPE layer under vacuum to get the compound. Distilled out the compound under vacuum at 140-150°C to get the pure compound VIII. Yield= 84.0 % EXAMPLE 6.0 Preparation of crude mixture of l-bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX and 2-fluoro-l-isopropyI-4-methoxybenzene of Formula X: To the methanol (5.0 V) was added compound of Formula VIII (170.0 g), Palladium carbon (10.0 %) and sodium bicarbonate (0.5 mole equivalent) under hydrogen pressure 10.0 kg. Stirred the reaction at 40°C for 3.0 h. Filtered off the reaction mass and distilled out the methanol under vacuum. Charged DM water and IPE to the compound. Separated the layers and distilled out the IPE layer under vacuum to get the crude mixture containing compound of Formula IX and X. Yield=129.0g EXAMPLE 7.0 Preparation of l-bromo-4-fluoro-5-isopropyl-2-methoxybenzene of Formula IX: Charged crude mixture containing compound of Formula IX and X as obtained from above step (148.0 g) and added acetonitrile (5.0V) and NBS (1.55 mole eq) under stirring at 40°C for 3-4 h. Distilled out the acetonitrile under vacuum. Added IPE and DM water to the compound. Separated the layers and distilled out IPE layer under vacuum to get the compound IX, Yield=176.0g EXAMPLE 8.0 Preparation of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid of Formula XI: Charged Compound IX (150.0 g) in THF (3V) and Toluene (3.5V) and added triisopropyl borate (2.0 mole equivalent) at 25°C. Cooled to -80°C. Added n-BuLi (1.85 mole equivalent) drop wise at temperature -70°C under nitrogen. Stirred at - 70°C for 2.5 h and adjusted the pH (4-3.5) by using 3M H2SO4. Added toluene and separated the layers. Washed the organic layer with KOH solution. Adjusted the pH of KOH layer to 2-3 by H2SO4 solution. Filtered the reaction mass to get the compound XL Yield=76.0 %. EXAMPLE 9.0 Preparation of l-chloro-2-(chloromethyl)-4-(trifluoromethyl)benzene of Formula XV: Formula XIV Formula XV To 4-chlorobenzotrifluoride (Compound XIV) (250.0 g) was added paraformaldehyde (1.3 mole equivalent) at -5°C to 0°C. Added chlorosulphonic acid (1.15 mole equivalent) slowly to the above solution. Stirred the reaction mass at 25-30°C for 36-40 h. Separated the layers and added potassium carbonate to the organic layer. Stirred and filtered the solution to get the compound XV. Yield=93.63% EXAMPLE 10.0 Preparation of 2-chloro-5-(trifluoromethyl)benzyI acetate of Formula XVI: F3CXX.c. ;3C,0^or O Formula XV Formula XVI Charged Acetic Acid (5.0 mole equivalent), sodium acetate (1.5 mole eq) and heated the reaction mass to 120°C. Added Compound of Formula XV (285.0 g) and heated the reaction mass at 140°C for 16-18h. Distilled out the acetic acid followed i by addition of DM water to the reaction mass and separated the layers to get the compound XVI. Yield=90.35 % EXAMPLE 11.0 Preparation of (2-chloro-5-(trifluoromethyl)phenyl)methanol of Formula XII: F3CXX,

Documents

Application Documents

# Name Date
1 201711005050-Other Patent Document-130217.pdf 2017-02-14
1 201711005050-RELEVANT DOCUMENTS [25-09-2023(online)].pdf 2023-09-25
2 201711005050-IntimationOfGrant22-02-2022.pdf 2022-02-22
2 201711005050-Other Patent Document-130217-.pdf 2017-02-14
3 201711005050-PatentCertificate22-02-2022.pdf 2022-02-22
3 201711005050-Form 5-130217.pdf 2017-02-14
4 201711005050-Form 2(Title Page)-130217.pdf 2017-02-14
4 201711005050-FER.pdf 2021-10-17
5 201711005050-Form 1-130217.pdf 2017-02-14
5 201711005050-CLAIMS [31-07-2021(online)].pdf 2021-07-31
6 abstract.jpg 2017-04-15
6 201711005050-COMPLETE SPECIFICATION [31-07-2021(online)].pdf 2021-07-31
7 201711005050-Power of Attorney-310717.pdf 2017-08-11
7 201711005050-CORRESPONDENCE [31-07-2021(online)].pdf 2021-07-31
8 201711005050-OTHERS-310717.pdf 2017-08-11
8 201711005050-FER_SER_REPLY [31-07-2021(online)].pdf 2021-07-31
9 201711005050-Other Patent Document-310717.pdf 2017-08-11
9 201711005050-OTHERS [31-07-2021(online)].pdf 2021-07-31
10 201711005050-FORM 18 [22-12-2020(online)].pdf 2020-12-22
10 201711005050-Form 5-310717.pdf 2017-08-11
11 201711005050-Form 2(Title Page)-310717.pdf 2017-08-11
11 201711005050-Form 5-220118 -.pdf 2018-02-21
12 201711005050-Form 1-310717.pdf 2017-08-11
12 201711005050-Power of Attorney-190218.pdf 2018-02-20
13 201711005050-Form 1-220118.pdf 2018-02-13
13 201711005050-Form 6-310717.pdf 2017-08-28
14 201711005050-Form 2(Title Page)-220118.pdf 2018-01-29
14 201711005050-Other Patent Document-220118.pdf 2018-01-29
15 201711005050-Form 3-220118.pdf 2018-01-29
16 201711005050-Form 2(Title Page)-220118.pdf 2018-01-29
16 201711005050-Other Patent Document-220118.pdf 2018-01-29
17 201711005050-Form 6-310717.pdf 2017-08-28
17 201711005050-Form 1-220118.pdf 2018-02-13
18 201711005050-Power of Attorney-190218.pdf 2018-02-20
18 201711005050-Form 1-310717.pdf 2017-08-11
19 201711005050-Form 2(Title Page)-310717.pdf 2017-08-11
19 201711005050-Form 5-220118 -.pdf 2018-02-21
20 201711005050-FORM 18 [22-12-2020(online)].pdf 2020-12-22
20 201711005050-Form 5-310717.pdf 2017-08-11
21 201711005050-Other Patent Document-310717.pdf 2017-08-11
21 201711005050-OTHERS [31-07-2021(online)].pdf 2021-07-31
22 201711005050-FER_SER_REPLY [31-07-2021(online)].pdf 2021-07-31
22 201711005050-OTHERS-310717.pdf 2017-08-11
23 201711005050-CORRESPONDENCE [31-07-2021(online)].pdf 2021-07-31
23 201711005050-Power of Attorney-310717.pdf 2017-08-11
24 201711005050-COMPLETE SPECIFICATION [31-07-2021(online)].pdf 2021-07-31
24 abstract.jpg 2017-04-15
25 201711005050-Form 1-130217.pdf 2017-02-14
25 201711005050-CLAIMS [31-07-2021(online)].pdf 2021-07-31
26 201711005050-Form 2(Title Page)-130217.pdf 2017-02-14
26 201711005050-FER.pdf 2021-10-17
27 201711005050-PatentCertificate22-02-2022.pdf 2022-02-22
27 201711005050-Form 5-130217.pdf 2017-02-14
28 201711005050-Other Patent Document-130217-.pdf 2017-02-14
28 201711005050-IntimationOfGrant22-02-2022.pdf 2022-02-22
29 201711005050-RELEVANT DOCUMENTS [25-09-2023(online)].pdf 2023-09-25
29 201711005050-Other Patent Document-130217.pdf 2017-02-14

Search Strategy

1 searchstrategyE_02-02-2021.pdf

ERegister / Renewals

3rd: 13 May 2022

From 13/02/2019 - To 13/02/2020

4th: 13 May 2022

From 13/02/2020 - To 13/02/2021

5th: 13 May 2022

From 13/02/2021 - To 13/02/2022

6th: 13 May 2022

From 13/02/2022 - To 13/02/2023

7th: 18 Jan 2023

From 13/02/2023 - To 13/02/2024

8th: 26 Dec 2023

From 13/02/2024 - To 13/02/2025

9th: 09 Dec 2024

From 13/02/2025 - To 13/02/2026