GUPTA GOPESH (IN)
SONI CHANDRESH (IN)
GUPTA HANUMAN PRASAD (IN)
KUMAR KAPIL (IN)
ANAND RAJDEEP (IN)
| US2085736A | 1937-07-06 | |||
| CN102951996A | 2013-03-06 |
E. T. MCBEE ET AL: "Some Dihalo-(trifluoromethy1)-benzenes", J.A.C.S. 1951 73(8), 1 January 1951 (1951-01-01), pages 3932 - 3934, XP055245974, Retrieved from the Internet
SANDRA BARTOLI ET AL: "Electrophilic Bromination of meta-Substituted Anilines with N-Bromosuccinimide: Regioselectivity and Solvent Effect", SYNTHESIS, vol. 2009, no. 08, 16 March 2009 (2009-03-16), STUTTGART, DE., pages 1305 - 1308, XP055245795, ISSN: 0039-7881, DOI: 10.1055/s-0028-1088016
INA EHLERS ET AL: "Modular Synthesis of Triazole-Containing Triaryl [alpha]-Helix Mimetics", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2011, no. 13, 18 March 2011 (2011-03-18), pages 2474 - 2490, XP055025283, ISSN: 1434-193X, DOI: 10.1002/ejoc.201001531
AVINASH T. SHINDE ET AL: "A Practical Iodination of Aromatic Compounds by Using Iodine and Iodic Acid", SYNTHETIC COMMUNICATIONS, vol. 40, no. 23, 3 November 2010 (2010-11-03), PHILADELPHIA, PA; US, pages 3506 - 3513, XP055246169, ISSN: 0039-7911, DOI: 10.1080/00397910903457332
| We claim: 1. A process for the preparation of compound of Formula I, comprising; Formula I wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Y is selected from X and -NRiR2; Ri and R2, independent of each other, are selected from the group consisting of hydrogen, Ci_4 alkyl and -COR; R is Ci_4 alkyl, a) halogenating a compound of Formula II in the presence of a halogenating agent to obtaina reaction mixture containing a compound of Formula I, Formula II wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Y is selected from X and -NRiR2; Ri and R2, independent of each other, are selected from the group consisting of hydrogen, C1-4 alkyl and -COR; R is Ci_4 alkyl; b) isolating the compound of Formula I from the reaction mixture, wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile, and alcohol solvent, or mixture thereof. 2. A process for the preparation of compound of Formula la, comprising; a) halogenating a compound of Formula Ila in the presence of a halogenating agent to obtain a compound of Formula lib, Formula Ila Formula lib wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Ri and R2, independent of each other, are selected from the group consisting of hydrogen, C1-4 alkyl and -COR; R is Ci_4 alkyl; b) converting the compound of Formula lib into a compound of Formula la in a reaction mixture, and Formula la X 2 is selected from fluorine, chlorine and bromine; X 1 , and X have the same meaning as described earlier, c) isolating the compound of Formula la from the reaction mixture, wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile and alcohol solvent or mixture thereof. 3. The process of claim 1 or 2, wherein the halogenating agent is selected from the group consisting of brominating agent, fluorinating agent, chlorinating agent, and iodinating agent. 4. The process of claim 3, wherein the brominating agent is selected from bromine or ΗΒΓ/Η202. 5. The process of claim 1 or 2, wherein the alcohol solvent may be selected from methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, n- pentanol and 2-pentanol or mixture thereof. 6. The process of claim 1 or 2, wherein the halogenation takes place at temperature in the range of 15°C to 100°C. 7. The process of claim 6, wherein the halogenation takes place at temperature in the range of 25°C to 50°C. 8. The process of claim 1 or 2, wherein the compounds of Formula I and/or Formula la are isolated by filtration, layer separation, decantation, evaporation, concentration, crystallization and distillation or mixture thereof. |
BENZOTRIHALIDE
FIELD OF THE INVENTION The present invention provides a process for the preparation of compound of Formula I.
BACKGROUND OF THE INVENTION
The substituted benzotrihalide of Formula I finds a wide range of purposes, mainly for organic reagents, pharmaceutical intermediates and agrochemical intermediates;
Formula I wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Y is selected from X and -NRiR 2 ; Ri and R 2 , independent of each other, are selected from the group consisting of hydrogen, Ci_ 4 alkyl and -COR; R is CM alkyl.
The Chinese patent Publication No. 102951996 describes a following process for the synthesis of 2-bromo-5-fluorobenzotrifluoride:
The present inventors observed that nitration, as mentioned in above scheme, results in numerous isomeric nitro compounds, thereby resulting in need of numerous purification steps and high yield loss. While working for present invention, the present inventors observed that the present process is economic, simple and has an advantage of high conversion, selectivity, yield and low effluent load.
OBJECTS OF THE INVENTION
An object of the present invention is to provide a process for the preparation of compound of Formula I:
Formula I
Another object of the present invention is to provide a process for the preparation of compound of Formula la:
Formula la SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for the preparation of compound of Formula I, comprising;
Formula I
wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Y is selected from X and -NRiR 2 ; Ri and R 2 , independent of each other, are selected from the group consisting of hydrogen, Ci_ 4 alkyl and -COR; R is Ci_ 4 alkyl; a) halogenating a compound of Formula II in the presence of a halogenating agent to obtain a reaction mixture containing a compound of Formula I,
Formula II
X and Y have the same meaning as described earlier; b) isolating the compound of Formula I from the reaction mixture, wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile, and alcohol solvent or mixture thereof.
In another aspect, the present invention provides a process for the preparation of compound of Formula la, comprising; a) halogenating a compound of Formula Ila in the presence of a halogenating agent to obtain a compound of Formula lib,
Formula Ila Formula lib
X , independent of each other, is selected from fluorine, chlorine, bromine and iodine; Ri, R 2 and X have the same meaning as described earlier b) converting the compound of Formula lib into a compound of Formula la in a reaction mixture, and
Formula la
X 2 is selected from fluorine, chlorine and bromine; X 1 , and X have the same meaning as described earlier, c) isolating the compound of Formula la from the reaction mixture, wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile, and alcohol solvent or mixture thereof.
DESCRIPTION OF THE INVENTION
In an aspect, the present invention provides a process for the preparation of compound of Formula I, comprising;
Formula I wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Y is selected from X and -NRiR 2 ; Ri and R 2 , independent of each other, are selected from the group consisting of hydrogen, Ci_ 4 alkyl and -COR; R is Ci_ 4 alkyl, a) halogenating a compound of Formula II in the presence of a halogenating agent to obtain a reaction mixture containing a compound of Formula I,
Formula II
X and Y have the same meaning as described earlier; b) isolating the compound of Formula I from the reaction mixture, wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile, alcohol solvent and mixture thereof.
In another aspect, the present invention provides a process for the preparation of compound of Formula la, comprising; halogenating a compound of Formula Ila in the presence of a halogenating agent to obtain a compound of Formula lib,
Formula Ila Formula lib a) X , independent of each other, areis selected from the group consisting of fluorine, chlorine and bromine; Ri,R 2 and X have the same meaning as described earlier, b) converting the compound of Formula lib into a compound of Formula la in a reaction mixture, and
Formula la
2 1
X is selected from fluorine, chlorine and bromine; X , and X have the same meaning as described earlier, c) isolating the compound of Formula la from the reaction mixture, wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile, and alcohol solvent or mixture thereof.
The compound of Formula II and Formula Ila may be prepared by any method known in the art or the method disclosed in present art. The halogenating agent is selected from the group consisting of brominating agent, fluorinating agent, chlorinating agent, and iodinating agent. The brominating agent is selected from bromine or HBr/H 2 0 2. The alcohol solvent may be selected from the group consisting of methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, n- pentanol, 2-pentanol and mixture thereof. The halogenation may take place at a temperature of about 15°C to about 100°C, for example, at about 25°C to about 50°C. The halogenation of Formula II and/or Formula Ila may take about 1.0 hour to about 24 hours, for example, about 12 hours.
The compound of Formula I and/or Formula la may be isolated by filtration, layer separation, decantation, evaporation, concentration, crystallization and distillation or mixture thereof. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1
Preparation of N-(4-Bromo-3-Trifluoromethylphenyl)Acetamide
N-(3-Trifluoromethyl-phenyl)-acetamide (10 g), acetic acid (50 g) and hydrobromic acid (47%, 8.5 g) were taken together in a reaction vessel and temperature was maintained at 25°C. The hydrogen peroxide (50%, 3.32 g) was added to the reaction mixture and temperature was maintained at 25°C. The reaction assembly inertized by nitrogen gas and mixture was further stirred for 30 minutes. The progress of the reaction was monitored by Gas Chromatography. The sodium bisulphite (30% aqueous solution) was added to the mixture and mixture was extracted twice with methylene dichloride. The organic layer was recovered to obtain the title compound.
Yield (%): 90
Example 2
Preparation of 4-Bromo-3-trifluoromethyl-phenylamine
Charged 4-Bromo-3-(Trifluoromethyl phenyl) acetamide (lOOgm., 0.35 moles) and 14.7% aqueous solution of hydrochloric acid (224gm., 0.88 moles) at RT to a reaction flask. The temperature of the reaction mixture is raised to 90°C and maintained for 5-6 hrs. Monitor the reaction by HPLC. After complete conversion, the reaction mixture is cooled to 60-65°C. Charged 40% aqueous solution of NaOH (142gm., 1.42moles) to neutralize the reaction mass. The organic phase was separated and title compound was isolated.
Yield (%): 94% Example 3
Preparation of 2-bromo-5-iodo benzotrifluoride
Charged 35% aqueous hydrochloric acid solution (47gm., 0.44 moles), water (95gm) and 5-amino-2-bromo-benzotrifluoride (20gm., O.083moles) in the reaction flask. Cooled reaction mass to 5°C and charged chilled 15% aqueous solution of sodium nitrite (40gm., 0.09moles) in small portions maintaining 0°C. After complete addition of sodium nitrite, stirred the reaction mass at 0°C to 5°C for 1.0 hour to get diazonium salt solution. Then charged an aqueous solution of potassium iodide (14gm., 0.08 moles) and further heated the reaction mixture to reflux point using a reflux condenser until no more gas is evolved then allowed to cool and stand undisturbed until the heavy organic layer has settled. The title compound was isolated.
Yield (%): 75%
Example 4
Preparation of 2-bromo-5-chloro benzotrifluoride
The diazonium salt solution was prepared as exemplified in example 3. The cold diazonium salt solution was poured into the well stirred and cooled mixture of CuCl (8.9gm., 0.091moles) in concentrated hydrochloric acid (46gm., 0.44moles). The cold mixture is allowed to warm up to room temperature and stirring is continued for 2 to 3 hours. Further heat the reaction mixture to 60 - 70°C to complete the reaction and title compound was isolated.
Yield (%): 65% Example 5
Preparation of 2,5-dibromo benzotrifluoride
Prepared diazonium salt solution as given in example 3, then cold diazonium salt solution is poured rapidly into the well stirred and cooled mixture of CuBr (13gm., 0.091moles) in concentrated hydro bromic acid(71gm., 0.44moles). The cold mixture is allowed to warm up to room temperature and stirred for 2 to 3 hours. The reaction mixture was heated to 60 - 70°C to obtain title compound.
Yield (%): 63%
Example 6
Preparation of l-Bromo-4-fluoro-2-trifluoromethyl-benzene
5-Amino-2-bromo-benzotrifluoride (48gm., 0.20 moles) was taken in autoclave reactor and reaction mass was cooled to - 10°C. The anhydrous hydrofluoric acid (104gm., 5.2moles) was added to the reaction mass and the temperature of the reaction mass was maintained at - 5°C. The sodium nitrite (15gm., 0.22moles) was added to the reaction mixture in small portions. After complete addition of sodium nitrite, the reaction mass was stirred at - 5°C to 0°C for 1.0 hour. The reaction mass was heated to 125°C and the temperature was maintained for 30 minutes. The reaction mixture is poured into cooled water and the title product was isolated. Yield (%): 80%