Field of the Invention
This invention relates to a process for the preparation of substituted amino benzophenones and more particularly 2-.aminobenzophenones of the following general
formula

(Formula Removed)
Background of the Invention
The 2-aminobenzophenones are important industrial chemicals as intermediates leading to numerous CNS drugs of the 1,4-benzodiazepine class which are used clinically for example Valium, Librium, Nitrazepam, Flurazepam Oxazepam, Alprozalam amd Triazolam. The key factor in synthesis of these substances is the construction of 2-aminobenzophenones and suitably substituted 2-aminobenzophenone moiety.
Reference may be made to L. H Sternbach, R. I. Fryer, W. Metlesics, G. Sack, A. Stempel, J. Ors. Chem., 1962, 27, 3781 wherein 2-aminobenzophenone leads to numerous CNS drugs of the benzodiazepine group.
Another reference may be made to Coombs, R. V., Danna, R. P., Denzer, M., Hardtmann. G.E.. Huesi. B.. Koletar, G., Ott, H., Jukniewicz, E. J. Med. Chem. 1973. 16, 1237 wherein chlorodiazepoxide, proquazone, amfemac amd nitrazepam, which are drugs in the market are prepared from 2-aminobenzophnones
Still another reference may be made to Walesh, D. A. Synthesis, 1980, 677 wherein the key factor in the synthesis of these drug molecule is the construction of a suitably substituted 2-aminobenzophenone moiety is described.
The compounds of formula 1 of most interest in the invention bear either a chloro or bromo radical at the 5-position of the benzophenone molecule. Such a compound is 2-amino-5-chloro-benzophenone.
The methods hitherto employed for the manufacture of ortho alkylamino benzophenones almost invariably use 2-amino benzophenones as the starting material. In one of the known methods the 2-amino group is protected by reaction with benzene sulfonyl chloride or p-toluene sulfonyl chloride (PTS) and the sulfonamide obtained is alkylated with an alkylating agent. Removal of the protective group from the protected 2- alkylamino group by hydrolysis gives 2-alkylamino benzophenones. This method may be represented by the following reaction scheme 1.
(Figure Removed)

Scheme 1
The above method suffers from two major drawbacks, i.e. it involves isolation of several intermediates, which is both cumbersome and expensive, and the yield of the final product is very poor.
Reference may be made to Sternbach, L. H., Reeder, E., Keller, O., and Metlesics, W. J Org Chem, 1961, 26, 4480 wherein synthesis of 2-aminobenzophenones from substituted anilines under high temperature condition is described.
Another reference may be made to Walker, G. N. J. Ore. Chem, 1962, 27, 1929 wherein expensive palladium is used for the reduction of 2,1-benzisoxazoles.
Still another reference may be made to Nine, R. Y., Madan, P. B. and Sternbach, L. H. J. Heterocyclic Chem., 1974, 11, 107 wherein functional groups susceptable to reduction cannot be tolerated.
Another reference may be made to Konwar P., Boruah, R. C., Sandhu, J. S., Chem. Ind, 1989, 191, wherein aluminium triiodide has been used to promote the cleavage of 2,1-benzisoxazoles to give 2-aminobenzophenones under reflux conditions.
Still another reference may be made to Fan, X., Zhang, Y., Tetrhedron Lett., 2002, 43, 7001, wherein treatment of expensive samarium diiodide with 3-aryl-2,l-benzisoxazoles undergo reductive cleavage of the N—O bond leading to 2-aminobenzophenones in good yields upon protonation (Scheme 2).
(Figure Removed)
Scheme 2
Still another reference may be made to Boruah, R. C., Sandhu, J. S., Thyasarajan, G. J. Heterocyclic Chem., 1979, 16, 1087 wherein halogen enters in the carbocyclic ring, by cleaving 2,1-benzisoxazoles with thionyl chloride and the corresponding 1,4-benzodiazapines are pharmacologically less active due to a chloro substituent in the 9-position, references on this may be made to Sternbach, J. C. E. In The Benzodiazepines; Garattini, S., Mussini, S., Randall, L P.. Eds., Raven Press: New York, 1973: p-15.
Another known method employs direct alkylation of 2-aminobenzophenones by methyl ^-toluene sulphonate. In this case the yields and purity of the product are far from satisfactory. Moreover, catalytic hydrogenation of 2,1-benzisoxazoles involves expensive
platinum or supported palladium. Thionylchloride catalysed cleavage of 2,1-benzisoxazoles gave 2-aminobenzophenone with the entry of halogen atom in to the carbocyclic ring and the corresponding 1,4-benzodiazepines are pharmologically less active due to a chloro substituent in the 9 position.
Summary of the Invention
Accordingly, the present invention provides a process for the preparation of substituted amino benzophenones of the general formula (I):
(Formula Removed)
Wherein R1 is Cl, Br or NO2; R2 is H or CH3 and R3 is H or OH group and the said process comprising reacting a compound of the formula (II),
(Formula Removed)

Wherein R1, R2 and R3 is as defined above, with a mixture of ferric chloride, ammonia solution and iodine in a solvent selected from a group consisting of tetrahydrofuran, dichloromethane, hexane, and stirring the reaction mixture at a temperature ranging between 20 to 45°C temperature for a period in range of 2-3 h followed by distilling of THF adding water and dilute HC1 to make the solution material, drying using a agent selected from magnesium and sodium, particularly anhydrous sodium sulphate to obtain the compound of formula 1.
In an embodiment of the present invention, the distillation of organic solvent is effected at a
temperature range of 25-55 °C .
In another embodiment of the present invention, the product obtained from the reaction is
pure and the yield is 73-81%.
In further embodiment of the present invention, the catalyst ferric chloride and iodine used is
in 1 mol%.
Detailed Description
The present method appears to be superior as well as novel for the production of 2-
aminobenzophenones from readily available ferric chloride, ammonia solution and iodine
which shows high selectivity and conversions are also high.
According to the present investigation a process for the manufacture of substituted aminobenzophenones of general formula (I) is developed, which comprises reaction a compound of the following formula.
(Formula Removed)
In which R1 is Cl, Br, NO2 CH3CO; R2 is H, CH3 and R3 is H, OH group.
The process according to the invention uses substituted anthranils (II) as the starting material and these may readily be prepared by reaction of aromatic nitro compounds optionally substituted with Cl & Br atoms, with benzyl cyanide in strongly basic alcoholic (e.g. methanolic) solution. Reduction of the anthranils (II) may be effected by the use of ferric chloride, ammonia solution and iodine in THF. The above sequence of reactions may be schematically represented as follows (Scheme 3), in which R1 is Cl, Br, NO2 CH3CO; R2 is H, CH3 and R3 is H, OH group.


(Figure Removed)

Scheme 3
In an embodiment to the present invention, the products can be prepared in high yields.
In another embodiment of the present invention, the process avoids the need for isolation of intermediates, thereby avoiding any losses during such isolation.
Still in another embodiment of the process, the catalysts used are very cheap and the method is easy to handle.
In yet another embodiment of the process, the organic solvent used may be such as dichloromethane and tetrahydrofuran. The sodium thiosulphate solution used may be in the range of 5%.
The compounds (I) are very important, and are particularly useful in the manufacture of a number of pharmaceutical products including tranquilizer "Diazepam" and related benzodiazepine derivatives.
The details of the method disclosed in this invention have been described in the following specific which are provided to illustrate the invention only and these should not be construed to limit the scope of the present investigation.
EXAMPLeE 1 a) Preparation of 2-amino-5-chlorobenzophenone.
A mixture of anhydrous ferric chloride (0.168 g, 1 mmol) and iodine (0.25 g, 1 mmol) in dry THF (20 ml) was stirred at room temperature. The mixture was made basic by adding 2 ml of ammonia solution. To the resulting red suspension was added 3-phenyl-5-chloro anthranil (115 mg, 0.5 mmol). The mixture was stirred at room temperature for two hours and on completion (vide TLC), THF was distilled in a
rotary evaporator and water (30 ml) was added to it. Then dilute HC1 was added to make the solution neutral and extracted with dichloromethane (2x25 ml). The combined organic extracts were washed subsequently with saturated solution of Na2S2Os (15 ml), Na2CO3 (15 ml), finally with sodium chloride (15 ml) and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure and purification of the residue through column chromatography (eluent, hexane:dichloromethane = 1:1) afforded the corresponding 2-aminobenzophenone. The yield of the dry 2-amino-5-chloro benzophenone was 81% (95 mg). The product obtained as a bright yellow needles mp. 98-100 °C. The product gave a single spot on TLC (silica gel plates with benzene as mobile phase)
EXAMPLE 2
b) Preparation of 2-amino-5-bromobenzophenone.
A mixture of anhydrous ferric chloride (0.168 g, 1 mmol) and iodine (0.25 g, 1 mmol) in dry THF (20 ml) was stirred at room temperature. The mixture was made basic by adding 2 ml of ammonia solution. To the resulting red suspension was added 3-phenyl-5-bromo anthranil (138 mg, 0.5 mmol). The mixture was stirred at room temperature for 2.5 h and on completion (vide TLC), THF was distilled in a rotary evaporator and water (30 ml) was added followed by dilute HC1 to make it neutral and extracted with dichloromethane (2x25 ml). The combined organic extracts were washed subsequently with saturated Na2S2O3 solution (15 ml), Na2CO3 (15 ml), sodium chloride (15 ml) and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure and purification of the residue through column chromatography (eluent, hexane:dichloromethane = 1:1) afforded the corresponding 2-aminobenzophenone in 80% yield (110 mg). The product obtained as a bright yellow needles mp. 110-111 °C. The product gave a single spot on TLC (silica gel plates with benzene as mobile phase)
EXAMPLE 3
c) Preparation of 2-amino-4-methyl-5-chlorobenzophenone.
A mixture of anhydrous ferric chloride (0.168 g, 1 mmol) and iodine (0.25 g, 1 mmol) in dry THF (20 ml) was stirred at room temperature. The mixture was made basic by adding 2 ml of ammonia solution. To the resulting red suspension was added 3-
phenyl-4-methyl-5-chloro anthranil (122 mg, 0.5 mmol). The mixture was stirred at room temperature for 2.5 h and on completion (vide TLC), THF was distilled in a rotary evaporator and water (30 ml) was added followed by dilute HC1 to make it neutral and extracted with dichloromethane (2x25 ml). The combined organic extracts were washed subsequently with saturated solution of Na2S2O3 (15 ml), Na2CO3 (15 ml), sodium chloride (15 ml) and dried over anhydrous Na2SO4 After removal of the solvent under reduced pressure and purification of the residue through column chromatography (eluent, hexane:dichloromethane = 1:1) afforded the corresponding 2-aminobenzophenone in 78% yield (96 mg). The product obtained as a yellow crystals mp. 122-124 °C. The product gave a single spot on TLC (silica gel plates with benzene as mobile phase)
EXAMPLE 4
d) Preparation of 2-amino-5-nitrobenzophenone.
A mixture of anhydrous ferric chloride (0.168 g, 1 mmol) and iodine (0.25 g, 1 mmol) in dry THF (20 ml) was stirred at room temperature. The mixture was made basic by adding 2 ml of ammonia solution. To the resulting red suspension was added 3-phenyl-5-nitro anthranil (120 mg, 0.5 mmol). The mixture was stirred at room temperature for 3 h and on completion (vide TLC), THF was distilled in a rotary evaporator and water (30 ml) was added followed by dilute HC1 to make it solution neutral and extracted with dichloromethane (2x25 ml). The combined organic extracts were washed subsequently with saturated solution of Na2S2O3 (15 ml), Na2CO3 (15 ml), NaCl (15 ml) and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure and purification of the residue through column chromatography (eluent, hexane:dichloromethane =1:1) afforded the corresponding 2-aminobenzophenone in 75% yield (90 mg). The product obtained as a yellow needles mp. 152-154 °C. The product gave a single spot on TLC (silica gel plates with benzene as mobile phase)
EXAMPLE 5
e) Preparation of l-(p-hydroxyphenyl)-2-amino-5-chloro-benzophenone.
A mixture of anhydrous ferric chloride (0.168 g, 1 mmol) and iodine (0.25 g, 1 mmol) in dry THF (20 ml) was stirred at room temperature. The mixture was made basic by
adding 2 ml of ammonia solution. To the resulting red suspension was added 3-(p-hydroxyphenyl)-5-chloro anthranil (122 mg, 0.5 mmol). The mixture was stirred at room temperature for 2.5 h and on completion (vide TLC), THF was distilled in a rotary evaporator and water (30 ml) was added followed by dilute HC1 to make it neutral and extracted with dichloromethane (2x25 ml). The combined organic extracts were washed subsequently with saturated solution of Na2S2O3 (15 ml), Na2CO3 (15 ml), NaCl (15 ml) and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure and purification of the residue through column chromatography (eluent, hexane: dichloromethane = 1:1) afforded the corresponding 2-aminobenzophenone in 75% yield (90 mg). The product obtained as a light yellow crystals mp. 172-174 °C. The product gave a single spot on TLC (silica gel plates with benzene as mobile phase)

We claim:-

1.

A process for preparation of substituted amino benzophenones of the general formula (I):
(Formula Removed)

Wherein R1 is selected from Cl, Br, NO2; R2 is H or CH3 and R3 is H or OH group and the said process comprising reacting a compound of the formula (II),

(Formula Removed)

2.
3.

Wherein R1, R2 and R3 is as defined above, with a mixture of ferric chloride,
ammonia solution and iodine in a solvent selected from a group consisting of
tetrahydrofuran, dichloromethane, hexane and stirring the reaction mixture at a
temperature ranging between 20 to 45°C for a period in range of 2-3 h followed by
distillation of solvent, adding water and dilute HC1 to make the solution neutral to
obtain the compound of formula 1
A process as claimed in any preceding claim, wherein the distillation of organic
solvent is effected at a temperature in the range of 25-55 °C.
A process as claimed in claim 1 to 6, the product obtained from the reaction is pure
and the yield is 73-81%.

4. A process as claimed in claim 1 to 7, wherein the catalyst ferric chloride and iodine
used is in 1 mol%.
5. An improved process for preparation of substituted aminobenzophenones
substantially as hereinbefore described with reference to the examples.