60/456,270, filed on March 20,2003, the contents of which are incorporated herein by reference.

Each of the applications and patents cited in this text, as well as each document or reference cited in each of the applications and patents (including during the prosecution of each issued patent;"application cited documents"), and each of the U. S. and foreign applications or patents corresponding to and/or claiming priority from any of these applications and patents, and each of the documents cited or referenced in each of the application cited documents, are hereby expressly incorporated herein by reference. More generally, documents or references are cited in this text, either in a Reference List before the claims, or in the text itself; and, each of these documents or references ("herein-cited references"), as well as each document or reference cited in each of the herein-cited references (including any manufacturer's specifications, instructions, etc. ), is hereby expressly incorporated herein by reference. Documents incorporated by reference into this text may be employed in the practice of the invention.

FIELD OF THE INVENTION The present invention provides for, inter alia, a process for the preparation of thieno-benzodiazepine derivatives. A general reaction scheme is outlined in Scheme 1. R R4 /CN R7-CH2CHo + H2C + HSR' t CN Izs) S 3 NC NC R3 Rs/N R R R R R3 zu R3 NR1R2 R R 8 R'NH2 NR'R' R'-YC. NHR R'N=C R4 N Rs R6 I R6 R8 R3 f s R N S R R6 H Scheme 1. General reaction scheme for the synthesis of thieno-benzodiazepine derivatives.

BACKGROUND OF THE INVENTION Antipsychotic drugs are known for treating serious mental conditions such as psychosis, including but not limited to schizophrenioa and schizophreniform illnesses. These drugs include thieno-benzodiazepines having the following structural nucleus: Several analogs of the above structure with various substituents at positions 1,2, 5-8, and 10, have shown interesting biological activity. A large number of patents have issued of which United Kingdom Patent Nos. 980 853 ; 1 291 684 ; 1 380 242; 1 380 243; 1 380 244 and United States Patents Nos. 2,983, 992; 3,102, 116 ; 3,109, 843; 3,136, 815; 3,474, 099; 3,654, 286; 3,749, 786 and 3,842, 082, which are incorporated herein by reference, represent only a very small proportion. In addition, British Patent 1 533 235 discloses 7-fluoro-2-methyl-10- (4-methyl-l- piperazinyl) -4H-thieno [2, 3-bl [1, 5] -benzo diazepine, which was developed to the stage of being clinically administered to psychiatric patients suffering from schizophrenia. US 6,008, 216 discloses, 2-methyl-4- OH- thieno [2,3-b] [1, 5] benzodiazepine, which is currently being marketed in the US as an antipsychotic agent for the treatment of schizophrenia and bipolar disorder.

A general reaction scheme is required to synthesize thieno-benzodiazepine derivatives in which analogs with varying substituents can be prepared in a convenient manner and subjected to biological evaluations. Several thieno- benzodiazepine derivatives are disclosed in British Patent 1 533 235 and 980 853, and are incorporated herein by reference. The reaction scheme should involve a general approach to synthesize thieno-benzodiazepine derivatives which are compatible with the various substituents. Additionally, the general approach should allow thieno-benzodiazepine derivatives to be prepared by combinatorial methods.

For a general review on combinatorial synthesis, see E. M. Gorden et al., J. Med.

Che7n., 37; 1385-1401 (1994); R. A. Houghten, Curr. Biol., 4; 564-567 (1994); R.

Frank, J. Biotechnol., 41; 259-72 (1995); and P. M. Doyle, J. Chem. Technol Biotech7lol., 64; 317-324 (1995).

SUMMARY OF THE INVENTION This invention relates to a general multistep process for preparing thieno- benzodiazepine derivatives of formula I In particular, this invention provides for a process in which phenylamino-thiophene carbonitrile derivatives of formula II undergo protection, cyclization, derivatization, and deprotection to afford thieno-benzodiazepine derivatives of formula I. This invention also provides for a method of preparing the phenylamino-thiophene carbonitrile derivatives of formula II by preparing precursor thienophene derivatives and coupling said derivatives to nitrobenzene derivatives. Also provided are the products prepared from the process described herein.

DETAILED DESCRIPTION This invention provides for a process for the preparation of thieno- benzodiazepine derivatives of the formula I wherein

Rl and R2 are optionally substituted hydrocarbyl or cyclohydrocarbyl, or R and R ? together with the adjacent nitrogen atom form an optionally substituted 5-to 8-membered ring whereby one or more carbon atoms can be optionally substituted by a heteroatom selected from the group consisting of O, S, and N, R3, R4, R5, and R6 are independently hydrogen, optionally substituted alkyl, alkenyl, cycloalkyl, alkoxy, amino, alkythio, aryl, sulfonamide, or halogen selected from the group consisting ofF, Cl, Br, and I, or hydroxy, or two adjacent substituents, i. e., R4 and R5, form an optionally substituted 5-to 8- membered polycyclic group, R7 is optionally substituted alkyl, alkenyl, alkynyl, alkanoyl, nitro, phenyl, or halogen selected from the group consisting ofF, Cl, Br, and I ; or a salt thereof, said process comprising (1) protecting the compound of formula II or a salt thereof, with a protecting group of formula R8_y wherein R8 is a nitrogen protecting group, and Y is a leaving group, to produce the first intermediate compound of formula III or a salt thereof, (2) cyclizing the first intermediate compound with a catalyst to produce a

second intermediate compound of formula IV or a salt thereof, (3) contacting an amine of the formula HNRIR2 to the second intermediate compound to obtain a third intermediate compound of formula V or a salt thereof, wherein Rl and R2 are defined above, and (4) deprotecting the third intermediate compound to obtain a compound of formula I.

A general reaction scheme for this sequence of reactions is shown in Scheme 1.

As used throughout this application, the term"hydrocarbyl"denotes a monovalent, straight chain or branched chain aliphatic substituent consisting solely of carbon and hydrogen. The hydrocarbyl group can be saturated or unsaturated in one or more positions. Among the hydrocarbyl groups are included alkyl groups containing from 1 to 30 carbon atoms and alkenyl and alkynyl groups containing 'from 2 to 30 carbon atoms. The alkyl, alkenyl, or alkynyl groups can be unsubstituted or substituted, preferably from 1 to 7, on one or more, positions with lower alkyl or from 1 to 3 positions with lower alkoxy, hydroxy, oxo, acetalized oxo, lower alkanoyl, aroyl, lower alkanoyloxy, or aroyloxy groups.

The term"cyclohydrocarbyl"denotes a monovalent, mono-or poly- cycloaliphatic or aryl substituent consisting solely of carbon and hydrogen. The

cycloaliphatic group can be saturated or unsaturated in one or more positions. The term"cyclohydrocarbyl"also includes polycycloaliphatic substituents, i. e. , a cycloalkyl group condensed with one or more saturated or unsaturated cycloalkyl groups. The cyclohydrocarbyl is unsubstituted or substituted in one or more positions with lower alkyl, lower alkoxy, hydroxy, oxo, acetalized oxo, lower alkanoyl, aroyl, lower alkanoyloxy, or aroyloxy.

The terms"polycycle"or"polycyclic group"refer to two or more cyclic rings (e. g. , cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles) in which two or more carbons are common to two adjoining rings, e. g. , the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged"rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyl, selenoethers, ketones, aldehydes, or esters, or the like.

A nitrogen protecting group is defined as any protecting group which can prevent the nitrogen atom from undergoing a derivatization reaction. Derivatization reactions include alkylation, acylation, displacement, substitution, elimination, oxidation, and the like. Suitable protecting groups for amines as well as suitable conditions for protecting and deprotecting amines are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein, which are incorporated herein by reference.

Preferred protecting groups include optionally substituted methyl or benzyl carbamates, benzyl, or benzoyl.

Deprotecting is the process of removing the protecting group. Different protecting groups require different reaction conditions for their removal. Various reaction conditions for effecting deprotection are described in T. W. Greene and G.

M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein, which are herein incorporated by reference.

Leaving groups include halogens consisting ofF, Cl, Br, and I, substituted sulphonyloxy such as tosyloxy, methanesulphonyloxy, or trifluoromethanesulphonyloxy, substituted benzoyloxy with one or more electron- withdrawing substituents such as nitro or chloro, trifluoroacetoxy, or

diarylphosphoryloxy, for example diphenyl-phosphonyloxyhalogens, azide and azo derivatives, nitro, amines substituted with two groups selected from loweralkyl or aromatic hydrocarbon and loweralkyl quaternary derivatives thereof, and pyridyl.

A catalyst aids in improving the rate of a reaction. Suitable catalysts include Lewis acids such as bismuth chloride, copper chloride, iron chloride, lead chloride, stannous chloride, and zinc chloride.

The concept of phase transfer catalysis has been reported in the literature for a number of reactions. In a biphasic solvent system, the phase transfer catalyst serves to carry the base from the aqueous layer into the organic layer. Several phase transfer catalysts and conditions are listed in A. W. Herriott et al., J Am. Chem.

Soc., 97; 2345-2349 (1975); E. V. Dehmlow, Angew. Chem., Internat. Edit., 13; 170-179 (1974); C. M. Starks, J. Am. Chem. Soc., 93; 195-199 (1971); and J. Dock, Synthesis, 441-456 (1973).

The phase transfer catalyst is preferably a quaternary salt or a crown ether.

More preferably, the phase transfer catalyst is selected from one of the following: butylpyridinium bromide, tetrabutylammonium bisulphate, benzyltriethylammonium bromide, benzyltrietliylammonium chloride, benzyltrimethylammonium chloride, benzyltrimethylammonium fluoride, hexadecyltriethylammonium bromide, hexadecyltriethylphosphonium bromide, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, dibutyldimethylammonium chloride, decyltriethylammonium bromide, hexadecyltributylphosphonium bromide, heptylpyridinium bromide, hexadecyltributylphosphonium chloride, hexyltriethylammonium bromide, dodecylpyridinium bromide, dodecyltriethylammonium bromide, methyltrinonylammonium chloride, methyltriphenylammonium bromide, tetrabutylammonium bromide or bisulphate, tetrabutylammonium chloride, tetrabutylammonium cyanide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylphosphonium chloride, tricaprylylmethylammonium chloride, tetraethylammonium chloride, tetramethylammonium bromide, trioctylethylphosphonium bromide, trioctylmethylammonium chloride, trioctylpropylammonium chloride, tetrapropylammonium bromide, tetraphenylarsonium chloride, tetraphenylphosphonium bromide,

tetraphenylphosphonium chloride, benzyltrimethylammonium hydroxide, 18-crown- 6, dibenzo-18-crown-6, dicyclohexyl-18-crown-6 or mixtures thereof.

Step (1) of this process involves the protection of the phenylamino-thiophene carbonitrile derivative, formula II, with a nitrogen protecting group of formula R8-Y.

Various reagents for effecting the protection are described in T. W. Greene and G.

M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991. The preferred protecting groups include those where R8 is selected from the group consisting of alkyl or benzyl carbamates, or optionally substituted benzyl or benzoyl, and Y is selected from the group consisting ofF, Cl, Br, I, and N3. A most preferred protecting group is benzyl bromide, that is, when R8 is benzyl and Y is Br. This reaction is carried out in the presence of a base, a phase transfer catalyst, and an organic solvent. Suitable bases include, but are not limited, to carbonates such as sodium carbonate or potassium carbonate, hydroxides such as sodium hydroxide or potassium hydroxide, and hydrides such as sodium hydride.

One preferred base is potassium hydroxide. One preferred phase transfer catalyst is benzyltriethylammonium chloride. Suitable organic solvents include, but are not limited to, polar aprotic solvents such as dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide, or N, N dimethylformamide. One preferred organic solvent is dichloromethane.

Step (2) of this process involves the cyclization of a compound of formula III with a catalyst. Suitable catalysts include, but are not limited to, Lewis acids such as bismuth chloride, copper chloride, iron chloride, lead chloride, stannous chloride, and zinc chloride. In a preferred embodiment of the present invention, the catalyst is a hydrated form of stannous chloride, including, for example, stannous chloride dihydrate and stannous chloride pentahydrate. The reaction is carried out in the presence of acidic conditions and polar organic solvents at elevated temperatures.

Acidic conditions include the use of, but are not limited to, aqueous hydrochloric acid, trifluoroacetic acid, sulfuric acid, nitric acid, perchloric acid, and hydrofluoric acid. Aqueous hydrochloric acid (18 %) is preferred. Polar organic solvents, or aqueous mixtures of polar organic solvents, include, but are not limited to, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, ethyl acetate, acetone, and acetonitrile. Aqueous 95 % ethanol is preferred. Elevated temperatures, for

example up to 100 °C, can be used to hasten the reaction and a preferred temperature range for carrying out the reaction is from 78 °C to 100 °C.

Step (3) of this process involves the reaction between the second intermediate compound of formula IV and an amine of formula HNRIR2. In an embodiment of the present invention, Rl and R2 together with the adjacent nitrogen atom form an optionally substituted ring selected from the group consisting of pyrrolidine, piperidine, morpholine, piperazine, pyrrole, pyridine, pyrazine, thiazole, oxazole, isoxazole, and imidazole. Preferably, R1 and R2 together with the adjacent nitrogen atom form an optionally substituted piperazine ring. More preferably, the optionally substituted ring is 1-methylpiperazione. The reaction can be carried out using an excess of amine at elevated temperatures. In the case where the amine is a liquid material, the amine can serve as the reaction medium. If the amine is a solid material, then suitable organic solvents such as toluene, anisole, or chlorobenzene can be used as a reaction medium. If desired, elevated temperatures, for example up to 200 °C, can be used to hasten the reaction and a preferred temperature range for carrying out the reaction is from 80 °C to 120 °C.

Step (4) of this process involves deprotecting the compound of formula VIII to produce the target compound of formula I. Various reaction conditions for effecting deprotection are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991. The progress of the reaction can be monitored by thin-layer chromatography, or high- performance liquid chromatography (HPLC). In a preferred embodiment of the present invention, when the protecting group is a compound of the formula R8-Y, and R is benzyl, and Y is bromine, then the preferred reaction condition for performing the deprotection reaction includes the use of a mixture of a mineral acid and an organic acid at elevated temperatures. Examples of mineral acids include, but are not limited to hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acid. Examples of organic acids include, but are not limited to formic, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicylic, o-acetoxybenzoic, nicotinic or isonicotinic acid, or organic sulphonic acids for example methane, sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2 sulphonic acid. The preferred mineral acid is hydrochloric acid and the preferred organic acid is acetic acid. Elevated temperatures, for example up to

100 °C, can be used to hasten the reaction and a preferred temperature range for carrying out the reaction is from 60 °C to 70 °C. It will be appreciated that the compound of formula I may be isolated per se or may be converted to a salt using conventional methods.

The term pharmaceutically acceptable salt is defined as non-toxic addition salts with acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, formic, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicylic, o-acetoxybenzoic, nicotinic or isonicotinic acid, or organic sulphonic acids for example methane, sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2 sulphonic acid.

Apart from pharmaceutically acceptable acid addition salts, other salts are also included within the scope of acid addition salts such as, for example, those with picric or oxalic acid; they may serve as intermediates in the purification of the compounds or in the preparation of other, for example, pharmaceutically acceptable, acid addition salts, or are useful for identification, characterization or purification of the bases.

A further aspect of the present invention provides for a process wherein a compound of formula VI or a salt thereof, is prepared from sulfur, malononitrile, and a compound of formula VIII R--CHz--CHO VIII wherein R7 is defined above (see Scheme 1). This process is conducted at reduced temperatures and contains a mixture of a base and an organic solvent. The base can be selected from the group consisting of, but not limited to, n-butyl lithium, sodium hydroxide, sodium hydride, sodium amide, triethylamine, and potassium carbonate.

The preferred base is triethylamine. The organic solvent is preferably a polar aprotic solvent selected from the group consisting of, but not limited to, acetonitrile, dimethyl sulfoxide, and N, N-dimethylformamide. The most preferred solvent is N, N-dimethylformamide. The reaction mixture is held at a reduced temperature during the addition of the base, preferably the reaction mixture is held between 0 and 10 °C, more preferably between 5 and 10 °C. After the addition of the base, the reaction temperature is allowed to reach 16 to 20 °C, preferably to 18 °C.

Another aspect of the present invention provides for a process wherein the compound of formula II, or a salt thereof, is prepared by coupling a compound of formula VI or a salt thereof, wherein R7 is defined above, with a compound of formula VII wherein R3, R4, R5, and R6 are defined above, and X is a leaving group (see Scheme 1). The thienophene starting materials used in this process of the invention are either known compounds, see, for example, Chem. Berichte, 99; 94-100 (1966), J.

Am. Chem. Soc., 68; 2232 (1946) and Dutch Patent Application No. 66 04742, or can be prepared by conventional techniques from known compounds. The leaving group X is preferably a halogen atom selected from the group consisting ofF, Cl, Br, and I, and more preferably is F. The reaction is performed in a polar aprotic solvent in the presence of a phase transfer catalyst. Preferred polar aprotic solvents

are acetonitrile, dimethyl sulfoxide, and N, N-dimethylformamide. The more preferred polar aprotic solvent is N, N-dimethylformamide. The more preferred phase transfer catalyst is a quaternary salt. In one aspect, the preferred phase transfer catalyst is benzyltriethylammonium chloride.

The following examples are provided to illustrate, but not limit, the claimed invention.

EXAMPLES EXAMPLE 1: 2-Amino-5-methylthiophene-3-carbonitrile A mixture of sulfur (21.8 g), propionaldehyde (47.3 g) and N, N- dimethylformamide (135 mL) was placed in a 500 mL flask and cooled in an ice bath. Triethylamine (57.6 mL) was added dropwise over 30 minutes to the stirred reaction mixture and the temperature was maintained between 5-10 °C. The pot was warmed to 18 °C, and stirred at 182 °C over 50 minutes. A solution of malononitrile (45 g) in N, N-dimethylformamide (90 mL) was added dropwise at a temperature of 182 °C. After the addition was complete, the mixture was stirred at 18i2 °C for 45 minutes. The mixture was poured onto ice/water (1.2 L) while stirring. A solid precipitate was collected by filtration, washed thoroughly with water, and dried overnight in vacuo at 70 °C, (or fan-dried at 45 °C) to give 2- amino-5-methylthiophene-3-carbonitrile (58.5 g). Yield: 62.3%.

EXAMPLE 2 : 2- (2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred mixture of potassium hydroxide (59.1 g), benzyltriethylammonium chloride (1.2 g) and N, N-dimethylformamide (70 mL) in a 250 mL flask was added dropwise a solution of 2-amino-5-methylthiophene-3- carbonitrile (73 g) and 1-fluoro-2-nitrobenzene (74.5 g) in N, N dimethylformamide (175 mL) while maintaining the temperature between at 20-25 °C with an ice/salt bath. After the addition was complete, the mixture was stirred between 20-25 °C for 5 hours, then poured onto ice/water (400 mL), and extracted with dichloromethane (480 mL). The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane (240 mLx2). Water (400 mL) was added to the combined organic extracts, and the pH was adjusted between 8-9 with 2N

hydrochloric acid. The organic layer was separated and washed with water (400 mL). The solvent was removed under reduced pressure to afford a residue that was crystallized from ethanol (300 mL) to give 2- (2-nitroanilino)-5-methylthiophene-3- carbonitrile (82.2 g). Yield: 60% EXAMPLE 3 : 2-[2-Nitrophenyl-(N-benzyl) amino]-5-methylthiophene-3- carbonitrile Amixture of 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (100 g), dichloromethane (915 mL), benzyl bromide (69. 8 g), and benzyltriethylammonium chloride (BTEA) (1.8 g) was stirred in a 2L flask. A solution of 50% potassium hydroxide (200 g) was added slowly at a temperature below 25 °C. After the addition was complete, the mixture was stirred between 25-30 °C for 5 hours. Water (300g) was added, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (200 mLx2), and the organic layers were combined, washed with water (400 mLx2), and removed under reduced pressure. Toluene (110 mL) was added to the residue, the mixture was heated, and activated carbon was added. The mixture was filtered, allowed to cool, and crystallization occurred (6 g). The crystals were filtrated, washed with ethanol, and dried at 45 °C to give the 2- [2-nitrophenyl- (N-benzyl) amino] -5-methylthiophene-3-carbonitrile. Yield: 55-60%.

EXAMPLE 4: 4-Amino-2-methyl-10-benzyl-thieno [2, 3-b] [1, 5] benzodiazepine, hydrochloride A mixture of 2-[2-nitrophenyl-(N-benzyl) amino] -5-methylthiophene-3- carbonitrile (150 g) and 95% ethanol (720 mL) was stirred in a 2 L flask. A solution of stannous chloride dihydrate (304.5 g) in 18% hydrochloric acid (720 mL) was added. The mixture was stirred under reflux for 5 hours, then cooled to 20-25 °C.

The solid was filtrated, washed with ethanol (1200 mL) and water (200mlx2), then dried at 45 °C to give 4-amino-2-methyl-10-benzyl-thieno [2,3- b] [1, 5] benzodiazepine, hydrochloride (122. 4 g). Yield: 80%.

EXAMPLE 5 : 2-Methyl-10-benzyl-4- (4-methyl-1-piperazinyl)-thieno [2,3- b] [1, 5] benzodiazepine 4-Amino-2-methyl-10-benzyl-thieno [2,3-b] [1, 5] benzodiazepine hydrochloride (100 g) and N-methylpiperazine (500 mL) were stirred in a 1000 mL flask, and heated for 4 hours at 1202 °C. Piperazine was removed under reduced pressure and the residue was poured onto ice/water (2 Kg) with stirring. The precipitate was separated by filtration, washed with water (2 Lx2), and dried at 45 °C. The crude product was mixed with acetone (500 mL) in a 1000 mL flask, heated to reflux, and then filtrated. The filtrate was concentrated to approximately 100 mL, and cooled to crystallize. The crystals were filtrated, washed with acetone (50 mLx2), and dried at 45 °C to give the title product (50.9 g). Yield: 45%.

EXAMPLE 6: 2-Methyl-4- (4-methyl-1-piperazinyl)-lOH-thieno [2, 3-b] [1,5] benzodiazepine 2-Methyl-10-benzyl-4- (4-methyl-1-piperazinyl)-thieno [2,3-b] [1,5] benzodiazepine (15 g), acetic acid (15 mL), and 36% hydrochloric acid (80 mL) were mixed in a 250 mL flask and heated slowly to 60 °C over 2-2. 5 hours. The reaction mixture was maintained at this temperature for 4 hours. A sample of the reaction mixture was removed for HPLC analysis. The reaction was stopped after the content of the starting material was less than 15% or the content of product was greater than 70%.

A solution of 28% ammonia was added dropwise to the cooled mixture until the pH reached 6, and the mixture was stirred for 30 minutes. The solid was separated by filtration, and washed with dichloromethane (50 mL). Water (300mL) was added to the solid, the mixture was heated, and 28% ammonia was added dropwise until the pH was about 6.5. The mixture was extracted with dichloromethane (50 mlx2). An aqueous solution of 28% ammonia was added to the aqueous layer until the pH reached 9. The solid was filtrated, washed with water, and dried at 45 °C to give the crude product. Crystallization from ethyl acetate (70 mL) afforded a material which was recrystallized from 95% ethanol (70 mL) to give the title compound. Yield: 20- 30%.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art that certain changes and modifications can be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention, which is delineated by the appended claims.