SUMMARY OF THE INVENTION This invention provides a process for preparing a compound of the formula wherein: R, R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and halo ; comprising: (a) reacting a compound of formula 1 (i) with an amine of the formula NHR5R6, wherein R5 is hydrogen and R6 is Ci-Ce alkyl, aryl or heteroaryl ; R5 is C1-C6 alkyl, aryl or heteroaryl and R6 is hydrogen; R5 and R6 are independently

selected from the group consisting of Ci-Ce alkyl and aryl ; or R5 and R6, together with the nitrogen to which they are attached, form a ring comprising 4 to 6 carbon atoms or comprising 3 to 5 carbon atoms and one hetero moiety selected from the group consisting of-O-and-NR9-, wherein R9 is H, C1-C6 alkyl or phenyl ; in the presence of a palladium catalyst and carbon monoxide to obtain an amide of formula 2: (ii) with an alcohol of the formula R10OH, wherein Rio is C1-C6 lower alkyl or C3-C6 cycloalkyl, in the presence of a palladium catalyst and carbon monoxide to obtain the ester of formula 2A followed by reacting the compound of 2A with an amine of formula NHR5R6 to obtain the amide of formula 2; (b) reacting the amide of formula 2 with an iodo-substituted compound of formula 3 wherein Ri, R2, R3 and R4 are as defined above and R7 is Cl or Br, in the presence of a strong base to obtain a compound of formula 4 (c) cyclizing a compound of formula 4 with a reagent of the formula R8MgL, or when none of R, R1, R2, R3 and R4 are bromo, with a reagent of the formula R8Li, wherein R8 is Ci-Cg alkyl, aryl or heteroaryl and L is Br or Cl ; provided that prior to cyclization, compounds wherein R5 or R6 is hydrogen are reacted with a suitable N-protecting group.

This invention also claims the intermediate compound of formula 3, in particular a compound of formula 3 wherein R1 and R3 are hydrogen, R2 is chloro, and each of R4 and R7 are bromo, i. e., a

compound of formula 5: This invention also claims the intermediate compound of formula 4, in particular a compound of formula 4 wherein R1 and R3 are hydrogen, R2 is chloro, and each of R and R4 are bromo, i. e., a compound of formula 4A, or wherein R1, R2, R3 and R4 are hydrogen and R2 is chloro, i. e., a compound of formula 4B: Also claimed herein is a process for preparing a compound of formula 5 comprising: i) brominating 2-amino chlorobenzoic acid of formula 6 to obtain 2-amino-3-bromo-5-chlorobenzoic acid of formula 7 ii) iodonating the compound of formula 7 to obtain 2-iodo-3- bromo-5-chlorobenzoic acid of formula 8 iii) reducing the carboxylic acid of the halo-substituted benzoic acid of formula 8 to obtain the corresponding hydroxy-methyl compound of formula 9

iv) brominating the compound of formula 9.

Also claimed herein is a process for preparing a compound of formula 5A comprising : i) iodonating the compound of formula 7A to obtain 2-iodo-5-chlorobenzoic acid of formula 8A

ii) reducing the carboxylic acid of the halo-substituted benzoic acid of formula 8A to obtain the corresponding hydroxy-methyl compound of formula 9A

iii) brominating the compound of formula 9A.

Preferred compounds of formula I are those wherein R2 is halo.

Also preferred are compounds wherein R1 and R3 are each hydrogen.

Another group of preferred compounds is that wherein R, Ri, R3 and R4 are hydrogen and R2 is halo. Still another group of preferred compounds is that wherein Rl and R3 are each hydrogen and R and R2 are independently selected from the group consisting of halo. Yet another group of preferred compounds is that wherein R1 and R3 are each hydrogen and R, R2 and R4 are independently selected from the group consisting of halo. Halo is preferably Cl or Br.

DETAILED DESCRIPTION As used herein, the terms"alkyl"and"lower alkyl,"where not otherwise defined, mean straight or branched alkyl chains of 1 to 6 carbon atoms.

"Halo"refers to fluorine, chlorine, bromine or iodine radicals.

"Aryl"means phenyl, substituted phenyl wherein the substituents are 1 to 3 substituents independently selected from the group consisting of Ci to C6 alkyl and Ci to C6 alkoxy, benzyloxy or naphthyl.

"Heteroaryl"means a 5-or 6-membered aromatic ring comprising one or two nitrogen atoms, e. g., pyridyl, pyrimidyl, imidazolyl or pyrrolyl.

When R5 and R6, together with the nitrogen to which they are attached, form a ring comprising 4 to 6 carbon atoms, the rings so produced are exemplified by pyrrolidinyl, piperidinyl and perhydroazepine. When R5 and R6, together with the nitrogen to which they are attached, form a ring comprising 4 to 5 carbon atoms and a heteroatom, the rings so produced are exemplified by piperazinyl, N- methyl-piperazinyl, N-phenyl-piperazinyl and morpholinyl.

The compounds prepared by the process disclosed above are useful as intermediates in the procedures described in PCT/US96/19603 and U. S. 5,151,423 to obtain the desired compounds wherein the piperidinyl ring is N-substituted. Using those procedures, the compounds of the present invention are reacted with a substituted piperidine of the formula wherein L1 is a leaving group selected from the group consisting of Cl and Br, to obtain a compound of the formula

This compound is converted to the corresponding piperidylidene, the nitrogen is deprotected, and the compound is reduced to the piperidyl form. The piperidinyl nitrogen can then be reacted with a variety of compounds, e. g., an acyl compound such as an ester or acyl chloride to form the desired amide.

By using the intermediates prepared by the process of this invention, the desired tricyclic antihistamines and FPT inhibitors described above can be made by a seven-step process rather than the fifteen-step process disclosed in the art. The present process allows halo substitution at any of R1, R2, R3 and/or R4, while previously disclosed procedures were not operative for preparing compounds wherein R4 is halogen. Moreover, the present process, employing the iodo-substituted intermediate of formula 3, is regioselective, producing the compound of formula 4 in high yield ; without the iodo substituent, the reaction of step (b) produces undesirable mixtures of products, for example compounds wherein two compounds of formula 2 react in the presence of the strong base to produce a compound wherein the methyl group of one molecule joins to the carbonyl group of the other.

In step (a), the bromo-substituted pyridine of formula 1 is reacted with the amine NHR5R6 or with the alcohol of formula R10OH in the presence of a palladium catalyst, carbon monoxide (CO) and a base; when reacted with the alcohol, the product is then converted to an amide by reaction with an amine of the formula NHR5R6.

As defined above, the amines of formula NHR5R6 are exemplified by aniline, N-methylaniline, pyrrolidine, piperidine, perhydroazepine, piperazine, N-methyl-piperazine, N-phenyl-piperazine and morpholine.

Preferred amines are aniline and N-methylaniline, with aniline being most preferred. The amount of amine (NHR5R6) reacted ranges from 1 to 4 equivalents, and is preferably 1 to 1.5 equivalents.

Palladium catalysts are exemplified by PdX2/ligand at ratios of 1: 0.5 to 1: 3, preferably 1: 1 to 1: 2, at a range of 0.5 to 40 mol%, preferably 1 to 10 mol%, and most preferably 1 to 5 mol% ; Pd (PPh3) 4; (R11) 3P/Pd2 (dba) 3 ; and Pd/C, wherein X is OAc or Cl, ligand refers to P (Rll) 3 or a nitrogen-based ligand such as dipyridyl, 2-aminopyridine, 2-cyanopyridine, 2-dimethylaminopyridine, 1,10-phenanthroline, 2-

methoxypyridine or (S)- (-)-nicotine, and wherein Ac is acetyl, R11 is Ci to C6 alkyl or aryl, Ph is phenyl, and dba is dibenzylidene acetone.

Preferred catalysts are Pd (OAc) 2/dipyridyl, Pd (OAc) 2/P (R11) 3 and (PPh3) 2PdC) 2.

Suitable bases include, but are not limited to, C1 to C1o alkyl amines such as triethylamine (Et3N), t-butylamine and 1,8-diazabicyclo- [5, 4,0] undec-7-ene (DBU), and inorganic bases such as K2CO3, Na2CO3, Na2HP04 and NaOH. Preferred bases are K2CO3, DBU and Et3N, with 1,8-DBU being preferred for use with Pd (OAc) 2/dipyridyl and Et3N being preferred for use with (PPh3) 2PdCI2.

Suitable solvents are tetrahydrofuran (THF), dimethyl-formamide (DMF), acetonitrile (CH3CN) and toluene or a combination thereof.

CH3CN is preferred for reaction with an amine and a combination of CH3CN and toluene is preferred for reaction with an alcohol. The temperature range for the reaction is 35°C to 100°C, preferably about 55°C for reaction with the amine and preferably about 80°C for reaction with an alcohol. The reaction is carried out at a pressure of 5 psi to 500 psi, preferably 40 to 200 psi, and most preferably at 50 to 150 psi. The time for reaction ranges from 2 hours to 4 days, preferably 4 hours to 2 days, and most preferably 16 to 48 hours.

Conversion of the ester of formula 2A to the amide of formula 2 is accomplished by methods well known in the art, for example by reacting the ester directly with the amine or by using the conditions described by Basha et al in Tetrahedron Letters, (1977), p. 4171.

In step (b), the amide formed in step (a) is reacted with the iodo- substituted compound of formula 3 in a solvent such as THF, t-butyl methyl ether (t-BuOMe), diethyl ether (Et20), diglyme or a mixture thereof, preferably a mixture of THF and t-butyl methyl ether, in the presence of a strong base such as lithium diisopropylamide (LDA), lithium hexamethyidisilylamide or soium amide, preferably LDA. The concentration of the base ranges from 2.0 to 4.0 equivalents, preferably 2.0 to 2.2 equivalents. The iodo compound of formula 3 is reacted in a concentration range of 1.0 to 1.5 equivalents, preferably 1.1 equivalents.

The reaction is carried out in a temperature range of-78°C to-20°C, preferably-50°Cto-30°C.

In step (c), the product of step (b) is cyclized by treating with 1.0 to 3.0 equivalents, preferably 1.1 equivalents, of a reagent of the formula R8MgL, wherein R8 is C1-C6 alkyl such as iso-propyl ; aryl such as phenyl, 2,4,6-trimethylphenyl, 2-methylphenyl, 2-methoxy-phenyl, 2- methoxy-5-methylphenyl or 2,5-dimethoxyphenyl; or heteroaryl such as N-methyl-piperidyl and L is Br or Cl. Typical reagents of the formula R8MgL are isopropylmagnesium chloride, 2-mesitylmagnesium bromide, o-tolyl-magnesium bromide, 2-methoxy-phenylmagnesium bromide, 2-methoxy-5-methylphenylmagnesium bromide, 2,5-di- methoxyphenyl-magnesium bromide and N-methyl-piperidylmagnesium bromide. A preferred reagent of formula R8MgL is one wherein R8 is 2- methoxy-phenyl, e. g., 2-methoxyphenylmagnesium bromide. For compounds wherein none of R, R1, R2, R3 and R4 are bromo, the cyclization reagent can also be R8Li, wherein R8 is as defined above.

Preferred R8Li reagents are n-, sec-and tert-butyllithium, methyllithium and phenyllithium. Suitable solvents include t-BuOMe, Et20, THF and toluene, with THF being preferred. The temperature range for the reaction is-78°C to 25°C, preferably 0 to-40°C, and most preferably-25 to-15°C.

Before cyclization, a protecting step is necessary when one of R5 or R6 is hydrogen. A protecting group can be added either after step (a) or after step (b). A compound of formula 2 or 4 is suitably protected by methods well known in the art, using protecting groups well known in the art, for example by reacting with CH31 and a base such as NaNH2, LDA, butyl lithium, NaH, CaH2 or NaOH with a phase transfer cataylst, preferably NaH or NaOH with a phase transfer cataylst. Suitable phase transfer catalysts include C1 to C8 tertiary alkyl amine salts such as tetrabutylammonium bromide, tetrabutylammonium chloride or tetraoctylammonium bromide, benzyltriethylammonium chloride, trialkylsulfates, phosphorus salts and crown ethers. Base concentration ranges from 1 to 3 equivalents, preferably 1.5 equivalents, and phase transfer catalyst concentration ranges from 1.0 to 50 mol%, preferably 10 mol%. CH31 concentration ranges from 1.0 to 5 equivalents, preferably 1.5 equivalents. Suitable solvents for the methylation step are THF, DMF, N, N-dimethyl-acetamide and dimethylsulfoxide (DMSO),

with DMF being preferred. The temperature range for the reaction is -20°C to 20°C, preferably-10°C.

In the process for preparing the intermediate of formula 5, step (i) comprises brominating an amino, halo-substituted benzoic acid of formula 6 to obtain the corresponding 3-bromo-substituted benzoic acid of formula 7 by treating the compound of formula 6 with 1.0 to 2.0 equivalents, preferably 1.5 equivalent of bromine and an acid such as acetic acid (HOAc), HCI, CF3CO2H, CH3SO3H or CF3SO3H, preferably HOAc. The reaction is carried out at a temperature of 0 to 40°C, preferably 10 to 20°C.

In step (ii), the brominated benzoic acid of formula 7 is iodinated to obtain a compound of formula 8 by reacting with NaN02 or KN02, preferably NaN02, in an acid such as HCI, H2SO4, CH3SO3H or CF3CO2H, preferably H2SO4, and then treating the resultant product with Kl, Nal or tetrabutylammonium iodide, preferably Kl, in water. The nitrite concentration ranges from 1.0 to 4.0 equivalents, preferably 2.2 equivalents, and the iodide concentration ranges from 2 to 10 equivalents, preferably 5 to 7 equivalents. The reaction temperature ranges from-10 to 40°C, with a preferred range of-5 to 5°C.

In step (iii), the chloro-bromo-iodo benzoic acid of formula 8 is reduced to the corresponding alcohol by methods well known in the art.

Suitable reducing agents include, but are not limited to, BH3THF and B (OCH3) 3, BH3. (CH3) 2S (BMS) and B (OCH3) 3, NaBH4/SOC12, KBH4/SOC12, NaBH4/AIC13 and NaBH4/TiC4. Preferred reagents are BH3-THF or BMS in combination with B (OCH3) 3 or NaBH4 in combination with SOC12. As an example, the concentration of BMS ranges from 1.0 to 4.0 equivalents, preferaby 2.5 to 3.0 equivalents, and the concentration of B (OCH3) 3 ranges from 5 to 20 equivalents, preferably 10 to 16 equivalents. The temperature range for the reaction is from 0 to 30°C, preferably 15 to 25°C.

In step (iv) of the process for preparing the intermediate, the hydroxysubstituted compound is converted to the corresponding bromo- substituted compound by treatment with a brominating reagent such as SOBr2, PPh3 and Br2, or Br3P, preferably PPh3 and Br2. The amount of PPh3 and Br2 ranges from 1.0 to 2.0 equivalents, preferably being 1.1 to

1.4 equivalents. Suitable solvents are THF, CH3CN, EtCN and CH2CI2, with CH3CN being preferred. The temperature range for the reaction is 0 to 20°C, preferably 3 to 8°C.

In the process for preparing the intermediate of formula 5A, the benzoic acid of formula 7A is iodinated to obtain a compound of formula 8A, reduced to the alcohol of formula 9A, and brominated in the same manner as that described for the preparation of the compound of formula 5.

Starting materials of formula 1, NHR5R6, R8MgL and R8Li are known in the art or can readily be prepared by one skilled in the art.

Starting materials of formula 3 are known in the art or, where the starting material is of formula 5 or 5A, can be prepared by methods disclosed herein.

Following are specific examples of the procedures in the various steps of the process of this invention for preparing compounds of formula I and formula 3 ; although those skilled in the art will appreciate that similar procedures within the scope of the process of this invention can be used to prepare other compounds of formula I and formula 3.

Preparation 1 Step (i): To a solution of 200 g (1.05 mol) of 2-amino-5-chlorobenzoic acid in 3.4 L of HOAc at 15°C was added dropwise 184 g (1.15 mol) of Br2.

The mixture was stirred at 15°C for 4 hrs, quenched slowly into 8 L of water, and extracted with 2 X 2 L of t-BuOMe. The combined extract was washed with water, dried over MgS04 and concentrated. The crude product was treated with hot hexane, filtered and dried to give 210 g (80%) of 2-amino-3-bromo-5-chlorobenzoic acid as white solid. Mp.

225-228°C. 1H NMR (DMSO-d6) : b 7.70 (d, J = 2.6 Hz, 1 H), 7.69 (d, J = 2.6 Hz, 1 H), 6.8 (bs, 2 H). 13C NMR (DMSO-d6) : 8 168.16,147.06, 136.25,130.19,118.22,112.35,110.34. IR : 3480 (m), 3350 (m), 2920 (s), 1670 (s) cm-1. Analysis caicd. for C7H5BrCIN02 : C, 33.53, H, 2.00, N, 5.59; Found: C, 33.63, H, 2.12, N, 5.70.

Step (ii):

To 40 g (159 mmol) of the product of step (i) in 160 mL of conc.

H2SO4 at 0°C 24.1 g (350 mmol) of NaN02 was added slowly. The mixture was mechanically stirred at that temperature for 3 hrs and quenched into 1 L ice with strong agitation. The resulting solution was added slowly into 158 g (954 mmol) of KI in 2 L ice water and extracted with 2 X 1 L of EtOAc. The combined extract was washed with NaHS03, dried over MgS04 and concentrated. To the residue was added hexane and the precipitate was filtered and dried to give 50.4 g (87%) of 2-lodo- 3-bromo-5-chlorobenzoic acid as white solid. Mp. 174-176°C. 1H NMR (DMSO-d6) : 8 7.98 (d, J = 2.4 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H).

13C NMR (DMSO-d6): 8 168. 08,144.23,134.13,133.08,132.53, 126.91,99.88. IR : 3150 (m), 2920 (s), 1720 (s), 1650 (m) cm-1.

Step (iii):

To a 2 L flask with a mechanical stirrer, a thermometer, and an addition funnel, at r. t. were added sequentially 50 g (138 mmol) of the product of step (ii), 500 mL of THF, 229 mL (2.01 mol) of 2.0 M (CH30) 3B and 193 mL (386.4 mmol) of 2.0 M BH3' (CH3) 2S. The reaction mixture was stirred at r. t. for 18 hrs, quenched with 500 mL of CH30H and concentrated. The residue was dissolved with 1 L EtOAc, washed with brine, dried over MgS04, and concentrated to give 47 g (98%) of 2-iodo- 3-bromo-5-chlorobenzyl alcohol as a white solid.

Alternatively, the acid was reduced following a two-step, one-pot procedure: first, the acid was converted to its corresponding acid chloride and then treated with NaBH4. Mp. 99-101°C. 1H NMR (CDCI3) : 8 7. 55 (d, J = 2. 4 Hz, 1 H), 7.39 (d, J = 2. 4 Hz, 1 H), 4.61 (s, 2 H), 2.48 (bs, 1 H). 13C NMR (CDC13) : 8 146. 70,134.93,130.84,130.48,125.74, 100.45,69.99. IR : 3200 (s), 2920 (s) cm-1. Anal. calcd. for C7H7CIBrlO : C, 24.03, H, 2.00; Found: C, 24.35, H, 2.19.

Step (iv): To a 500 mL flask with a mechanical stirrer at 5°C were added 9.7 g (37 mmol) of PPh3, 100 mL CH3CN and 6 g (37 mmol) of Br2. The reaction mixture was stirred at 5°C for 1 hr, and 10 g (28.7 mmol) of the alcohol of step (iii) in 100 mL of CH3CN was added dropwise. The reaction mixture was allowed to warm to r. t., agitated for 1 hr, and concentrated. The residue was extracted with 2 X 400 mL CH2CI2, washed with brine, dried over MgS04 and concentrated. The phosphoxide was filtered after addition of hexane. The filtrate was passed through a pad of silca gel and concentrated to give 11.3 g (96%) of 2-iodo-3-bromo-5-chlorobenzylbromide as a white solid.

Alternatively, the alcohol was converted either to the bromide using SOBr2 in 90% yield, or to the corresponding chloride using SOC12. Mp. 75-77°C. 1 H NMR (CDC13) : 6 7.54 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 1 H), 4.60 (s, 2 H). 13C NMR (CDC13) : 8 143.94,134.66, 131.98,131.58,128. 15,104.71,39.52. IR : 2920 (s), 1540 (m) cm-1.

Preparation 2 To a 400 mL autoclave was charged 1.6 g (6.06 mmol) of 2,5- dibromo-3-methylpyridine, 0.45 g (0.64 mmol) of (PPh3) 2PdCI2, 30 mL of toluene/CH3CN (1: 1), 0.33 mL (95 mmol) of Et3N and 4 eq. of

CH30H. The autoclave was sealed, evacuated, flushed with nitrogen three times and charged with carbon monoxide to 80 psi. The autoclave was heated to 80°C for 16 hrs, cooled to r. t. and the excess carbon monoxide was evacuated under vacuum. The conversion was about 55% as determined by NMR. The contents of the autoclave were transferred into a flask for concentration. The residue was then purified on a silica gel column, eluting with hexane: EtOAc to give the ester as a white solid. M. p. 61-62°C. 1H NMR (CDC13) : 8 8.58 (d, J = 1.9 Hz, 1 H), 7.78 (d, J = 1.9 Hz, 1 H), 3.96 (s, 3H), 2.58 (s, 3H). 13C NMR (CDC13) : 5 165.82,147.94,145.17,142.20,137.63,123.56,52.74,19.96.

IR : 1715 cm-1.

Preparation 3 To a 4 L autoclave were added sequentially 250 g (949 mmol) of 2,5-dibromo-3-methylpyridine, 6.7 g (30 mmol) of Pd (OAc) 2,5.0 g (32 mmol) of dipyridyl, 10 L of toluene, 127 mL (1.1 mol) of aniline, and 277 mL (2.0 mol) of DBU. The autoclave was sealed, evacuated, purged with nitrogen, and charged with carbon monoxide to 80 psi. The reaction mixture was heated to 65°C for about 2 days with periodical refilling as necessary, and then cooled to r. t. The contents of the autoclave was vented under vacuum and flushed with nitrogen, then transferred to a 10 L flask with the aid of water and EtOAc. The mixture was concentrated and filtered through a pad of celite. The filtrate was extracted with 2 X 1 L of toluene. The combined extract was washed with brine, filtered and concentrated. The residue was recrystallized from hot i-PrOH and the precipitate was filtered, washed with M. L., and dried at 50°C to give 220 g (76%) of the amide as white solid.

Preparation 4 Step (i): To 75 g (394 mmol) of 2-amino-5-chlorobenzoic acid (90%) in 300 mL of conc. H2SO4 at 0°C was added slowly 60 g (870 mmol) of NaNO2. The mixture was mechanically stirred at that temperature for 5 hrs and at rt for 12 hrs, then quenched into 2 L ice with strong agitation.

The resulting solution was added slowly into 393 g (2.37 mol) of KI in 2 L ice water and extracted with 2 X 1 L of EtOAc. The combined extract was washed with NaHS03, dried over MgS04, concentrated and dried to give 124 g (>100%) of 2-iodo-5-chlorobenzoic acid as white solid.'H NMR (DMSO-d6) : 5 7.91 (d, J = 8.5 Hz, 1 H), 7.66 (d, J = 2.6 Hz, 1 H), 7.26 (dd, J = 8. 5,2.6,1H).

Step (ii): To a 2 L flask with a mechanical stirrer, a thermometer, and an addition funnel at r. t. were added sequentially 124 g (0.4 mol) of the product of Step (i), 700 mL of THF, 500 g (4.85 mol) of (CH30) 3B, and 560 mL (1.12 mol) of 2.0 M BH3-Me2S. The reaction mixture was stirred at r. t. for 18 hrs., quenched with 500 mL of CH30H and concentrated.

The residue was dissolved with 1 L EtOAc, washed with brine, dried over MgS04, and concentrated to give 121 g (>100%) of 2-iodo-5- chlorobenzyl alcohol as white solid.'H NMR (CDC13) : 8 7.64 (d, J = 8.3 Hz, 1 H), 7.41 (d, J = 2.5 Hz, 1 H), 6.93 (dd, J = 8. 3,2.5,1 H), 4.57 (s, 2H).

Step (iii):

To a 500 mL flask with a mechanical stirrer at 5°C were added 140 g (0.53 mol) of PPh3, 1100 mL CH3CN, and 85 g (0.53 mol) of Br2.

The reaction mixture was stirred at 5°C for 1 hr, and 121 g (about 0.4 mmol) of the alcohol of Step (ii) was added portionwise. The reaction mixture was allowed to warm to r. t., agitated for 1 hr, and concentrated.

The residue was extracted with 2 X 400 mL CH2CI2, washed with brine, dried over MgS04, and concentrated. The phosphoxide was filtered after addition of hexane. The filtrate was passed through a pad of silica gel and concentrated to give 2-iodo-5-chlorobenzylbromide as white solid (about 95% yield NMR (CDC13) : 8 7.68 (d, J = 8.5 Hz, 1 H), 7.38 (d, J = 2.5 Hz, 1 H), 6.90 (dd, J = 8.5,2.5 Hz, 1 H), 4.44 (s, 2H).

Alternatively, the alcohol was converted either to the bromide using SOBr2 in 90% yield, or to the corresponding chloride using SOC) 2.

Example 1 Step 1: To a 4 L autoclave were added sequentially 250 g (949 mmol) of 2,5-dibromo-3-methylpyridine, 21 g (30 mmol) of (Ph3P) 2PdCI2, 2 L of CH3CN, 100 mL (1.1 mol) of aniline, and 154 mL (1.5 mol) of Et3N. The autoclave was sealed, evacuated, purged with nitrogen and charged with carbon monoxide to 80 psi. The reaction mixture was heated to 60°C for about 3 days with periodical refilling as necessary, and then cooled to r. t. The contents of the autoclave was vented under vacuum, flushed with nitrogen and transferred to a 10 L flask with the aid of water and EtOAc. The mixtue was concentrated and filtered through a pad of celite. The filtrate was extracted with 2 X 1 L of EtOAc. The comibined extract was washed with brine, dried over MgS04, filtered and

concentrated. The residue was recrystallized from hot i-PrOH and the precipitate was filtered, washed with mother liquor and dried at 50°C to give 162 g (59%) of the amide as white solid. The solution yield was determined to be 71%. Mp. 103-104°C. 1H NMR (CDC13) : 810. 00 (bs, 1 H), 8.49 (d, J = 2.1 Hz, 1 H), 7.79 (d, J = 2.1 Hz, 1 H), 7.72 (d, J = 7.5 Hz, 2H), 7.37 (dd, J= 7. 5,7.4 Hz, 2 H), 7.13 (t, J = 7. 4 Hz, 1 H), 2.79 (s, 3 H).

13C NMR (CDCI3) : 8 162.79,146.34,145.21,143.29,137.91,137.72, 128.96,124.18,123.12,119.61,20.68. IR : 3320 (w), 2920 (s), 1700 (m) cm-1. Elemental analysis: calcd for C13H11BrN2O : C, 53.60, H, 3.78, N, 9.62; found: C, 53.50, H, 3.79, N, 9.51.

Step 2: To a solution of 0.98 mL (7 mmol) of i-Pr2NH in 5 mL t-BuOMe at -40°C was added 2.8 mL (7 mmol) of 2.5 M n-BuLi in hexanes. To a mixture of 1 g (3.44 mmol) of the product of Step 1 in 4 mL of THF and 10 mL of t-BuOMe at-50°C was added dropwise the LDA solution. The resulting purple solution was added dropwise at-40°C into 1.4 g (3.61 mmol) of the product of Preparation 1 in 10 mL of t-BuOMe. The mixture was allowed to warm to 0°C and was quenched with a solution of NH4CI. The precipitate was filtered, washed with brine and hexanes, and dried to give 1.47 g (69%) of the desired product. An analytical sample was purified on a silica gel column. Mp. 186-187°C. 1 H NMR (CDC13) : 510. 02 (s, 1 H), 8.54 (d, J = 2. 1 Hz, 1 H), 7.78 (d, J = 2. 1 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 2.4 Hz, 1 H), 7.39 (dd, J = 7.4, 8.4 Hz, 2H), 7.29 (d, J = 2. 4 Hzj 1 H), 7.14 (t, J = 7. 4 Hz, 1 H), 3.44-3.40 (m, 2H), 3.28-3.18 (m, 2H). 13C NMR (CDC13) : â 162. 40,148.14, 147.14,145.20,142.84,140.16,137.62,135.04,131.48,130.33, 129.10,128.14,124.44,123.43,119.83,105.42,44.21,33.67. IR : 2920 (s), 1680 (m) cm-1. HRMS : Calc'd for C20H1sBr2CIIN2O : 620.8265, Found: 620.8262 (MH+).

Step 3:

To 27.7 g (44.2 mmol) of the product of Step 2 in 750 mL of DMF at-10°C was added 1.5 g 80% NaH (66.3 mmol). After stirring at-10°C for 1 hr, 4.1 mL (66.3 mmol) of CH31 was added to the fiask. The mixture was mechanically stirred at-10°C for 1 hr, then quenched carefully into 2 L ice. The precipitate was filtered, washed with water and dried to give 23.7 g (85%) of the desired product as an off-white solid. Mp. 180- 181 °C. NMR indicates two rotamers. 1 H NMR (CDC13) : 8 8. 26 (d, J = 1.8 Hz, 1 H), 7.53 (d, J = 1. 8 Hz, 1 H), 7.52 (s, 1H), 7.18-7.10 (m, 6H), 3.15 (s, 3H), 3.17-3.10 (m, 2H), 2.83-2.79 (m, 2H). 13C NMR (CDC13) : 8 167.61,152.35,147.94,147.59,142.87,139.41,135.11,131.79, 130.51,129.06,129.04,127.98,127.04,126.65,120.21,105.08,43.9 7, 37.26,31.96. IR : 2920 (s), 1650 (m) cm-1. HRMS: Calc'd for C21H17Br2CIIN2O : 634.8420, Found: 634.8423 (MH+).

Step 4: Br, CI Guignard Br/1 \ CI Zen bu To a solution of 2 g (3.15 mmol) of the product of Step 3 in 40 mL of THF at-20°C was added dropwise 4.8 mL of 0.72 M 2-CH30C6H4MgBr (3.5 mmol) in THF. The mixture was stirred at-20°C for 20 min. and quenched with 5 mL of saturated NH4CI. The quenched solution was stirred at r. t. for 16 hrs. to complete the hydrolysis, concentrated and extracted with 2 X 10 mL of EtOAc. The combined extract was washed with brine, dried over MgS04 and concentrated.

The residue was chromatographed on silica gel, eluting with

hexane/EtOAc (9: 1) to give 0.84 g (66%) of the azoketone. The solution yield was determined to be 82% by HPLC. Mp. 198-200°C.

H NMR (CDCI3) : 8 8.74 (d, J = 1.8 Hz, 1 H), 7.75 (d, J = 1.8 Hz, 1 H), 7.55 (d, J = 1.8 Hz, 1 H), 7.20 (d, J = 1.8 Hz, 1 H), 3.25-3.19 (m, 2 H), 3.15-3.09 (m, 2 H). 13C NMR (CDCI3) : 8 194.17,150.21.149.39, 140.90,140.73,139.18,137.69,136.54,131.48,126.79,123.33, 119.88,32.78,31.59. IR : 2920 (s), 1690 (m) cm-1. Elemental analysis : Calcd. for C14H8Br2CI NO : C, 41.84, H, 1.99, N, 3.49; Found: C, 42.11 H, 2.07, N, 3.64. <BR> <P>Example 1 A Alternative route to the product of Example 1, Step 3: To a solution of 2.5 mL (18 mmol) of diisopropylamine in 10 mL dry THF at-60°C was added dropwise 7.2 mL (18 mmol) of 2.5 M n-BuLi.

To another flask containing 5 g (16.4 mmol) of the N-methyl amide starting material (prepared in a manner similar to that described in Example 1, Step 1) in 50 mL THF at-78°C was added the above LDA solution. After stirring at-78°C for 5 min., 20.8 mL (18 mmol) of a freshly prepared solution of ZnBr2 was added. To the resulting mixture was added 6.7 g (16.4 mmol) of 5-chloro-3-bromo-2-2iodobenzyl bromide in 10 mL THF. The reaction was heated to reflux for 2 hrs, quenched slowly into saturated NH4CI and extracted with toluene. The combined extract was washed with brine, dried over MgS04 and concentrated. The precipitate was filtered to give 4.6 g (44%) of the N-methylated product.

The HPLC solution yield was determined to be 60%.

Example 3 Step 1:

In a 150 mL autoclave were added sequentially 10 g (55 mmol) of 2-bromo-3-methylpyridine, 1.2 g (1.7 mmol) of (Ph3P) 2PdCI2, 50 mL of CH3CN, 8 mL (87 mmol) of aniline, and 18 mL (116 mmol) of DBU. The autoclave was sealed, evacuated, purged with nitrogen and charged with carbon monoxide to 80 psi. The reaction mixture was heated to 65°C for 9 h with periodical refilling of carbon monoxide as necessary, and then cooled to r. t. The contents of the autoclave was vented under vacuum, flushed with nitrogen and transferred into a separatory funnel with the aid of water and EtOAc. The phases were separated and the aqueous phase was extracted with 100 mL of EtOAc. The combined extract was washed with brine, dried over MgS04, filtered and concentrated. The residue was recrystallized from hot i-PrOH and water and the precipitated was filtered and dried at 50°C to give 6.9 g (59%) of the amide as white solid. The solution yield was determined to be 76%.

Mp. 66-67°C. 1 H N M R (C DC 13) : 5 10.23 (bs, 1H), 8.37 (dd, J = 4.6 Hz, 0.8 Hz, 1 H), 7.71 (m, 2H), 7.62 (dd, J = 6.95 Hz, 1 H), 7.31-7.36 (m, 3H), 7.10 (t, J = 7.42 Hz, 1H), 2.79 (s, 3H). 13C NMR (CDCI3) : 8 163. 52, 146.70,145.21,141.28,138.02,136.13,128.94,125.95,123.97, 119.62,20.80. R: 3330 (w), 2920 (s), 1680 (m) cm~1. Analysis. Calcd for C, 3H12N2O : C, 73.58, H, 5.66, N, 13.21; found: C, 73.29, H, 5.76, N, 12.81.

Step 2:

To a solution of 10 mL (70 mmol) of Pr2NH in 40 mL t-BuOCH3 at-40°C was added 28 mL (70 mmol) of 2.5 M n-BuLi in hexanes. To a mixture of 7.0 g (33.0 mmol) of the product of Step 1 in 30 mL of THF and 70 mL of t-BuOCH3 at-30°C was added dropwise the above LDA solution. The resulting purple solution was added dropwise at-30°C into 11.0 g (33.0 mmol) of 3-chloro-6-iodo benzyl bromide in 20 mL of THF and 50 mL of t-BuOCH3. The mixture was allowed to warm to 0°C and quenched with a solution NH4CI. The phases were separated and the aqueous phase was extracted with 100 mL of t-BuOCH3. The combined organic solution was washed with brine, dried over MgS04, filtered and concentrated. The crude product was used directly in the following step without further purification. 1H NMR (CDC13) : 8 10.24 (s, 1 H), 8.43 (dd, J = 4.57 Hz, J = 1.6 Hz, 1 H), 7.71 (m, 2H), 7.52 (dd, J = 7.8 Hz, 1,59 Hz, 1 H), 7.29-7.35 (m, 2H), 7.24 (d, J =2.61 Hz, 1 H), 7.08 (t, J = 7.43 Hz, 1 H), 6.81 (dd, J = 8.4 Hz, J = 2.6 Hz, 1 H), 3.40-3.44 (m, 2H), 3. 03-3.07 (m, 2H).

Step 3: To the residue (-33 mmol) of the product of Step 2 in 70 mL of DMF at 0°C was added 2.6 g 60% NaH (66 mmol). After stirring at 0°C for 1 hr, 2.5 mL (40 mmol) of CH31 was added to the flask. The mixture was mechanically stirred at 0°C for 15 min, then quenched carefully by ice. EtOAc (200 mL) was added and the solution was washed with water (100 x 5). The organic layer was concentrated to give 16 g residue, which was separated by column chromatography

(hexane/EtOAc) to give 10 g product, 64% yield, in two steps. Mp. 106- 107°C. NMR indicate two rotamers. 1 H NMR (CDC13) : 8 8.17 (d, J = 4.6 Hz, 1 H), 7.67 (d, J=8. 5Hz, 1H), 7.33 (d, J=7. 6Hz, 1H), 7.13 (d, J=2. 4 Hz, 1 H), 6.96-7.1 (m, 6H), 6.86 (dd, J = 8.5,2.4 Hz, 1 H), 3.49 (s, 3H), 2.90-2.96 (m, 2H), 2.74-2.80 (m, 2H). 13C NMR (CDC13) : 8 168.4, 153.9,146.5,145.4,143.1,140.4,137.0,134.6,133.2,129.7,128.8, 128.3,126.7,126.6,123.3,97.2,41.4,37.1,32.1.

Step 4:

To a solution of 2 g (4.2 mmol) of the product of Step 3 in 20 mL of THF at-78°C was added dropwise 2.52 mL of 2.0 n-BuLi (5.0 mmol) in cyclohexane. The mixture was stirred at-78°C for 10 min. and quenched with 30 mL of saturated NH4CI. The quenched solution was extracted with 2 X 50 mL of EtOAc. The combined extract was washed with brine, dried over MgS04 and concentrated. The residue was passed through silica gel, eluting with hexane/EtOAc (6: 4) to give 1.02 g (78%) of the title compound.'H NMR (CDC13) : 8 8.60 (dd, J = 4.6,1.5 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.55 (dd, J = 7.7,1.5 Hz, 1 H), 7.29 (dd, J=7. 7,4.6 Hz, 1 H), 7.24 (dd, J=8. 5,2.0Hz, 1H), 7.17 (d, J = 2. 0,1H), 3.15-3.20 (m, 4H). 13C NMR (CDC13) : 8 194.1,155.3,149.4,143.9, 139.6,138.2,137.4,136.4,133.6,130.3,127.9,126.8,35.2,33.1.

Example 4

To a solution of 1.88 g (4.68 mmol) of the product of Example 1 in 10 mL THF at-20°C was added dropwise 5.72 mL (5.15 mmol) of 0.9 M of the Grignard. The reaction was stirred at that temperature for 1 hr,

quenched into NH4C, and extracted with EtOAc. The combined extract was washed with brine, dried over MgS04 and concentrated. The residue was chromatographed on silica gel, eluting with EtOAc/hexane to give 1.4 g (60%) product as fluffy solid. Mp. 98-100°C. 1H NMR (CDC13) : 8 8.45 (d, J = 2.1 Hz, 1 H), 7.64 (d, J = 2.1 Hz, 1 H), 7.62 (d, J = 2.2 Hz, 1 H), 7. 07 (d, J = 2. 2 Hz, 1 H), 6.86 (s, 1 H), 3.68-3.58 (m, 1 H), 3.48-3.39 (m, 1 H), 3.06-2.8 (m, 4 H), 2.66-2.57 (m, 1 H), 2.23 (s, 3 H), 1.85-1.75 ° (m, 2 H), 1.68-1.58 (m, 1 H), 1.40-1.36 (m, 1 H), 0.91-0.85 (m, 1 H). 13C NMR (CDC13) : 5 156.54,145.04,141.25,140.57,139.09, 135.32,134.65,132.52,130.42,122.35,119.64,80.50,56.07,55.70, 45.94,44.98,34.27,30.83,26.20,26.09. IR : 3300 (w), 2920 (s), 1570 (w) cm-1.