CN1162404C - Process for the synthesis of intermediates useful in the preparation of tricyclic compounds - Google Patents

Abstract

The present invention discloses a process for the preparation of a compound of formula wherein, R, R¹、R²、R³And R⁴Independently selected from H, Br, Cl, F, alkyl or alkoxy. The method comprises the following steps: reacting a compound of formula (II) with a dehydrating agent to produce an imine of formula (IIa), wherein R^A、R^B、R^C、R^DAnd R^EIndependently selected from H, halogen, alkyl or alkoxy, R⁵Is aryl or heteroaryl; and (B) hydrolyzing the imine produced in step (A) to produce a compound of formula (I). The invention also discloses novel intermediates of formula (IIb), wherein R^A、R^B、R^C、R^DAnd R^EIndependently selected from H, halogen, alkyl or alkoxy, R⁵Is aryl or heteroaryl. Also disclosed are processes for preparing compounds of formula (III), which comprise: in the presence of a palladium catalyst, CO, a base and a catalyst selected from CH₃OCH₂CH₂OCH₃、CH₃OCH₂CH₂OCH₂CH₂OCH₃And CH₃OCH₂CH₂OCH₂CH₂OCH₂CH₂OCH₃With NH in the presence of an ether of (IV)₂R⁵Reaction, wherein X is H, Br, Cl or F, R⁵Is aryl or heteroaryl. The compounds prepared by the process are intermediates useful in the preparation of antihistamine or farnesyl protein transferase inhibitor compounds.

Description

Process for the synthesis of intermediates for the preparation of tricyclic compounds

technical field

The present invention provides an improved process for the preparation of intermediates useful in the preparation of tricyclic compounds known as antihistamines or farnesyl protein transferase (FPT) inhibitors. In particular, the compounds of the present invention are useful in the preparation of antihistamines as disclosed in US Patent Nos. 4,282,233 and 5,151,423 and FPT inhibitors as disclosed in PCT Publication No. WO97/23478 published on July 3, 1997.

Contents of the invention

The invention provides a method for preparing a compound of formula (I),

Wherein, R, R ¹ , R ² , R ³ and R ⁴ are independently selected from H, Br, Cl, F, alkyl or alkoxy, and the method includes:

(A) formula (II) compound is reacted with dehydrating agent

Wherein, R ^A , R ^B , R ^C , R ^D and R ^E are independently selected from H, halogen, alkyl or alkoxy, ^R is aryl or heteroaryl,

An imine of the formula,

as well as

(B) hydrolyzing the imine produced in step (A) to generate the compound of formula (I). The present invention also provides novel intermediates of the following formula:

Wherein, R ^A , R ^B , R ^C , R ^D and ^RE are independently selected from H, halogen, alkyl or alkoxy, and R ⁵ is aryl or heteroaryl.

The present invention also provides a method for preparing the compound of formula (III):

include:

In the palladium catalyst, CO, base and selected from ethylene glycol dimethyl ether (ie CH ₃ OCH ₂ CH ₂ OCH ₃ ), 2-methoxyethyl ether (ie CH ₃ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ ) and triglyme (ie CH ₃ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ ) ether, the compound of formula (IV) is reacted with NH ₂ R ⁵ :

Wherein X is H, Br, Cl or F, and ^R is aryl or heteroaryl.

In the presence of a strong base, a compound of formula (III) can react with a compound of the following structural formula to generate a compound of formula (II) wherein ^RA is Br, Cl or F,

wherein U is Br or Cl, ^RB , ^RC , ^RD and ^RE are as defined above.

The term "alkyl" as used herein refers to a straight or branched hydrocarbon chain of 1 to 6 carbon atoms.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Aryl" refers to phenyl, benzyl or polyaromatic rings (such as naphthyl), each of which can be optionally replaced by 1 to 3 independently selected from C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy and halogen substituents.

"Heteroaryl" refers to a 5- or 6-membered aromatic ring containing 1 or 2 nitrogen atoms, eg, pyridyl, pyrimidinyl, imidazolyl or pyrrolyl.

"Ac" means acetyl.

"Et" means ethyl.

"Ph" means phenyl.

The present process is a significant improvement over prior art processes for the preparation of tricyclic ketones of formula (I). For example, U.S. 4,731,447 discloses the following method:

In this method, before carrying out the next step (Friedel-Crafts cyclization), the product obtained from the hydrolysis step must be separated and purified, and compared with this method, the present invention prepares formula (I) compound The method provides a simpler synthesis that can be done in one pot.

PCT publication WO96/31478 published on October 10, 1996 discloses the following method:

A, B=H, halogen or C ₁ -C ₆ alkyl

In this method, a tert-butyl-substituted compound is reacted with POCl ₃ in toluene at reflux to form a nitrile, which is reacted with CF ₃ SO ₃ H to form an imine, which is hydrolyzed to form a ketone. Because the nitrile must be separated and purified before the nitrile reacts with CF ₃ SO ₃ H, so this method is a two-pot reaction, and compared with this method, the method of the present invention can be completed in one pot.

Compounds prepared by this method are useful as intermediates in the processes described in PCT Publication No. WO97/23478 and US Patent 5,151,423 to prepare the desired compounds in which the nitrogen of the piperidine ring is substituted. Using these procedures, compounds of the invention are reacted with substituted piperidines of the formula:

wherein ^L is a leaving group selected from Cl and Br,

Compounds of the formula:

Conversion of this compound to the piperidinylene and deprotection of the nitrogen reduces the compound to the pyridinyl form. The pyridyl nitrogen can be reacted with various compounds such as acyl compounds such as esters or acid chlorides to form the desired amides.

Alternatively, when a chiral FPT inhibitor such as those described in PCT Publication No. WO97/23478 is desired, the carbonyl oxygen can be removed by treatment with Zn and 2 equivalents of trifluoroacetic acid in acetic anhydride, and the present method can be converted to compound reduction. The reduced compound can then be combined with about 3.5 equivalents of lithium diisopropylamide, about 1.3 equivalents of quinine or a compound of the formula, about 1.2 equivalents of 4-methylsulfonyl-N-tert-butoxycarbonyl-piperidine and about 1.1 equivalent of water reacted in toluene,

The following chiral compounds are generated:

The chiral compound can then be deprotected by treatment with an acid such as sulfuric acid and reacted with a suitable acid such as N-acetyl-L-phenylalanine to form a stable salt, which can then be replaced with the desired acyl group groups will acylate stable salts.

Compounds of formula (I) can be converted to other compounds of formula (I) using methods well known in the art, i.e. compounds wherein R, R ¹ , R ² , R ³ or R ⁴ are hydrogen can be converted to the corresponding compounds wherein R , R ¹ , R ² , R ³ or R ⁴ are halogen compounds. A process step is given in WO 97/23478 in which, for example, a compound wherein R ² is chlorine, R ¹ , R ³ and R ⁴ are hydrogen and pyridyl nitrogen protected with a -COOCH ₂ CH ₃ group is combined with _KNO3 reaction, the resulting nitro-substituted compound is reduced to an amine, the resulting compound is reacted with _Br2 , and the amino group is removed to obtain a compound in which ^R2 is chlorine, ^R4 is bromine and ^R1 and ^R3 are hydrogen compound of.

Preferred compounds of formula (I) are those wherein ^R2 is chlorine, bromine or fluorine, more preferably chlorine or bromine, most preferably chlorine. Another preferred group of compounds are those wherein R, ^R1 , ^R3 and ^R4 are independently hydrogen and ^R2 is chlorine, bromine or fluorine, more preferably chlorine or bromine, most preferably chlorine. Yet another group of preferred compounds is that wherein ^R1 , ^R3 and ^R4 are independently hydrogen and R and ^R2 are independently selected from chlorine, bromine and fluorine, more preferably selected from chlorine and bromine, most preferably R is bromine and ^R2 is a compound of chlorine. Yet another group of preferred compounds is that wherein R ^and R are independently hydrogen and ^R , ^R and ^R are independently selected from chlorine, bromine and fluorine, more preferably selected from chlorine and bromine, most preferably R is bromine , R ² is chlorine and R ⁴ is a compound of bromine. These preferred compounds can be prepared from compounds of formula (II) having halogen substituents at the corresponding positions. It will be appreciated by those skilled in the art that when the compound of formula (II) has iodine substituents, those iodine substituents will be replaced by hydrogen when the method is carried out.

^R5 is preferably aryl, most preferably phenyl, 4-methoxyphenyl, 4-chlorophenyl or 3-chlorophenyl.

The dehydrating agent is preferably selected from P ₂ O ₅ , P ₂ O ₃ , P ₂ O ₃ Cl ₄ , POCl ₃ , PCl ₃ , PCl ₅ , C ₆ H ₆ P(O)Cl ₂ (phenylphosphonic dichloride), PBr ₃ , PBr ₅ , SOCl ₂ , SOBr ₂ , COCl ₂ , H ₂ SO ₄ , peracid or peracid anhydride, the dehydrating agent is more preferably selected from P ₂ O ₅ , P ₂ O ₃ Cl ₄ , PBr ₃ , PCl ₅ , POCl ₃ , C ₆ H ₆ P(O)Cl ₂ , (CF ₃ SO ₂ ) ₂ O, and (CF ₃ CF ₂ SO ₂ ) ₂ O.

Step (A) of the process is preferably carried out by contacting a reaction mixture of a compound of formula (II) and a dehydrating agent with a further agent selected from Lewis acids or peracids. Non-limiting examples of Lewis acids include _AlCl3 , _FeCl3 , _ZnCl2 , _AlBr3 , _ZnBr2 , _TiCl4 , and _SnCl4 . Among the aforementioned Lewis acids, AlCl ₃ , ZnCl ₂ , FeCl ₃ , SnCl ₄ and ZnBr ₂ are particularly preferred. Non-limiting examples _of peracids include _CF3SO3H ,

and HF/BF ₃ . Among the aforementioned peracids, CF ₃ SO ₃ H is particularly preferred. Contacting with the Lewis acid or peracid can be accomplished by adding the Lewis acid or peracid before, simultaneously with or after the reaction of the dehydrating agent with the compound of formula (II). Particularly preferred combinations of dehydrating agents and Lewis acids or peracids include P ₂ O ₅ /CF ₃ SO ₃ H, PCl ₅ /AlCl ₃ , POCl ₃ /ZnCl ₂ , PCl ₅ /FeCl ₃ , PCl ₅ /SnCl ₄ and POCl ₃ /ZnBr ₂ .

When step (A) uses a dehydrating agent other than an anhydride, the amount of the dehydrating agent used is preferably 1 to 20 equivalents, more preferably 1 to 10 equivalents, most preferably 1.0 to 8.0 equivalents. When peracid anhydride is used as the dehydrating agent, the amount of the dehydrating agent is preferably 0.5 to 10 equivalents, more preferably 1.0 to 5.0 equivalents, most preferably 1.2 to 2.0 equivalents. When a Lewis acid is used in addition to the dehydrating agent, the Lewis acid is used in an amount of preferably 1 to 20 equivalents, more preferably 1.5 to 10 equivalents, most preferably 2 to 5 equivalents. When a peracid is used in addition to the dehydrating agent, the peracid is used in an amount of preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents, most preferably 2 to 4 equivalents.

Step (A) is preferably carried out at a temperature of from 10 to 120°C, more preferably from 15 to 90°C, most preferably from 20 to 90°C. The reaction time is 1 to 60 hours, preferably 2 to 40 hours, most preferably 5 to 35 hours.

It is preferred to add water to hydrolyze the imine generated in step (A), the preferred amount of water is 1 to 10 times the volume of the amide of formula (II), more preferably 1.5 to 7 times the volume, most preferably 2 to 5 times the volume. The hydrolysis is preferably carried out at a temperature of from 20 to 120°C, more preferably from 30 to 100°C, most preferably from 40 to 80°C.

Preference is given to carrying out steps (A) and (B) in an aprotic organic solvent. The aprotic organic solvent is preferably selected from dichloroethane, dichloromethane, benzene and halogenated aromatic solvents such as chlorobenzene, dichlorobenzene, trichlorobenzene and trifluoromethylbenzene.

The starting compound of formula (II) can be prepared in the following scheme:

As shown in the above scheme (where R ^A , R ^B , R ^C , R ^D , ^RE and R ⁵ are as defined above), in a palladium catalyst (such as Pd(OAc) ₂ /bipyridine or (Ph ₃ P) ₂ PdCl ₂ ), carbon monoxide and a base, in a suitable solvent such as tetrahydrofuran (“THF”), dimethylformamide (“DMF”), acetonitrile (CH ₃ CN) and toluene or combinations thereof, most preferably acetonitrile ( CH ₃ CN)) reacts pyridine compound 1 with NH ₂ R ⁵ to generate amide compound 2 , wherein the reaction temperature is about 35 to 100°C, preferably about 55°C, and the reaction pressure is about 5 to 500psi, preferably about 50 to 150psi . Non-limiting examples of bases suitable for the foregoing reactions include _C1 to _C10 alkylamines such as triethylamine, tri-n-butylamine and 1,8-diazabicyclo[5.4.0]undecene-7 ("DBU"), and inorganic _bases such as _K2CO3 , _Na2CO3 , _{Na2HPO4 ,} and _NaOH . The base is preferably selected from K ₂ CO ₃ , DBU and triethylamine, DBU is preferably used with Pd(OAc) ₂ /bipyridyl, triethylamine is preferably used with (Ph ₃ P) ₂ PdCl ₂ . In the presence of a strong base such as lithium diisopropylamide ("LDA"), n-butyllithium, lithium hexamethyldisilylamide or sodium amide, preferably LDA or n-butyllithium, in a suitable solvent Amide compound 2 is reacted with compound 3 , eg, in THF, at a temperature of about -50 to -20°C, preferably about -30 to -20°C to form the compound of formula (II).

It is also possible to choose the scheme shown below to prepare amide compound 2 :

Pyridinecarboxylic acid compound 4 is reacted with an organic base such as triethylamine followed by an acid chloride such as pivaloyl chloride or a chloroformate such as _C2H5 in a suitable solvent such as dichloromethane at about -30 to ₀ °C. OCOCl reacts to form mixed anhydrides. _NH2R5 ^, neat or dissolved in a suitable solvent, is added to the mixture at -30°C to 0°C to generate amide compound 2 .

In the palladium catalyst, carbon monoxide, alkali and selected from ethylene glycol dimethyl ether (ie CH ₃ OCH ₂ CH ₂ OCH ₃ ), 2-methoxyethyl ether (ie CH ₃ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ ) and triglyme (ie CH ₃ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ ) in the presence of the ether, the compound of formula (IV) reacts with NH ₂ R ⁵ to prepare the compound of formula (III). X is preferably Br, Cl or F, most preferably Br, and R is ^preferably phenyl, 4-methoxyphenyl, 4-chlorophenyl or 3-chlorophenyl. Non-limiting examples of palladium catalysts that can be used in the process include Pd(OAc) ₂ , PdCl ₂ , (PPh ₃ ) ₂ PdCl ₂ , PdBr ₂ and (PPh ₃ ) ₄ Pd, with Pd(OAc) ₂ and PdCl ₂ being particularly preferred. . The process is carried out at a temperature of about 35 to 120°C, preferably about 40 to 100°C, most preferably about 45 to 90°C and a pressure of about 5 to 500 psi, preferably about 30 to 150 psi, most preferably about 40 to 100 psi. Non-limiting examples of bases suitable for the foregoing reactions include _C1 to _C10 alkylamines such as diisopropylethylamine, diisopropylbenzylamine, tri-n-butylamine, triisopropylamine, triethylamine, tert-butylamine and 1,8-diazabicyclo[5.4.0]undecene-7 (“DBU”), and inorganic bases such as K ₂ CO ₃ , KHCO ₃ , Na ₂ CO ₃ , NaHCO ₃ , Na ₃ PO ₄ , Na ₂ HPO ₄ and NaOH. The base is preferably selected from _K2CO3 , DBU, triethylamine and diisopropylethylamine, most preferably _from DBU and diisopropylethylamine. The process is preferably carried out in solvents other than ethylene glycol dimethyl ether, 2-methoxyethyl ether or triglyme. Non-limiting examples of suitable solvents include toluene, dichlorobenzene, acetonitrile, trifluoromethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran and xylene, particularly preferably Toluene and Chlorobenzene. Since ethylene glycol dimethyl ether, 2-methoxyethyl ether or triglyme acts as a ligand for the palladium catalyst, the process can be carried out without bipyridine as a ligand. The amount of NH ₂ R ⁵ used is preferably 0.9 to 5 equivalents, more preferably 1.0 to 3 equivalents, most preferably 1.1 to 1.5 equivalents. The amount of the base used is preferably 0.8 to 10 equivalents, more preferably 1.0 to 5 equivalents, most preferably 1.2 to 2.0 equivalents. The amount of ethylene glycol dimethyl ether, 2-methoxyethyl ether or triglyme is preferably 0.2 to 5.0 times the volume of 2,5-dibromo-3-methylpyridine used, more preferably 0.4 to 2.0 volumes, most preferably 0.5 to 1.5 volumes. The amount of other solvents (such as toluene or chlorobenzene) is preferably 1.0 to 20 times the volume of 2,5-dibromo-3-picoline used, more preferably 1.5 to 10 times the volume, most preferably 2 to 5 times the volume .

The starting materials used in the aforementioned methods, namely compound 1 , NH ₂ R ⁵ , compound 3 and compound 4 are well known in the art or can be easily prepared by those skilled in the art.

The following examples illustrate the above-mentioned invention in detail, but these examples are not intended to limit the scope of the invention. Other reagents and analogous methods within the scope of the invention will be apparent to those skilled in the art.

Detailed ways

Example A

250g (949mmol) 2,5-dibromo-3-picoline, 4.5g (20mmol) Pd(OAc) ₂ , 127mL (1.1mol) aniline, 210mL (1.4mol) 1,8-diazabicyclo[ 5.4.0] Undecene-7, 500 mL of toluene and 250 mL of ethylene glycol dimethyl ether were continuously added into a 4-liter autoclave. The autoclave was sealed, evacuated, purged with nitrogen, and charged with carbon monoxide to 80 psi. The reaction mixture was heated to 65°C, periodically filled with carbon monoxide, if necessary, kept at this temperature for about 2 days, and then cooled to room temperature. Under vacuum and nitrogen purge, the contents of the autoclave were drained and transferred to a 10-liter flask with the aid of water and toluene. 25 grams of activated charcoal (Darco) and 25 grams of diatomaceous earth (Supercel) were added to the mixture. Filter the material through a pad of Celite, washing the material with toluene. The filtrate was extracted with 2 x 1 liter of toluene. The combined extracts were washed with brine and concentrated to 750ml. Residual toluene was removed with isopropanol (i-PrOH). The filter residue was recrystallized from hot isopropanol (i-PrOH) and the precipitate was filtered. Washing with isopropanol and drying at 50°C yielded 220 g (76%) of the amide as a white solid.

preparation 1

400 g (2.21 mol) of 2-bromo-3-picoline, 8.2 g (12 mmol) of (Ph ₃ P) ₂ PdCl ₂ , 1.0 L of acetonitrile, 295 g (3.16 mol) of aniline and 515 g (3.38 mmol) of DBU were added continuously 4 liter autoclave. The autoclave was sealed, evacuated, purged with nitrogen, and charged to 80 psi with carbon monoxide. The reaction mixture was heated to 65°C, periodically charged with carbon monoxide, if necessary, kept at that temperature for 9 hours, and then cooled to room temperature. Under vacuum and nitrogen purge, the contents of the autoclave were vented and transferred to a separatory funnel with the aid of water and acetonitrile. 40 grams of activated charcoal (Darco) and 40 grams of diatomaceous earth (Supercel) were added to the mixture. The material was stirred for 30 minutes, filtered and washed with acetonitrile. The filtrate was concentrated to a final volume of 1.6 liters. 3.0 liters of water were added to precipitate the product as a yellow solid. The solid was filtered and dried to yield 427 g (90%) of the amide. Mp.66-67°C. ¹ H NMR (CDCl ₃ ): δ10.23 (bs, 1H), 8.37 (dd, J=4.6Hz, 0.8Hz, 1H), 7.71 (m, 2H), 7.62 (dd, J=6.95Hz, 1H) , 7.31-7.36 (m, 3H), 7.10 (t, J=7.42Hz, 1H), 2.79 (s, 3H). ¹³ CNMR (CDCl ₃ ): δ163.52, 146.70, 145.21, 141.28, 138.02, 136.13, 128.94, 125.95, 123.97, 119.62, 20.80. IR: 3330(w), 2920(s), 1680(m) em ^-1 . _Anal . Calcd. for _C13H12N2O : C, 73.58, H, 5.66, _N , 13.21; Found: C, 73.29, H, 5.76, N, 12.81.

preparation 2

A 1.5M solution of lithium diisopropylamide mono(tetrahydrofuran) (225 mL, 0.336 mol) was added dropwise to amide 1 dissolved in THF (400 mL) and diisopropylamine (7.05 mL, 0.050 mol) at -25°C (50g, 0.168mol) solution. The resulting dianion solution was aged at -20 to -25°C for 1 hour and quenched with 3-chlorobenzyl chloride (22.0 mL, 0.176 mol). The mixture was allowed to warm to 0 °C and after 1 h, was quenched in saturated aqueous ammonium chloride. The phases were separated and the aqueous layer was extracted with tert-butyl methyl ether (350 mL). The combined organic solutions were washed with brine solution and concentrated to an oil. The product was then crystallized from isopropanol (200 mL) to yield 62.7 g (89.8%) of the coupled product. Mp.102-103°C. ¹ H NMR (CDCl ₃ ): δ10.07(s, 1H), 8.56(d, J=2.1Hz, 1H), 7.77(dd, J=8.7Hz, 1.1Hz, 2H), 7.70(d, J= 2.1Hz, 1H), 7.42(t, J=8.4Hz, 2H), 7.28(d, J=2.4Hz, 1H), 7.16-7.25(m, 4H), 3.49-3.53(m, 2H), 2.99- 3.03 (m, 2H). ¹³ C NMR (CDCl ₃ ): δ162.45, 146.85, 145.17, 143.16, 142.95, 140.95, 137.70, 134.10, 129.63, 129.06, 128.74, 126.90, 126.33, 124.36, 123.24, 136.95, 126.90, 126.33, 124.36, 123.24, 136.95, IR: 2930(s), 1690(m) cm ^-1 . _Anal. Calcd. for _{C20H16BrClN2O} : C, 57.83, H, 3.85, N _, 6.75; Found: C, 58.05, H, 4.06, N, 6.80.

preparation 3

A solution of 2.5M butyl lithium in hexane (185 mL, 0.462 mol) was added dropwise to a solution of amide 2 (50 g, 0.231 mol) in THF (500 mL) at -25°C. The resulting dianion solution was aged at -20 to -25°C for 1 hour and quenched with 3-chlorobenzyl chloride (31.0 mL, 0.248 mol). The mixture was allowed to warm to 0°C and, after 1 hour, was quenched in saturated aqueous ammonium chloride. The phases were separated and the aqueous layer was extracted with tert-butyl methyl ether (350 mL). The combined organic solutions were washed with brine solution and concentrated to an oil. The product was then crystallized from isopropanol (200 mL) to yield 71.6 g (91.5%) of the coupled product. Mp.80-81°C. ¹ H NMR (CDCl ₃ ): δ10.23(s, 1H), 8.48(dd, J=4.6Hz, 1.6Hz, 1H), 7.78(dd, J=0.8Hz, 8.4Hz, 2H), 7.48(dd , J=7.9Hz, 1.5Hz, 1H), 7.39-7.12(m, 8H), 3.54-3.50(m, 2H), 3.02-2.98(m, 2H). ¹³ C NMR (CDCl ₃ ): δ164.09, 147.63, 146.72, 144.63, 141.91, 140.16, 138.97, 134.98, 130.55, 130.05, 129.82, 128.03, 127.16, 127.03, 125.17, 320.84, IR: 2930(s), 1690(m) cm ^-1 . _Anal. Calcd. for _C20H17ClN2O : _C , 71.43, H, 5.06, N, 8.33; Found: C, 71.37, H, 5.12, N, 8.35.

Example 1

100 g (241 mmol) of amide 3 , 137 g (963 mmol) of P ₂ O ₅ and 700 mL of chlorobenzene were added to an oven-dried 3-liter three-necked flask equipped with a mechanical stirrer, thermometer and addition funnel. 64.2 mL (722 mmol) of trifluoromethanesulfonic acid was added dropwise to the above slurry while keeping the temperature below 35 °C. The resulting mixture was heated to 80 to 85°C and stirred at this temperature for about 20 hours. The mixture was cooled to 45° C., and 102 g (722 mmol) of P ₂ O ₅ dissolved in 300 mL of chlorobenzene was added to the mixture. The mixture was heated to 80 to 85°C and stirred at this temperature for 20 hours. To the resulting mixture was added 500 mL of water at 10°C. The mixture was heated to 70°C and hydrolyzed for 2 hours. The reaction mixture was cooled to room temperature, and 200 mL of n-butanol was added to the mixture. The phases were separated and the organic layer was washed with brine, dilute sodium hydroxide solution and dilute hydrochloric acid solution. The organic layer was concentrated to 300 mL. The product was precipitated by adding 500 mL of THF and 2.4 equivalents of concentrated hydrochloric acid. The solid was filtered off, washed with cold n-butanol and dried to yield 61.7 g (71%) of the cyclic ketone as the hydrochloride salt. The analysis was carried out in the case of free base. Mp.119-120°C. ¹ H NMR (CDCl ₃ ): δ8.66 (d, J=2.0Hz, 1H), 7.96 (d, J=8.0Hz, 1H), 7.75 (d, J=1.5Hz, 1H), 7.27 (dd, J=8.0Hz, 2.0Hz, 1H), 7.18(d, J=1.0Hz, 1H), 3.17-3.09(m, 4H). ¹³ C NMR (CDCl ₃ ): δ192.7, 153.3, 150.6, 143.8, 140.7, 140.1, 139.3, 136.2, 133.9, 130.6, 128.4, 124.4, 35.4, 33.5. IR (KBr, liquid paraffin) 1660, 1590, 1290 cm ^-1 . _Anal. Calcd. for _C14H9BrClNO : C, 52.11, H, 2.80, N, 4.34, Br, 24.80, Cl, 11.00; Found: C, 52.03, H, 2.82, N, 4.38, Br, 24.95, Cl , 10.09.

Example 2

Add 68.35g (481mmol) of P ₂ O ₅ , 170mL of dichloroethane and 10g (24mmol) of amide 3 into an oven-dried 250mL three-necked flask equipped with a mechanical stirrer. The mixture was heated to 55 to 60°C for 16 hours to give about 70% imine product as determined by HPLC relative to standards. The imine is hydrolyzed using the procedure described in Example 1 to obtain the desired tricyclic ketone.

Example 3

Add 250 mL of dichloroethane, 4.2 g (15 mmol) of P ₂ O ₅ , 2 mL (12 mmol) of trifluoromethanesulfonic anhydride and 2 mL (30 mmol) of trifluoromethanesulfonic acid into an oven equipped with a mechanical stirrer, a thermometer and an addition funnel. Dry 250mL three-necked flask. 5.0 g (14.9 mmol) of amide 4 were added to this mixture. The mixture was heated to 80°C for 18 hours. The mixture was cooled to 10 °C and 70 mL of water was added. The mixture was heated to 70°C and hydrolyzed for 1 hour. The reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to 5-6 with sodium hydroxide. The phases were separated and the aqueous layer was extracted with tert-butyl methyl ether. The combined organic layers were washed successively with ammonium chloride and sodium bicarbonate solutions, and the organic layers were concentrated to obtain a residue. The product was precipitated by addition of tert-butyl methyl ether. The solid was filtered off, washed with cold tert-butyl methyl ether, and dried to yield 2.4 g (68.5%) of a yellow solid. The NMR spectrum of the product was identical to that of the expected cyclized ketone.

Example 4

8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one

A mixture of trifluoromethanesulfonic acid (63.2 mL, 0.71 mol) and phosphorus oxychloride (66.4 mL, 0.71 mol) dissolved in chlorobenzene (400 mL) was stirred at room temperature for half an hour. A solution of N-phenyl-3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxamide 4 (120 g, 0.36 mol) dissolved in chlorobenzene (240 mL) was added to the above mixture. The mixture was heated to 110°C for 18 hours, then cooled to 50°C. 400 mL of water was added and the biphasic mixture was heated to 80°C for half an hour. The mixture was cooled to room temperature, stirred vigorously for 10 minutes, and then left to stand for 10 minutes. The product was removed by filtration and partitioned between water (300 mL) and toluene (500 mL). The pH of the aqueous phase was adjusted to 10 with 10 M sodium hydroxide solution. 100 mL of the organic phase was removed by distillation under reduced pressure. Activated carbon (5.5 g) was added to the mixture and the mixture was filtered through a pad of celite. Under vacuum, the solution was concentrated to 300 mL, and 150 mL of n-hexane was added to the mixture. The mixture was cooled to 0-10°C and stirred at this temperature for 1 hour before filtration. The product was washed with 100 mL of cold toluene and then air dried for several hours. Yield = 44.1 g (50.8%).

Example 5

8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one

PCl ₅ (95%, 97.5 g, 0.45 mol) was added to N-phenyl-3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxamide dissolved in dichloromethane (500 mL) 4 (100g, 0.30mol) solution. The resulting mixture was stirred at room temperature for 1 hour. Then AlCl ₃ (158.5 g, 1.19 mol) was added to the mixture, followed by stirring at room temperature for 1 hour. The solution was then poured onto ice (500 g) and the resulting mixture was heated to reflux for 1 hour before cooling to room temperature. The pH of the aqueous phase was adjusted to 14 with 10M sodium hydroxide (700 mL), and the resting suspension was filtered through a sintered glass funnel. The collected solid was washed with dichloromethane (2 x 100 mL). The organic layer in the filtrate was separated and washed with 1M hydrochloric acid (1×200+1×100 mL). The organic layer was concentrated to an oil under vacuum, 100 mL of toluene was added, and the mixture was concentrated under vacuum again. The oil was dissolved in toluene (150 mL), and activated carbon (3.5 g) was added thereto. The mixture was filtered through a pad of celite, then hexane (100 mL) was added to the filtrate. The mixture was cooled to 0 °C for 1 hour before being filtered. The collected product was dried overnight in a vacuum oven at 60°C. Yield = 44.2 g (61%).

Example 6

N-(4-chlorophenyl)-3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxamide ( 30 g, 0.081 mol) solution was added dropwise to a solution of PCl ₅ (95%, 26.6 g, 0.121 mol) dissolved in dichloromethane (60 mL). The resulting mixture was stirred at 5 to 10°C for 1 hour. It was then allowed to warm to room temperature over 30 minutes. _AlCl3 (43.1 g, 0.323 mol) was then added to the mixture in four portions over 45 minutes while keeping the temperature below 30°C. The mixture was stirred for 1 hour, then poured onto ice (300 g). The dichloromethane in the mixture was removed by distillation, and the remaining aqueous solution was heated to 80° C. for 1 hour. Trisodium citrate dihydrate (70 g, 0.24 mol) was added thereto, followed by adjusting its pH to 7 with aqueous sodium hydroxide solution (10 M, 140 mL). Toluene (150 mL) was added, followed by a solution of maleic anhydride (12.0 g, 0.122 mol) dissolved in toluene (50 mL). The resulting mixture was stirred for half an hour, and the pH of the mixture was adjusted to 12 with aqueous sodium hydroxide solution (10 M, 60 mL). The mixture was heated to 70°C and the phases were separated. The aqueous phase was further extracted with toluene (2 x 90 mL), and the combined organic layers were washed with water (90 mL). HPlC analysis indicated 95% ketone product in solution. The product mixture was recrystallized from toluene/hexanes to give the desired tricyclic ketone (13.96 g, 71%) as an off-white solid.

Example 7

5 g (85.5 mmol) of sodium chloride, 20 g (45.7 mmol) of amide 3 and 100 mL of chlorobenzene were added to a 250 mL three-necked flask equipped with a magnetic stirrer, thermometer and reflux condenser. Under nitrogen atmosphere, the mixture was stirred at room temperature for 15 minutes. 16 g (76.8 mmol) of PCl ₅ were added to the resulting solution while keeping the temperature below 40 °C. The reaction mixture was stirred at 30 to 35°C for 2 hours. 15.6 g (96.2 mmol) _FeCl3 was added to the reaction mixture, after which the reaction mixture was heated to 30-35°C for 3 hours, then to 80-85°C for about 18 hours, followed by HPLC analysis. The reaction mixture was cooled to 10-20°C and 50 mL of acetone was added thereto. The mixture was stirred for 15 minutes and poured slowly into 200 mL of an aqueous solution of 30 g (224 mmol) D,L-malic acid. After stirring at room temperature for 1 h, the product was sequentially extracted with 200 mL and 100 mL of EtOAc. The combined organic layers were washed with 200 mL of an aqueous solution of 20 g (149 mmol) D,L-malic acid. 50 mL of acetone, 20 mL of methanol and 10 mL of 48% HBr (88 mmol) solution were added to the combined organic layers. The mixture was stirred at 45°C for 2 hours to complete the hydrolysis, then it was cooled to 5-10°C with an ice bath. The precipitate was filtered, washed with 50 mL of acetone, and dried in a vacuum oven at 25 °C to yield 16.1 g (82%) of the cyclized product.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. All such substitutions, modifications and variations are within the spirit and scope of the invention.

Claims (14)

1. the method for preparation formula (I) compound,

Wherein R, R ¹, R ², R ³And R ⁴Be independently selected from H, Br, Cl or F, this method comprises:

(A) with formula (II) compound be selected from PO ₅, POCl ₃And PCl ₅Dewatering agent reaction,

R wherein ^A, R ^B, R ^C, R ^DAnd R ^EBe independently selected from hydrogen or halogen, R ⁵Be phenyl or 4-chloro-phenyl-, generate the imines of following formula:

And

(B) with imines hydrolysis production (I) compound that produces in the step (A).

2. the described method of claim 1, wherein, R, R ¹, R ³And R ⁴Be hydrogen, R ²Be chlorine.

3. the described method of claim 2, wherein, by with the reaction mixture of formula (II) compound and dewatering agent be selected from AlCl ₃, FeCl ₃, ZnCl ₂, AlBr ₃, ZnBr ₂, TiCl ₄And SnCl ₄Lewis acid or be selected from CF ₃SO ₃H, FSO ₃H,

Other reagent contact of peracid carry out step (A).

4. the described method of claim 3, wherein, dewatering agent is selected from P ₂O ₅, POCl ₃, PCl ₅, and other reagent are selected from CF ₃SO ₃H, FeCl ₃And AlCl ₃

5. the described method of claim 1, wherein, R ¹, R ³And R ⁴Be hydrogen, R is a bromine, R ²Be chlorine.

6. the described method of claim 5, wherein, by with the reaction mixture of formula (II) compound and dewatering agent be selected from AlCl ₃, FeCl ₃, ZnCl ₂, AlBr ₃, ZnBr ₂, TiCl ₄And SnCl ₄Lewis acid or be selected from CF ₃SO ₃H, FSO ₃H,

Other reagent contact of peracid carry out step (A).

7. the described method of claim 6, wherein, dewatering agent is selected from P ₂O ₅, POCl ₃, PCl ₅, and other reagent are selected from CF ₃SO ₃H, FeCl ₃And AlCl ₃

8. the described method of claim 1, wherein, R ¹And R ³Be hydrogen, R and R ⁴Be bromine, and R ²Be chlorine.

9. the described method of claim 8, wherein, by reaction mixture and AlCl with formula (II) compound and dewatering agent ₃, FeCl ₃, ZnCl ₂, AlBr ₃, ZnBr ₂, TiCl ₄And SnCl ₄Lewis acid or be selected from CF ₃SO ₃H, FSO ₃H,

Other reagent contact of peracid carry out step (A).

10. the described method of claim 9, wherein, dewatering agent is selected from P ₂O ₅, POCl ₃, PCl ₅, and other reagent are selected from CF ₃SO ₃H, FeCl ₃And AlCl ₃

11. the compound of following formula

R wherein ^A, R ^B, R ^C, R ^DAnd R ^EBe independently selected from hydrogen or halogen, R ⁵Be phenyl or 4-chloro-phenyl-.

12. the described compound of claim 11, wherein, R ^A, R ^B, R ^DAnd R ^ERespectively be hydrogen, R ^CBe chlorine.

13. the described compound of claim 11, wherein, R ^B, R ^DAnd R ^ERespectively be hydrogen, R ^ABe bromine, and R ^CBe chlorine.

14. the described compound of claim 11, wherein, R ^AAnd R ^ERespectively be bromine, R ^BAnd R ^DRespectively be hydrogen, and R ^CBe chlorine.