A NOVEL SYNTHESIS FOR HETEROARYLAMINE COMPOUNDS

Abstract: Disclosed is a novel method of producing heteroaryl amines of formula (I), wherein X, Y and Z are described herein, the heteroarylamines are useful in the production of heteroaryl ureas which are key component in pharmaceutically active compounds possessing a heteroaryl urea group.

Description: A NOVEL SYNTHESIS FOR HETEROARYLAMINE COMPOUNDS FIELD OF INVENTION: This invention relates to the synthesis of heteroarylamine compounds which are useful in the production of heteroaryl ureas a key component in pharmaceutically active compounds possessing a heteroaryl urea group. BACKGROUND OF THE INVENTION Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory and autoimmune diseases. Examples of such compounds are reported in WO 99/23091 and in WO 98/52558. A key step in the synthesis of these compounds is the formation ofthe urea bond. Various methods have been reported to accomplish this. For example, as reported in the above references, an aromatic or heteroaromatic amine, ArιNH 2 , may be reacted with an aromatic or heteroaromatic isocyanate, Ar NCO, to generate the urea Ar 1 NHC(O)NHAr 2 . Scheme I If not commercially available, one may prepare the isocyanate by reaction of an aryl or heteroaryl amine Ar 2 -NH with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937) or trichloromethyl chloroformate (diphosgene) (K. Kurita, T. Matsumura and Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanate Ar 2 -NCO, followed by reaction with ArιNH 2 to provide the urea. Other approaches to forming the urea reported in the chemical literature include reaction of a carbamate with an aryl or heteroaryl amine, (see for example B. Thavonekham, Synthesis, 1997, 1189 and T. Patonay et al., Synthetic Communications, 1996, 26, 4253) as shown in Scheme II. US Provisional Application No. 60/143,094 also discloses a process of making heteroaryl ureas by reacting particular carbamate intermediates with the desired arylamine. Scheme II U.S. Application no. 09/505,582 and PCT/US00/03865 describe cytokine inhibiting ureas ofthe following formula : An intermediate required to prepare preferred compounds described therein has a 1,4- disubstituted naphthalene as Ar 2 and is illustrated in the formula below. The preparation of these intermediates require the coupling ofthe naphthyl ring with X. Preferred X include aryl and heteroaryl groups. Previously described methods, including U.S. Application No. 09/505,582 and PCT/USOO/03865 achieve the coupling of these aromatic residues by using a coupling reaction catalyzed by a transition metal, such as palladium, in the presence of a ligand, such as triphenyl phosphine. Coupling methods include Stille coupling, requiring the preparation of a tributylstannyl intermediate, or a Suzuki coupling, requiring the preparation of a boronic acid intermediate (Scheme III). Scheme III M = Sn(Bu) 3 or B(OH) 2 Some steps in these methods require cooling to extreme temperatures (-78 °C). Others require reaction under high pressure, require chromatography to purify the product, or use expensive reagents. For these reasons, these methods are not suitable for large-scale or industrial-scale production. SUMMARY OF THE INVENTION It is an object of the invention to provide a novel method of producing heteroaryl amines ofthe formula(I) : wherein X, Y and Z are described below, the heteroarylamines are useful in the production of heteroaryl ureas as mentioned above. DETAILED DESCRIPTION OF THE INVENTION Disclosed herein is a novel process for preparing preferred heteroarylamine intermediates including those heteroarylamine intermediates described in U.S. Application No. 09/505,582, and PCT/US00/03865. The processes described herein have several advantages. They use inexpensive starting materials and reagents, the reactions are run at moderate temperatures, there are no high-pressure reactions and chromatography is not required. The novel feature ofthe invention is the construction of naphthalene ring, as exemplified in Scheme I below, from the appropriately substituted carboxylic acid 5, which in turn was synthesized beginning from a novel ester of the formula (II) and a diester such as diethyl succinate. Any of the compounds of the formula (II) as described herein can be synthesized from readily available and cost efficient starting materials such as example 1 below. This invention provides a novel strategy for the synthesis of heteroarylamine compounds ofthe formula (I): wherein: the naphthyl ring is further optionally substituted by one or more Ri or R 2 ; X is chosen from a C 5- 8 cycloalkyl and cycloalkenyl optionally substituted with one to two oxo groups or one to three C 1-4 alkyl, C 1-4 alkoxy or C 1-4 alkylamino chains each being branched or unbranched; aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H- imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, nitrile, amino, mono- or di-(C 1-3 alkyl)amino, mono- or di-(C 1-3 alkylamino)carbonyl, NH 2 C(O), C 1-6 alkyl-S(0) m or halogen; Y is chosen from a bond and a C 1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C 1-4 alkyl optionally substituted by one or more halogen atoms; Z is chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl, each being optionally substituted with one to three halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, amino, mono- or di-(C 1-3 alkyl)amino, C 1-6 alkyl-S(O) m , CN, CONH 2 , COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkyl or C 1-6 alkoxy; tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomoφholinyl, thiomorpholinyl sulfoxidyl, thiomorpholinyl sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being optionally substituted with one to three nitrile, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, amino, mono- or di-(C 1-3 alkyl)amino-C 1-3 alkyl, CONH 2 , phenylamino-Cι -3 alkyl or C 1-3 alkoxy-Cι -3 alkyl; halogen, C 1-4 alkyl, nitrile, amino, hydroxy, C 1-6 alkoxy, NH C(O), mono- or di(C 1-3 alkyl) aminocarbonyl, mono- or di(C 1-3 alkyl)amino, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to Cι -3 alkyl or C 1-5 alkoxyalkyl, pyridinyl-C 1-3 alkyl, imidazolyl-C 1-3 alkyl, tetrahydrofuranyl-C 1-3 alkyl, nitrile-C 1-3 alkyl, carboxamide-C 1-3 alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkoxy, hydroxy or mono- or di-(C 1-3 alkyl)amino, C 1-6 alkyl-S(O) m , or phenyl- S(O) m , wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkoxy, hydroxy, halogen or mono- or di-(C 1-3 alkyl)amino; C 1-6 alkyl-S(O) m , and phenyl-S(O) m , wherein the phenyl ring is optionally substituted with one to two halogen, Cι -6 alkoxy, hydroxy or mono- or di-(C 1-3 alkyl)amino; Ri and R 2 are independently chosen from: a C 1-6 branched or unbranched alkyl optionally partially or fully halogenated, C 1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, C 1-3 alkyl-S(O) m optionally partially or fully halogenated and phenylsulfonyl; and m is 0, 1 or 2. The process of the invention in its broadest generic aspect is provided below and exemplified in a non-limiting embodiment shown in Scheme 1 : said process comprising: a) reacting a Z-Y-X-COO-R x ester (II) wherein R x is C 1-5 alkyl or aryl with a di-alkyl or diaryl ester (III) in a suitable solvent protic or aprotic, polar or nonpolar, preferably aprotic such as THF, DME, DMSO, ether, dioxane, CH 2 C1 2 , CHC1 3 , toluene, pyridine or DMF, or suitable alcohols, preferably the solvent is chosen from THF and DMSO, more preferably THF, and a suitable base such as organic or inorganic bases such as NaH, NaNH 2 , sodium alkoxides such as Na-t-butoxide, Na-ethoxide, NaOH, pyridine, TEA, DBU or BuLi, preferably NaH or Na t-butoxide, and optionally where appropriate as in Example 3, in the presence of an additive such as DMPU and HMPA, preferably DMPU, under the temperature of about 0 to 200 °C for a reaction time of about 5 min to 24 h, preferably when using the preferred solvent THF at 60- 70 °C for about 8 h and isolating the compound intermediate (IV). Examples 1 & 2 are representative methods for preparation of compounds of the formula(II), methods of preparing other compounds ofthe formula(II) is within the skill in the art. (II) (III) (IV) b) subjecting the product of step a) to acidic or basic hydrolysis, preferably acidic hydrolysis, and decarboxylation under suitable acid conditions apparent to those skilled in the art, such as cone. H 2 SO 4 in HO Ac at a temperature of about 50 to 200 °C and for about 5 min to 24 hours, preferably about 100 °C for about 7 h; followed by esterification under appropriate conditions with a C 1-5 alcohol, preferably EtOH; subsequent phenyl nucleophilic addition via for example a phenyl Grignard reagent PhMgBr, phenylLi, phenylZnCl, preferably phenyl Grignard, the phenyl being optionally substituted by Ri and/or R 2 ; reductive cleavage under appropriate conditions such as HCOONH 4 / Pd/C / EtOH to form a carboxylic acid compound which on treatment with a strong mineral acid such as H 2 SO , HO, MeSO 3 H, CF 3 SO 3 H, PPA or Lewis acid such as SnCl , A1C1 3 , BF 3 -OEt 2 and Yb(OTf) 2 , preferably PPA, optionally in a suitable solvent at RT to 200°C, preferably about 110°C, to form a product intermediate ofthe formula(V), and isolating the product: (V); c) reacting the product from step b) with HNR y R z or it's respective salt thereof, to form an enamine or imine, preferably an oxime, compound of the formula(VI) under suitable conditions. (V) (VI) wherein R y is C 1-5 alkyl or hydrogen, R z is C 1-5 alkyl, hydrogen or OH with the proviso that when formula (VI) is an enamine tautomer then R y and R z are both -salkyl, or when formula (VI) is an imine tautomer then R z is OH, -salkyl or hydrogen and R y is not present: enamine imine In a preferred but nonlimiting embodiment, forming an oxime by adding NH 2 OHHCl (where R y is H and R z is OH) in a suitable solvent such as EtOH with a suitable base such as NaOH at about RT for about 1 to 24 h, preferably 18 h; c) 1) where the product of step c) is an imine, preferably an oxime (R y = H, R z = OH), preferably in a one pot reaction acylating and reducing the product of step c) under conditions known in the art, a preferred but non-limiting example is acetylating/reducing conditions, such as treating compound (VI) with acetic anhydride, acetic acid and a suitable reducing agent such as Fe, SnCl and Zn, preferably Fe, at about 55°C for about 5 hours; then treating the unsaturated amide product (8) under oxidizing conditions capable of forming the naphthalene ring of the formula(ι) above, for example, treating the amide product(8) with an oxidizing reagant such as DDQ, O 2 , CrO 3 and KMnO 4 , preferably DDQ, in a nonpolar solvent such as methylene chloride, at about 0 to 50 °C, preferably RT for about 0.5 to 10 h, preferably 5 h; followed by deprotection by methods known in the art to provide the formation of formula (I): or 2) where the product of step c) is an enamine, oxidizing the enamine under suitable oxidizing conditions to form the naphthalene ring, then deprotecting the nitrogen to form the amine of the formula (I). In a non-limiting example, R y and R z are benzyl, oxidation to the naphthalene ring may be accomplished as described above, and debenzylation may be accomplished by methods known to those skilled in the art, for example H 2 /palladium C. Compounds of the formula (I) possessing a particularly desired Ar-X-Y-Z combination can be synthesized without undue experimentation by variations apparent to those of ordinary skill in the art in view of the teachings in this specification and the state of the art. More specific examples of possible X-Y-Z combinations are to be found in PCT application no. PCT/US00/03865 and US application no.09/505,582 each of which is incorporated herein by reference in their entirety. In another embodiment of the invention there is provided a novel process of making compounds ofthe formula(I) as described above and wherein: X is chosen from a C 5-8 cycloalkyl and cycloalkenyl optionally substituted with one to two oxo groups or one to three C 1-4 alkyl, C 1-4 alkoxy or C 1-4 alkylamino chains each being branched or unbranched; aryl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C 1-4 alkyl, nitro, nitrile, mono- or di-(Cι -3 alkyl)amino, mono- or di-(C 1-3 alkylamino)carbonyl, NH 2 C(O), C 1-6 alkyl-S(O) m or halogen; Y is chosen from a bond and a C 1-4 saturated or unsaturated carbon chain wherein one ofthe carbon atoms is optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C 1-4 alkyl optionally substituted by one or more halogen atoms; Z is chosen from: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C 1-3 alkyl, C 1-3 alkoxy, hydroxy, amino, mono- or di- (C 1-3 alkyl)amino or CONH 2 ; tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, C 1-3 alkyl, C 1-3 alkoxy, hydroxy, amino, mono- or di-(C 1-3 alkyl)amino or CONH 2 ; nitrile, C 1-6 alkyl-S(O) m , halogen, hydroxy, Cι -4 alkoxy, amino, mono- or di-(C 1-6 alkyl)amino, mono- or di-(C 1-3 alkyl)aminocarbonyl and NH 2 C(O). In yet another embodiment of the invention there is provided a novel process of making compounds ofthe formula(I) as described immediately above and wherein: X is chosen from aryl, pyridinyl, pyrimidinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C 1-4 alkyl, nitro, nitrile, mono- or di-(C 1-3 alkyl)amino, mono- or di-(C 1-3 alkylamino)carbonyl, NH 2 C(O), C 1-6 alkyl-S(O) m or halogen; Y is chosen from a bond and a C 1-4 saturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group; Z is chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl and pyrrolidinyl which are optionally substituted with one to two C 1-2 alkyl or C 1-2 alkoxy; tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl and tetrahydropyrimidonyl which are optionally substituted with one to two C 1-2 alkyl or C 1-2 alkoxy; and C 1-3 alkoxy. In yet still another embodiment of the invention there is provided a novel process of making compounds ofthe formula(I) as described immediately above and wherein: X is chosen from pyridinyl and pyrimidinyl, each being optionally independently substituted with one to three C 1-4 alkyl, nitro, nitrile, mono- or di-(Cι -3 alkyl)amino, mono- or di-(Cj -3 alkylamino)carbonyl, NH 2 C(O), Cι -6 alkyl-S(O) m or halogen; Y is chosen from a bond, -CH 2 -, -CH 2 CH 2 -, -C(O)-, -O-, -S-, -NH-CH 2 CH 2 CH 2 - , -N(CH 3 )- and -NH-; In yet a further embodiment of the invention there is provided a novel process of making compounds ofthe formula(I) as described immediately above and wherein: Y is chosen from -CH 2- , -NH-CH 2 CH 2 CH 2 - and -NH- and Z is morpholinyl. All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, "C 1-6 alkoxy" is a C 1-6 alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows: The term "aroyl" as used in the present specification shall be understood to mean "benzoyl" or "naphthoyl". The term "aryl" as used herein shall be understood to mean aromatic carbocycle or heteroaryl as defined herein. The term "carbocycle" shall be understood to mean an aliphatic hydrocarbon radical containing from three to twelve carbon atoms. Carbocycles include hydrocarbon rings containing from three to ten carbon atoms. These carbocycles may be either aromatic and non-aromatic ring systems. The non-aromatic ring systems may be mono- or polyunsaturated. Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be used interchangeably. The term "heterocycle", unless otherwise noted, refers to a stable nonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated. Each heterocycle consists of carbon atoms and one or more, preferably from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom ofthe cycle, which results in the creation of a stable structure. Unless otherwise stated, heterocycles include but are not limited to, for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl. The term "heteroaryl", unless otherwise noted, shall be understood to mean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms such as N,O and S. Unless otherwise stated, such heteroaryls include: pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[l,4]oxazin-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl. Terms which are analogs ofthe above cyclic moieties such as aryloxy or heteroaryl amine shall be understood to mean an aryl, heteroaryl, heterocycle as defined above attached to it's respective functional group. As used herein, "nitrogen" and "sulfur" include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. The term "halogen" as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine except as otherwise noted. DDQ - 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone; PPA - Polyphosphoric acid; HO Ac - acetic acid; RT or rt - room temperature; n-BuLi - n-Butyllithium DME - 1,2-Dimethoxyethane DMSO - Methyl sulfoxide DMF - N,N- Dimethylformamide DBU - l,8-Diazabicyclo[5.4.0]undec-7-ene DMPU - N,iY- Dimethylpropyleneurea HMPA - Hexamethylphosphoramide TEA - Triethylamine THF - Tetrahydrofuran. The compounds ofthe invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art. For example, a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by the invention. In order that this invention be more fully understood, the following examples are set forth in the overall reaction scheme below. These examples are for the purpose of illustrating preferred embodiments of this invention, and are not to be construed as limiting the scope ofthe invention in any way. Sample methods and starting materials to make compound (1) in Scheme I are shown in Examples 1 and 2 below. EXAMPLES SCHEME I Step 2 (3) (10) Example 1 Preparation of chloride: A solution of alcohol shown above (18.0 g, 100 mmol) in 200 mL of CH 2 C1 2 was prepared and cooled in an ice- water bath. A solution of SOCl 2 (22 mL, 300 mmol) in 100 mL of CH 2 C1 2 was added to the above solution at the rate to keep the internal temperature below 10 °C. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature over 2 h. The reaction mixture was evaporated to remove all volatile by rotavap. The residue was dissolved in 150 mL of CH 2 C1 2 and saturated sodium bicarbonate solution was added until pH = 9. The aqueous layer was extracted with CH 2 C1 2 . The combined organic layers were dried (MgS0 4 ) and concentrated to give 20.0 g (100%) ofthe desired chloride. 1H NMR (CDCL 3 ): δ 9.15 (s, 1H), 8.33 (d, J = 8 Hz, 1H), 7.58 (d, J = 8 Hz), 4.73 (s, 2H), 4.42 (q, J = 7 Hz, 2H), 1.42 (t, J = 7 Hz, 3H). Example 2 morpholine Preparation of morpholine moiety: A solution of chloride from Example 1 above (20 g, 100 mmol) and triethylamine (15.2 g, 150 mmol) in 125 mL of CH 2 C1 2 was prepared. 11 g (126 mmol) of morpholine was added and the reaction mixture was stirred at room temperature overnight (18 h). 100 mL of saturated sodium bicarbonate solution was added. The aqueous layer was extracted with CH 2 C1 2 (2 x 50 mL). The combined organic layers were dried (MgSO 4 ) and concentrated to give 24.3 g (97%) of desired product. 1H NMR (CDCL 3 ): δ 9.15 (s, 1H), 8.25 (d, J = 8 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 4.40 (q, J = 7 Hz, 2H), 3.73 (m, 6H), 2.51 (t, J = 4 Hz, 4H), 1.40 (t, J = 7 Hz, 3H). Example 3 Diester (2). To a mixture of ester 1 (10.0 g, 40 mmol), diethyl succinate (7.0 g, 40 mmol) and sodium hydride (60% dispersion in mineral oil, 3.20 g, 80 mmol) in dry THF (200 ml) was added DMPU (20 ml) and methanol (0.10 ml) and the mixture was refluxed for 2.5 h. Additional diethyl succinate (10.50 g, 60 mmol) and sodium hydride (4.80 g, 120 mmol) were added in five equal portions to the refluxing reaction mixture at 0.75 h intervals. Refluxing was continued for additional 1.5 h. The cooled reaction mixture was poured into a stirring mixture of 2N HC1 (200 ml) and ethyl acetate (200 ml). The aqueous phase was separated, the pH was adjusted to 8.5 with saturated sodium bicarbonate and it was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Evaporation of ethyl acetate gave almost pure 2 as yellowish brown oil (10.65 g, 70.4%). 1H NMR (CDC1 3 ) δ 1.16 (t, J= 7.2 Hz, 3H), 1.22 (t, J= 7.2 Hz, 3H), 2.51-2.53 (m, 4H), 3.02-3.20 (m, 2H), 3.72-3.75 (m, 6H), 4.10-4.15 (m, 4H), 4.78-4.80 (m, IH), 7.58 (d, J= 8.0 Hz, IH), 8.27 (d, J= 6.0 Hz, IH) and 9.18 (d, J= 2.1 Hz, IH). Example 4 Keto ester (3). Concentrated sulfuric acid (10 ml) was added carefully to the solution of the diester 2 (11.55 g, 30.5 mmol) in acetic acid (60 ml). The mixture was stirred at 100 °C for 6.5 h. After removing 30-40 ml of acetic acid under reduced pressure, ethanol (125 ml) was added to the residue and the reaction mixture was refluxed for 3.5 h. It was concentrated on a rotary evaporator followed by quenching with water. The mixture was extracted with ethyl acetate. The aqueous layer was separated, treated with saturated NaHCO 3 and extracted with methylene chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated to give 3 as red viscous oil in practically pure state (8.35 g, 89%). Analytically pure sample was obtained from a silica gel column using ethyl acetate hexane (1 : 1) as solvent for elution. 1H NMR (CDC1 3 ) δ 1.27 (t, J= 7.2 Hz, 3H), 2.50-2.53 (m, 4H), 2.76-2.79 (m, 2H), 3.28-3.31 (m, 2H), 3.72-3.75 (m., 6H), 4.15 (q, J= 7.2 Hz, 2H), 7.56 (d, J- 8.0 Hz, IH), 8.21 (d, J= 6.0 Hz, IH) and 9.13 (d, J= 2.0 Hz, IH). Example 5 Lactone (4). Phenylmagnesium bromide (1M/THF, 37.1 mmol, 37.1 ml) was added slowly to a stirring solution ofthe keto ester 3 (8.11 g, 26.5 mmol) in dry THF at -5 °C so that the reaction temperature stayed below 0 °C. The reaction mixture was stirred at this temperature for additional 0.5 h. After quenching with 10% ammonium chloride solution, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to give crude 4. An analytically pure sample was obtained from a silica gel column using ethyl acetate as solvent. 1H NMR (CDC1 3 ) δ 2.47-2.49 (m, 4H), 2.58-2.62 (m, 2H), 2.92 (m, 2H), 3.62 (s, 2H), 3.70-3.72 (m, 4H), 7.29-7.42 (m, 6H), 7.69-7.71 (m, IH) and 8.62 (d, J= 2.0 Hz, IH). Example 6 Acid (5). To the solution of crude lactone 4 (from above) in reagent alcohol (100 ml) was added ammonium formate (5.0 g) and 10% Pd/C (0.66 g) and the reaction mixture was refluxed for 2.5 h. The catalyst was filtered and the filtrate was concentrated. A saturated solution of NaHCO 3 was added until the pH was 8.5. It was extracted with ethyl acetate to remove non-acidic impurities. The pH of the aqueous phase was then lowered to 6.5-7 with 2N HCl and it was extracted with CH C1 2 , dried over anhydrous sodium sulfate and concentrated to give 5 as light brown viscous oil (3.7 g, 41% over two steps). 1H NMR (CDC1 3 ) δ 2.27-2.42 (m, 4H), 2.54-2.56 (m, 4H), 3.65 (s, 2H), 3.71- 3.3.73 (m, 4H), 4.09-4.13 (m, IH), 7.22-7.31 (m, 6H), 7.49-7.51 (m, IH) and 8.51 (s, IH). Example 7 Tetralone (6). A mixture of acid 5 (3.6 g, 10.6 mmol) and polyphosphoric acid (85 g.) was stirred at 110 °C for 1.5 h. After cooling, the reaction mixture was quenched with cold water and treated with 2N NaOH to bring the pH up to ~5. It was extracted with CH 2 C1 , dried over anhydrous sodium sulfate and evaporated to give almost pure ketone 6 as brown viscous oil (3.1 g, 90%). An analytically pure sample was obtained from preparative TLC using ethyl acetate as a solvent. 1H NMR (CDC1 3 ) δ 2.23-2.35 (m, IH), 2.45-2.78 (m, 7H), 3.68-3.77 (m, 6H), 4.32-4.36 (m, IH), 6.94 (d, J= 6.4 Hz, IH), 7.34- 7.7.47 (m, 4H), 8.13 (d, J= 6.4 Hz, IH) and 8.45 (d, J= 2.0 Hz, IH). Example 8 Oxime (7). A solution of NaOH (IN, 17.6 ml, 17.6mmol) was added to a stirring solution of hydroxylamine hydrochloride (1.19 g, 17.1 mmol) in water (10 ml) at 0 °C over five minutes followed by addition of the solution of ketone 6 (3.06 g, 9.5 mmol) in reagent alcohol (20 ml). After stirring the reaction mixture at room temperature for 18 h, it was diluted with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to give crude product. It was purified by silica gel chromatography using ethyl acetate as the solvent to give 7 as a colorless oil. It solidified on standing (2.00 g, 62%). 1H NMR (CDC1 3 ) δ 2.02-2.12 (m, IH), 2.16-2.26 (m, IH), 2.50-2.60 (m, 4H), 2.70-2.90 (m, 2H), 3.7 (s, 2H), 3.72-3.78 (m, 4H), 4.15-4.20 (m, 4H), 6.90-6.95 (m, IH), 7.20-7.35 (m, 3H), 7.98-8.02 (m, IH), 8.4 (s, IH) and 9.05 (bs, IH). Example 9 Amide (8). A solution of oxime 7 (1.42 g, 4.2 mmol) in acetic anhydride (15 ml) and acetic acid (1ml, 16.8mmol) was stirred at room temperature for 0.5 h. Iron powder (0.63 g, 10 mgatom) was added and the mixture was stirred at 55 °C for 5 h. The reaction mixture was cooled, ethyl acetate was added and the resulting mixture was filtered. The filtrate was evaporated to dryness. Water was added, the pH was adjusted to ~8 with 2N NaOH and again extracted with ethyl acetate. It was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with 2.5% MeOH/CH 2 Cl 2 to give 8 as yellow viscous oil (1.08 g, 71%). 1H NMR (CDC1 3 ) 2.18 (s, 3H), 2.50-2.51 (m, 4H), 2.63-2.66 (m, 2H), 3.62-3.73 (m, 6H), 6.30- 6.31 (m, IH), 6.87-6.97 (m, 2H), 7.14-7.33 (m, 5H), 7.51-7.53 (m, IH) and 8.41 (bs, IH). Example 10 N-Acetyl naphthalene (9). A solution of amide 8 (0.36 g, 0.99 mmol) in methylene chloride (5 ml) was added fairly rapidly to a suspension of DDQ (0.34 g, 1.5 mmol) in methylene chloride (15 ml) at room temperature. After stirring the black reaction mixture for 0.25 h., it was quenched with NaOH (2N, 7 ml). The organic phase was separated, dried and evaporated to give yellow residue. It was passed through a plug of silica gel to give pure 9 (0.21 g, 59%). 1H NMR (CDC1 3 ) δ 2.37 (s, 3H), 2.59-2.62 (m, 4H), 3.70- 3.79 (m, 6H), 7.35-7.55 (m, 5H), 7.75-7.96 (m, 4H) and 8.66 (bs, IH). Example 11 Naphthyl amine (10). An aqueous solution of NaOH (3N, 6 ml) was added to a stirring solution of 9 (0.195 g, 0.54 mmol) in reagent alcohol (4 ml) and the mixture was refluxed for 5 h. The reaction mixture was cooled, diluted with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 10 as yellow foam (014 g, 80%). 1H NMR (CDC1 3 ) δ 2.59-2.61 (m, 4H), 3.75- 3.80 (m, 6H), 4.28 (bs, 2H), 6.85 (d, J= 7.60 Hz, IH), 7.23-7.26 (m, IH), 7.44-7.51 (m, 3H), 7.75-7.77 (m, IH), 7.82 (d, J= 8.0 Hz, IH), 7.89 (d, J= 8.0 Hz, IH) and 8.67 (d, J= 2.0, IH).

Claims: WHAT IS CLAIMED IS: 1. A process of making a compond of the formula(I) : wherein: the naphthyl ring is further optionally substituted by one or more Ri or R 2 ; X is chosen from a C 5-8 cycloalkyl and cycloalkenyl optionally substituted with one to two oxo groups or one to three C 1- alkyl, C 1- alkoxy or C 1-4 alkylamino chains each being branched or unbranched; aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H- imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C 1-4 alkyl, C 1- alkoxy, hydroxy, nitro, nitrile, amino, mono- or di-(C 1-3 alkyl)amino, mono- or di-(C 1-3 alkylamino)carbonyl, NH 2 C(O), d-6 alkyl-S(O) m or halogen; Y is chosen from a bond and a C 1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C 1- alkyl optionally substituted by one or more halogen atoms; Z is chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl, each being optionally substituted with one to three halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, amino, mono- or di-(C 1-3 alkyl)amino, -6 alkyl-S(O) m , CN, CONH 2 , COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkyl or C 1-6 alkoxy; tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, thiomorpholinyl sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being optionally substituted with one to three nitrile, Cι -6 alkyl, C 1-6 alkoxy, hydroxy, amino, mono- or di-(C 1-3 alkyl)amino-C 1-3 alkyl, CONH , phenylamino-C 1-3 alkyl or C 1-3 alkoxy-C 1-3 alkyl; halogen, C 1-4 alkyl, nitrile, amino, hydroxy, C 1-6 alkoxy, NH 2 C(O), mono- or di(C 1-3 alkyl) aminocarbonyl, mono- or di(C 1-3 alkyl)amino, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C 1-3 alkyl or C 1-5 alkoxyalkyl, pyridinyl-Cι -3 alkyl, imidazolyl-C 1-3 alkyl, tetrahydrofuranyl-C 1-3 alkyl, nitrile-C 1-3 alkyl, carboxamide-C 1- alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkoxy, hydroxy or mono- or di-(Cj -3 alkyl)amino, Cι_ 6 alkyl-S(O) m , or phenyl- S(O) m , wherein the phenyl ring is optionally substituted with one to two halogen, -6 alkoxy, hydroxy, halogen or mono- or di-(C 1-3 alkyl)amino; C 1-6 alkyl-S(O) m , and phenyl-S(O) m , wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkoxy, hydroxy or mono- or di-(C 1-3 alkyl)amino; R 1 and R 2 are independently chosen from: a Cι- 6 branched or unbranched alkyl optionally partially or fully halogenated, C 1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, C 1-3 alkyl-S(O) m optionally partially or fully halogenated and phenylsulfonyl; m is 0, 1 or 2; said process comprising: i) reacting a Z-Y-X-COO-R x ester (II) with a di-ester (III), wherein R x in both (II) and (III) is independently C 1-5 alkyl or aryl, in a suitable solvent and a suitable base and optionally in the presence of an additive at a temperature of about 0 to 200 °C for a reaction time of about 5 min to 24 h, and isolating the compound intermediate (IV): Z-Y-X-COOR X ,- (II) (HI) (IV) ii) hydrolysing the product of step i) with acidic or basic hydrolysis, and decarboxylating under suitable acid conditions at a temperature of about 50 to 200 °C and for about 5 min to 24 hours; followed by esterifying under appropriate conditions with a C 1-5 alcohol; subsequent phenyl nucleophilic addition wherein the phenyl is optionally independently substituted by Ri and R 2 ; cleaving by reductive cleavage under appropriate conditions to form a carboxylic acid compound, and treating with a strong mineral acid optionally in a suitable solvent at RT to 200°C, to form a product intermediate of the formula(V), and isolating the product: (V); iii) reacting the product from step ii) with HNR y R z or it's respective salt thereof, to form an enamine or imine compound ofthe formula(VI) under suitable conditions at about RT for about 1 to 24 h: (V) (VI) wherein R y is Ci-salkyl or hydrogen, R z is C 1-5 alkyl, hydrogen or OH with the proviso that when formula (VI) is an enamine tautomer then R y and R z are both C 1-5 alkyl, or when formula (VI) is an imine tautomer then R z is OH, C 1-5 alkyl or hydrogen and R y is not present: enamine imine iv) where the product of step iii) is an imine, in a one pot reaction acylating and reducing the product (VI); then treating the product of such reaction under oxidizing conditions capable of forming the naphthalene ring in the formula(I), followed by deprotecting under suitable conditions; or where the product of step iii) is an enamine, oxidizing the enamine under suitable oxidizing conditions to form the naphthalene ring, then deprotecting the amino nitrogen to form the formula (I): 2. The process according to claim 1 wherein: X is chosen from a C 5-8 cycloalkyl and cycloalkenyl optionally substituted with one to two oxo groups or one to three Cι -4 alkyl, C 1- alkoxy or C 1-4 alkylamino chains each being branched or unbranched; aryl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C 1- alkyl, nitro, nitrile, mono- or di-(Cι -3 alkyl)amino, mono- or di-(C 1-3 alkylamino)carbonyl, NH 2 C(O), C 1-6 alkyl-S(O) m or halogen; Y is chosen from a bond and a C 1- saturated or unsaturated carbon chain wherein one ofthe carbon atoms is optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C 1-4 alkyl optionally substituted by one or more halogen atoms; Z is chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C 1-3 alkyl, C 1-3 alkoxy, amino, hydroxy, mono- or di- (C 1-3 alkyl)amino or CONH 2 ; tetrahydropyranyl, tefrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, C 1-3 alkyl, C 1-3 alkoxy, hydroxy, amino, mono- or di-(C 1-3 alkyl)arnino or CONH 2 ; nitrile, C 1-6 alkyl-S(O) m , halogen, hydroxy, C 1-4 alkoxy, amino, mono- or di-(C 1-6 alkyl)amino, mono- or di-(C 1-3 alkyl)aminocarbonyl andNH 2 C(O). 3. The process according to claim 2 wherein: X is aryl, pyridinyl, pyrimidinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C 1-4 alkyl, nitro, nitrile, mono- or di-(C 1-3 alkyl)amino, mono- or di-(Q. 3 alkylamino)carbonyl, NH 2 C(O), C 1-6 alkyl-S(O) m or halogen; Y is chosen from a bond and a C 1-4 saturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group; Z is chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl and pyrrolidinyl which are optionally substituted with one to two C 1-2 alkyl or C 1-2 alkoxy; tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl and tetrahydropyrimidonyl which are optionally substituted with one to two C 1-2 alkyl or C 1-2 alkoxy; and C 1-3 alkoxy. 4. The process according to claim 3 wherein X is chosen from pyridinyl and pyrimidinyl, each being optionally independently substituted with one to three C 1-4 alkyl, nitro, nitrile, mono- or di-(Cι -3 alkyl)amino, mono- or di-(C 1-3 alkylamino)carbonyl, NH 2 C(O), C 1-6 alkyl-S(O) m or halogen; Y is chosen from a bond, -CH 2 -, -CH 2 CH 2 -, -C(O)-, -O-, -S-, -NH-CH 2 CH 2 CH 2 - , -N(CH 3 )- and -NH-. 5. The process according to claim 5 wherein: Y is chosen from -CH 2- , -NH-CH 2 CH 2 CH 2 - and -NH- and Z is morpholinyl. 6. The process according to claims 1,2,3,4 or 5 wherein: in step i) : the solvent is aprotic chosen from THF, DME, DMSO, ether, dioxane, CH 2 C1 2 , CHC1 3 , toluene, pyridine and DMF; the base is chosen from NaH, NaNH 2 , Na t-butoxide, NaOH, pyridine, TEA, Na ethoxide, DBU and BuLi; the additive is chosen from DMPU and HMPA; and the reaction time is about 8 h. in step ii): the hydrolysis is acidic; the decarboxylation acidic conditions are cone. H SO 4 in HOAc, the temperature is about 100 °C and the time is about 7 h; the esterification is with CH 3 CH 2 OH; the phenyl nucleophilic addition is via a phenyl Grignard reagent PhMgBr; the reductive cleavage is with HCOONEU / Pd/C / EtOH; the added mineral acid is PPA and at a temperature of 110°C; in step iii): forming an oxime under oxime formation conditions by adding HNR y R z wherein said HNR y R z is the amine salt NH 2 OH.HCl, in EtOH with NaOH for about 18 h; in step iv): the product of step iii) is acetylated with acetic anhydride and acetic acid then reducing compound (VI) with Fe at about 55°C for about 5 hours; the oxidizing conditions are treating the product with DDQ in a nonpolar solvent, at about 0 to 50 °C, at about 0.5 to 10 h. 7. The process according to claim 6 wherein: in step i) : the solvent is THF; the temperature is 60-70 °C; the base is chosen from NaH and Na t-butoxide; the additive is DMPU; and in step iv): for the for the oxidizing step the the nonpolar solvent is methylene chloride, the temperature is about RT and the time is about 5 h.

Inventors: KAPADIA SURESH R, SONG JINHUA J, YEE NATHAN, KAPADIA, SURESH, R., SONG, JINHUA, J., YEE, NATHAN
Applicants: BOEHRINGER INGELHEIM PHARMA, BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.
Application year: 2001
Main classification: C07D213
IPC codes: C07D213, C07D405