WO2005051904A2

WO2005051904A2 - Novel processes for the synthesis of cyclopropyl compounds

Info

Publication number: WO2005051904A2
Application number: PCT/US2004/034943
Authority: WO
Inventors: Srinivasan Raj Nagarajan; Hwang-Fun Lu
Original assignee: Pharmacia LLC
Current assignee: Pharmacia LLC
Priority date: 2003-10-23
Filing date: 2004-10-22
Publication date: 2005-06-09
Anticipated expiration: 2006-04-23
Also published as: WO2005051904A3

Abstract

This invention relates to processes for the preparation of cyclopropyl compounds of Formula: (I) wherein: x is an integer selected from the group consisting of 0, 1 and 2; R1 and R2 are independently selected from the group consisting of H, C1-C6 alkyl, and halo; and R3, R4, R5, R6 and R7 are independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, and halo.

Description

NOVEL PROCESSES FOR THE SYNTHESIS OF CYCLOPROPYL COMPOUNDS

FIELD OF THE INVENTION

[0001] The following invention is directed to methods for the synthesis of cyclopropyl compounds useful, for example, in the scale up synthesis of cyclopropyl α_vβ or dual α_vβ₃/α_vβ₅ antagonists.

BACKGROUND OF THE INVENTION

[0002] Cyclopropyl compounds are known to be useful intermediates for chemical synthesis of a variety of drugs, and particularly as antagonists of the α_vβ₃ integrin. Antagonists of αvβ₃ or dual α_vβ3 αvβ₅ antagonists are useful therapeutic agents for treating many pathological conditions, including the treatment or prevention of osteopenia or osteoporosis, or other bone disorders; neointimal hyperplasia, which can cause artherosclerosis or restenosis after vascular procedures; periodontal disease; the treatment of neoplasia; pathological angiogenesis or neovascularization such as tumor metastasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis, or osteoarthritis. [0003] Cyclopropyl compounds that antagonize the α_vβ₅ and/or the α_vβ₃ receptor have been reprinted in the literature.

[0004] For example, WO 01/96334 (herein incorporated by reference) provides heteroarylalkanoic acid compounds useful as α_vβ₃ and/or α_vβ₅ inhibitors. [0005] WO 97/36858 (herein incorporated by reference) describes cyclopropyl alkanoic acid derivatives useful as α_vβ₃ and/or α_vβ₅ inhibitors. [0006] Cycloalkyl alkanoic acids are also described as α_vβ₃ and/or α_vβ₅ inhibitors, as published in WO 01/96307 (herein incorporated by reference). [0007] Further, methods of synthesis of cycloalkyl alkanoic acids have been published. For instance, WO 01/96307 discloses the synthesis of this key intermediate starting from p-hydroxycinnamic acid (SCHEME 1). SCHEME 1

3. HC1

[0008] In this scheme, the phenolic group was protected as its TBDMS ether and the acid to its TBDMS ester in one step. The ester moiety was reduced to the corresponding allyl alcohol. Simmons-Smith cyclopropanation with diethylzinc/diiodomethane afforded l-(p- silyloxy(TBDM)phenyl)-2-(hydroxy-methyl)cyclopropane. This was oxidized to l-(p- silyloxy(TBDM)phenyl)-2-cyclopropyl-aldehyde and was subjected to wittig reaction to give the enol ether. The enol ether was hydrolyzed to the l-(p-hydroxyphenyl)cyclopropane-2- acetaldehyde. The result of this three-step synthetic manipulation was one carbon homologation of l-(p-hydroxy-phenyl)-2-cyclopropylaldehyde. The l-(p- hydroxyphenyl)cyclopropane-2-acet-aldehyde was oxidized to the acid using Tollen's reagent. The acid was converted to the ester to give 1 -(p-hydroxyphenyl)cyclopropane acetic acid. [0009] However, it would be beneficial to develop a process for the production of cyclopropyl acetic acid with shorter reaction times and higher yields.

SUMMARY OF INVENTION

[0010] It is now provided a more efficient and higher yield means of synthesizing cyclopropyl compounds, and in another embodiment, l-(p-hydroxyphenyl)cyclopropane acetic acid, an intermediate used in the scale up synthesis of cyclopropy; α_vβ₃ or dual α_vβ₃/α_vβ₅ antagonists. [0011] The present invention discloses a method for the preparation of a cyclopropyl amide compound having the structure of Formula I:

wherein: x is an integer selected from the group consisting of 0, 1 and 2; R¹ and R² are independently selected from the group consisting of H, Cι-C₆ alkyl, and halo; R³, R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of H, Ci- C₆ alkyl, and halo; and the method comprises contacting a Weinreb amide compound having the structure of Formula II:

under conditions sufficient for cycloprotination, thereby producing the cyclopropyl amide compound.

[0012] In another embodiment, the present invention describes a method for the preparation of a cyclopropyl aldehyde compound having the structure of Formula III:

wherein: R³, R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of H, Ci- C₆ alkyl, Cι-C₆ alkoxy, and halo; and the method comprises contacting a cyclopropyl amide compound having the structure of Formula IV:

with a reducing agent.

[0013] In another embodiment, the present invention describes a method for the preparation of a cyclopropyl aldehyde compound having the structure of Formula III,

wherein: R³, R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of H, Ci- C₆ alkyl, Cι-C₆ alkoxy, and halo; and the method comprises contacting a cyclopropyl amide compound having the structure of Formula IV,

with a reducing agent to form an alcohol; converting the alcohol to an aldehyde; and contacting the aldehyde with methoxymethylphosphorane.

[0014] In another embodiment, the present invention describes a method for the preparation of a cyclopropyl acetaldehyde compound having the structure of Formula V:

wherein: R³, R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of H, Ci- C₆ alkyl, Cι-C₆ alkoxy, and halo; and the method comprises contacting a cyclopropyl aldehyde compound having the structure of Formula III

with an oxidizing agent to create an acid ester; contacting the acid ester with an alcohol and a mineral acid; and contacting the ester with a Lewis acid. [0015] In another embodiment, the present invention describes a method for the preparation of a cyclopropyl acetamide compound having the structure of Formula VI:

wherein: R³, R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of H, Ci- C₆ alkyl, Cj-C₆ alkoxy, and halo; and the method comprises contacting a acitamide compound having the structure of Formula VII:

with DME, CH₂Ci₂, and a Simmons-Smith reagent.

[0016] In another embodiment, the present invention discloses a process for the preparation of an ester of l-(p-hydroxyphenyl)cyclopropane acetic acid comprising reacting a compound of Formula VIII:

wherein R is

or with a carboxyl-activating compound and a coupling agent to convert R into an amine- reactive intermediate; contacting the amine-reactive intermediate with an amine to form a Weimeb amide; cyclopropanating the Weinreb amide; converting the Weimeb amide to an acid; esterfiying the acid; and deprotecting the phenolic group.

[0017] The process of the present invention provides advantages over the prior art

(Scheme 1), namely: a. In Scheme 2, the number of steps for the cyclopropanation has been reduced from two to one; b. In Scheme 3 and Scheme 4, the number of steps has been reduced from eight to six by the advanced addition of the carbon to the carboxylic acid chain. [0018] This intermediate is used, for example, in the scale up synthesis of non- peptidic selective α_vβ₃ and or α_vβ₅ antagonists of the formula found in WO 01/96307:

DETAILED DESCRIPTION OF THE INVENTION

[0019] Disclosed are methods for the preparation of cyclopropyl compounds, and corresponding acid salts thereof.

Definitions [0020] The following is a list of definitions of various terms used herein:

[0021] As used herein, the term "alkyl" refers to a straight chain or branched chain hydrocarbon radical having from about 1 to about 10 carbon atoms, and in another embodiment from 1 to about 6 carbon atoms. Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.

[0022] As used herein, the term "alkoxy" refers to straight or branched chain oxy containing radicals of the formual -OR¹⁰, wherein R¹⁰ is an alkyl group as defined herein. Examples of alkoxy groups encompassed include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t-butoxy and the like. [0023] As used herein, the term "alkoxyalkyl" refers to alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. [0024] The terms "hydroxy" and "hydroxyl" as used herein are synonymous and are i— OH represented by a radical of the formula °*

[0025] As used herein, the term "halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

[0026] As used herein, the term "carboxyl" or "carboxy" refers to a radical of the formula -COOH. [0027] As used herein the term "carboxyl ester" refers to a radical of the formula -COOR¹¹ wherein R¹¹ is selected from the group consisting of H, alkyl, aralkyl or aryl as defined above.

[0028] As used herein, the term "amino" is represented by a radical of the formula -

NH₂. [0029] As used herein, the term "methylenedioxy" refers to the

radical and the term "ethylenedioxy" refers to the radical

[0030] As used herein, the term "acylamino" refers to a radical of the formula

, wherein R is alkyl, aralkyl or aryl as defined above.

[0031] As used herein, the term "amido" refers to a radical of the formula O II •~ C-NH₂. [0032] As used herein, the term "alkylamino" refers to a radical of the formula -

NHR , wherein R is an alkyl as defined above.

[0033] As used herein, the term "mineral acid" refers to an inorganic acid. In one embodiment of the present invention, the mineral acid is hydrochloric acid or sulfuric acid. [0034] As used therein the term "Weimeb amide" refers to a radical of the formula

[0035] The following is a list of abbreviations and the corresponding meanings as used interchangeably herein: 1H-NMR = proton nuclear magnetic resonance AcOH = acetic acid Bn = benzyl Boc = tert-butoxycarbonyl Cat. = catalytic amount CH₂CI₂ = dichloromethane CH₃CN = acetonitrile CHN analysis = carbon/hydrogen/nitrogen elemental analysis DIBAL = diisobutylaluminum hydride DI water = deionized water DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide EDC = N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide Et = ethyl Etl = ethyliodide Et₂O = diethyl ether Et₃N = triethylamine EtOAc = ethyl acetate EtOH = ethanol g = gram(s) HOBt = 1 -Hydroxybenzotriazole HPLC = high performance liquid chromatography i-Pr = iso propyl i-Prop = iso propyl

K₂CO₃ = potassium carbonate

KOH = potassium hydroxide L = Liter

LiOH = lithium hydroxide

Me = methyl

Mel = methyl iodide

MeOH = methanol Mg = milligram

MgSO₄ = magnesium sulfate ml = milliliter mL = milliliter

MS = mass spectroscopy MTBE = methyl t-butyl ether

N₂ = nitrogen

NaH = sodium hydride

NaHCO₃ = sodium bicarbonate

NaOH = sodium hydroxide NaOMe = sodium methoxide

Na₂PO₄ = sodium phosphate

Na₂SO₄ = sodium sulfate

NH₄HCO₃ = ammonium bicarbonate

NH₄ ⁺HCO₂ ^" = ammonium formate NH₄OH = ammonium hydroxide

NMR = nuclear magnetic resonance

Pd = palladium

Pd/C = palladium on carbon

Ph = phenyl Pt = platinum

Pt/C = platinum on carbon

RPHPLC = reverse phase high performance liquid chromatography

RT = room temperature t-BOC = tert-butoxycarbonyl TFA = trifluoroacetic acid THF = tetrahydrofuran Δ = heating the reaction mixture [0036] In another embodiment, acid salts of the cyclopropyl compounds of the present invention are contemplated. Such acid salts may be hydrochloric, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic and trifluoromethanesulfonic. In one embodiment, the acid salt is (2-{4-[2-(5,6,7,8-tetrahydro-l, 8-naphthyridin-2- yl)ethoxy]phenyl}cyclopropyl) acetic acid hydrochloride.

Synthetic Schemes

[0037] The general synthetic sequences of the present invention are outlined in

Schemes 2-5 and Examples 1-4. Both an explanation of, and the actual procedures for the various embodiments of the present invention are described where appropriate. The following Schemes and Examples are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit.

[0038] The novel method described in SCHEME 2 uses the commercially available p- methoxycinnamic acid, which is converted to the Weinreb amide. Reaction of this amide with sulfur ylide generated by the reaction of trimethylsulfoxonium iodide and sodium hydride afforded the amide of 1 -(p-methoxyphenyl)cyclopropane-2-acetic acid. Conversion of this to 1 -(p-hydroxyphenyl)cyclopropane acetic acid followed the same sequence as above (reduction to aldehyde and homologation, esterification and deprotection). The advantage of this method is the use of trimethylsulfoxonium ylide for the cyclopropanation.

SCHEME 2

[0039] The carboxyl-activating compound used in step 1 of Scheme 2 may be any compound which converts carboxyl (COOH) groups into amine-reactive intermediates, such as active carboxyl moieties (e.g., p-methoxycinnamic acid) or other chemical groups capable of reacting with amines. One class of carboxyl activating compounds useable for this purpose are the carbodiimides (e.g., l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC); dihexylcarbodiimide (DCC); l-ethyl-3-(4-azonia-4,4-dimethylpentyl) carbodiimide iodide (EAC). In at least some applications of the method, l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide hydrochloride (EDC) is the carboyl-activating agent.

Other types of carboxyl-activating compounds which may be useable for this purpose include: isoxazolium derivatives (e.g., N-ethyl-5-phenylisoxazolium-3'-sulfonate (syn. "Woodward's Reagent K"); chloroformates (e.g., ethylchloroformate or p-nitrophenylchloroformate); carbonyldiimadazole (e.g., l,l'-carbon-yldiimidazole); n-carbalkoxydihy-droquinolines (e.g., n-(ethoxycarbonyl)-2-ethoxy- 1 ,2-dihydroquinoline (EEOD) and n-(isobutoxycarbonyl)-2- isobutoxy- 1 ,2-dihydroquinoline (IIDQ).

[0040] For purposes of this application the term "strong base" refers to a substance sufficiently basic to induce cyclization by abstracting a proton from the amide NH2 group. Suitable strong bases include alkali metal hydroxides, such as sodium hydride, potassium hydride, and the like, preferably in powdered form; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like; alkaline earth hydrides, such as calcium hydride, barium hydride, and the like, preferably in powdered form; and other strong bases known in the art. In one embodiment, the strong bases include powdered sodium hydroxide and powdered potassium hydroxide.

[0041] Suitable polar aprotic solvents include dimethylsulfoxide; N,N-disubstituted amides, such as dimethylformamide, dimethylacetamide, l-methyl-2-pyrrolidinone, and the like; ketones, such as acetone, methyl ethyl ketone, and the like; and alcohols, such as methanol, ethanol, propanol, isopropyl alcohol, and the like. In one embodiment, the polar aprotic solvent is dimethylsulfoxide. [0042] For purposes of this application, reducing agents suitable for the conversion of amides to aldehydes. Representative reducing agents include, for example, diisobutyl aluminum hydride.

[0043] Another method of synthesis is described in SCHEME 3. This approach avoids the homologation steps described in the two previous schemes. The β-γ unsaturated acid is synthesized starting from p-anisaldehyde and the phosphorane made from 2- carboxypropyltriphenylphosphonium bromide and sodium hydride using the method described by Sun Lumin and J. R. Falck, Michal L. Schwartzman Tetrahedron Letters, 32 1991, 2315-2318. The Weimeb amide of the acid was then cyclopropanated using Simmons- Smith reagent to give the Weimeb amide of l-(p-methoxyphenyl)cyclopropane-2-acetic acid. The acid was esterified and the phenolic group deprotected using BBr₃ to give the key intermediate, l-(p-hydroxyphenyl)cyclopropaneacetic acid.

SCHEME 3

84%

[0044] The carboxyl-activating compound used in step 2 of Scheme 3 may be any compound which converts carboxyl (COOH) groups into amine-reactive intermediates, as described in Scheme 2.

[0045] The Weimeb amide can be cyclopropanated using Simmons-Smith conditions such as treatment of diiodomethane with Zn—Cu couple or treatment of a dihalomethane with Et₂Zn in solvents such as ether or methylene chloride. In one embodiment, the process is carried out in the presence of metallic zinc catalyst in an ether solvent under anhydrous conditions. The conditions depend on the particular reactants involved but generally they include those known in the literature for the Simmons-Smith reaction (see Org. React. (N.Y.), 1973, 20, 1 and J. Org. Chem., 1985, 50, 4640). [0046] Typically, the process is carried out in the presence of a zinc-copper couple (see J. Chem. Soc, 1978, p. 1025). Zinc-silver, zinc-platinum, and zinc-palladium couples may be substituted for or used in conjunction with the zinc-copper couple (see J. Org. Chem., 1964, 29, 2049).

[0047] Other catalysts which are employed in the process of the invention include the art-recognized nickel and cobalt complexes. Increased yields may be realized if a Lewis acid or alkali halide is used in conjunction with these catalysts.

[0048] The catalyst system for the process of this invention may also comprise a zinc- based couple in the further presence of a metallo-hydride reducing agent. Suitable metallo- hydride reducing agents are described in U.S. Pat. No. 4,472,313, herein incorporated by reference in its entirety.

[0049] While members of the general class of metallo-hydride reducing agents, may be employed, such as lithium aluminium hydride, or alkali metal borohydrides, the preferred metallic hydride reducing agents are those which are soluble in the ether medium, and in another embodiment organometallic hydrides of which suitable classes include those of W²

W'A- ^■H

formula (a): ^w , wherein: A signifies an alkali metal or one equivalent of an alkaline earth metal, e.g. sodium or lithium; and each of W¹, W² and W³ is, independently, a hydrogen atom, or an alkyl or alkoxy radical of 1 to 6 carbon atoms; or an alkoxyalkoxy or alkyleneoxyalkyl radical having from 2 to 6 carbon atoms; provided that at least one of W¹, W² and W³ is other than a hydrogen atom; W⁴

or of formula (b): ^{w A H}, wherein: W⁴ and W⁵, which may be the same or different, each signify a hydrogen atom or an alkyl radical or 1 to 6 carbon atoms; provided that at least one of W⁴ and W⁵ is alkyl. [0050] A suitable hydride reagent of formula (a) is sodium dihydridobis-(2- methoxyethoxy)aluminate (SDBA), which is obtainable commercially under the brand name "Vitride®", or RED-AL®, and has the following structure:

An important property of this hydride reducing agent (VIII) is that it is soluble in a variety of solvents.

[0051] In carrying out the process it is preferred that the zinc and compound of general formula (III) each be present in molar excess, e.g., in a molar ratio of from about 2 to 6 times preferably from about 3.5 to 5 that of the compound of general formula (II). The hydride reducing agent (IX) however, need be present only in catalytic amounts, e.g., from about 0.5% to 3%, or in another embodiment from about 1.0 to 2.0%, of the molar amount of the compound of general formula (II).

[0052] Examples of suitable solvents are diethyl ether, tetrahydrofuran dibutyl ether, dimethoxyethane, toluene, xylene, and mixtures thereof. The reaction may be facilitated by sonocation (the use of ultrasound).

[0053] The temperature at which the reaction is carried out will depend largely on the choice of solvent but it will normally be in the range of from about -20°C. to about 30°C, or in another embodiment, from about -20°C. to about 0°C.

[0054] Another variation of this method is shown in SCHEME 4. Palladium catalyzed butynylation of iodanisole gave 4-(p-methoxyphenyl)-3-butyn-l-ol. Reduction of the triple bond to trans double bond is accomplished by reduction with lithium aluminum hydride. Small amount of cis compound are also formed. Cyclopropanation is accomplished using Simmons-Smith reagent. Oxidation of the alcohol l-(p-methoxyphenyl)cyclopropane-

2-acetic acid is accomplished by treatment with Jones reagent. Esterification and deprotection are carried out as described in SCHEME 3.

[0055] The carboxyl-activating compound used in step 2 of Scheme 4 may be any compound which will convert carboxyl (COOH) groups into amine-reactive intermediates, as described in Scheme 2.

SCHEME 4

[0056] Each one of the schemes provides an advantage over the previous methods of preparation in ease of synthesis, scalability and shorter synthetic sequence. [0057] The synthesis of 2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)-l-ethanol is shown in SCHEME 5. The synthesis of this compound has been described in the literature A. E. Moorman, C. H. Yen, S. Yu, Syn Commun. 17, 1695-1699 (1987), E. M. Hawes and D. G. Wibberley, J. Chem. Soc. (C), 1966, 315 and WO 0033838. Mitsunobu coupling of this compound with the phenolic intermediate is accomplished using polymer supported trphenylphosphine and DEAD. This method has the advantage over the previous methods in purification as the polymer supported triphenyl-phosphineoxide can be filtered off.

SCHEME 5

2 iOH

[0058] The final product is a mixture of two diasteromers. The mixture is separated on a ChiralPak AS column to give two diasteromerically pure compounds. [0059] This invention describes three new methods for preparing the intermediate 1 -

(p-hydroxyphenyl)cyclopropane acetic acid. These methods each have advantage over the previously known procedures. This invention also describes a modified Mitsunobu coupling procedure, which is an improvement over the Mitsunobu procedure described in WOO 196307 A2. An HPLC based separation method is also described for obtaining pure diastereomers. EXAMPLE 1

Ethyl [2-(4-hydroxyphenyl)cyclopropyl]acetate.

The title compound is prepared according to previously described SCHEME 2.

STEP 1 [0060] (2E)-N-Methoxy-3-(4-methoxyphenyl)-N-methylprop-2-enamide "

[0061] Method A: To a solution of trans - 4-methoxycinnamic acid (15 g, 84 mmol) in dry DMF (100 mL) was added 4-methylmorpholine (11 g, 92 mmol) at -5°C and stirred 25 minutes at -5°C. To the above solution was added isobutylchloroformate (12.6g, 92 mmol) and stirred for 10 minutes at -5°C followed by adding N, O-dimethylhydroxyamine HC1 (9 g, 92 mmol) neat then 4-methylmorpholine (11 g, 108mmol). During the addition, temperature went from -5°C to 10°C. Reaction mixture was stirred 6 hours at room temperature. Reaction was quenched with HC1 (0.5 N, 200 mL) at 4°C then extracted with CH₂CI₂ (3X250mL). Combined organic solution was washed with NaOH (0.5 N, 2x200 mL), brine (1x200 mL). Concentrated under vacuum. Concentrated residue was brought up to ether (600 mL) and washed with half saturated NaCl (2x200 mL), brine, dried over Na₂SO₄, concentrated and dried to give 19 g oil. The crude material was used for next reaction with further purification. NMR (CDC13) 57.65 (d, 1H, J = 15.7Hz), 7.5 (m, 2H), 6.9 (m, 3H), 3.8 (s, 3H), 3.75 (s, 3H), 3.3 s, 3H). HRMS calcd for Cι₂H₁₅NO₃ (M+H): 222.1125. Found 222.1143. [0062] Method B: The above compound is also prepared by the following alternate procedure. [0063] To a solution of trans-4-methoxycinnamic acid (40 g, 0.22 mole) in dry DMF

(300 mL) was added EDC (47.2 g, 0.22 mol) and HOBT (33.28 g, 0.22 mol), stirred at room temperature for one hour. To the above solution was added solid N, O- dimethylhydroxylamine HC1 (24 g, 0.22 mole) followed by triethylamine (34.4 mL, 0.22 mol). The reaction mixture was stirred overnight at room temperature. Reaction mixture was brought up to CH₂CI₂ (700 mL) and washed with IN HC1 (2x300 mL), saturated NaHCO₃ (2x300 mL), brine (2x300 mL). Dried over MgSO . Concentrated residue was brought up to ether (500mL) and washed with half saturated NaCl (2xl50mL), brine (2xl50mL), dried over MgSO₄. Concentrated and dried to give 40 g clear oil. NMR (CDCI₃) δ 7.65 (d, 1H, J = 15.7Hz), 7.5 (m, 2H), 6.9 (m, 3H), 3.8 (s, 3H), 3.3 (s, 3H).

STEP 2

[0064] N-Methoxy-2-(4-methoxyphenyl)-N-methylcyclopropanecarboxamide

(reference: Can. J. Chem. 77:1123-1136, 1999)

[0065] To a solution of trimethylsulfoxonium iodide (38g, 173 mmol) in DMSO (100 mL) under nitrogen was cooled with a room temperature water bath. To the solution was added NaH, 60% in mineral oil (7 g, 170 mmol) portion wise over 20 minutes. The suspension solution was stirred for one hour. A solution of olefin amide (19 g, 86 mmol) in DMSO (100 mL) was added and the reaction mixture was stirred for 6 hours. The reaction mixture was quenched by pouring it into saturated NH₄C1 (500 mL). The mixture was extracted with CH2CI2 (3x300 mL). The combined organic layer was washed with brine, dried over Na2SO4, filleted and concentrated. The concentrated residue was chromatographed on silica gel (30% to 40% ethyl acetate in hexane) to give 14.3 g oil (71%). NMR (CDC1₃) δ 7.1 (m, 2H), 6.8 (m, 2H), 3.8 (s, 3H), 3.7 (s, 3H), 3.2 (s, 3H), 2.4-2.5 (m, 1H), 2.3-2.4 (m, 1H) 1.5-1.6 (m, 1H), 1.2-1.3 (m, 1H). HRMS calcd for Cι₃H,₇NO₃ (M+H): 236.1281. Found 236.1287. STEP 3

[0066] 2-(4-Methoxyphenyl)cyclopropanecarbaldehyde

[0067] To the cycloproplyl amide (15.6 g, 66 mmol) in dry THF (lOOmL) under nitrogen at -78°C was added DIBAL (1M in hexane, 100 mmol). The reaction was complete in one hour. Reaction mixture was poured into saturated potassium sodium tartrate (250 mL) and stirred for one hour. Solution was extracted with ethyl acetate (3x250 mL). Combined organic solution was washed with brine and dried over Na2SO4 concentrated and dried to give 12 g white solid. NMR (CDC1₃) δ 9.3 (d, IH, J=4.7 Hz), 7.0 (m, 2H), 6.8 (m, 2H) 3.8 (s, 3H), 2.6 (m, IH), 2.1 (m, IH), 1.7 (m, IH), 1.0 (m, IH). M+H=176. The crude material was used for the next reaction without further purification.

STEP 4 [0068] [2-(4-Methoxyphenyl)cyclopropyl]acetaldehyde.

[0069] To the solution of (methoxymethyl)triphenylphosphonium chloride (24.5 g,

0.071 mole) in dry THF (50 mL) at 4°C was added lithium bis(trimethylsilyl)amide (1M in THF, 72 mL). The reaction mixture was stirred for 20 minutes at 4°C. To the solution was added the aldehyde (8.4 g, 0.0477 mol) from step 3 in THF (100 mL). Ice bath was removed 30 minutes later and reaction was stirred one hour at room temperature. The reaction mixture was poured into water (350 mL). Extracted with ether (3x200 mL), washed with brine, dried over Na₂SO₄. Concentrated. The concentrated residue was chromatographed on silica gel (5% ethyl acetate in hexane) to remove the polar spot. Fractions containing top two spots (very close together) were combined, dried to give 9.5 g. To the resulting methoxy olefin in THF (50 mL) was added HC1 (1.5N, 50 mL) and refluxed for 2 hours. The reaction was cooled to room temperature. Neutralized by adding sat/NaHCO₃ slowly and extracted with ether. Combined organic solution was concentrated and chromatographed on silica gel (20% ethyl acetate in hexane) to give 7.1 g (79%) oil. NMR (CDC1₃) δ 9.8 (t, IH, J=1.9 Hz), 7.0 (m, 2H), 6.8 (m, 2H), 3.85 (s, 3H) 2.5 (m, 2H), 1.7 (m, IH), 1.25 (m, IH), 1.0 (m, IH), 0.8 (m, IH).

STEP 5

[0070] [2-(4-Methoxyphenyl)cyclopropyl] acetic acid

[0071] To the aldehyde (15.5 g, 0.08 mole) from STEP 4 in ethanol (100 mL) was cooled in ice bath then added silver nitrate (27.4g in 36mL distilled water) followed by NaOH (12.8 g in 36 mL distilled water). Ice bath was removed 20 minutes later. The reaction was stirred 30 minutes at room temperature. Solid in the reaction mixture was filtered out through celite and washed with water (200 mL). Filtrate was concentrated to remove ethanol. The aqueous solution was washed with ether (3x100 mL) then acidified by adding concentrated HC1. The acidified aqueous solution was extracted with CH₂C1₂.

Combined organic solution was washed with brine, died over NA2SO4. Dried to give 15.5 g (92%) yellow solid. NMR (CD3OD) δ 7.0 (m, 2H), 6.8 (m, 2H), 3.7 (s, 3H), 2.3 (m, 2H), 1.7 (m, IH), 1.2 (m, IH), 0.9 (m, IH), 0.7 (m, IH). HRMS calcd for C12H14O3 (M-H): 205.0859. Found 205.0858.

STEP 6

[0072] Ethyl [2-(4-methoxyphenyl)cyclopropyl]acetate

[0073] To the acid from step 5 (15.4 g, 75 mmol) in ethanol (40 mL) was added 4N

HC1 in dioxane (50 mL) under nitrogen. The reaction mixture was stirred 3 hours at room temperature. The reaction mixture was concentrated. The concentrated residue was dissolved in ethyl acetate (450 mL) and washed with saturated NaHCO3, brine, dried over Na2SO4 to give 18 g oil. NMR (CDC1₃) δ 7.0 (m, 2H), 6.8 (m, 2H), 4.2 (q, 2H, J=7.1 Hz), 3.75 (s, 3H), 2.3-2.4 (m, 2H), 1.7 (m, IH) 1.2-1.4 (m, 4H), 0.9 (m, IH), 0.7 (m, IH). HRMS calcd for C14H18O3 (M+H): 235.1329. Found: 235.1358

STEP 7 [0074] Ethyl [2-(4-hydroxyphenyl)cyclopropyl] acetate

[0075] To the methoxy ethyl ester (6.7 g, 29 mmol) in CH₂C1₂ (50 mL) at -2°C was added BBr3 (1 M in CH₂C1₂, 57.3 mL). Temperature was kept under 2°C during the addition. The reaction was stirred 50 minutes at 2°C. The reaction was quenched with ethanol (100 mL) very slowly. Temperature was kept under 14°C. The reaction was stirred one hour at room temperature. Saturated NaHCO was added at 0°C. Ethanol was removed. Extracted with CH₂C1₂ (3x150 mL), brine, MgSO . Dried to give 6.5 g dark oil. Chromatographed on silica gel (35% ethyl acetate in hexane) to give 5.4 g oil (86%). NMR (CDC1₃) δ (m, 2H), 6.7 (m, 2H), 4.2 (q, 2H, J=7.1 Hz), 2.4 (d, 2H), 1.7 (m, IH) 1.2-1.4 (m, 4H), 0.9 (m, IH), 0.7 (m, IH). HRMS calcd for C₁₃H₁₆O₃ (M+H): 221.1172. Found 221.1151.

EXAMPLE 2 Ethyl [2-(4-hydroxyphenyl)cyclopropyl]acetate.

The title compound is prepared according to previously described SCHEME 3.

STEP 1 [0076] 4-(p-Methoxyphenyl)-but-3-enoic acid.

[0077] A mixture of 2-carboxypropyltriphenyl-phosphonium bromide (210 g, 506 mmol) and p-anisaldehyde (62.1 mL) in dimethylsulfoxide (600 mL) was added slowly to a suspension of sodium hydride (41 g, 60% suspension in mineral oil) in tetrahydrofuran (300 mL). The reaction mixture was stirred mechanically for 18 h and was quenched with water (1 L) followed by addition of sodium hydroxide (100 mL, 2.5M) and was extracted with ether. The aqueous layer was acidified to afford oil. The oil was extracted with ethyl acetate (2 L), dried and was concentrated. The residue was added hexane and ethyl acetate and was cooled. The desired product precipitated and was filtered and was washed with hexane to afford 90 g (92%) as a yellow crystalline solid. Η NMR (CD₃OD) δ 7.29 (m, 2H), 6.83 (m, 2H), 6.42 (d, IH, J=15.8 Hz), 6.11-6.18 (m, IH), 3.76 (s, 3H), 3.17 (m, 2H). Anal. Calcd for CI 1H12O3: Mol Wt, 192.0786. Found: Mol. Wt, 192.1176 (HRMS).

STEP 2 [0078] (N-Methoxy-N-methyl)-4-(p-Methoxyphenyl)-but-3-enamide.

[0079] A mixture of 4-(p-methoxyphenyl)-but-3-enoic acid (81.51 g, 0.425 mole),

HOBt (57.6 g), EDC (81.4 g) in dimethylformamide (1.5 L) was stirred mechanically. N- methyl-O-methylhydroxylamie hydrochloride (41.5 g) was added followed by triethylamine (120 mL) to the reaction mixture and stirring continued for 18 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (1L) and sodium bicarbonate (saturated solution, 0.75 L). The organic layer was washed with water (1 L), brine (1 L), dried and was concentrated to afford a residue. A solution of the residue was passed through a thick pad of silica gel (40% ethyl acetate in hexane) to afford 40.8 g (39%) of the desired product. 'H NMR (CD₃OD) δ 7.29 (m, 2H), 6.83 (m, 2H), 6.44 (d, IH, J=15.8 Hz) 6.11-6.18 (m, IH), 3.75 (s, 3H), 3.74 (s, 3H), 3.35 (m, 2H), 3.19 (s, 3H). Anal. Calcd for C₁₃Hι₇NO₃: Mol Wt, 235.1208. Found: Mol. Wt, 236.1255 (M+H, HRMS). STEP 3

[0080] N-Methoxy-N-methyl- 1 -(p-Methoxyphenyl)-2-cyclopropaneacetamide .

[0081] Iodochloromethane (247 g, 102 mL, 1.4 Mol) was added to a solution of dimethoxyethane (73 mL) in dichloromethane (1 L) at -15°C. A solution of diethylzine (704 mL, 1M in hexane) was added slowly maintaining the temperature at -15°C. The reaction mixture was stirred for 20 min and (N-methoxy-N-methyl)-4-(p-methoxyphenyl)-but-3- enamide 82.06 g (0.349 mmol) in dichloromethane (500 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 18h. It was quenched with hydrochloric acid (IN, 1 L). The organic layer was washed with water (1L), brine (1L), dried and was concentrated. The residue was passed through a pad of silica gel (30% ethyl acetate in hexane) to afford 89 g (98%) of the desired product as oil. Η NMR (CD₃OD) δ 7.03 (d, 2H, J=8.7 Hz), 6.78 (d, 2H, J=8.6 Hz), 3.75 (s, 3H), 3.66 (s, 3H), 3.18 (s, 3H), 2.40- 2.61 (m, 2H), 1.7-1.73 (m, IH), 1.32-1.37 (m, IH), 0.88-0.94 (m, IH), 0.78-0.83 (m, IH).

Anal. Calcd for C₁₄H19NO₃: Mol Wt, 249.1365. Found: Mol. Wt, 250.1405 (M+H, HRMS).

STEP 4

[0082] l-(p-Methoxyphenyl)cyclopropane-2-acetic acid.

[0083] Sodium hydroxide (100 mL, 2.5 M) was added to a solution of N-methoxy-N- methyl-l-(p-methoxyphenyl)-2-cyclopropaneacetamide (89 g) in ethanol (300 mL) and was stirred for 24 hours at room temperature. The solvent was removed in vacuo and the residue was portioned between ether (400 mL) and water (1 L). The aqueous layer was acidified to afford 65 g (88%) of the desired product as a crystalline powder. 1H NMR (CD3OD) δ 7.02 (d, 2H, J=8.6 Hz), 6.79 (d, 2H, J=8.6 Hz), 3.76 (s, 3H), 2.39-2.50 (m, 2H), 1.7-1.76 (m, IH), 1.29-1.41 (m, IH), 0.92-0.97 (m, IH) 0.80-0.84 (m, IH). Anal. Calcd for Cι₂H_MO₃: Mol Wt, 206.0943. Found: Mol. Wt, 206.0901.

STEP 5

[0084] Ethyl l-(p-methoxyphenyl)cyclopropane-2-acetate.

[0085] A mixture of l-(p-methoxyphenyl)cyclopropane-2-acetic acid (65 g, 301 mmol), ethanol (500 mL) and hydrochloric acid (10 mL) was heated at reflux for 18 hours. The solvent was removed in vacuo and the residue in ether (500 mL) was washed with saturated bicarbonate (200 mL), dried and was concentrated to afford 60 g (82%) of the desired product as oil. Η NMR (CD₃OD) δ 7.02 (d, 2H, J=8.5 Hz), 6.79 (d, 2H, J=8.5 Hz), 4.14 (q, 2H, J=7.2 Hz), 3.76 (s, 3H), 2.30-2.40 (m, 2H), 1.69-1.73 (m, IH), 1.23-1.31 (m, 4H), 0.89-0.94 (m, IH), 0.76-0.81 (m, IH). Anal. Calcd for C,₄H₁₈O₃: Mol Wt, 234.1256. Found: Mol. Wt, 252.1582 (M+NH4, HRMS).

STEP 6 [0086] Ethyl 1 -(p-hydroxyphenyl)cyclopropane-2-acetate.

[0087] Boron tribromide (246 mL, 1M) in dichloromethane was added slowly to a solution of ethyl l-(p-methoxyphenyl)cyclopropane-2-acetate (60 g, 246 mmol) in dichloromethane (1L) at 0°C and the reaction mixture was stirred at room temperature for 18 h. It was cooled to 0°C and was quenched with excess ethanol. The reaction mixture was concentrated and the residue in ethyl acetate (1 L) was washed with saturated sodium bicarbonate (500 mL), washed with brine (500 mL), dried and was concentrated. The residue was purified by passing through a thick pad of silica and eluting with 20% ethyl acetate in hexane to afford 50.2 g (89%) of the desired product. Η NMR (CD₃OD) δ 6.93 (d, 2H, J=8.6 Hz), 6.71 (d, 2H, J=8.6Hz), 4.15(q, 2H, J=7.1 Hz), 2.37 (d, 2H, J=7.2 Hz), 1.66-1.71 (m, IH) 1.23-1.28 (m, 4H), 0.87-0.91 (m, IH), 0.75-0.79 (m, IH). Anal. Calcd for C₁₃H₁₆O₃: Mol. Wt, 220.1099. Found: Mol. Wt, 238.1410 (M+NH4, HRMS).

EXAMPLE 3 Ethyl [2-(4-hydroxyphenyl)cyclopropyl]acetate.

The title compound was prepared according to previously described SCHEME 4.

STEP 1 [0088] 4-(p-Methoxyphenyl)-3-butyn- 1 -ol.

[0089] A solution of 4-iodoanisole (200 g, 0.8547 mole) and 3-butyn-l-ol (64 mL) in triethylamine (1 L) was degassed and stirred using mechanical stirrer under nitrogen. A mixture of dichlorobis(triphenylphosphine) Palladium (II) (4.80 g), and cuprous iodide (2.46 g) was added to the mixture. The reaction mixture was slowly warmed up and reached the boiling point of triethylamine in 45 minutes. The reaction cooled down to room temperature in 90 minutes and the reaction mixture was poured in to water (1L) and ethyl acetate (1.5 L). The organic layer was washed with water (1L), brine (1L), dried and was concentrated. The residue was purified using a thick pad of silica gel (30% ethyl acetate in hexane) to afford 120 g (80%) of the desired product as a crystalline solid. 1H NMR (CD₃OD) δ 7.28 (d, 2H, J=8.7 Hz), 6.82 (d, 2H, J=8.7 Hz), 3.76 (s, 3H) 3.68 (t, 2H, J=6.7 Hz), 2.56 (t, 2H, J=6.8 Hz). Anal. Calcd for C_uHι₂O₂: Mol. Wt, 176.0837. Found: Mol. Wt, 176.0839. STEP 2

[0090] 4-(P-Methoxyphenyl)-3-buten-l-ol.

[0091] LAH (250 mL, 1M) was added slowly to a solution of 4-(p-methoxyphenyl)-3- butyn-1-ol (43.83 g, 249 mmol) at 0°C. The temperature was maintained at 0°C during the addition and for additional 10 minutes. The reaction mixture was then heated at reflux for 4h and cooled again to 0°C. A solution of sodium hydroxide (2.5 M) was carefully added until the supernatant was clear and the reaction mixture was heated at reflux for 5 min, then cooled and filtered. The filtrate was concentrated and recrystallized from hexane ethyl acetate to afford the desired trans alcohol. A small percentage of cis isomer was observed in the NMR and varying amounts of cis isomer was obtained with increasing amounts of the starting material. Η NMR (CD₃OD) δ 7.26 (m, 2H), 6.81 (m, 2H), 6.38 (d, IH, J=15.9 Hz), 6.05- 6.13 (m, IH), 3.75 (s, 3H), 3.63 (t, 2H, J-6.7 Hz), 2.38 (m, 2H). Anal. Calcd for C_uHι₄O₂: Mol. Wt, 178.0994. Found: Mol. Wt, 178.0991.

STEP 3 [0092] l-(p-Methoxyphenyl)-2-(2-hydroxyethyl)cyclopropane.

[0093] Iodochloromethane (93.2 g, 0.528 mmol) was added to a solution of dimethoxyethane (27.6 mL) in dichloromethane (400 mL) at -15°C. A solution of diethylzinc (264 mL, 1M in hexane) was added slowly maintaining the temperature at -15°C. The reaction mixture was stirred for 20 min and 4-(p-methoxyphenyl)-3-buten-l-ol (23.5 g, 132.02 mmol) in dichloromethane (200 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 18h. It was quenched with hydrochloric acis (IN, 200mL). The organic layer was washed with water (1L), brine (1L), dried and was concentrated. The residue was passed through a pad of silica gel (30% ethyl acetate in hexane) to afford 20 g (79%) of the desired product as oil. Η NMR (CD₃OD) δ 6.95 (m, 2H), 6.75 (m, 2H), 3.71 (s, 3H) 3.64 (t, 2H, J=6.6 Hz), 1.54-1.61 (m, 3H), 0.68-0.99 (m, 3H). Anal. Calcd for Cι₂Hι₆O₂: Mol. Wt. 192.1150. Found: Mol. Wt, 192.1163

STEP 4

[0094] l-(p-Methoxyphenyl)cyclopropane-2-acetic acid.

[0095] Jones reagent (500 mL) was added to a solution of l-(p-methoxyphenyl)-2-(2- hydroxyethyl)cyclopropane (70 g) in acetone (IL) and was stirred for lh. Isopropyl alcohol (200 mL) was added and the reaction mixture was filtered and the filtrate was concentrated. The residue in ethyl acetate (2 L) was extracted with aqueous sodium hydroxide (500 mL). The aqueous layer was acidified and was filtered to afford 30 g of the desired product as a solid. Η NMR (CD₃OD) δ 7.02 (d, 2H, J=8.6 Hz), 6.79 (d, 2H, J=8.6 Hz), 3.76 (s, 3H), 2.39-2.50 (m, 2H), 1.7-1.76 (m, IH), 1.29-1.41 (m, IH), 0.92-0.97 (m, IH), 0.80-0.84 (m, IH). Anal. Calcd for Cι₂Hι₄O₃: Mol. Wt, 206.0943. Found: Mol. Wt, 206.0901.

STEP 5 and STEP 6

[0096] Ethyl l-(p-hydroxyphenyl)cyclopropane-2-acetate.

[0097] Starting from l-(p-methoxyphenyl)cyclopropane-2-acetic acid, the desired product was obtained using the procedure described in STEPS 5 and 6 for EXAMPLE 2.

EXAMPLE 4

(2-{4-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethoxy]phenyl}cyclo-propyl)acetic acid hydrochloride.

The title compound was prepared according to previously described SCHEME 5.

STEP 1

[0098] 2-Methyl-l,8-naphthyridin

[0099] To a solution of 2-amino-3-pyridinecarboxaldehyde (2 g, 16 mmol) in ethanol

3 mL) was added acetone (1.9 g, 32 mmol) and piperidine (0.34 g, 4 mmol and the reaction mixture was refluxed 24 hours. Reaction mixture was cooled to room temperature then concentrated in vacuum. Ether was added to concentrated residue. Solid was filtered and dried to give 1.62 g (69%) yellow solid. NMR (CD₃OD) δ 8.39-8.99 (m, IH), 8.36-8.39 (m, IH), 8.30 (d, 2H, J = 8.33 Hz), 7.52-7.58 (m, 2H), 2.76 (s, 3H). M + H - 145.

STEP 2 [00100] 2-Methyl-5,6,7,8-tetrahydro-l,8-naphthyridine

[00101] To a solution of 2-methyl-l ,8-naphthyridine (2 g, 13.9 mmol) in ethanol (35 mL) was added 10% Pd/C, and the reaction mixture was stirred under H₂ (10 psi) for 24 hours. Palladium was filtered out through celite and washed with excess ethanol. The filtrate was concentrated under vacuum to give 1.7 g (83%) pink solid. NMR (CD₃OD) δ 7.07 (d, IH, J = 7.38 Hz), 6.32 (d, IH, J = 7.25 Hz), 3.36-3.33 (m, 2H), 2.76-2.65 (m, 2H), 2.22 (s, 3H), 1.87-1.82 (m, 2H). M+H=149.15. STEP 3 [00102] 2-Methyl-8-(tert-butoxycarbonyl)-5 ,6,7,8-tetrahydro- 1 ,8-naphythyridine

[00103] 2-methyl-5,6,7,8-tetrahydro-l ,8 naphthyridine (9.5 g, 0.064 mol) and di-tert- butyl dicarbonate (27.8 g, 0.12 mol), are dissolved in methylenechloride (20 mL). The mixture was concentrated under vacuum. The concentrated residue was heated at 55 °C overnight, the reaction mixture was purified on silica gel (30% ethyl acetate in hexane) to give 8 g (50 %) solid. Η NMR (CDDI₃) δ7.29 (d, IH, J = 7.6 Hz), 6.81 (d, IH, J = 7.6 Hz), 3.75 (t, 2H, J=6.0 Hz), 2.72 (t, 2H, J=6.6 Hz), 2.49 (s, 3H), 1.91 (t, 2H, J=6.0 Hz).

STEP 4 [00104] Ethyl [8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro- 1 ,8-naphthyridin-2- yl] acetate

[00105] To a solution of 2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-l,8- naphthyridine (1.4 g, 5.6 mmol) and diethyl carbonate (2.5 g, 20 mmol) in THF (10 mL) was added LDA (8 mL of 2M solution in hexane) at -78 °C and stirred at -78 °C for 40 minutes. The reaction was quenched with saturated NH₄C1 and extracted with ethyl acetate (2x100 mL). Combined organic solution was concentrated and purified on silica gel column to give 1.5 g (83%) yellow oil. NMR (CD₃OD) δ 7.39 (d, IH, J = 7.4 Hz), 7.0 (d, IH, J = 7.61 Hz), 4.20-4.10 (m, 2H), 3.80-3.74 (m, 4H), 2.75 (t, 2H, J = 6.59 Hz), 1.97-1.88 (m, 2H), 1.51 (s, 9H), 1.25 (t, 3H, J = 7.1 Hz). M + H = 321.

STEP 5 [00106] 2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethanol.

[00107] To a solution of ethyl [8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro- 1 ,8- naphthyridin-2-yl] acetate (3.8 g, 11.8 mmol) in THF (20 mL) was added LiBH₄ (7.6 mL of 2M solution in hexane, 15.2 mmol), the reaction was refluxed 3 hours. The reaction mixture was cooled in ice bath and quenched with water. The mixture was extracted with ethyl acetate (3x50 mL). The combined organic solution was dried over MgSO₄, concentrated and dried under vacuum to give 2.9 g oil. The oil was taken up in methylenechloride (10 mL) and 4N HC1 in dioxane (10 mL) was added. The solution was stirred 4 hours at room temperature then concentrated under vacuum. To the concentrated residue was added 1 :1/1N NaOH:brine (50 mL) and extracted with methylenechloride (3x80 mL). The combined organic solution was concentrated and purified on silica gel to give 1 g (47%) oil. NMR (CD₃OD) δ 7.10 (d, IH, J = 7.38 Hz), 6.36 (D, lh, J = 7.4 Hz), 3.77 (t, 2H, J = 6.8 Hz), 3.45 (t, 2H, J = 5.57 Hz), 2.71-2.66 (M, 4H), 1.88-1.82 (m, 2H). M + H = 179

STEP 6

[00108] Ethyl (2-{4-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)ethoxy]phenyl}cyclo-propyl)acetate.

[00109] To a solution of 2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)-l -ethanol (3.9 g,

22 mmol) and PPI1₃ polymer bound (8.9 g, 22 mmol) in dry THF (20mL) was added ethyl 1- (p-hydroxyphenyl)cyclopropane-2-acetate (3.2 g, 14.5 mmol) in dry THF (30mL) followed by diisopropyl azodicarboxylate (4.8 mL, 22 mmol). The reaction mixture was stirred at room temperature. After 18 hours PPI1₃O polymer was filtered through celite and washed with excess THF. The filtrate was concentrated and chromatographed on silica gel (30% ethyl acetate in hexane) to give 3g (54%) yellow solid. NMR (CD₃OD) δ 7.11 (d, IH, J = 7.2 Hz), 6.98-6.95 (m, 2H), 6.75 (m, 2H), 6.43 (d, IH, J=7.4 Hz), 4.17-4.09 (m, 4H), 3.35 (t, 2H, J = 5.5 Hz), 2.91 (t, 2H, J = 6.8 Hz), 2.68 (t, 2H, J=6.2 Hz), 2.42-2.29 (m, 2H), 1.88-1.82 (m, 2H), 1.71-1.66 (m, IH), 1.24-1.13 (m, 4H), 0.88-0.84 (m, IH), 0.78-0.74 (m, IH). HRMS calcd for C₂₃H₂₈N₂O₃ (M+H): 381.2173. Found 381.2193. STEP 7

[00110] (2-{4-[2-(5,6,7,8-Tetrahydro-l,8-naphthyridin-2- yl)ethoxy]phenyl}cyclopropyl)-acetic acid trifluoroacetate.

[00111] The ethyl ester (3.7 g, 9.8 mmol) was dissolved in 40 mL 50% acetonitrile in water in LiOH (1.64 g, 39 mmol) was added. The reaction mixture was heated at 50 °C for two hour then acidified by adding TFA. The residue was purified on reverse phase HPLC to give 3 g (66%) clear oil. NMR (400 MHz CD₃OD) δ 7.57 (d, 1 H, J = 7.4 Hz), 7.01-6.98 (m, 2 H), 6.79-6.76 (m, 2 H), 6.70 (d, 1 H, J = 7.4 Hz), 4.22 (t, 2 H, J = 6.0 Hz), 3.48 (t, 2H, J = 5.71 Hz), 3.10 (t, 2 H, J = 5.98 Hz), 2.80 (t, 2 H, J = 6.24 Hz), 2.88-2.40 (m, 2H), 1.96-190 (m, 2H), 1.71-1.68 (m, IH), 1.24-1.20 (m, IH), 0.88-0.85 (m, 1 H), 84-0.76 (m, 1 H). HRMS calcd for C₂ιH₂₄N₂O₃ (M+H): 353.1865. Found 353.1876.

STEP 8

[00112] (2-{4-[2-(5,6,7,8-Tetrahydro-l,8-naphthyridin-2- yl)ethoxy]phenyl}cyclopropyl)-acetic acid hydrochloride

[00113] A. The product from STEP 7 (6g, 13 mmol was dissolved in 50% CH₃CN in water (100 mL). The solution was passed through a Bio-Rad AG 2-X8 (200-400 Mesh, chloride form, 100 g) column. The column was eluted with 50% CH₃CN in water. The collected solution was lyophilized to give 4.8 g yellow solid (96%). NMR (400 MHz, CD₃OD) δ7.59 (d, IH, J=7.2 Hz), 7.01-6.98 (m, 2H), 6.79-6.76 (m, 2H), 6.71 (d, IH), 4.22 (t, 2H), 3.48 (t, 2H), 3.10 (t, 2 H), 2.80 (t, 2H, J = 6.2 Hz), 2.40-2.28 (m, 2H), 1.96-1.90 (m, 2H), 1.71-1.68 (m, IH), 1.24-1.20 (m, IH), 0.88-0.85 (m, IH), 0.84-0.76 (m, IH). [00114] B. The separation of diasteromers of ethyl (2-{4-[2-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)ethoxy]-phenyl}cyclopropyl)acetate: The isomeric mixture of ethyl (2-{4- [2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethoxy]phenyl}cyclo-propyl)acetate (48 g) was separated on ChiralPak AS column (isopropyl-alcohol:heptane:diethylamine/30:70:0.1) to give 21 g ethyl ester of isomer A and 20 g ethyl ester of isomer B. The ethyl ester of isomer A (10 g, 26 mmol) was dissolved in 50% acetonitrile in water (100 mL) then treated with lithium hydroxide (4.4 g, 104 mmol). The solution was heated at 55°C for 3h. The solution was then cooled to room temperature and acidified by adding TFA. The crude material was purified on reverse phase HPLC to give 11 g TFA salt to isomer A of (2-{4-[2-(5,6,7,8- tetrahydro-l,8-naphythyridin-2-yl)ethoxy]phenyl}cyclopropyl)acetic acid. The TFA salt was passed through Bio-Rad AG 2-X8 (200-400 Mesh, Chloride form, 100 g) column and was eluted with 50% acetonitrile in water to give 9.5 g (94%) HC1 salt of isomer A of (2-{4-[2- (5,6,7, 8-tetrahydro-l,8-naphthyridin-2-yl)ethoxy]phenyl}cyclopropyl)acetic acid. NMR (400 MHz, CD₃OD) δ 7.57 (d, IH, J = 7.4 Hz), 7.0 (d, 2H, J + 8.6 Hz), 6.8 (d, 2H, J = 8.6 Hz), 6.71 (d, IH, J = 7.4 Hz), 4.22 (t, 2H, J = 6.0 Hz), 3.48 (t, 2H, J = 5.6 Hz), 3.10 (t, 2H, J = 5.9 Hz), 2.80 (t, 2H, J = 6.2 Hz), 2.40-2.28 (m, 2H), 1.96-1.90 (m, 2H), 1.71-1.67 (m, IH), 1.22- 1.18 (m, IH), 0.88-0.84 (m, 1 H), 0.80-0.76 (m, IH). HRMS calcd for C₂ιH₂₄N₂O₃ (M+H): 353.1860. Found 353.1864.

[00115] C. The ethyl ester of isomer B (10 g, 26 mmol) was hydrolyzed and converted to 9.1 g (89%) HC1 salt by using the above procedure. NMR (400 MHz, CD₃OD) δ 7.59 (d, IH, J = 7.4 Hz), 7.0 (d, 2H, J = 8.6 Hz), 6.8 (m, 2H), 6.71 (d, IH, J = 7.4 Hz), 4.22 (t, 2H, J = 6.0 Hz), 3.48 (t, 2H, J = 5.6 Hz), 3.11 (t, 2H, J = 5.9 Hz), 2.80 (t, 2H, J = 6.2 HZ), 2.40-2.28 (m, 2H), 1.96-1.90 (m, 2H), 1.71-1.67 (m, IH), 1.22-1.18 (m, IH), 0.88-0.84 (m, IH), 0.80- 0.76 (m, 1 H). HRMS calcd for C₂ιH₂₄N₂O₃ (M+H): 353.1860. Found 353.1862.

Claims

WHAT IS CLAIMED IS:

1. A method for the preparation of a cyclopropyl amide compound having the structure of Formula I:

wherein: x is an integer selected from 0, 1 or 2; R¹ and R² are independently selected from the group consisting of H, C C₆ alkyl, and halo; R³, R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of H, Ci- C₆ alkyl, C C₆ alkoxy, and halo; the method comprising contacting a Weimeb amide compound having the structure of Formula II:

wherein x, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above, under conditions sufficient for cycloprotination to produce the cyclopropyl amide compound.

2. The method of claim 1, wherein the conditions sufficient for cycloprotination are selected from the group consisting of the generation of a Simmons-Smith reagent, and the addition of Me₃SOI with a strong base.

3. The method of claim 2, wherein the Simmons-Smith reagent is generated with a carbenoid moiety selected from the group consisting of CH₂I₂, ICH₂C1, CH₂C1₂ and CH₂Br₂ and a Zinc couple selected from the group consisting of Zn(Cu), Zn(Ag), Znl₂, R⁸ZN, wherein R⁸ is selected from the group consisting of (CH₂C1), (CH₂I) and Et₂.

4. The method of claim 2, wherein the strong base is selected from the group consisting of an alkali metal hydride, an alkali metal alkoxide, and an alkaline earth hydride in a polar aprotic solvent.

5. The method of claim 4, wherein the polar aprotic solvent is selected from the group consisting of dimethylsulfoxide, THF, dioxane and N,N-disubstituted amide.

6. The method of claim 5, wherein the N,N-disubstituted amide is selected from the group selected from dimethylformamide, dimethylacetamide and l-methyl-2-pyrrolidinone.

7. The method of claim 1 wherein R⁵ is methoxy.

8. The method of claim 7, wherein R³, R⁴, R⁶ and R⁷ are independently selected from the group consisting of H, methoxy and halo.

9. The method of claim 8, wherein x is an integer selected from 1 or 2, and R and R are H.

10. A method for the preparation of a cyclopropyl aldehyde compound having the structure of Formula III:

wherein: R³, R⁴, R⁶ and R⁷ are independently selected from the group consisting of H, Cι-C₆ alkyl, Cι-C₆ alkoxy and halo; the method comprising contacting a cyclopropyl amide compound having the structure of Formula IV:

wherein R³, R⁴, R⁵, R⁶ and R⁷ are as defined above with a reducing agent.

11. The method of claim 10, wherein the reducing agent is DIB AH.

12. The method of claim 10 wherein R is methoxy.

13. A method for the preparation of a cyclopropyl aldehyde compound having the structure of Formula III,

wherein: R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from the group consisting of H, Ci- C₆ alkyl, Cι-C₆ alkoxy, and halo, the method comprising contacting a cyclopropyl amide compound having the structure of Formula IV

wherein R³, R⁴, R⁵, R⁶ and R⁷ are as defined above with a reducing agent to form an alcohol; converting the alcohol to an aldehyde; and contacting the aldehyde with methoxymethylphosphorane.

14. The method of claim 13, wherein the reducing agent is LiBH₄.

15. A method for the preparation of a cyclopropyl acetaldehyde compound having the structure of Formula V :

wherein: R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from the group consisting of H, C_\- C₆ alkyl, C_!-C₆ alkoxy, and halo; and the method comprises contacting a cyclopropyl aldehyde compound having the structure of Formula III

wherein: R³, R⁴, R⁵, R⁶ and R⁷are independently selected from the group consisting of H, Ci- C alkyl, Cι-C₆ alkoxy, and halo, with an oxidizing agent to create an acid ester; contacting the acid ester with an alcohol and a mineral acid to create a second ester; and contacting the second ester with a Lewis acid.

16. The method of claim 15, wherein the oxidizing agent is selected from the group consisting of DMSO, PCC, MgO₂, eerie ammonium nitrate, and Pb(OAc)₄.

17. The method of claim 15, wherein the alcohol is selected from the group consisting of ethanol, methanol, and isopropyl.

18. The method of claim 15, wherein the mineral acid is hydrochloric acid or sulfuric acid.

19. The method of claim 15, wherein the Lewis acid is selected from the group consisting of BBR₃, BCI₃, TMSI, and A1C1₃ with ethanethiol.

20. A method for the preparation of a cyclopropyl acetamide compound having the structure of Formula VI:

wherein: R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from the group consisting of H, Ci- C₆ alkyl, Cι-C₆ alkoxy, and halo; the method comprising contacting an acetamide compound having the structure of Formula VII:

wherein R³, R⁴, R⁵, R⁶ and R⁷ are as defined above with DME, CH₂C1₂, and a Simmons- Smith reagent.

21. The method of claim 20, wherein the Simmons-Smith reagent is generated with a carbenoid moiety selected from the group consisting of CH₂I₂, ICH₂C1, CH₂d₂ and CH₂Br₂; and a Zinc couple selected from the group consisting of Zn(Cu), Zn(Ag), Znl₂, wherein R⁸ is selected from the group consisting of (CH2CI), (CH₂I) and Et₂.

22. A process for the preparation of an ester of 1 -(p-hydroxyphenyl)cyclopropane acetic acid, the method comprising: reacting a compound of Formula VIII:

wherein R⁹ is

or with a carboxyl-activating compound and a coupling agent to convert R¹ into an amine-reactive intermediate; contacting the amine-reactive intermediate with an amine to form a Weimeb amide; cyclopropanating the Weimeb amide; converting the Weimeb amide to an acid; esterfiying the acid; and deprotecting the phenolic group.

23. The process of claim 22, wherein the carboxyl-activating compound is selected from the group consisting of DDC, WSC, a carodiimides, EAC, and EDC.

24. The process of claim 22, wherein the coupling agent is selected from the group consisting of HOBt, HO-At uranium salt, HO-At phosphonium salt, HO-At immonium salt, and 1 H-Benzotriazolium- 1 - [bis(dimethylamine)m ethylene] -5-chloro-hexafluorophosphate( 1 • ),3-oxide.

25. The process of claim 24 wherein the amine is Me-NH-OMe.

26. The process of claim 24 wherein the cycloprotination of the Weimeb amide is selected from the group consisting of the generation of a Simmons-Smith reagent, and the addition of Me₃SOI with a strong base.

27. The process of claim 23 wherein the carboxyl-activating compound is l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC).

28. The process of claim 25 wherein the coupling agent is HOBt.