WO2009097405A2

WO2009097405A2 - Compounds and methods for preparing diazaspiro derivatives

Info

Publication number: WO2009097405A2
Application number: PCT/US2009/032400
Authority: WO
Inventors: Yuelian Xu; Linghong Xie; Bingsong Han; George D. Maynard; Bertrand L. Chenard; Andrew J. Staab
Original assignee: Neurogen Corporation
Priority date: 2008-01-30
Filing date: 2009-01-29
Publication date: 2009-08-06
Also published as: WO2009097405A3

Abstract

Compounds and methods are provided for the synthesis of diazaspiro derivatives of the Formula: wherein R is as described herein. Such compounds are useful, for example, as intermediates in the synthesis of biologically active compounds.

Description

COMPOUNDS AND METHODS FOR PREPARING DIAZASPIRO DERIVATIVES

FIELD OF THE INVENTION

This invention relates generally to the synthesis of diazaspiro derivatives, which generally find use as intermediates in the synthesis of substituted diazaspiro compounds.

BACKGROUND OF THE INVENTION

Diazaspiro derivatives have been used as intermediates in the preparation of certain biologically active compounds (see, e.g., PCT International Publication Nos. WO 01/30780, WO 05/040167, WO 05/097795, WO 06/006490, WO 07/000463, WO 07/030061, WO07/133561 and WO 07/033561). The preparation of the diazaspiro derivative 3-benzyl-3,9-diazaspiro[5.5]undecane has been described, for example, in US Patent No. 6,291,469 and PCT International Publications WO 07/033561, WO 97/11940 and WO 05/097795, by reduction of 9-phenylmethyl-3,9- diazaspiro[5.5]undecan-2,4-dione with lithium aluminum hydride. Existing methods for preparing such diazaspiro derivatives, however, suffer from certain disadvantages (e.g., US Patent No. 5,451,578, PCT International Publication Nos. WO 07/033561 and WO 06/044504, and /. Med. Chem. 2004, 47: 1900-118), including the necessity for extreme conditions, the inefficiency of certain steps, the difficulty of applying the methods on an industrial scale, and environmental concerns. For example, the Guareschi reaction used to prepare the precursor l,5-dicyano-2,4-dioxo-9-phenylmethyl-3,9- diazaspiro[5.5]undecane requires reaction in an anhydrous environment in the presence of gaseous ammonia dissolved in ethanol. This reaction is inefficient, and requires long reaction times. In addition, current environmental regulations make it impractical to produce gaseous NH₃ in ethanol on a large scale.

Accordingly, there is a need in the art for improved methods for synthesizing diazaspiro derivatives. The present invention fulfills this need, and provides further related advantages.

SUMMARY OF THE INVENTION

The present invention provides compounds and methods useful for the synthesis of diazaspiro derivatives of Formula 5 :

Formula 5 wherein R is substitution such as Ci-Cgalkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted. Within certain aspects, the present invention provides compounds of Formula 3: Formula 3

and salts thereof, wherein R is Ci-C₈alkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted.

Within other aspects, the present invention provides processes for preparing a compound of Formula 2:

R— N X N H Formula 2

and salts thereof, wherein R is Ci-Qalkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted, the process comprising reacting a compound of Formula 1 :

Formula 1

with a cyanoacetate ester in an aqueous solution of ammonium hydroxide for a time and under conditions effective to provide a compound of Formula 2 or a salt thereof.

Within other aspects, the present invention provides processes for preparing a compound of Formula 3 or a salt thereof, wherein R is Ci-Cgalkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted, the process comprising hydrolyzing a compound of Formula 2 with an aqueous sulfuric acid solution for a time and under conditions effective to provide a compound of Formula 3 or a salt thereof. In certain embodiments of such aspects, the step of hydrolyzing the compound of Formula 2 comprises: (i) reacting the compound of Formula 2 with an aqueous solution of sulfuric acid in a concentration ranging from 50% to 98% by weight for at least one hour to form an acidic reaction mixture; (ii) diluting the acidic reaction mixture with water in an amount ranging from 10% to 60% of the amount of sulfuric acid; and

(iii) heating the diluted reaction mixture to a temperature ranging from 70 ⁰C to 120 ⁰C for at least one hour.

Within further aspects, the present invention provides processes for preparing a compound of Formula 4:

Formula 4

or a salt thereof, wherein R is d-C₈alkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted, the process comprising hydrolyzing and decarboxylating a compound of Formula 3 for a time and under conditions effective to provide a compound of Formula 4 or a salt thereof.

Within still further aspects, the present invention provides processes for preparing a compound of Formula 3, or a salt thereof, the process comprising:

(1) reacting a compound of Formula 1 or a salt thereof with cyanoacetate ester in an aqueous solution of ammonium hydroxide for a time and under conditions effective to provide a compound of Formula 2 or a salt thereof; and

(2) hydrolyzing the compound of Formula 2 or salt thereof with an aqueous sulfuric acid solution for a time and under conditions effective to provide a compound of Formula 3 or a salt thereof.

Within still further aspects, the present invention provides processes for preparing a compound of Formula 4, or a salt thereof, the process comprising: (1) hydrolyzing a compound of Formula 2:or a salt thereof with an aqueous sulfuric acid solution for a time and under conditions effective to provide a compound of Formula 3; and (2) hydrolyzing and decarboxylating the compound of Formula 3 for a time and under conditions effective to provide a compound of Formula 4 or a salt thereof.

Within other aspects, the present invention provides processes for preparing a compound of Formula 4, or a salt thereof, the process comprising:

(1) reacting a compound of Formula 1 or a salt thereof with a cyanoacetate ester in an aqueous solution of ammonium hydroxide for a time and under conditions effective to provide a compound of Formula 2 or a salt thereof; and

(2) hydrolyzing the compound of Formula 2 or salt thereof with an aqueous sulfuric acid solution for a time and under conditions effective to provide a compound of Formula or a salt thereof; and

(3) hydrolyzing and decarboxylating the compound of Formula 3 for a time and under conditions effective to provide a compound of Formula 4 or a salt thereof.

These and other aspects of the present invention will become apparent upon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention provides compounds and methods useful for synthesizing diazaspiro derivatives.

TERMINOLOGY

Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Compound descriptions are intended to encompass compounds with all possible isotopes of atoms occurring in the compounds. Isotopes are those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ¹¹C, ¹³C and ¹⁴C.

The term "diazaspiro derivative" refers to any compound that satisfies Formula 5, above, or is a pharmaceutically acceptable salt of such a compound.

A "pharmaceutically acceptable salt" of a compound recited herein is an acid or base salt that is suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutically acceptable anions for use in salt formation include, but are not limited to, acetate, 2-acetoxybenzoate, ascorbate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carbonate, chloride, citrate, dihydrochloride, diphosphate, edetate, estolate (ethylsuccinate), formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxymaleate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methylbromide, methylnitrate, methylsulfate, mucate, nitrate, pamoate, pantothenate, phenylacetate, phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfamate, sulfanilate, sulfate, sulfonates including besylate (benzenesulfonate), camsylate (camphorsulfonate), edisylate (ethane- 1 ,2-disulfonate), esylate (ethanesulfonate) 2-hydroxyethylsulfonate, mesylate (methanesulfonate), napsylate, triflate (trifluoromethanesulfonate) and tosylate (p-toluenesulfonate), tannate, tartrate, teoclate and triethiodide. Similarly, pharmaceutically acceptable cations for use in salt formation include, but are not limited to ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, and metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile, is preferred.

It will be apparent that compounds and salts thereof provided herein may, but need not, be formulated as a hydrate, and that such hydrates are encompassed by the formulas, names and structures recited herein. In addition, the various non-hydrate solvates, non-covalent complexes, crystal forms and polymorphs of the compounds provided herein are within the scope of the present invention.

As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon. Alkyl groups include groups having from 1 to 8 carbon atoms (Ci-C₈alkyl), from 1 to 6 carbon atoms (d-C₆alkyl) and from 1 to 4 carbon atoms (d-C₄alkyl), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec -butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. "Co-C_nalkyl" refers to a single covalent bond (C₀) or an alkyl group having from 1 to n carbon atoms; for example "C₀-C₄alkyl" refers to a single covalent bond or a Ci-C₄alkyl group.

"Alkylene" refers to a divalent alkyl group, as defined above. C₀-C₄alkylene is a single covalent bond (C₀) or an alkylene group having from 1 to 4 carbon atoms.

"Alkenyl" refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C₂-C₈alkenyl, C₂-Cgalkenyl and C₂- C₄alkenyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, such as ethenyl, allyl or isopropenyl. "Alkynyl" refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include C₂-C₈alkynyl, C₂-Cgalkynyl and C₂-C₄alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.

A "cycloalkyl" is a group that comprises one or more rings, each of which is saturated and/or partially saturated, and each of which has only carbon ring members. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, and partially saturated variants of the foregoing, such as cyclohexenyl. Cycloalkyl groups do not comprise an aromatic ring or a heterocyclic ring. Certain cycloalkyl groups are C₃-Ci₀cycloalkyl, which comprise one or more cycloalkyl rings which may be fused, pendant, spiro or bridged, and C₃-Cvcycloalkyl, in which the cycloalkyl group contains a single ring having from 3 to 7 ring members, all of which are carbon. A "(C₃-C₈cycloalkyl)Co-C₂alkyl" is a

C₃-C₈cycloalkyl group linked via a single covalent bond or a methylene or ethylene group.

By "alkoxy," as used herein, is meant an alkyl group as described above attached via an oxygen bridge. Alkoxy groups include Ci-Qalkoxy and C₁-QaIkOXy groups, which have from 1 to 8 or from 1 to 6 carbon atoms, respectively. Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert- butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy are representative alkoxy groups.

Similarly, "alkylthio" refers to an alkyl group as described above attached via a sulfur bridge. Ci-Cβalkylthio has from 1 to 6 carbon atoms in the alkyl portion.

The term "oxo," as used herein refers to an oxygen substituent of a carbon atom that results in the formation of a carbonyl group (C=O). An oxo group that is a substituent of a nonaromatic carbon atom results in a conversion of -CH₂- to -C(=O)-. The term "alkanoyl" refers to an acyl group (e.g., -(C=O)-alkyl), in which carbon atoms are in a linear or branched alkyl arrangement and where attachment is through the carbon of the keto group. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C₂alkanoyl group is an acetyl group having the formula -(C=O)CH₃; "Cialkanoyl" refers to -(C=O)H. Alkanoyl groups include, for example, C_r Cβalkanoyl groups, which have from 1 to 6 carbon atoms.

Similarly, "alkyl ether" refers to a linear or branched ether substituent (i.e., an alkyl group that is substituted with an alkoxy group). Alkyl ether groups include C₂-C₆alkyl ether and C₂-C₄alkyl ether groups, which have 2 to 6 or 4 carbon atoms, respectively. A C₂alkyl ether has the structure -CH₂-O- CH₃.

The term "alkoxycarbonyl" refers to an alkoxy group attached through a keto (-(C=O)-) bridge (i.e., a group having the general structure -C(=O)-O-alkyl). Alkoxycarbonyl groups include, for example, d-C₆alkoxycarbonyl groups, which have from 1 to 6 carbon atoms in the alkyl portion of the group (i.e., the carbon of the keto bridge is not included in the indicated number of carbon atoms). "Cialkoxycarbonyl" refers to -C(=O)-O-CH₃; C₃alkoxycarbonyl indicates -C(=O)-O-(CH₂)₂CH₃ or - C(=O)-O-(CH)(CH₃)₂.

"Alkylsulfonyl" refers to groups of the formula -(SO₂)-alkyl, in which the sulfur atom is the point of attachment. Alkylsulfonyl groups include Ci-C₈alkylsulfonyl and d-C₆alkylsulfonyl groups, which have from 1 to 8 or from 1 to 6 carbon atoms, respectively. "(C₁-C₈alkylsulfonyl)C₀-C₄alkyl" is a Ci-Cgalkylsulfonyl group that is linked via a single covalent bond or via a Ci-C₄alkylene group.

The term "aminocarbonyl" refers to an amide group (i.e., -(C=O)NH₂). The term "mono- or di-(Ci-C₆alkyl)aminocarbonyl" refers to groups of the formula -(C=O)-N(R)₂, in which the carbonyl is the point of attachment, one R is Ci-C₆alkyl and the other R is hydrogen or an independently chosen d-Cgalkyl. "Aminosulfonyl" refers to groups of the formula -(SO₂)-NH₂, in which the sulfur atom is the point of attachment. The term "mono- or di-(Ci-C₆alkyl)aminosulfonyl" refers to groups that satisfy the formula -(SO₂)-NR₂, in which the sulfur atom is the point of attachment, and in which one R is d- C₆alkyl and the other R is hydrogen or an independently chosen d-C₆alkyl.

"Mono- or di-(Ci-C₈alkyl)aminosulfonylCo-C₄alkyl" is an aminosulfonyl group in which one or both of the hydrogen atoms is replaced with d-C₈alkyl, and which is linked via a single covalent bond

(i.e., mono- or di-(Ci-C₈alkyl)aminosulfonyl) or a Ci-C₄alkylene group (i.e., -(Ci-C₄alkyl)-( SO₂)N(Cr

C₈alkyl)₂). If both hydrogen atoms are so replaced, the Ci-C₈alkyl groups may be the same or different.

"Alkylamino" refers to a secondary or tertiary amine that has the general structure -NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl is selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups. Such groups include, for example, mono- and di-(Ci-C₆alkyl)amino groups, in which each Ci-C₆alkyl may be the same or different.

The term "halogen" refers to fluorine, chlorine, bromine or iodine. A "haloalkyl" is an alkyl group that is substituted with 1 or more independently chosen halogens (e.g., "Ci-Cβhaloalkyl" groups have from 1 to 6 carbon atoms). Examples of haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; and 1,2,2,2-tetrafluoro- 1-trifluoromethyl-ethyl. Typical haloalkyl groups are trifluoromethyl and difluoromethyl. Similarly, the term "haloalkoxy" refers to a haloalkyl group as defined above attached via an oxygen bridge. "Ci- Cghaloalkoxy" groups have 1 to 6 carbon atoms.

A "carbocycle" or "carbocyclic group" comprises at least one ring formed entirely by carbon- carbon bonds (referred to herein as a carbocyclic ring), and does not contain a heterocycle. Unless otherwise specified, each ring within a carbocycle may be independently saturated, partially saturated or aromatic, and is optionally substituted as indicated. A carbocycle generally has from 1 to 3 fused, pendant or spiro rings; carbocycles within certain embodiments have one ring or two fused rings. Typically, each ring contains from 3 to 8 ring members (i.e., C₃-C₈); C₅-C₇ rings are recited in certain embodiments. Carbocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Certain carbocycles are C₅-C₁₀ (i.e., contain from 6 to 10 ring members, and one or two rings). Certain representative carbocycles are cycloalkyl as described above. Other carbocycles are aryl (i.e., contain at least one aromatic carbocyclic ring, with or without one or more additional aromatic and/or cycloalkyl rings). Such aryl carbocycles include, for example, 6- to 10-membered aryl groups such as phenyl, naphthyl (e.g., 1-naphthyl and 2-naphthyl), fluorenyl, indanyl and 1,2,3,4- tetrahydronaphthyl.

A "heterocycle" or "heterocyclic group" has from 1 to 3 fused, pendant or spiro rings, at least one of which is a heterocyclic ring (i.e., one or more ring atoms is a heteroatom independently chosen from O, S and N, with the remaining ring atoms being carbon). Additional rings, if present, may be heterocyclic or carbocyclic. Typically, a heterocyclic ring comprises 1, 2, 3 or 4 heteroatoms; within certain embodiments each heterocyclic ring has 1 or 2 heteroatoms per ring. Each heterocyclic ring generally contains from 4 to 8 ring members (rings having from 5 or 6 ring members are recited in certain embodiments) and heterocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Certain heterocycles comprise a sulfur atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SO₂. Heterocycles may be optionally substituted with a variety of substituents, as indicated. Unless otherwise specified, a heterocycle may be a heterocycloalkyl group (i.e., each ring is saturated or partially saturated) or a heteroaryl group (i.e., at least one ring within the group is aromatic), such as a 5- to 10-membered heteroaryl (which may be monocyclic or bicyclic) or a 6-membered heteroaryl (e.g., pyridyl or pyrimidyl). A N- linked heterocycloalkyl is linked via a ring nitrogen atom. A "4- to 7-membered heterocycloalkyl" is a heterocycloalkyl ring with 4, 5, 6 or 7 ring members. A "4- to 10-membered heterocycloalkyl" is a heterocycloalkyl group one or more rings such that the total number of ring members ranges from 4 to 10. A "(4- to 8-membered heterocycloalkyl)C₀- C₂alkyl" is a 4- to 8-membered heterocycloalkyl group linked via a single covalent bond or a methylene or ethylene group.

A "substituent," as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a ring substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Substituents of aromatic groups are generally covalently bonded to a ring carbon atom. The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent, such that the valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.

Groups that are "optionally substituted" are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically 1, 2, 3, 4 or 5 positions, by one or more suitable groups (which may be the same or different). Optional substitution is also indicated by the phrase "substituted with from 0 to X substituents," where X is the maximum number of possible substituents. Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substitutents).

COMPOUNDS AND METHODS FOR PREPARING DIAZASPIRO DERIVATIVES

As noted above, the present invention provides compounds and methods useful in the synthesis of diazaspiro derivatives of Formula 5 and salts thereof (e.g., pharmaceutically acceptable salts thereof), in which R is any suitable substituent, such as d-C₈alkyl, benzyl or an aryl or heteroaryl moiety (e.g., Cβ-Cioaryl or 5- to 10-membered heteroaryl), each of which is optionally substituted. Methods recited herein provide advantages over previously described methods, including improved efficiency, the use of milder conditions, and improved suitability for large-scale synthesis (e.g., the use of gaseous ammonia can be avoided).

Compounds of Formula 5 are generally useful for the synthesis of biologically active compounds, including histamine H3 receptor antagonists of the formula:

wherein: ^R2"NOC^N"RI Ri is Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₈cycloalkyl)Co-C₂alkyl or (4- to 8-membered heterocycloalkyl)Co-C₂alkyl, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 4 substituents independently chosen from oxo, nitro, halogen, amino, cyano, hydroxy, aminocarbonyl, Ci-Cβalkyl, Ci-Cgalkenyl, Ci-Cghaloalkyl, C₁- C₆haloalkoxy, Ci-C₆alkylthio, C₂-C₆alkyl ether, Ci-C₆alkanoyl, mono- or di-(Ci-C₆alkyl)amino, mono- or di-(Ci-C₆alkyl)aminocarbonyl, C₃-C₇cycloalkyl and 4- to 7-membered heterocycloalkyl; R₂ is:

(i) d-Cgalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, CrC₆alkylsulfonyl, C_rC₆alkanoyl, C₁- dalkoxycarbonyl, mono- or di-(C₁-Cgalkyl)amino, mono- or di-(C₁-C₆alkyl)aminocarbonyl or mono- or di-(Ci-C₆alkyl)aminosulfonyl, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 4 substituents independently chosen from R_a; or

(ii) a group of the Formula W-Y-; wherein W is C₃-Ciocycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 4 substituents independently chosen from R_a, and Y is absent or d-C₆alkylene; and Each R_a is independently:

(i) halogen, cyano, hydroxy, amino, nitro, aminocarbonyl or oxo;

(ii) CrQalkyl, d-Qhaloalkyl, (C₃-C₈cycloalkyl)Co-C₄alkyl, C₁-QaIkOXy, d-C₈alkoxycarbonyl, d-dalkanoyl, d-dalkylsulfonyl, mono- or di-(C₁-C₈alkyl)amino, mono- or di-(C_r

C₈alkyl)aminocarbonyl or mono- or

each of which is optionally substituted and each of which is preferably substituted with from 0 to 4 substituents independently chosen from halogen, oxo, amino, C₁-C₄alkyl, C₂-dalkenyl, d-C₈alkoxy; or (iii) (6- to 10-membered aryl)-L-, or (5- to 10-membered heterocycle)-L-, wherein L is a single covalent bond, O, SO₂, C(=O), (CH₂)_n-NH-C(=O) or (CH₂)_n-O-C(=O) and n is 0, 1 or 2; each of which aryl or heterocycle is optionally substituted, and each of which aryl or heterocycle is preferably substituted with from 0 to 3 substituents independently chosen from:

(a) halogen, cyano, hydroxy, amino, nitro, aminocarbonyl, oxo, d-dalkyl, d-Cghaloalkyl, C₁- daminoalkyl, C₂-C₆alkyl ether, d-C₆alkoxy, d-dalkoxycarbonyl, d-dalkanoyl, C₁- dalkylsulfonyl, mono- or di-(C₁-C₆alkyl)amino, mono- or di-(CrC₆alkyl)aminocarbonyl or mono- or di-(C₁-C₆alkyl)aminosulfonyl; (b) (5- to 10-membered, N-linked heterocycloalkyl)-(CO)_p-, wherein p is 0 or 1, which heterocycloalkyl is substituted with from 0 to 3 substituents independently chosen from halogen, d-C₄alkyl, C₂-C₄alkenyl, d-C₄alkoxy and C₂-C₄alkyl ether; and (c) groups that are taken together to form a fused, partially or fully saturated 5- or 6-membered ring that is optionally substituted (e.g., with from 0 to 2 substituents independently chosen from oxo and d-C₄alkyl).

Such H3 receptor antagonists are described in PCT International Application Publication No. WO 07/033561. In particular, paragraphs at page 34, line 3 to page 39, line 35, are hereby incorporated by reference for their teaching of dosages and formulations, and paragraphs at page 40, line 9 to page 45, line 7 are hereby incorporated by reference for their teaching of methods of use. Representative synthetic examples provided therein for preparing H3 receptor antagonists from the diazaspiro derivatives disclosed herein include those at page 48, line 25 to page 52, line 12, which examples are hereby incorporated by reference for their teaching of the synthesis of H3 receptor antagonists. The methods provided herein are summarized in Scheme 1, in which the variable R is as described above. In certain embodiments, R is benzyl that is optionally substituted with from 1 to 4 substituents independently chosen from halogen, C₁-C₄alkyl, nitro and methoxy. In further embodiments, R is unsubstituted benzyl. In general, unless otherwise specified, starting materials and reagents for the methods provided herein are commercially available from suppliers such as Sigma- Aldrich Corp. (St. Louis, MO), or may be synthesized from commercially available precursors using well known protocols.

Scheme 1

1 ) NaOH,

Step 3

2) Cone. HCI

5 Step 4 4

Within step 1, a compound of Formula 2, or a salt thereof, is prepared by reacting a compound of Formula 1 (e.g., N-benzyl-piperidone) with a cyanoacetate ester (e.g., ethyl cyanoacetate or methyl cyanoacetate) in an aqueous solution of ammonium hydroxide for a time and under conditions effective to provide a compound of Formula 2 (e.g., l,5-dicyano-2,4-dioxo-9-phenylmethyl-3,9- diazaspiro[5.5]undecane) or a salt thereof. The use of an aqueous solution of ammonium hydroxide instead of gaseous ammonia lessens the environmental concerns associated with this reaction; thus, in certain embodiments, the reaction is performed without added gaseous ammonia. An organic solvent is generally used; typically the organic solvent is an alcohol (e.g., methanol or ethanol) or other polar solvent. In certain embodiments, the molar ratio of ethyl cyanoacetate to compound of Formula 1 ranges from 1 :2 to 4:1; in further embodiments, the molar ratio of ethyl cyanoacetate to compound of Formula 1 ranges from 1 to 3 (e.g., 2). In a preferred embodiment, the solution comprising cyanoacetate ester and solvent is cooled (e.g., to below 10 ⁰C) prior to addition of compound of Formula 1, or salt thereof, and ammonium acetate (e.g., 0% to 50%, such as about 10%) is added along with the compound of Formula 1. Ammonium hydroxide is then added in portions; in certain embodiments, the molar ratio of ammonium hydroxide to compound of Formula 1 ranges from 1 :2 to 10: 1; in further embodiments, the molar ratio of ammonium hydroxide to compound of Formula 1 ranges from 1 :2 to 5:1. In general, reaction is complete in less than 48 hours, typically less than 36 hours and preferably less than 24 hours. In certain embodiments, the reaction mixture is maintained below 10 ⁰C (e.g., for about an hour at 0-5 ⁰C), and is then allowed to warm to room temperature and stirred for about 20 hours. To isolate the compound of Formula 2, if desired, water is added to the suspension and the mixture is heated, and then acid (e.g., 12N hydrochloric acid) is added (e.g., until the pH of the mixture is 4). The compound of Formula 2 is isolated by cooling, followed by filtration.

In step 2, a compound of Formula 3, or a salt thereof, is prepared by hydrolyzing a compound of Formula 2, or a salt thereof. This step is preferably performed in two stages. In the first stage, the compound of Formula 2 is reacted with an acid, preferably an aqueous solution of sulfuric acid in a concentration ranging from 50% to 98% by weight (in certain embodiments, the sulfuric acid concentration ranges from 85% to 90%; e.g., 88%, by weight). The molar ratio of sulfuric acid to compound of Formula 2 typically ranges from 1 to 10, and preferably ranges from 2 to 6. Preferably, the compound of Formula 2 is added to the sulfuric acid solution in portions and at a temperature that is sufficiently low to control the temperature of the exothermic reaction (e.g., to around 40 ⁰C). Once all portions have been added, the reaction is incubated at a temperature between 10 ⁰C and 110 ⁰C, preferably below 70 ⁰C (e.g., around 60 ⁰C). The reaction is allowed to proceed for at least an hour, and typically for a few hours (e.g., 3-5 hours).

In the second stage, the reaction mixture that results from the first stage is diluted by adding water in an amount ranging from 10% to 60% of the amount of sulfuric acid in the mixture. The mixture is then heated to a temperature ranging from 70 ⁰C to 120 ⁰C, preferably to a temperature ranging from 90 ⁰C to 110 ⁰C (e.g., 100 ⁰C), generally for at least one hour (e.g., for 1-2 hours). A suspension of product is obtained, and the reaction mixture may then be cooled (e.g., to 10-20 ⁰C for a few hours) to obtain the sulfate salt of the compound of Formula 3, which may be isolated by filtration and dried for use in step 3.

Without wishing to limit the scope of the present invention, Applicants believe that step 2 proceeds via intermediates 6 and 7, as illustrated in Scheme 2.

Within step 3, a compound of Formula 4 or a salt thereof is prepared by hydrolyzing and decarboxylating a compound of Formula 3 or a salt thereof, for a time and under conditions effective to provide the compound of Formula 4 or a salt thereof. This step is preferably performed in two stages. In the first stage, an aqueous sodium hydroxide solution is use to hydrolyze the compound of

Formula 3. The compound of Formula 3 or salt thereof, is preferably added to the sodium hydroxide solution at a low temperature (e.g., ranging from 0 ⁰C to -20 ⁰C ) to allow for control of the exothermic reaction and the release of gaseous ammonia and carbon dioxide. Following the addition of compound, suitable reaction temperatures typically range from 40 ⁰C to 90 ⁰C (e.g., about 70 ⁰C), with reaction times of at least an hour (e.g., 1-4 hours) generally sufficient. The concentration of sodium hydroxide in the reaction mixture typically ranges from 2N to 15N, preferably from 3N to 7N (e.g., about 5 N), with a preferred molar ratio of sodium hydroxide to compound of Formula 3 ranging from 5 to 20 (e.g., ranging from 5 to 10, such as 7). This stage results in a hydrolyzed intermediate.

In the second stage, the hydrolyzed intermediate is acidified and decarboxylated. This stage is preferably performed by adding concentrated hydrochloric acid in an amount sufficient to achieve a pH ranging from 3 to 4. The acid is typically added dropwise and the temperature of the solution is maintained around 40 ⁰C to 60 ⁰C. The amount of concentrated hydrochloric acid added is preferably about 10% to 15% by weight of the hydrolyzed intermediate solution. Following acid addition, the reaction mixture is preferably maintained at a temperature ranging from 70 ⁰C to 90 ⁰C (e.g., 70 ⁰C to 75 ⁰C) until the reaction is complete. A suspension of compound of Formula 4 is obtained, and the reaction mixture may then be cooled (e.g., to 10-20 ⁰C for 1-3 hours) to obtain the HCl salt of the compound of Formula 4, which may be isolated by filtration and dried.

Without wishing to limit the scope of the present invention, Applicants believe that step 3 proceeds via intermediates 8 and 9, as illustrated in Scheme 3. Thus, the reaction with NaOH yields the monoacid sodium salt 9, which is decarboxylated by the addition of the acid to yield the compound of Formula 4 as the HCl salt.

In step 4, the imide group is reduced to an amine. Any suitable reducing agent may be used, such as LAH or Red-Al, using methods known in the art. In embodiments in which LAH is used, the reaction may be conveniently performed with THF or diethyl ether as a solvent under refluxing conditions. If Red-Al is used as the reducing agent, the reaction may be conveniently performed with toluene or xylene as the solvent at an elevated temperature (e.g., ranging from 120 ⁰C to 140 ⁰C).

Certain embodiments of the compounds and methods provided herein are illustrated in Scheme 4. Scheme 4

The following Examples are offered by way of illustration and not by way of limitation. Unless otherwise specified, all reagents and solvent are of standard commercial grade and are used without further purification. Starting materials are available from commercial suppliers, such as Sigma-Aldrich (St. Louis, MO), or are synthesized using procedures that are known in the art.

EXAMPLES

Mass spectroscopy data in the following Examples is Electrospray MS, obtained in positive ion mode using a Waters ZMD II Mass Spectrometer (Waters Corp.; Milford, MA), equipped with a Waters 600 pump (Waters Corp.; Milford, MA), Waters 996 photodiode array detector (Waters Corp.; Milford, MA), and a Gilson 215 autosampler (Gilson, Inc.; Middleton, WI). MassLynx™ (Waters Corp.; Milford, MA) version 4.0 software with OpenLynx Global Server™, OpenLynx™ and AutoLynx™ processing is used for data collection and analysis. MS conditions are as follows: capillary voltage = 3.5 kV; cone voltage = 30 V, desolvation and source temperature = 250⁰C and 120⁰C, respectively; mass range = 100-750 with a scan time of 0.5 seconds and an interscan delay of 0.1 seconds.

Analyses are performed as follows. Sample volume of 1-10 microliter is injected onto a 30x4.6mm XBridge™ C18, 5μm, column (Waters Corp.; Milford, MA), and eluted using a 2-phase linear gradient at a flow rate of 4.0 mL/min. Sample is detected using total absorbance count at the 220 and 254 nm. The elution conditions are: Mobile Phase A - 95% 10 mM ammonium formate, 5% MeOH; Mobile Phase B - 95% Methanol, 5% water with 0.025% formic acid. The following gradient is used: 0-2.0 min 5-100% B, hold at 100% B to 3.5 min, return to 5% B at 3.51 min. Run time is 4 min. Certain abbreviations used in the following Examples and elsewhere herein are:

Ac acetate CDCl₃ deuterated chloroform δ chemical shift

EtOAc ethyl acetate

EtOH ethanol

Eq. equivalent(s)

¹H NMR proton nuclear magnetic resonance h hour(s)

Hz hertz

LAH lithium aluminium hydride

LC-MS liquid chromatography/mass spectrometry

MS mass spectrometry

(M+l) mass + 1

MeOH methanol min minute(s)

Red-Al Sodium bis(2-methoxyethoxy)aluminium hydride rv'p retention time

THF tetrahydrofuran

EXAMPLE 1. PREPARATION OF Q-BENZYL^^-DIOXO-S^-DIAZASPΓRO^IUNDECANE-I^- DICARBONITRILE

This Example illustrates the synthesis of 9-benzyl-2,4-dioxo-3,9-diazaspiro[5,5]undecane-l,5- dicarbonitrile:

In a 5L three-necked round flask equipped with a reflux condenser, a thermometer and an agitator, ethyl cyanoacetate (678.72 g, 6 mol) and MeOH (820 mL) are added. The solution is cooled to 5-8 ⁰C while stirring. Ammonium acetate (15.4 g, 0.2 mol) followed by 1-benzylpiperidone (378.5 g, 2 mol) are added. The mixture is cooled below 8 ⁰C. Ammonium hydroxide (384 mL, 27% in water, 2.76 mol) is added over 30 min. During the addition, the temperature of the reaction mixture is maintained below 10 ⁰C. The solution is further stirred for 1 h at 0-5 ⁰C. The reaction mixture is allowed to warm to 20 ⁰C (room temperature). The suspension is stirred at room temperature for 20 h. Water (800 mL) is added to the suspension and the mixture is heated to 55 ⁰C. 12N hydrochloric acid (about 200 mL) is added until the pH of the mixture is 4 while keeping temperature below 70 ⁰C.

The mixture is cooled to 10 ⁰C, stirred for 30 min and then filtered. The filter cake is washed with water (2 L). After drying in the air, 9-benzyl-2,4-dioxo-3,9-diazaspiro[5,5]undecane-l,5-dicarbonitrile (545 g) is obtained as a yellowish powder in 85% of yield. LC-MS (M+l) 323.16; R_τ = 1.51 min.

EXAMPLE 2. PREPARATION OF DIΓMIDE: I'-BENZYL^H^H^H^H-SPIROPJ-DIAZABICYCLOP.S.I] NONANE-9,4'-PIPERIDINE]-2,4,6,8-TETRONE This Example illustrates the preparation of l'-benzyl-2H,4H,6H,8H-spiro[3,7- diazabicyclo[3.3.1]nonane-9,4'-piperidine]-2,4,6,8-tetrone

To a solution of 88% sulfuric acid (400 mL, made by adding 98% sulfuric acid (352 mL) to water (48 mL) in a 5L flask) at room temperature is added 9-benzyl-2,4-dioxo-3,9- diazaspiro[5,5]undecane-l,5-dicarbonitrile (200 g) portionwise while stirring. The suspension is heated at 60 ⁰C for 4 h. Water (140 mL) is added to the above solution over 5 min. The reaction mixture is heated at 100⁰C for 1 h to form a solid, and then the water (IL) is added. The suspension is cooled to 10 ⁰C and is stirred for 30 min. The solid is filtered, washed with cold water (1 L), and dried under vacuum to give 220 g of the title compound as a white solid, which is used in the next step without further purification. LC-MS (M+l) 341.98; R_τ = 2.65 min.

EXAMPLE 3. PREPARATION OF 9-BENZYL-3,9-DIAZASPIRO[5.5]UNDECANE-2,4-DIONE

This Example illustrates the preparation of 9-benzyl-3,9-diazaspiro[5.5]undecane-2,4-dione hydrochloride:

To a 5 L flask, crude l'-benzyl-2H,4H,6H,8H-spiro[3,7-diazabicyclo[3.3.1]nonane-9,4'- piperidine]-2,4,6,8-tetrone (220 g) is added and then 5N NaOH (1 L, 10 eq.) is added. The solution is heated at 70 ⁰C for 4 h. The mixture is cooled to 45 ⁰C, and then concentrated HCl (12N, about 300 mL) is added slowly until the pH of the solution is around 7. The mixture is heated to 70-75 ⁰C, and concentrated HCl (about 100 mL) is added drop wise to control the rate of CO₂ evolution until the pH is adjusted to around 3-4. The mixture is further heated at 70-75 ⁰C for 1 h. The resulting suspension is cooled to 10 ⁰C and stirred for 1 h. The solid is filtered and washed with water (500 mL). The solid is air dried to give the title compound as the HCl salt (109 g, 57% yield in overall two steps). LC-MS (M+l) 273.06; R_τ = 0.93 min. ¹H NMR (DMSO-d6) 1.06-1.80 (m, 4H), 2.39 (m, 2H), 2.74(m, 2H), 3.09 (m, 4H), 4.26 (s, 2H), 7.42 (m, 3H), 7.56 (m, 2H), 10.59 (s, IH), 10.86 (s, IH). EXAMPLE 4. PREPARATION OF S-BENZYL-S^-DIAZASPIRO^^IIUNDECANE

This Example illustrates the preparation of 3-benzyl-3,9-diazaspiro[5,5]]undecane:

by reduction with LAH. To a suspension of 9-benzyl-3,9-diazaspiro[5.5]undecane-2,4-dione hydrochloride (10Og,

323.8 mmol) in THF (500 mL), is added LAH ( IM in THF, 1.1 L, 3.5 eq.) slowly at room temperature over 30 min. The resulting mixture is heated under reflex overnight (about 20-24 h). The mixture is cooled to room temperature, and quenched by the addition of water (42.9 mL, the amount equal to the weight of LAH (42.9g)), 15% NaOH (42.9 mL, equal to the amount of water) and water (128.9 mL) slowly. Na₂SO₄ (80 mg) is added and the mixture is stirred for 30 min. t-Butylmethyl ether (300 mL) is added and the mixture is stirred for 30 min. The mixture is filtered through a Celite pad and washed with t-butylmethyl ether. The filtrate is dried over Na₂SO₄, filtered and the solvent is removed to give the title compound (72.1 g, 91%) as a white solid, LC-MS ( M+l) 245.10; R_τ = 1.56 min. ¹H NMR (CDCl₃) ¹H NMR (CDCl₃) δ 7.23-7.31 (5H, m), 3.49 (2H, s), 2.77 (4H, t), 2.38 (4H, t), 1.69 (IH, s), 1.52 (4H, t), 1.41 (4H, t).

EXAMPLE 5. PREPARATION OF HEMI FUMARATE OF 3-BENZYL-S^-DIAZASPIRO[S-S]UNDECANE

This Example illustrates the preparation of the hemi fumarate of 3-benzyl-3,9- diazaspiro [5.5]undecane :

Crude 3-benzyl-3,9-diazaspiro[5.5]undecane (72.1 g, 0.295 mol) (from Example 4) is suspended in wo-propanol (200 mL) and heated at 65 ⁰C under nitrogen to form a clear Solution B. Fumaric acid (17. Ig, 0.147 mol) is suspended in wo-propanol (190 mL) and reflux to form a clear Solution A. Solution A is added to Solution B in one portion while stirring under nitrogen. The resulting clear solution becomes cloudy in a minute and more precipitate forms. The heat bath is removed and resulting mixture is stirred overnight under nitrogen. The mixture is filtered under nitrogen and washed with small amount of wo-propanol (-60 mL). The product is dried under high vacuum to give the title compound as a white loose powder. 74.5 g (yield 83.5%, and overall yield in 76%). LC-MS (M+l) 245.12; R_τ = 1.54 min. ¹H NMR (CD₃OD) 1.60-1.72 (m, 8H), 2.50-2.60 (m, 4H), 3.10-3.16 (m, 4H), 3.64 (s, 2H), 6.64 (s, IH), 7.26-7.38 (m, 5H). EXAMPLE 6. PREPARATION OF DIHYDROCHLORIDE OF 3-BENZYL-S₅Q-DIAZASPIRO[S-S]UNDECANE

This Example illustrates the preparation of the dihydrochloride of 3-benzyl-3,9- diazaspiro [5.5]undecane :

Crude 3-benzyl-3,9-diazaspiro[5.5]undecane (52.31 g, 0.214 mol) is dissolved in EtOH (157 mL) under nitrogen to form a clear Solution A. Concentrated HCl solution (36%, 43.36 g, 0.428 mol) is diluted in EtOH (173 mL) and the solution is cooled to 10 ⁰C with an ice/water bath for form Solution B. Solution A is added slowly to Solution B while stirring under nitrogen. The resulting suspension is stirred at 10 ⁰C for 1 h. The formed solid is filtered and washed with acetone (200 mL) and then tert-butyl methyl ether (200 mL). The solid is air-dried to give the title compound as a white powder (42.9 g, 63.2% overall yield for reduction and salt formation steps). LC-MS (M+l) 245.12; R_τ = 1.54 min. ¹H NMR (CD₃OD) 1.68-1.72 (m, 4H), 1.94-2.02 (m, 4H), 3.20-3.28 (m, 5H), 3.30- 3.40 (m, 6H), 4.36 (s, IH), 7.49-7.56 (m, 5H).

EXAMPLE 7. PREPARATION OF S-BENZYL-S^-DIAZASPIRO^SIJUNDECANE This Example illustrates the preparation of 3-benzyl-3,9-diazaspiro[5,5]]undecane:

by reduction with Red- Al. O

A suspension of imide (10.52 g, 38.6 mmol) in xylene (150 mL) is cooled to 0 ⁰C. Red-Al (65%, 94 mL, 309 mmol) is added dropwise while maintaining the internal temperature below 30 ⁰C. The mixture is stirred at ambient temperature for 30 min, and then gradually heated to 127 ⁰C. The mixture is heated at 127 ⁰C for 17 h, and then cooled to 0 ⁰C by an ice bath. NaOH aqueous solution (20%, 300 mL) is added over 5 min and the mixture is stirred at 0 ⁰C for 30 min. The suspension is diluted with water (100 mL) and the layers are separated. The aqueous layer is extracted twice with EtOAc (100 mL) and the combined extracts are washed with brine (200 mL) and dried over Na₂SO/_t. Evaporation of the solvent affords the title compound as a light yellow solid (9.31 g, 98.5%). LC-MS ( M+l) 245.10; R_τ = 1.54 min. ¹H NMR (CDCl₃) ¹H NMR (CDCl₃) δ 7.23-7.31 (5H, m), 3.49 (2H, s), 2.77 (4H, t), 2.38 (4H, t), 1.69 (IH, s), 1.52 (4H, t), 1.41 (4H, t).

EXAMPLE 8. REPRESENTATIVE REACTION CONDITIONS

A. STEP 1 OF SCHEME 1

Representative reaction conditions for step 1 include, but are not limited to, those illustrated in Table I. Table I

Ethyl Ammonium

Benzylpiperidone cyanoacetate Ammonium hydroxide Temperature

Example [mol] [mol] acetate [mol] [mol] [³C] Yield

1 0.078 0.233 0.0026 0.088 5 44

2 0.078 0.233 0.0078 0.221 5 89

3 0.078 0.171 0.0078 0.221 8 59

4 1 2.2 0.1 3.14 8 61

5 1 3 0.1 3.01 5 89

6 2 6 0.2 6.2 10 85

B. STEP 2 OF SCHEME 1

Representative reaction conditions for step 2 include, but are not limited to, those illustrated in Table II, in which the compounds of Formula 2 and Formula 3 are as shown below:

Table II

Compound 2 Concentration Amount of Temperature H₂O Temperature

[mol] of H₂SO₄ [%] H₂SO₄ [ml_] PC] [Stage 1] [mL] [^sC][stage 2]

1 0.059 65 78 100 0 25

2 0.059 88 80 60 14 120

3 0.059 88 40 60 14 100

4 0.059 65 39 100 0 25

5 0.059 88 80 60 27 100

6 0.059 88 40 60 40 100

7 0.059 88 40 60 40 80

8 0.059 50 80 60 0 100

9 0.621 88 400 60 140 100

10 0.31 1 88 200 60 70 100

1 1 0.31 1 88 400 60 140 100

12 0.622 88 400 70 140 100

13 0.776 88 500 100 500 100

14 0.932 88 600 60 210 95

C. STEP 3 OF SCHEME 1

Representative reaction conditions for step 3 include, but are not limited to, those illustrated in Table III, in which the compounds of Formula 3 and Formula 4 are as shown below:

Table III

Compound 3 Amount Temperature Concentrated Temperature implθ NaOH [N]

[mol] [mL] PC] [Stage 1] HCI [mL] [^sC][stage 2]

1 0.009 5 6 80 3 100

2 0.003 5 5 55 3 80

3 0.003 5 10 55 6 80

4 0.003 10 10 55 6 90

5 0.01 5 7 55 10 80

6 0.077 10 56 55 40 80

7 0.029 5 59 55 to pH ~3 80

8 0.029 10 30 55 to pH ~ 3 80

9 0.05 5 60 55 to pH ~3 80

10 0.005 5 6 80 to pH ~ 3 80

1 1 0.005 2.5 12 80 to pH~ 3 80

12 0.114 5 176 80 70 80

13 0.292 5 621 45 155 70

14 0.322 5 620 80 210 80

15 0.144 5 289 66 to pH~ 3 70

16 0.5 5 1000 70 to pH~ 3 70

17 0.676 5 1300 70 to pH~ 3 65

18 0.478 5 1000 70 to pH~ 3 75

19 0.751 5 1500 70 to pH~ 3 70

From the foregoing description, it will be apparent that variations and modifications may be madee invention described herein. Such embodiments are also within the scope of the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula 3 :

Formula 3

or a salt thereof, wherein R is CVCgalkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted.

2. A compound or salt thereof according to claim 1, wherein R is benzyl that is optionally substituted with from 1 to 4 substituents independently chosen from halogen, Ci-C₄alkyl, nitro and methoxy.

3. A compound or salt thereof according to claim 2, wherein R is unsubstituted benzyl.

4. A process for preparing a compound of Formula 2:

or a salt thereof, wherein R is Ci-C₈alkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted, the process comprising reacting a compound of Formula 1 :

Formula 1

or a salt thereof with a cyanoacetate ester in an aqueous solution of ammonium hydroxide for a time and under conditions effective to provide a compound of Formula 2 or a salt thereof.

5. A process according to claim 4, wherein R is benzyl that is optionally substituted with from 1 to 4 substituents independently chosen from halogen, d-C₄alkyl, nitro and methoxy.

6. A process according to claim 5, wherein R is unsubstituted benzyl.

7. A process according to any one of claims 4-6, wherein the molar ratio of cyanoacetate ester to compound of Formula 1 ranges from 1 :2 to 4:1.

8. A process according to claim 7, wherein the molar ratio of cyanoacetate ester to compound of Formula 1 ranges from 1 :1 to 3: 1.

9. A process according to any of claims 4-8, wherein the molar ratio of ammonium hydroxide to compound of Formula 1 ranges from 1 :2 to 10:1.

10. A process according to claim 9, wherein the molar ratio of ammonium hydroxide to compound of Formula 1 ranges from 1 :2 to 5: 1.

11. A process according to any one of claims 4-10, wherein the reaction is performed without added gaseous ammonia.

12. A process for preparing a compound of Formula 3:

Formula 3

or a salt thereof, wherein R is Ci-C₈alkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted, the process comprising hydrolyzing a compound of Formula 2:

R-N X NH Formula 2

N or a salt thereof with an aqueous sulfuric acid solution for a time and under conditions effective to provide a compound of Formula 3 or a salt thereof.

13. A process according to claim 12, wherein R is benzyl that is optionally substituted with from 1 to 4 substituents independently chosen from halogen, C₁-C₄alkyl, nitro and methoxy.

14. A process according to claim 13, wherein R is unsubstituted benzyl.

15. A process according to any one of claims 12-14, wherein the step of hydrolyzing comprises:

(i) reacting the compound of Formula 2 or a salt thereof with an aqueous solution of sulfuric acid in a concentration ranging from 50% to 98% by weight for at least one hour to form an acidic reaction mixture; (ii) diluting the acidic reaction mixture with water in an amount ranging from 10% to 60% of the amount of sulfuric acid; and (iii) heating the diluted reaction mixture to a temperature ranging from 70 ⁰C to 120 ⁰C for at least one hour.

16. A process according to claim 15, wherein the concentration of sulfuric acid ranges from 85% to 90%.

17. A process according to claim 15, wherein the molar ratio of sulfuric acid to compound of Formula 2 ranges from 1 :1 to 10:1.

18. A process according to claim 15, wherein the molar ratio of sulfuric acid to compound of Formula 2 ranges from 2:1 to 6: 1.

19. A process according to any one of claims 15-18, wherein the step of heating takes place at a temperature ranging from 90 ⁰C to 110 ⁰C.

20. A process for preparing a compound of Formula 4:

Formula 4

or a salt thereof, wherein R is Ci-C₈alkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted, the process comprising hydrolyzing and decarboxylating a compound of Formula 3:

Formula 3

or a salt thereof for a time and under conditions effective to provide a compound of Formula 4 or a salt thereof.

21. A process according to claim 20, wherein R is benzyl that is optionally substituted with from 1 to 4 substituents independently chosen from halogen, Ci-C₄alkyl, nitro and methoxy.

22. A process according to claim 21, wherein R is unsubstituted benzyl.

23. A process according to any one of claims 20-22, comprising:

(i) reacting the compound of Formula 3 or salt thereof with an aqueous solution of sodium hydroxide at a temperature ranging from 40 ⁰C to 90 ⁰C to form a hydrolyzed intermediate; and (ii) acidifying the hydrolyzed intermediate to form a compound of Formula 4 or salt thereof.

24. A process according to claim 23, wherein the sodium hydroxide is present in step (i) at a concentration ranging from 2N to 15N.

25. A process according to claim 24, wherein the sodium hydroxide is present in step (i) at a concentration ranging from 3N to 7N.

26. A process according to any one of claims 23-25, wherein the step of acidifying comprises (a) adding concentrated hydrochloric acid to the hydrolyzed intermediate to achieve a pH ranging from 3 to 4, and (b) heating the pH-adjusted solution to a temperature ranging from 70 ⁰C to 90 ⁰C.

27. A process for preparing a compound of Formula 3:

Formula 3

or a salt thereof, wherein R is Ci-Cgalkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted, the process comprising: (1) reacting a compound of Formula 1 :

Formula 1

with cyanoacetate ester in an aqueous solution of ammonium hydroxide for a time and under conditions effective to provide a compound of Formula 2: Formula 2

or a salt thereof; and

28. A process according to claim 27, wherein R is benzyl that is optionally substituted with from 1 to 4 substituents independently chosen from halogen, d-C₄alkyl, nitro and methoxy.

29. A process according to claim 28, wherein R is unsubstituted benzyl.

30. A process according to any one of claims 27-29, wherein the molar ratio of cyanoacetate ester to compound of Formula 1 ranges from 1 :2 to 4:1.

31. A process according to claim 30, wherein the molar ratio of cyanoacetate ester to compound of Formula 1 ranges from 1 :1 to 3 : 1.

32. A process according to any of claims 27-31, wherein the molar ratio of ammonium hydroxide to compound of Formula 1 ranges from 1 :2 to 10:1.

33. A process according to claim 32, wherein the molar ratio of ammonium hydroxide to compound of Formula 1 ranges from 1 :2 to 5: 1.

34. A process according to any one of claims 27-33, wherein the reaction is performed without added gaseous ammonia.

35. A process according to any one of claims 27-34, wherein the step of hydrolyzing the compound of Formula 2 or salt thereof comprises:

(i) reacting the compound of Formula 2 or salt thereof with an aqueous solution of sulfuric acid in a concentration ranging from 50% to 98% by weight for at least one hour to form an acidic reaction mixture; (ii) diluting the acidic reaction mixture with water in an amount ranging from 10% to 60% of the amount of sulfuric acid; and (iii) heating the diluted reaction mixture to a temperature ranging from 70 ⁰C to 120 ⁰C for at least one hour.

36. A process according to claim 35, wherein the concentration of sulfuric acid ranges from 85% to 90%.

37. A process according to claim 35, wherein the molar ratio of sulfuric acid to compound of Formula 2 ranges from 1 :1 to 10:1.

38. A process according to claim 37, wherein the molar ratio of sulfuric acid to compound of Formula 2 ranges from 2:1 to 6: 1.

39. A process according to any one of claims 35-38, wherein the step of heating takes place at a temperature ranging from 90 ⁰C to 110 ⁰C.

40. A process for preparing a compound of Formula 4:

Formula 4

or a salt thereof, wherein R is Ci-Cgalkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted, the process comprising:

(1) hydrolyzing a compound of Formula 2:

R-N X NH Formula 2

N or a salt thereof with an aqueous sulfuric acid solution for a time and under conditions effective to provide a compound of Formula 3:

Formula 3

or a salt thereof; and

(2) hydrolyzing and decarboxylating the compound of Formula 3 or salt thereof for a time and under conditions effective to provide a compound of Formula 4 or a salt thereof.

41. A process according to claim 40, wherein R is benzyl that is optionally substituted with from 1 to 4 substituents independently chosen from halogen, d-C₄alkyl, nitro and methoxy.

42. A process according to claim 41, wherein R is unsubstituted benzyl.

43. A process according to any one of claims 40-42, wherein the step of hydrolyzing the compound of Formula 2 or salt thereof comprises:

44. A process according to claim 43, wherein the concentration of sulfuric acid ranges from 85% to 90%.

45. A process according to claim 43, wherein the molar ratio of sulfuric acid to compound of Formula 2 ranges from 1 :1 to 10:1.

46. A process according to claim 45, wherein the molar ratio of sulfuric acid to compound of Formula 2 ranges from 2:1 to 6: 1.

47. A process according to any one of claims 43-46, wherein the step of heating takes place at a temperature ranging from 90 ⁰C to 110 ⁰C.

48. A process according to any one of claims 40-47, wherein the step of hydrolyzing and decarboxylating the compound of Formula 3 or salt thereof comprises:

(iv) reacting the compound of Formula 3 or salt thereof with an aqueous solution of sodium hydroxide at a temperature ranging from 40 ⁰C to 90 ⁰C to form a hydrolyzed intermediate; and (v) acidifying the hydrolyzed intermediate to form a compound of Formula 4 or salt thereof.

49. A process according to claim 48, wherein the sodium hydroxide is present in step (iv) at a concentration ranging from 2N to 15N.

50. A process according to claim 49, wherein the sodium hydroxide is present in step (iv) at a concentration ranging from 3N to 7N.

51. A process according to any one of claims 48-50, wherein the step of acidifying comprises (a) adding concentrated hydrochloric acid to the hydrolyzed intermediate to achieve a pH ranging from 3 to 4, and (b) heating the pH-adjusted solution to a temperature ranging from 70 ⁰C to 90 ⁰C.

52. A process for preparing a compound of Formula 4:

Formula 4

or a salt thereof, wherein R is Ci-C₈alkyl, benzyl, aryl or heteroaryl, each of which is optionally substituted, the process comprising:

(1) reacting a compound of Formula 1 :

J, I Formula 1

or a salt thereof with a cyanoacetate ester in an aqueous solution of ammonium hydroxide for a time and under conditions effective to provide a compound of Formula 2:

Formula 2

or a salt thereof; and

(2) hydrolyzing the compound of Formula 2 or salt thereof: with an aqueous sulfuric acid solution for a time and under conditions effective to provide a compound of Formula 3:

Formula 3

or a salt thereof; and

(3) hydrolyzing and decarboxylating the compound of Formula 3 or salt thereof for a time and under conditions effective to provide a compound of Formula 4 or a salt thereof.

53. A process according to claim 52, wherein R is benzyl that is optionally substituted with from 1 to 4 substituents independently chosen from halogen, Ci-C₄alkyl, nitro and methoxy.

54. A process according to claim 53, wherein R is unsubstituted benzyl.

55. A process according to any one of claims 52-54, wherein the molar ratio of cyanoacetate ester to compound of Formula 1 ranges from 1 :2 to 4:1.

56. A process according to claim 55, wherein the molar ratio of cyanoacetate ester to compound of Formula 1 ranges from 1 :1 to 3 : 1.

57. A process according to any of claims 52-56, wherein the molar ratio of ammonium hydroxide to compound of Formula 1 ranges from 1 :2 to 10:1.

58. A process according to claim 57, wherein the molar ratio of ammonium hydroxide to compound of Formula 1 ranges from 1 :2 to 5: 1.

59. A process according to any one of claims 52-58, wherein the reaction is performed without added gaseous ammonia.

60. A process according to any one of claims 52-59, wherein the step of hydrolyzing the compound of Formula 2 or salt thereof comprises:

61. A process according to claim 60, wherein the concentration of sulfuric acid ranges from 85% to 90%.

62. A process according to claim 60, wherein the molar ratio of sulfuric acid to compound of Formula 2 ranges from 1 :1 to 10:1.

63. A process according to claim 62, wherein the molar ratio of sulfuric acid to compound of Formula 2 ranges from 2:1 to 6: 1.

64. A process according to any one of claims 60-63, wherein the step of heating takes place at a temperature ranging from 90 ⁰C to 110 ⁰C.

65. A process according to any one of claims 62-64, wherein the step of hydrolyzing and decarboxylating the compound of Formula 3 or salt thereof comprises:

66. A process according to claim 65, wherein the sodium hydroxide is present in step (iv) at a concentration ranging from 2N to 15N.

67. A process according to claim 66, wherein the sodium hydroxide is present in step (iv) at a concentration ranging from 3N to 7N.

68. A process according to any one of claims 65-67, wherein the step of acidifying comprises (a) adding concentrated hydrochloric acid to the hydrolyzed intermediate to achieve a pH ranging from 3 to 4, and (b) heating the pH-adjusted solution to a temperature ranging from 70 ⁰C to 90 ⁰C.