WO1999019297A1

WO1999019297A1 - Synthesis of azetidine derivatives

Info

Publication number: WO1999019297A1
Application number: PCT/US1998/021786
Authority: WO
Inventors: Zhengming Chen; Hartmuth C. Kolb; Paul Richardson; Zhi-Min Huang
Original assignee: Coelacanth Chemical Corporation
Priority date: 1997-10-15
Filing date: 1998-10-15
Publication date: 1999-04-22
Also published as: AU1089599A; WO1999019297A9

Abstract

The present invention provides compound having formula (I) useful as building blocks for combinatorial libraries and methods of making such compounds. Also provided are compositions comprising the compounds.

Description

SYNTHESIS OF AZETIDINE DERIVATIVES

REFERENCE TO PRIOR APPLICATIONS

This application is a continuation of U.S. Provisional Application entitled BUILDING BLOCKS FOR COMBINATORIAL LIBRARIES, filed on October 15, 1997 (U.S. Prov. App. Ser. No. 60/062,470), the entire teachings of which are incorporated herein by reference.

FIELD OF THE INVENTION The present invention relates to building blocks for the creation of a high degree of structural diversity among compounds within a combinatorial library. Provided herewith are compounds that may serve as building blocks and methods for generating such compounds.

BACKGROUND OF THE INVENTION

Combinatorial chemistry refers to techniques for creating a multiplicity of compounds, referred to as a "library", and then testing the library or each member of the library for biological activity. In recent years, combinatorial chemistry has become an important tool for the drug discovery efforts of many pharmaceutical companies.

An important goal of any combinatorial chemistry program is the creation of a high degree of structural diversity among the compounds in the library. One requirement for obtaining a combinatorial library with a high degree of structural diversity is to prepare the library with building blocks which are, themselves, structurally diverse. A "building block" is a reagent or compound which can combine (i.e., react) with one or more other reagents to yield the compounds which, together, form a combinatorial library. Thus, it would be desirable to have a collection of structurally diverse building blocks, each of which is individually capable of reacting or combining with the same reagent(s) to form a combinatorial library. SUMMARY OF THE INVENTION

The present invention provides a compound having the formula:

FORMULA I wherein R, Ri , R are independently selected from the group consisting of hydrogen, Cj-C_ό lower alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ alkylcarbonyl, C₃-C₆ cycloalkyl, trifluoromethylcarbonyl, or (CH )_n-ρhenyl or -(CH₂)_n- heteroaryl where n is 0 to 4 and where the phenyl or the heteroaryl is optionally substituted with 1 to 3 halogens, Cι-C₆ lower alkyl, Cι-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, or Cι-C₆ carboxyalkyl; aryl or heteroaryl carbonyl which may be optionally substituted with 1 to 3 halogens, Cι-C₆ lower alkyl, C]-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, or Cj- C₆ carboxyalkyl; in addition, R] and R , together with the nitrogen to which each is attached, may form azide or a ring having the following structure: f (CH₂)^ NH W— R₃

where n is 1, 2, or 3;

W is N, CH, or O, provided that when W is O, R₃ does not exist;

R₃ is hydrogen, Cι-C₆ lower alkyl, C₂-C₆ alkenyl, C -C₆ alkynyl, C -C₆ alkylcarbonyl, C -C₆ cycloalkyl, carboxy, C₂-C₆ alkoxycarbonyl, aryl or heteroaryl, each of which is optionally mono-, di-, or trisubstituted with straight or branched chain lower alkyl having 1 to 6 carbon atoms, halogen, trifluoromethyl, hydroxy, straight or branched chain lower alkenyl having 2 to 6 carbon atoms, trifluormethoxy, or amino, dialkylamino having 2 to 6 carbon atoms, -CO₂R where R is alkyl having 1-6 carbon atoms, -(CH )_m-O-R₅ where m is 1-6 and R₅ is hydrogen or lower alkyl having 1-6 carbon atoms. In another aspect, the present invention provides building blocks for combinatorial libraries.

In another aspect, the present invention provides a composition comprising a compound having structural formula I as defined above in combination with a acceptable carrier.

The foregoing merely summarizes certain aspects of the present invention and is not intended, nor should it be construed, as limiting the invention in any manner. All patents and other publications referenced herein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

The present invention relates to building blocks for the synthesis of a collection of compounds as a combinatorial library. As used herein, a "collection of compounds" comprises at least three different compounds, also referred to as the "disclosed building blocks" or the "member compounds". Preferably, the collection comprises at least five different compounds, more preferably at least thirty different compounds. In one aspect, the collection comprises at least fifty different compounds. Each of the disclosed building blocks is: 1) substantially pure; 2) is substantially free of contamination by the other building herein; and 3) contains at least one reactive group. Optionally, a building block can contain one or more non- reactive functional groups. As used herein, "substantially pure" means, for example, that the disclosed building block is at least about 80% pure, and preferably at least about 90% pure and more preferably at least about 95% pure. As used herein, "substantially free of contamination by other members of the collection" means, for example, that the disclosed building block contains less than 5% of the other building blocks in the collection and more preferably less than 1.0% of the other building blocks in the collection, and even more preferably less than 0.1% of the other building blocks in the collection.

A "reactive functional group" allows the compound in the collection to be reacted directly with other reagents or compounds to form a member of a combinatorial library or a precursor thereof. "Reacted directly" means, for example, that the reactive functional group can react and form covalent bonds with the other compounds without the need of intervening reactions such as a deprotection reaction. The reactive functional group determines the interconnection chemistries, i.e., the manner in which the disclosed building block can be reacted with other building blocks of the combinatorial library. Examples of reactive functional groups include a hydroxyl group, a primary amine group, a secondary amine group, a thiol, a carboxylic acid, an ester, an aldehyde, an azide, a nitrile, an isonitrile, an epoxide, an aziridine, an isocyanate, a thioisocyanate and a halide.

A "non-reactive functional group" is inert under the reaction conditions employed for interconnecting the disclosed building blocks with other building blocks used to prepare a member of a combinatorial library or a precursor thereof, unless the non-reactive functional group is, for example, first activated or undergoes a deprotection reaction. Examples of non-reactive functional groups include an ether, a thioether, a tertiary amine, an alkene, an alkyne, an alkoxycarbonyl, a ketal or an acetal.

As noted above, a member compound has at least one reactive functional group. More than one reactive functional group can be present in a member compound, provided that the reactivity of each reactive functional group is orthogonal to the reactivities of the other functional groups, i.e., each reactive functional group can selectively react in the presence of the others.

A reactive functional group can be introduced into the building block or member compound by, for example, formation of a carbon-heteroatom bond between a precursor compound and a reagent. Specific examples are provided in the following paragraphs.

The formation of a carbon-heteroatom bond between a precursor compound and a reagent can occur by reacting an electrophilic precursor compound and a nucleophilic reagent. One example of a reactive functional group which can be introduced by this type of transformation is a secondary amine R'NH-, which is formed from the reaction of an electrophilic precursor compound and R¹NH₂, or the anion thereof (or by the reaction of a carbonyl group with a primary amine under reducing conditions). RI is an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. Examples of other nucleophilic reagents which can introduce reactive functional groups into a member compound by this type of transformation include H₃N, H₂O, R^]NH₂, RVNH, R^πSH, R^πOH, an acyl thiol (RC(O) -SH) or the anions thereof. Reaction of these nucleophilic reagents with an electrophilic precursor can introduce H₂N-, HO-, R*NH-, R'R^ΠN-, R"S-, R^ΠO, -SH, respectively, into the member compound. R ' is an aliphatic or aromatic group substituted with at least one reactive functional group. Yet another example of a suitable nucleophilic reagent for this type of transformation is R^ιπR^IVNH, or the anion thereof, wherein R^Iπ and R^IV, together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring or is substituted with a reactive functional group. The reaction of this nucleophilic reagent with an electrophilic precursor can introduce R ' R N- into a member compound.

Examples of other reactive functional groups which can be introduced into a member compound include H₂N-, HO-, C1-, Br-, I-, CN-, N₃-, NC-, which are formed by the reaction of a suitable electrophilic precursor compound with NH (or NH₂ ^"), H₂O (or OH^"), Cl^", Br^", T, CN^", N₃ ^", and trimethylsily cyanide, respectively. The nucleophile can also be a part of the elecrophilic precursor, i.e., the reaction is intramolecular, respectively. The nucleophile can also be part of the electrophilic precursor, i.e., the reaction is intramolecular. Epoxides and aziridines are examples of reactive functional groups formed in this manner. Examples of suitable electrophilic precursors which can be used to introduce reactive functional groups into a building block by reaction with a nucleophilic reagent include alkyl halies, aryl halides, alkyl sulfates, alkyl sulfonates, epoxides and aziridines.

A reactive functional group can also be formed by converting a reactive functional group present in a member compound to a different reactive group. One example of this type of reaction is the conversion of a primary amine to isocyanate by reaction with phosgene or Cl-COO-C(CL ) or the replacement of a halide with an amine. Alternatively, a reactive functional group can be formed by removing a protecting group present in a member compound. Examples include cleaving a tert- butoxycarbonyl group (hereinafter "BOC") to regenerate a free primary or secondary amine or hydrolyzing an acetal or ketal to liberate an aldehyde or ketone, respectively.

The formation of a carbon-heteratom bond between a precursor compound and reagent can also occur by reacting a nucleophilic precursor compound, e.g., a compound containing one or more double and/or triple bonds, and an electrophilic reagent. For example, -Cl, -Br-, -I, -OH, -O-, -N₃, and an aziridine can be formed by reacting a compound containing one or more double and/or triple bonds with, for example, SC1₂, RSC1, SBr₂, SI , N-bromosuccinimide, meta-chloroperbenzoic acid, NaN3 or tosyl chloramine. A non-reactive functional group can be introduced into a building block or member compound by formation of a carbon-heteroatom bond between a precursor compound and a reagent, for example, by reacting an electrophilic precursor compound and a neucleophilic reagent. Examples of suitable electrophilic precursor compounds are as described above for introducing reactive functional groups into building blocks. Examples of suitable nucleophilic reagents for introducing non- reactive functional groups into a building block include R^VR^V1NH, R^VSH, R^vOH, or the anions thereof. R and R^VI are independently an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. Substituted aliphatic and substituted aromatic groups represented by R^v and R^VI can contain non- reactive functional groups but no reactive functional groups. These nucleophilic reagents, together with a suitable electrophilic precursor compound, can be used to introduce R^VR^V1N-, R^VS- and R^vOH, respectively into a building block. Another example of a suitable necleophilic reagent for introducing a non-reactive functional group into the building block is R^VI,R^VIIINH, or the anion thereof. R^v" and R^vιπ, together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic group which does not contain -NH- in the non-aromatic heterocyclic ring and is not substituted with a reactive functional group. By using R^VIIR^VII1NH or its anion and a suitable eletrophilic precursor compound, R^V1IR^VIIIN- can be introduced into a building block. Yet another example of a suitable nucleophilic reagent for introducing a non-reactive functional group into a building block is R^VINH₂, or the anion thereof. Use of this reagent and a precursor molecular having at least to electrophilic sites results in the formation of a non-reactive R^IVN< functional group.

Methods of preparing compounds which are members of the collections described herein are disclosed in the attached Appendix. Other methods of preparing certain compounds which are members of the collections disclosed herein are described in copending U.S. Provisional Application entitled BUILDING BLOCKS FOR COMBINATORIAL LIBRARIES (U.S. Prov. App. Ser. No. 60/062,470 filed October 15, 1997), the entire teachings of which are incorporated herein by reference. The disclosed building blocks can be formed from virtually any combination of the eletrophilic precursor compounds and the nucleophilic reagents which are disclosed herein or from the nucleophilic precursor compounds (e.g., compounds containing one or more units of unsaturation) and the electrophilic reagents which are disclosed herein, provided that at least one reactive group is present in the building block. In one embodiment, the collection includes building block. In one embodiment, the collection includes building blocks which are formed from an electrophilic precursor compound and a nucleophilic reagent disclosed herein or from a nucleophilic precursor compound containing one or more units of unsaturation and an electrophilic reagent disclosed herein. In another embodiment, the collection consists of building blocks from an electrophilic precursor compound and a nucleophilic reagent disclosed herein or from a nucleophilic precursor compound containing one or more units of unsaturation and an electrophilic reagent disclosed herein. In a preferred embodiment, the collection includes the building blocks disclosed herein. In another preferred embodiment, the collection consists of the building blocks disclosed herein.

The novel compounds encompassed by the instant invention can be described by the general Formula I set forth above or the pharmaceutically acceptable non-toxic salts thereof. In a preferred embodiment, the present invention provides a compound of

Formula I wherein R, Ri, R₂ are independently selected from the group consisting of hydrogen, Cι-C₆ lower alkyl, C -C₆ alkylcarbonyl, trifluoromethylcarbonyl, or

(CH )_n -phenyl where n is 0 to 4 and where the phenyl is optionally substituted with halogen, Cι-C₆ lower alkyl, C]-C₆ carboxy, C₂-C₆ alkylcarbonyl; in addition, Ri and R , together with the nitrogen to which each is attached, may form azide or a structure shown below:

In another preferred embodiment, a compound of Formula I has R is selected from CH -phenyl, H, t-butyl,

O O

I I I I

-C-CF₃ and C CH₃

In yet another preferred embodiment, a compound of Formula I is provided wherein R is CH₂-phenyl and wherein Rj, R and the N to which each is attached form azide or a structure selected from:

Yet another preferred compound of Formula I is provided wherein R is hydrogen and wherein R_{1 }} R₂ and the N to which each is attached form a structure selected from:

In a preferred embodiment, a compound of Formula I is provided where R is t- butyl and where Ri, R and the N to which each is attached form one of the following structures:

In another preferred embodiment of Formula I, R is

O

I I

-C-CF₃

and Ri, R and the N to which each is attached form one of the following structures: In yet another preferred embodiment of Formula I, R is

O -C-CH₃

and Ri, R₂ and the N to which each is attached form a structure selected from:

The most preferred compounds include the following and their pharmaceutically acceptable salts: 2-methoxyphenylpiperazine; l-(2-pyridyl)- piperazine; 1-pyrimidylpiperazine; 1-phenylpiperazine; 1-methylpiperazine; morpholine; piperidine; pyrrolidine; dimethylamine; methylamine; isopropylamine; methallyamine; sodium azide; azetidin-3-ol; 2-methoxyphenlpiperazine; 1(2- hydroxyethyl)-piperazine; piperazine; 1 -tert-butoxycarbonyl perhydrodiazepine; 1- methylpiperazine; 1-phenylpiperazine; 1-pyrimidylpiperazine; 4- fluorophenylpiperazine; 4-methoxyphenylpiperazine; 4-methylphenylpiperazine; 4- trifluoromethoxyphenylpiperazine; 4-trifluoromethylphenylpiperazine; 1 -(2-pyridyl)- piperazine; 4-fluorophenylpiperazine; 4-methoxyphenylpiperazine; 4- trifluorophenylpiperazine; 1 -tert-butoxycarbonylpiperazine; 1 -tert-butoxycarbonyl perhydrodiazepine; 1-methylpiperazine; 1-phenylpiperazine; and, 1- pyrimidylpiperazine and the pharmaceutically acceptable salts thereof.

Unless otherwise stated, the following definitions relate to this disclosure. "Alkyl" means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms (unless stated otherwise; preferably C]-C₆) and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and the like.

"Halo" includes fluoro, chloro, bromo, and iodo.

"Alkenyl" means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one double bond and includes ethenyl, 3-buten-l-yl, 2-ethenylbutyl, 3-hexen-l-yl, and the like. "Alkynyl" means straight and branched hydrocarbon radicals having from 2 to

10 carbon atoms and one triple bond. Typical C₂-Cι₀ alkynyl groups include propynyl, 2-butyn-l-yl, 3-pentyn-l-yl, and the like. "Cycloalkyl" means a cyclic hydrocarbyl group such as cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl, and the like.

"Alkoxy" refers to the alkyl groups mentioned above bound through a single oxygen atom, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

"Carboalkoxy" as used herein refers to an organic acid esterified with a lower alcohol or amidated with an amine, respectively. Such groups include, for example,

"Alkanoyl" or "alkylcarbonyl" groups are alkyl as previously defined linked through a carbonyl, i.e., Cι-Cιo-C(O)- or C₂-C₆-C(O)-.. Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.

"Acyl" means an alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., R-C(=O)-. For example, acyl includes a Ci-Cio alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR'R" or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like.

The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted by N, NR, phenyl, substituted phenyl, thio, Ci-Cio alkyl (preferably

Cι-C₆), Ci-Cio alkoxy (preferably Cι-C₆), hydroxy, carboxy, -Cio alkoxycarbonyl

(preferably Cι-C₆), halo, nitrile, cycloalkyl, or a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. "Substituted nitrogen" means nitrogen bearing Cr o alkyl (preferably Cι-C₆) or (CH )_nPh where n is 1, 2, or 3.

Examples of substituted alkyl groups include 2-aminoethyl,

2-diethylaminoethyl, 2-dimethylamino-propyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanyl-sulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl,

4-chlorobutyl, 3-cyclopropylpropyl, 3-morpholinopropyl, piperazinylmethyl, and

2-(4-methylpiperazinyl)ethyl.

Examples of substituted alkynyl groups include 2-methoxyethynyl,

2-ethylsulfanyethynyl, 4-(l -piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like. Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 3 -diethylamino-2-hydroxy-propoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.

Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-l-yl,

5-ethylmethylamino-3-pentyn-l -yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl-3- imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl,

3-chlorophenylmethyl, and the like.

As used herein, "aliphatic groups" comprise straight chained, branched or cyclic Cι-C₈ hydrocarbons which are completely saturated or which contain one or more units of unsaturation.

Suitable substituents for an aliphatic group or an aromatic group comprise reactive functional groups and non-reactive functional groups, as described above.

The terms "Ar" and "aryl" refer to unsubstituted and substituted aromatic groups. Heteroaryl groups are aryls having from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, benzofuranyl, indoyl, and the like.

Aromatic groups may also comprise carbocyclic aromatic groups such as phenyl, 1 -naphthyl, 2-naphthyl, 1-anthracyl and 2-anthacyl, and heterocyclic aromatic groups such as N-imidazolyl, 2-imidazole, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidy, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazole, 4-thiazole, 5-thiazole, 2- oxazolyl, 4-oxazolyl and 5-oxazolyl.

In addition, aromatic groups may comprise fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include 2-benzothienyl, 3 -benzothienyl, 2- benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2- benzothiazole, 2-benzooxazole, 2-benzimidazole, 2-quinolinyl, 3-quinolinyl, 2- benzothiazole, 2-benzooxazole, 2-benzimidazole, 2-quinolinyl, 3-quinolinyl, 1- isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridinyl. Preferred Ar groups are phenyl and substituted phenyl. The alkyl and alkoxy groups can be substituted as defined herein. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl.

The compounds of the instant invention may be prepared using the chemical synthesis described below:

1 2 3 4

The methods provided by the instant invention further provide for mesylate displacement, debenzylation (R = Bn to R = H), acylative dealkylation (R = tBu to R = H), and an improved acylative dealkylation method (R = tBu to R = H).

The starting azetidinols may be prepared utilizing a modified procedure of Gaertner (J. Org. Chem., 1967, 32. 2972) according to the following sequence:

The synthesis of substituted azetidines by a mesylate displacement has been utilized previously (Okutani, et al. Chem. Pharm. Bull., 1974, 22, 1490; Suzuki, et al. U.S. Patent No. 3,929,765). The deficiencies associated with those methods include poor yield due to formation of considerable amounts of side products and impedence of product isolation and purification. The present invention provides a solution to such difficulties.

For instance, in practicing the present invention, mesylation is carried out at low temperature to minimize side reactions; mesylate is used immediately to prevent decomposition; the displacement reaction is carried out in water; and, by-products are easily removed (a feature of Clickchem™). In addition, the product crashes out of solution (particularly in the case of aromatic nucleophiles were a slight excess of the mesylate is employed). Furthermore, use of the tert-butyl group leads to a cleaner displacement reaction thus leading to a more easily purifiable product. The majority of known studies on substituted azetidines have avoided benzyl as the protecting group, and have instead used benzhydryl (Chatterjee, et al. Synthesis, 1973, 153). Isolated examples of removal of a benzyl group from this type of system do exist, though harsh conditions have been employed. Provided herein is a method for the removal of a benzyl group (debenzylation, R=Bn to R=H) under relatively mild conditions.

Acylative dealkylation is also contemplated by the instant invention. The procedure using acetic anhydride was developed by Dave (J. Org. Chem., 1996, 61, 5453), though its use was limited to three substrates due probably to difficulty in isolating the products. The present invention solves certain difficulties associated with the method of Dave by: using a co-solvent; providing a modified work-up that makes product isolation easier; extend the scope of the process of Dave to a number of new substrates; and, providing an improved method for hydrolysis of the amide bond using hydrogen chloride gas in ethanol.

The present invention also extends the scope of the acylative dealkylation method, and provides a method that allows the deprotection of acid sensitive compounds. For instance, several of the substrates in the current study contain acid- sensitive functional groups and cannot, therefore, be deprotected by either of the methods described above. The instant invention provides a new method for the cleavage of the tert-butyl group in these systems (Nussbaumer, et al., Tetrahedron, 1991, 47, 4591). As with the acetic anhydride method, the instant invention provides a two step method first involving formation of the trifluoroacetamide followed by cleavage under basic conditions. The advantages of the instant invention include: the reaction takes place at 0°C; only slightly more than a stoichiometric amount of trifluoroacetic anhydride is required; the reaction is very rapid (with the addition of one equivalent of triethylamine, the reaction is complete within one hour); the work- up is simple; the reaction is very clean, thus simplifying product isolation; amide hydrolysis is also rapid and takes place at room temperature.

The following nonlimiting examples illustrate the inventors' preferred methods for preparing the compounds of the invention. The following examples are provided for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Those skilled in the art will appreciate that modifications and variations of the following examples can be made without exceeding the spirit or scope of the present invention and claims.

EXAMPLES I. Synthesis N-t-butyl-3-hydroxyazetidine

A. iV-tert-butyl-3-trimethylsiloxyazetidine A solution of t-butylamine (146.3 g, 2 mol) and epichlorohydrin (156 ml, 2 mol) in hexane (1.5 L) was stirred at room temperature for 2 days. The initial clear solution turnedcloudy after 48 hrs. Hexamethyldisilazane (211 ml, 1 mol) and CH₃CN (500 mL) were added to this mixture, and the resulting solution was refluxed overnight. The solvent was removed in vacuo to give a red brown oil, which was then dissolved in acetonitrile (IL). Triethylamine (303.1 g, 3 mol) was added, and the mixture was refluxed for 3 days (a white solid was observed to precipitate from solution within 24 hrs). After being allowed to cool to room temperature, triethylamine hydrochloride was filtered off, and the solid washed with petroleum ether. Removal of the solvent in vacuo gave a yellow oil, which was distilled (oil bath 75 °C) to give the silyl ether (400 g, 95% pure, 97% yield) as a colorless oil (b.p. 45 °C/2-3 mmHg).

B. JV-t-butyl-3-hydroxyazetidine

N-t-butyl-O-trimethylsilylazetidine (400 g, 2 mol) was added portionwise to 3Ν Hydrochloric acid solution (733 mL) at room temperature, and the resulting mixture was stirred at ambient temperature. An exothermic reaction took place. After

1 hour, the pink mixture was extracted once with ether (ca. 500 mL) to remove the silyl ether. A solution of NaOH (100 g) in water (250 mL) was added to the aqueous layer and the resulting white suspension was saturated with K₂CO₃. The crude product was separated, and the aqueous layer was extracted with CH₂C1₂ (500 mL x 2). The organics were combined, dried over Na₂SO₄, filtered, and evaporated in vacuo. The residue (colorless oil) solidified underhigh vacuum to afford the product as a white crystalline solid (165 g, 64%).

II. Benzyl displacement reactions

A. 2-methoxyphenylpiperazine

To a solution of triethylamine (171ml, 1.23mol) and N-benzylazetidin-3-ol (lOOg, O.όlmol) in methylene chloride (700ml) at -40°C was added methanesulfonyl chloride (58ml, 0.75mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (3 x 750ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as an orange oil (176.9g).

Immediately, triethylamine (128ml, 0.92mol), 2-methoxyphenylpiperazine (118g, O.όlmol) and water (100ml) were added to the crude mesylate, and the reaction was heated to 50°C. TLC analysis after 15 minutes indicated almost complete consumption of the starting mesylate. The reaction was allowed to stir at 50°C for 3 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) was added, and the organic layer was separated. The aqueous was extracted with methylene chloride (2 x 250ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a yellow oil. Purification of the product was carried out by passing it through a pad of silica gel eluting with a gradient ranging from 20% ethyl acetate in hexanes to neat ethyl acetate. The product (82.4g, 38%>) was obtained as a slightly yellow liquid which upon cooling gave a white solid.

2. l-(2-pyridyl)-piperazine

To a solution of triethylamine (171ml, 1.23mol) and N-benzylazetidin-3-ol

(lOOg, O.όlmol) in methylene chloride (700ml) at -40°C was added methanesulfonyl chloride (58ml, 0.75mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 800ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as an orange oil.

Immediately, triethylamine (130ml, 0.92mol), l-(2-pyridyl)-piperazine (lOOg, O.όlmol) and water (130ml) were added to the crude mesylate, and the reaction was heated to 50°C. The reaction was allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) was added, and the organic layer was separated. The aqueous was extracted with methylene chloride (2 x 400ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a yellow oil. Purification of the product was carried out by passing it through a pad of silica gel eluting with a gradient ranging from 20%) ethyl acetate in hexanes to neat ethyl acetate. The product (119.1g, 63%) was obtained as a slightly yellow liquid which upon cooling gave a yellow solid. 1 -pyrimidylpiperazin e

To a solution of triethylamine (171ml, 1.23mol) and N-benzylazetidin-3-ol (lOOg, O.όlmol) in methylene chloride (700ml) at -40°C was added methanesulfonyl chloride (58ml, 0.75mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 800ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as an orange oil .

Immediately, triethylamine (130ml, 0.92mol), 1-pyrimidylpiperazine (lOOg, O.όOmol) and water (130ml) were added to the crude mesylate, and the reaction was heated to 50°C. The reaction was allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) was added, and the organic layer was separated. The aqueous was extracted with methylene chloride (2 x 400ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a yellow oil. Purification of the product was carried out by passing it through a pad of silica gel eluting with a gradient ranging from 20% ethyl acetate in hexanes to neat ethyl acetate. The product (124.3g, 65%) was obtained as a colorless solid. 1-Phenylpiperazine

To a solution of triethylamine (171ml, 1.23mol) and N-benzylazetidin-3-ol (lOOg, O.όlmol) in methylene chloride (700ml) at -40°C was added methanesulfonyl chloride (58ml, 0.75mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 800ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as an orange oil.

Immediately, triethylamine (130ml, 0.92mol), 1-phenylpiperazine (l lOg, 0.68mol) and water (130ml) were added to the crude mesylate, and the reaction was heated to 50°C. The reaction was allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) was added, and the organic layer was separated. The aqueous was extracted with methylene chloride (2 x 400ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as an orange oil. Purification of the product was carried out by passing it through a pad of silica gel eluting with a gradient ranging from 20% ethyl acetate in hexanes to neat ethyl acetate. A precipitate was noticed in several of the fractions, which contained the product, and this was removed by filtration. The product (104g, 55%) was obtained as a slightly yellow liquid. 1-Methylpiperazine

Immediately, triethylamine (130ml, 0.92mol), 1-methylpiperazine (70ml, 0.63mol) and water (130ml) were added to the crude mesylate, and the reaction was heated to 50°C. The reaction was allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) was added, and the organic layer was separated. The aqueous was extracted with methylene chloride (2 x 500ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a yellow oil. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 95 : 5 ; ethyl acetate : triethylamine. The product (31.6g, 21%>) was obtained as an orange oil.

Morpholine

Immediately, triethylamine (130ml, 0.92mol), morpholine (60ml, 0.69mol) and water (200ml) were added to the crude mesylate. After the initial exotherm had ceased, the reaction was heated gently at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) was added, and the reaction was extracted with ether (3 x 500ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a colorless oil. Removal of excess volatiles was achieved by heating the residue to 60°C under vacuum (ImmHg) for 12 hours, and the product (105g, 74%) was then used without any further purification.

Piperidine

Immediately, piperidine (182ml, 1.84mol) and water (130ml) were added to the crude mesylate, and the reaction was heated to 50°C. The reaction was allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) was added, and the organic layer was separated. The aqueous was extracted with diethyl ether (2 x 250ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as an orange oil. Purification of the product was carried out by passing it through a pad of silica gel eluting with a gradient ranging from 20% ethyl acetate in hexanes to neat ethyl acetate. The product (76. lg, 54%) was obtained as a colorless liquid.

8. Pyrrolidine

To a solution of N-benzyl-3-hydroxyazetidine (20g, 0.12mol) in chloroform (250ml) was added triethylamine (43ml, 0.31mol). The solution was cooled to below - 20°C, and a solution of methanesulfonyl chloride (17ml, 0.22mol) in chloroform (50ml) was added in a dropwise fashion. Upon completion of the addition, the reaction was poured into saturated sodium bicarbonate solution (300ml). The organic layer was separated, and the aqueous layer was extracted with a further portion of chloroform (50ml). The combined organic extracts were dried over sodium bicarbonate, and the solvent removed in vacuo to afford the crude mesylate.

To the mesylate was added pyrrolidine (52ml, O.όmol). The reaction was heated to 55-60°C, and stirred for 2 hours. After being allowed to cool, the reaction was poured into saturated sodium bicarbonate solution (200ml) extracted with diethyl ether (2 x 250ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo. The product was placed on the high vacuum lines for 12 hours to remove residual pyrrolidine, after which N-benzyl-3- pyrrolidinoazetidine (23.8g, 90%) was obtained as an orange oil, which was used without further purification.

Dimethylamine

To a solution of N-benzyl-3-hydroxyazetidine (25g, 0.15mol) in chloroform (250ml) was added triethylamine (54ml, 0.39mol). The solution was cooled to below - 20°C, and a solution of methanesulfonyl chloride (22ml, 0.28mol) in chloroform (70ml) was added in a dropwise fashion. Upon completion of the addition, the reaction was poured into saturated sodium bicarbonate solution (400ml). The organic layer was separated, and the aqueous layer was extracted with a further portion of chloroform (100ml). The combined organic extracts were dried over sodium bicarbonate, and the solvent removed in vacuo to afford the crude mesylate.

To the mesylate was added aqueous dimethylamine (173ml, 40%>, 1.57mol). The reaction was heated to 55-60°C, and stirred for 12 hours. After being allowed to cool, solid sodium bicarbonate (lOg) was added, and the reaction was extracted with diethyl ether (3 x 400ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford N-benzyl-3- dimethylaminoazetidine (29g, 99%>) as a slightly yellow liquid, which was used without further purification.

10. Ammonia

To a solution of N-benzy 1-3 -hydroxyazeti dine (20g, 0.12mol) in methylene chloride (250ml) was added triethylamine (68ml, 0.49mol). The solution was cooled to below -20°C, and a solution of methanesulfonyl chloride (17ml, 0.22mol) in methylene chloride (50ml) was added in a dropwise fashion. Upon completion of the addition, the reaction was poured into saturated sodium bicarbonate solution (300ml). The organic layer was separated, and the aqueous layer was extracted with a further portion of methylene chloride (100ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude mesylate.

To the mesylate was added aqueous ammonia (130ml, 2.29mol, 30%). The reaction was heated to 55-60°C, and stirred for 12 hours. After being allowed to cool, solid sodium bicarbonate (lOg) was added, and the mixture was extracted with diethyl ether (3 x 250ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to give the crude product. Distillation (78-82°C/ ImmHg) affords N-benzyl-3-aminoazetidine (6.8g, 34%o) as a colourless liquid.

11. Methylamine

To a solution of N-b enzy 1-3 -hydroxy azetidine (25g, 0.15mol) in chloroform

(250ml) was added triethylamine (54ml, 0.39mol). The solution was cooled to below - 20°C, and a solution of methanesulfonyl chloride (22ml, 0.28mol) in chloroform (70ml) was added in a dropwise fashion. Upon completion of the addition, the reaction was poured into saturated sodium bicarbonate solution (400ml). The organic layer was separated, and the aqueous layer was extracted with a further portion of chloroform (100ml). The combined organic extracts were dried over sodium bicarbonate, and the solvent removed in vacuo to afford the crude mesylate.

To the mesylate was added aqueous methylamine (180ml, 2.7mol, 40%). The reaction was heated to 55-60°C, and stirred for 12 hours. After being allowed to cool, solid sodium bicarbonate (lOg) was added, and the mixture was extracted with diethyl ether (2 x 400ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to give N-benzyl-3-methylaminoazetidine (6.0g, 22%o) as a slightly yellow liquid. Further purification can be carried out by distillation (75-78°C/ ImmHg) to afford N-benzyl-3-methylaminoazetidine as a colourless liquid.

12. Isopropylamine

To a solution of N-benzyl-3-hydroxyazetidine (20g, 0.12mol) in methylene chloride (250ml) was added triethylamine (68ml, 0.49mol). The solution was cooled to below -20°C, and a solution of methanesulfonyl chloride (17ml, 0.22mol) in methylene chloride (50ml) was added in a dropwise fashion. Upon completion of the addition, the reaction was poured into saturated sodium bicarbonate solution (300ml). The organic layer was separated, and the aqueous layer was extracted with a further portion of methylene chloride (100ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude mesylate. To the mesylate was added triethylamine (45ml, 0.32mol), and isopropylamine

(31ml, 0.48mol). The reaction was heated to 55-60°C, and stirred for 12 hours. After being allowed to cool, solid sodium bicarbonate (lOg) was added, and the mixture was extracted with diethyl ether (3 x 250ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to give the crude product. Distillation (89-98°C/ ImmHg) affords N-benzyl-3-isopropyaminoazetidine (10.27g, 41%)) as a colourless liquid. 13. Methallylamine

Immediately, triethylamine (125ml, 0.92mol), methallylamine (87g, 1.23mol) and water (130ml) were added to the crude mesylate. The reaction was heated gently at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) was added, and the reaction was extracted with ether (2 x 500ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product (98g) as an orange oil, which was dissolved in ethyl acetate (425ml). This solution was added in a dropwise manner at 0°C to a solution of acetyl chloride (69.4ml, 0.98mol) in methanol (105ml) and ethyl acetate (215ml). Immediately, a white precipitate was noticed. After being stirred for 1 hour at 0°C, the precipitate was filtered, and washed with ether. Recrystallisation from methanol/methyl tert-butyl ether gave the tø-hydrochloride salt as a white solid (53g, 30%).

A sample of the hydrochloride salt (16g) was cooled to 0°C, and saturated sodium bicarbonate solution (320ml) was added. After the vigorous effervesence had subsided, the aqueous solution was extracted with methylene chloride (2 x 400ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product (11.2g) as a slightly yellow oil. 14. Sodium azide

Immediately, triethylamine (130ml, 0.92mol), sodium azide (80g, 1.22mol) and water (200ml) were added to the crude mesylate. The reaction was heated gently at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) was added, and the reaction was extracted with methylene chloride (2 x 300ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a colorless oil, which contained a small amount of precipitate. The precipitate was removed by filtration. Distillation (116-118°C/lmmHg) followed by filtration through a short pad of silica gel (eluting with 80 : 20 ; hexanes : ethyl acetate) gave the product as a colorless liquid (25.7g, 22%).

Debenzylation reactions

1. Azetidin-3-ol

Hydrochloride Salt Hydrochloride Salt

In a Parr shaker pressure bottle, the hydrochloride salt (122g, 0.62mol) was dissolved in methanol (IL), and palladium hydroxide (12g, 20%> on carbon) was added. The bottle was evacuated, and then pressurised under hydrogen (40psi) and shaken whilst being heated to 60°C. On reaching the desired temperature, the pressure increased to 60psi, and shaking continued for a further 90 hours (during this time the hydrogen pressure was recharged four times after samples had been removed for NMR analysis to monitor the progress of the reaction). The heater was then turned off, and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure had been released, the bottle was opened, and the reaction was filtered through celite washing with methanol (2.5L). The solvent was removed in vacuo to afford the crude product as a white solid. Recrystallisation from ethanol/methyl tert-butyl ether afforded the product (33.2g, 50%) as colorless needles.

2-methoxyphenylpiperazine

Hydrochloride Salt Hydrochloride Salt

In a Parr shaker pressure bottle, the hydrochloride salt (185g, 0.41mol) was dissolved in methanol (IL), and palladium hydroxide (21g, 20% on carbon) was added. The bottle was evacuated, and then pressurised under hydrogen (40psi) and shaken whilst being heated to 60°C. On reaching the desired temperature, the pressure was increased to όOpsi, and shaking continued for a further 48 hours (during this time the hydrogen pressure was recharged twice). The heater was then turned off, and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure had been released, the bottle was then opened, and the reaction was filtered through celite washing with hot methanol (8L) followed by water (3L).

Removal of the methanol afforded approximately 80g of a yellow solid (>85% pure by 1H NMR). The impurities were removed by washing the solid with hot methanol, and filtration. Excess methanol was removed by azeotroping the solid obtained with toluene using a Dean-Stark trap. Removal of the toluene gave 62g

(44%o) of the product as a brown powder.

The water was removed form the aqueous wash in vacuo, and the product was further dried by placing it on the vacuum lines for 12 hours. 58g (42%) of product was obtained as a brown powder. 3. Morpholine

Hydrochloride Salt Hydrochloride Salt

In a Parr shaker pressure bottle, the hydrochloride salt (162g, 0.53mol) was dissolved in methanol (IL), and palladium hydroxide (16.2g, 20% on carbon) was added. The bottle was evacuated, and then pressurised under hydrogen (40psi) and shaken whilst being heated to 60°C. On reaching the desired temperature, the pressure increased to όOpsi, and shaking continued for a further 110 hours (during this time the hydrogen pressure was recharged four times after samples had been removed for NMR analysis to monitor the progress of the reaction). The heater was then turned off, and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure had been released, the bottle was opened, and the reaction was filtered through celite washing with methanol (3L). The solvent was removed in vacuo to afford the crude product as a white solid. Recrystallisation from methanol/methyl tert-butyl ether followed by refluxing the solid obtained with toluene using a Dean-Stark apparatus to remove excess methanol afforded the product (76. Ig, 67%>) as a colorless powder.

Piperidine

Hydrochloride Salt Hydrochloride Salt

In a Parr shaker pressure bottle, the hydrochloride salt (l lόg, 0.39mol) was dissolved in methanol (1.15L), and palladium hydroxide (12.2g, 20% on carbon) was added. The bottle was evacuated, and then pressurised under hydrogen (40psi) and shaken whilst being heated to 60°C. On reaching the desired temperature, the pressure increased to όOpsi, and shaking continued for a further 72 hours (during this time the hydrogen pressure was recharged three times after samples had been removed for NMR analysis to monitor the progress of the reaction). A further portion of palladium hydroxide (8g) was added, and the reaction heated at 60°C under hydrogen pressure (όOpsi) for a further 24 hours. The heater was then turned off, and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure had been released, the bottle was opened, and the reaction was filtered through celite washing with methanol (2.5L). The solvent was removed in vacuo to afford the crude product as a white solid. Recrystalhsation from methanol/methyl tert- butyl ether followed washing with ether afforded the product (54g, 67%) as a colorless powder.

5. l-(2-hydroxyethyl)-piperazine

Hydrochloride Salt Hydrochloride Salt

In a Parr shaker pressure bottle, the hydrochloride salt (l lόg, 0.39mol) was dissolved in methanol (1.15L), and palladium hydroxide (12.2g, 20%> on carbon) was added. The bottle was evacuated, and then pressurised under hydrogen (40psi) and shaken whilst being heated to 60°C. On reaching the desired temperature, the pressure increased to όOpsi, and shaking continued for a further 72 hours (during this time the hydrogen pressure was recharged three times after samples had been removed for NMR analysis to monitor the progress of the reaction). A further portion of palladium hydroxide (2g) was added, and the reaction heated at 60°C under hydrogen pressure (όOpsi) for a further 24 hours. The heater was then turned off, and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure had been released, the bottle was opened, and the reaction was filtered through celite washing with methanol (3L). The solvent was removed in vacuo to afford the crude product as an oily solid, which was slurried with wo-propanol (250ml) and methanol (100ml) and heated to reflux for 15 minutes. After being allowed to cool, the product (54g, 62%) was collected by filtration, washing the solid obtained with wo-propanol. IV. tert-Butyl displacement reactions 1. l-(2-pyridy I) -piperazine

To a solution of triethylamine (128ml, 0.92mol) and N-tert-butyl-azetidin-3-ol (80g, 0.62mol) in methylene chloride (750ml) at -40°C was added a solution of methanesulfonyl chloride (60ml, 0.78mol) in methylene chloride (100ml) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 750ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil.

Immediately, triethylamine (100ml, 0.72mol), l-(2-pyridyl)-piperazine (lOOg, 0.62mol) and water (100ml) were added to the crude mesylate, and the reaction was heated to 50°C for 12 hours. After being allowed to cool, solid sodium bicarbonate (lOg) was added, and the reaction mixture was extracted with methylene chloride (3 x 500ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 80 : 15 : 5 ; ethyl acetate : hexanes : triethylamine. The product (56g, 33%) was obtained as a colorless solid.

2. Piperazine

To a solution of triethylamine (160ml, 1.15mol) and N-tert-butyl-azetidin-3-ol (lOOg, 0.78mol) in methylene chloride (800ml) at -40°C was added a solution of methanesulfonyl chloride (75ml, 0.97mol) in methylene chloride (150ml) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 750ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil. Immediately, triethylamine (125ml, 0.90mol), piperazine (330g, 3.84mol) and water (600ml) were added to the crude mesylate, and the reaction was heated to 50°C for 12 hours. After being allowed to cool, solid sodium bicarbonate (lOg) was added, and the reaction mixture was extracted with chloroform (3 x 700ml). The combined organic extract⁰, were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a viscous yellow oil. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 70 : 15 : 15 ; ethyl acetate : hexanes : triethylamine. The product (72g, 47%) was obtained as a colorless oil.

3. 1-tert-Butoxycarbonyl perhydrodiazepine

To a solution of triethylamine (160ml, 1.15mol) and N-tert-butyl-azetidin-3-ol (lOOg, 0.78mol) in methylene chloride (800ml) at -40°C was added a solution of methanesulfonyl chloride (75ml, 0.97mol) in methylene chloride (150ml) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 750ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil. Immediately, triethylamine (125ml, 0.90mol), 1-tert-Butoxycarbonyl perhydrodiazepine (171g, 0.86mol) and water (130ml) were added to the crude mesylate, and the reaction was heated to 50°C for 12 hours. After being allowed to cool, the reaction mixture was saturated with potassium carbonate and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a viscous yellow oil. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 35 : 60 : 5 ; ethyl acetate : hexanes : triethylamine. The product (82g, 34%) was obtained as a slightly yellow solid.

1-Methylpiperazine

To a solution of triethylamine (160ml, 1.15mol) and N-tert-butyl-azetidin-3-ol (lOOg, 0.78mol) in methylene chloride (500ml) at -40°C was added a solution of methanesulfonyl chloride (72ml, 0.93mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 500ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil.

Immediately, triethylamine (160ml, 1.15mol), 1-methylpiperazine (102ml, 0.86mol) and water (150ml) were added to the crude mesylate. The reaction was very exothermic. After being stirred for 90 minutes, TLC analysis indicated complete consumption of the mesylate. The reaction was extracted with chloroform (2 x 500ml), and the combined extracts were dried over magnesium sulfate. The solvent was removed in vacuo, and the compound placed under high vacuum for 30 minutes. The product oil (71g, 43%>) was eluted off the gummy solid, and used without any further purification.

5. 1-Phenylpiperazine

To a solution of triethylamine (160ml, 1.15mol) and N-tert-butyl-azetidin-3-ol (100g, 0.78mol) in methylene chloride (600ml) at -10°C was added a solution of methanesulfonyl chloride (74ml, 0.94mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 500ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil.

Immediately, triethylamine (160ml, 1.15mol), 1-phenylpiperazine (112g, 0.69mol) and water (150ml) were added to the crude mesylate. After being stirred for 60 minutes, TLC analysis indicated complete consumption of the mesylate, and a solid precipitate was noticed. The reaction was quenched by addition of hexane : diethyl ether (1 : 1, 200ml) and water (100ml). The solid was filtered and washed with hexane : diethyl ether (1 : 1) and water and dried under vacuum. The product (123g, 65%>) was obtained as a colorless solid, and used without further purification.

1 -Pyrim idylpiperazin e

To a solution of triethylamine (115ml, 0.83mol) and N-tert-butyl-azetidin-3-ol (71.5g, 0.55mol) in methylene chloride (500ml) at -10°C was added a solution of methanesulfonyl chloride (51ml, O.όόmol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 500ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil. Immediately, triethylamine (115ml, 0.83mol), 1 -pyrimidylpiperazine (80g,

0.48mol) and water (150ml) were added to the crude mesylate. After being stirred for 12 hours, TLC analysis indicated complete consumption of the mesylate, and a solid precipitate was noticed. The reaction was quenched by addition of water (200ml). The solid was filtered and washed with ether (200ml). After being dried under vacuum, the product (lOOg, 74%) was obtained as a colorless solid, and used without further purification.

7. 4-Fluorophenylpiperazine

To a solution of N-t-butyl-3-hydroxyazetidine (68 g, 0.53 mol) in 500 ml of CH₂C1₂ with Et₃Ν (58.6g, 0.58 mol), was added dropwise methanesulfonyl chloride (44.8 ml, 0.58 mol) at - 40°C. The cooling bath was removed after completion of addition. The resulting mixture was stirred at ambient temperature for 30 min. Then 300 ml of NaHCO₃ (sat.) was added, and the mixture allowed to stir for 15 min. The organic layer was separated and the water layer was extracted once with CH₂C1 (ca. 500 mL). The organics were combined, and evaporated in vacuo while the bath temperature not exceeding 25°C. The residue (yellow oil) was directly used in the replacement reaction (1H NMR shows the mesylate is about 90% pure). To this mesylate was added 4-fluorophenylpiperazine (114 g, 0.68 mol) with 300 ml water and 80 g of Et₃N (0.8 mol). The mixture was stirred at 40°C over night. After cooling down, white crystals crashed out and were filtered and checked by 1H NMR to be 90% pure product with 10%) unreacted piperazine. The water layer was extracted with CH₂C1₂ (3 x 300ml). The organics were combined and dried over K₂CO₃ and solvent was removed to apply for column filtration with 5% Et₃N, 45% EtOAc, 50% Hexane, then 10 % Et₃N, 50 % EtOAc, 40% Hexane to give 105 g of white solids as product (yield: 69%, 2 steps). 8. 4-Methoxyphenylpiperazine

To a solution of triethylamine (125.7ml, 0.9mol) and N-tert-butyl-azetidin-3- ol (106g, 0.82mol) in methylene chloride (1000ml) at -40°C was added a solution of methanesulfonyl chloride (69.6ml, 0.9mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 750ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil. Immediately, triethylamine (171ml, 1.23mol), l-(4-methoxylphenyl)- piperazine (192.3g, lmol) and water (300ml) were added to the crude mesylate, and the reaction was heated to 50°C for 12 hours. After being allowed to cool, the reaction mixture was extracted with methylene chloride (3 x 500ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 35 : 60 : 5

; ethyl acetate : hexanes : triethylamine to furnish 123 g of product (yield: 51.6%) was obtained as a colorless solid.

9. 4-Methylphenylpiperazine

To a solution of triethylamine (125.7ml, 0.9mol) and N-tert-butyl-azetidin-3- ol (106g, 0.82mol) in methylene chloride (1000ml) at -40°C was added a solution of methanesulfonyl chloride (69.6ml, 0.9mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 750ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil. Immediately, triethylamine (171ml, 1.23mol), l-(4-methylphenyl)-piperazine

(176.3g, lmol) and water (300ml) were added to the crude mesylate, and the reaction was heated to 50°C for 12 hours. After being allowed to cool, colorless crystals crushed out of the solution, which is filtered off and washed by small amount of water to obtain 80 g of product. Then the remaining reaction mixture was extracted with methylene chloride (3 x 500ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 35 : 60 : 5 ; ethyl acetate : hexanes : triethylamine to furnish 41 g of product. A total of 121 g product (yield: 55.5%) was obtained as a colorless solid. 10. 4-Trifluoromethoxyphenylpiperazine

To a solution of triethylamine (84.1ml, O.όlmol) and N-tert-butyl-azetidin-3- ol (71g, 0.55mol) in methylene chloride (1000ml) at -40°C was added a solution of methanesulfonyl chloride (46.8ml, O.όlmol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 750ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil.

Immediately, triethylamine (127ml, 0.92mol), l-(4- trifluoromethoxylphenyl)piperazine (l lOg, 0.5mol) and water (300ml) were added to the crude mesylate, and the reaction was heated to 50°C for 12 hours. After being allowed to cool, the reaction mixture was extracted with methylene chloride (3 x 500ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 35 : 60 : 5 ; ethyl acetate : hexanes : triethylamine to furnish 87.1 g of product (yield: 51%) was obtained as a colorless solid.

11. 4-Tήfluoromethylphenylpiperazine

To a solution of triethylamine (114.5ml, 0.82mol) and N-tert-butyl-azetidin-3- ol (96.5 g, 0.75mol) in methylene chloride (1000ml) at -40°C was added a solution of methanesulfonyl chloride (63.7ml, 0.82mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicated that the reaction was complete. The reaction was washed with saturated sodium bicarbonate (2 x 750ml), dried over magnesium sulfate and the solvent removed in vacuo to afford the crude mesylate as a colorless oil.

Immediately, triethylamine (171ml, 1.23mol), l-(4-trifluoromethylphenyl)- piperazine (189.5g, 0.823mol) and water (300ml) were added to the crude mesylate, and the reaction was heated to 50°C for 12 hours. After being allowed to cool, the reaction mixture was extracted with methylene chloride (3 x 500ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 35 : 60 : 5 ; ethyl acetate : hexanes : triethylamine to furnish 96 g of product (yield: 38.4%>) was obtained as a colorless solid.

V. Acylative dealkylation I

l-(2-pyridyl)-piperazine

To a solution of the vigorously stirred substrate (55.3g, 0.20mol) in ether (85ml) at 0°C was added acetic anhydride (110ml, 1.17mol). Upon completion of the addition, boron trifluoride ethereate (8ml) was added in a slow dropwise fashion. The reaction was then heated to reflux for 24 hours. After being allowed to cool, the reflux condenser was replaced by a distillation head, and excess acetic anhydride (ca. 70ml was collected. 45-48°C / 2mmHg) was removed by distillation under reduced pressure. The viscous black residue was poured into a mixture of 50% potassium hydroxide (120ml) and ice water (400ml) ensuring the resulting solution is at basic pH. After being allowed to stir for 30 minutes at 0°C, the aqueous solution was extracted with methylene chloride (3 x 400ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 80 : 10 : 10 ; ethyl acetate : methanol : triethylamine. The product (40.4g, 77%) was obtained as a slightly yellow solid. 4-Fluorophenylpiperazine

acetic anhydride *- reflux

To N-t-butyl-3-arylpiperazinylazetidine (105 g, 0.36 mol) in a 500 ml round bottom flask in an ice water bath was added slowly pre-cooled acetic anhydride 200 ml, followed by 10 ml of BF₃ etherate (2M). The mixture was then refluxed over 38 hrs until the starting material was completely consumed. Then about 100 ml of acetic anhydride was distilled out under water pump and the resulting brown oil was poured into 400 ml of ice with 200 ml of 50%KOH. Check pH (pH = 14). The mixture was extracted by CH C1₂ (500 ml X 3). The organics was dried (K₂CO₃) and solvent was removed. The crude product was column filtered through a short pad of silica gel to give 95 g of product (yield 95%) as an off white solid.

3. 4-Methoxyphenylpiperazine ^e

acetic anhydride reflux

To a solution of the vigorously strrred substrate (123g, 0.46mol) in ether (85ml) at 0°C was added acetic anhydride (210ml, 2.3mol). Upon completion of the addition, boron trifluoride ethereate (10ml) was added in a slow dropwise fashion. The reaction was then heated to reflux for 24 hours. After being allowed to cool down, the reflux condenser was replaced by a distillation head, and excess acetic anhydride (ca. 100 ml, 45-48°C / 2mmHg) was removed by distillation under reduced pressure. The viscous black residue was poured into a mixture of 50% potassium hydroxide (120ml) and ice water (400ml) ensuring the resulting solution is at basic pH. After being allowed to stir for 30 minutes at 0°C, the aqueous solution was extracted with methylene chloride (3 x 600ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 80 : 10 : 10 ; ethyl acetate : methanol : triethylamine. The product (93g, 70%>) was obtained as a slightly yellow solid.

4-Methylphenylpiperazine

To a solution of the vigorously stirred substrate (121g, 0.41mol) in ether (85ml) at 0°C was added acetic anhydride (210ml, 2.3mol). Upon completion of the addition, boron trifluoride ethereate (10ml) was added in a slow dropwise fashion. The reaction was then heated to reflux for 24 hours. After being allowed to cool, the reflux condenser was replaced by a distillation head, and excess acetic anhydride (ca. 100 ml, 45-48°C / 2mmHg) was removed by distillation under reduced pressure. The viscous black residue was poured into a mixture of 50% potassium hydroxide (120ml) and ice water (400ml) ensuring the resulting solution is at basic pH. After being allowed to stir for 30 minutes at 0°C, the aqueous solution was extracted with methylene chloride (3 x 400ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 80 : 10 : 10 ; ethyl acetate : methanol : triethylamine. The product (83.5g, 74.5%) was obtained as a slightly yellow solid.

5. 4-Trifluorophenylpiperazine

acetic anhydride »- reflux

To a solution of the vigorously stirred substrate (96g, 0.28mol) in ether (85ml) at 0°C was added acetic anhydride (210ml, 2.3mol). Upon completion of the addition, boron trifluoride ethereate (10ml) was added in a slow dropwise fashion. The reaction was then heated to reflux for 24 hours. After being allowed to cool down, the reflux condenser was replaced by a distillation head, and excess acetic anhydride (ca. 100 ml, 45-48°C / 2mmHg) was removed by distillation under reduced pressure. The viscous black residue was poured into a mixture of 50%> potassium hydroxide (120ml) and ice water (400ml) ensuring the resulting solution is at basic pH. After being allowed to stir for 30 minutes at 0°C, the aqueous solution was extracted with methylene chloride (3 x 600ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 80 : 10 : 10 ; ethyl acetate : methanol : triethylamine. The product (76g, 83%>) was obtained as a slightly yellow solid.

VI. Amide hydrolysis

1. 1 -(2-pyridyl)piperazin e

Hydrochloride salt

A steady stream of hydrogen chloride gas was bubbled through a stirred suspension of the amide (40.4g, 0.15mol) in ethanol (IL) for 10 minutes at 0°C. Upon completion, the suspension is heated to reflux for 12 hours. After being allowed to cool, the precipitated solid is collected by filtration and washed with methyl tert-butyl ether to yield the pure product (45g, 73%) as the hydrochloride salt.

2. 4-Methoxyphenylpiperazine

A steady stream of hydrogen chloride gas was bubbled through a stireed suspension of the amide (93g, 0.32mol) in ethanol (500ml) for 10 minutes at 0°C. Upon completion, the suspension is heated to reflux for 12 hours. After being allowed to cool, the precipitated solid is collected by filtration and washed with methyl tert- butyl ether to yield the pure product (70.5 g, 62%) as the hydrochloride salt. 4-Methylphenylpiperazine

HCI, ethanol ^- HCI relux

A steady stream of hydrogen chloride gas was bubbled through a stirred suspension of the amide (83.5g, 0.15mol) in ethanol (500ml) for 10 minutes at 0°C. Upon completion, the suspension is heated to reflux for 12 hours. After being allowed to cool, the precipitated solid is collected by filtration and washed with methyl tert- butyl ether to yield the pure product (93.5 g, 89.5%) as the hydrochloride salt.

4. 4-Trifluorophenylpiperazine

HCI, ethanol *~ HCI relux

A steady stream of hydrogen chloride gas was bubbled through a stirred suspension of the amide (76g, 0.24mol) in ethanol (500ml) for 10 minutes at 0°C. Upon completion, the suspension is heated to reflux for 12 hours. After being allowed to cool, the precipitated solid is collected by filtration and washed with methyl tert- butyl ether to yield the pure product (44 g, 64%) as the hydrochloride salt. 5. 4-Fluorophenylpiperazine

To N-acetyl-3-arylpiperazinylazetidine (95 g, 0.34 mol) in 500 ml of ethanol in a round bottom flask, HCI gas was bubbled in for 10 min. The resulted yellow suspension was refluxed over night. After cooling down, the white solid was filtered off to give 61 g of desired product as a HCI salt (yield: 52%).

VII. Acylative dealkylation II

1. 1-tert-butoxycarbonylpiperazine

To a solution of the vigorously stirred substrate (49g, O.lόmol) and in methylene chloride (490ml) at 0°C was added trifluoroaceticacetic anhydride (35ml, 0.25mol) in a dropwise fashion. After being stirred for 4 hours, IH NMR analysis indicated the reaction to be 60% complete. Triethylamine (10ml) was added, and the reaction stirred for a further 30 minutes. The reaction was poured into saturated sodium bicarbonate (500ml), and extracted with methylene chloride (500ml). The combined organic extracts were dried over magnesium sulfate. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 50 :50 ; ethyl acetate : hexanes. The product (42.9g, 78%) was obtained as a colorless solid.

1 -tert-butoxycarbonyl perhydrodiazepine

To a solution of the vigorously stirred substrate (82g, 0.26mol) and triethylamine (40ml, 0.29mol) in methylene chloride (820ml) at 0°C was added trifluoroaceticacetic anhydride (56ml, 0.39mol) in a dropwise fashion. After being stirred for 3 hours, IH NMR analysis indicated the reaction to be complete. The reaction was poured into saturated sodium bicarbonate (500ml), and extracted with methylene chloride (500ml). The combined organic extracts were dried over magnesium sulfate. Removal of the solvent in vacuo afforded the crude product as an orange solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 50 :50 ; ethyl acetate : hexanes. The product (72g, 76%>) was obtained as a yellow solid.

1-Methylpiperazine

To a solution of the vigorously stirred substrate (71g, 0.34mol) and triethylamine (47ml, 0.34mol) in chloroform (500ml) at 0°C was added trifluoroaceticacetic anhydride (57ml, 0.41mol) in a dropwise fashion. After being stined for 10 minutes, TLC analysis indicated that the starting material had been totally consumed. The reaction was poured into saturated sodium bicarbonate (500ml), and extracted with chloroform (500ml). The combined organic extracts were dried over magnesium sulfate. Removal of the solvent in vacuo afforded the product as an orange solid (83g, 98%) which was used without further purification.

1-Phenylpiperazine

To a solution of the vigorously strrred substrate (120g, 0.44mol) and triethylamine (12.2ml, 0.09mol) in chloroform (500ml) at 0°C was added trifluoroaceticacetic anhydride (93ml, 0.67mol) in a dropwise fashion. After being stirred for 1 hour, TLC analysis indicated that the starting material had been totally consumed. The reaction was poured into saturated sodium bicarbonate (500ml), and extracted with chloroform (500ml). The combined organic extracts were dried over magnesium sulfate. Removal of the solvent in vacuo gave the crude product. Recrystalhsation from hexanes : ethyl acetate gave the product as a white solid (105g, 76%).

1-Pyrimidylpiperazine

To a solution of the vigorously stirred substrate (lOOg, 0.36mol) and triethylamine (10.1ml, 0.07mol) in chloroform (500ml) at 0°C was added trifluoroaceticacetic anhydride (76ml, 0.55mol) in a dropwise fashion. After being stirred for 10 minutes, TLC analysis indicated that the starting material had been totally consumed. The reaction was poured into saturated sodium bicarbonate (500ml), and extracted with chloroform (500ml). The combined organic extracts were dried over magnesium sulfate. Removal of the solvent in vacuo gave the crude product. Recrystalhsation from hexanes : ethyl acetate gave the product as a white solid (88g, 77%). 6. 4-Trifluoromethoxyphenylpiperazine

To a solution of the vigorously stined substrate (52. Ig, 0.15mol) and in methylene chloride (490ml) at 0°C was added trifluoroaceticacetic anhydride (25.7ml,

0.18mol) in a dropwise fashion. After being stirred for 4 hours, IH NMR analysis indicated the reaction to be 60% complete. Triethylamine (10ml) was added, and the reaction stined for a further 30 minutes. The reaction was poured into saturated sodium bicarbonate (500ml), and extracted with methylene chloride (500ml). The combined organic extracts were dried over magnseium sulfate. The solvent was evaporated to give a yellow solid which was crystallized in ethyl acetate to give the product (47. Ig, 78.1%) as a solid.

VIII. Trifluoroacetamide hydrolysis

1. 1-tert-Butoxycarbonylpiperazine

To a solution of the amide (29.3g, 0.08mol) in methanol (720ml) and water

(70ml) at 0°C was added solid potassium carbonate (60g, 0.43mol). After being allowed to stir for 1 hour, the solvent was removed in vacuo. Chloroform (400ml) was added to the residual solid, and the mixture warmed gently with stining to break up the solid cake. After 45 minutes, solid potassium carbonate was added, and the mixture filtered washing the solids with chloroform (250ml). Removal of the solvent in vacuo afforded the crude product as a slightly green oil. Purification was carried out by filtration through a pad of silica gel eluting the product with 10 : 3 : 1 ; ethyl acetate : methanol : triethylamine. The product was obtained as a colorless solid (15g,

72%>), which became slightly yellow on exposure to air.

1-Methylpiperazine

To a solution of the amide (83. Ig, 0.33mol) in methanol (IL) and water (40ml) at 0°C was added solid potassium carbonate (85g, O.όlmol). The reaction was stined vigorously for 45 minutes after which time TLC analysis indicated that the starting material had been totally consumed. The reaction was passed through a short pad of silica gel washing with 90 : 10 ; methanol : triethylamine. Removal of the solvent afforded the crude product as a yellow solid. This solid was taken up in ethyl acetate (500ml), and heated to reflux. On cooling, the product (23g, 45%>) separated as a white solid, and was isolated by filtration.

/ -Ph enylpiperazin e

To a solution of the amide (105g, 0.34mol) in methanol (11) and water (40ml) at 0°C was added solid potassium carbonate (88g, 0.63mol). After being allowed to stir for 1 hour, the solvent was removed in vacuo. Chloroform (400ml) was added to the residual solid, and the mixture warmed gently with stirring to break up the solid cake. After 45 minutes, solid potassium carbonate was added, and the mixture filtered washing the solids with chloroform (250ml). Removal of the solvent in vacuo afforded the crude product as a light yellow solid. Recrystalhsation from hexanes : ethyl acetate gave the product (XX) as a colorless solid.

1-Pyrimidylpiperazine

To a solution of the amide (88g, 0.28mol) in methanol (11) and water (40ml) at 0°C was added solid potassium carbonate (72g, 0.52mol). After being allowed to stir for 1 hour, the solvent was removed in vacuo. Chloroform (400ml) was added to the residual solid, and the mixture warmed gently with stirring to break up the solid cake. After 45 minutes, solid potassium carbonate was added, and the mixture filtered washing the solids with chloroform (250ml). Removal of the solvent in vacuo afforded the crude product as a white solid. Recrystalhsation from hexanes : iso- propanol gave the product (XX) as a colorless solid.

5. 4-Trifluoromethoxyphenylpiperazine

A steady stream of hydrogen chloride gas was bubbled through a stined suspension of the amide (47. Ig, 0.12mol) in ethanol (500ml) for 10 minutes at 0°C. Upon completion, the suspension is heated to reflux for 12 hours. After being allowed to cool, the precipitated solid is collected by filtration and washed with methyl tert- butyl ether to yield the pure product (32 g, 65%) as the hydrochloride salt.

Those skilled in the chemical arts would recognize a wide variety of equivalents to the compounds and methods of the present invention.

Claims

WHAT IS CLAIMED IS:

A compound having the formula:

wherein R, R] , R are independently selected from the group consisting of hydrogen, C╬╣-C₆ lower alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ alkylcarbonyl, C₃-C₆ cycloalkyl, trifluoromethylcarbonyl, or (CH )_n-phenyl or -(CH₂)_n- heteroaryl where n is 0 to 4 and where the phenyl or the heteroaryl is optionally substituted with 1 to 3 halogens, Cj-C₆ lower alkyl, C╬╣-C₆ alkoxy, C -C alkylcarbonyl, carboxy, or C╬╣-C₆ carboxyalkyl; aryl or heteroaryl carbonyl which may be optionally substituted with 1 to 3 halogens, C]-C₆ lower alkyl, C╬╣-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, or Ci- C₆ carboxyalkyl; in addition, Ri and R , together with the nitrogen to which each is attached, may form azide or a ring having the following structure:

NH WΓÇö R₃

where n is 1,

2, or 3;

W is N, CH, or O, provided that when W is O, R does not exist;

R₃ is hydrogen, C╬╣-C₆ lower alkyl, C₂-C₆ alkenyl, C -C₆ alkynyl, C₂-C₆ alkylcarbonyl, C₃-C₆ cycloalkyl, carboxy, C -C₆ alkoxycarbonyl, aryl or heteroaryl, each of which is optionally mono-, di-, or trisubstituted with straight or branched chain lower alkyl having 1 to 6 carbon atoms, halogen, trifluoromethyl, hydroxy, straight or branched chain lower alkenyl having 2 to 6 carbon atoms, trifluormethoxy, or amino, dialkylamino having 2 to 6 carbon atoms, -CO₂R where R₄ is alkyl having 1-6 carbon atoms, -(CH )_m-O-R₅ where m is 1-6 and R₅ is hydrogen or lower alkyl having 1-6 carbon atoms. A compound of claim 1 having the formula:

wherein R, Ri, R are independently selected from the group consisting of hydrogen, Ci-C_╧î lower alkyl, C₂-C₆ alkylcarbonyl, trifluoromethylcarbonyl, or (CH )_n-phenyl where n is 0 to 4 and where the phenyl is optionally substituted with halogen, C╬╣-C₆ lower alkyl, C╬╣-C₆ carboxy, C₂-C₆ alkylcarbonyl; in addition, Ri and R , together with the nitrogen to which each is attached, may form azide or a structure selected from the group consisting of:

3. A compound of claim 1 wherein R is selected from the group consisting of

CH₂-phenyl, H, t-butyl,

0 O

C-CF₃ and ΓÇö C-CH₃

4. A compound of claim 1 wherein R is CH₂-phenyl and wherein Ri, R and the N to which each is attached form azide or a structure selected from the group consisting of:

5. A compound of claim 1 wherein R is hydrogen and wherein R_{l s} R₂ and the N to which each is attached form a structure selected from the group consisting of:

6. A compound of claim 1 wherein R is t-butyl and wherein R), R₂ and the N to which each is attached form a structure selected from the group consisting of:

7. A compound of claim 1 wherein R is

O

II

"C-CF₃

and wherein R_{l 9} R and the N to which each is attached form a structure selected from the group consisting of:

8. A compound of claim 1 wherein R is

O ΓÇö C-CH₃

and wherein R\ , R₂ and the N to which each is attached form a structure selected from the group consisting of:

9. A compound selected from the group consisting of 2- methoxyphenylpiperazine; l-(2-pyridyl)-piperazine; 1 -pyrimidylpiperazine; 1- phenylpiperazine; 1-methylpiperazine; morpholine; piperidine; pyrrolidine; dimethylamine; methylamine; isopropylamine; methallyamine; sodium azide; azetidin-3-ol; 2-methoxyphenlpiperazine; 1 (2-hydroxyethyl)-piperazine; piperazine; 1 -tert-butoxycarbonyl perhydrodiazepine; 1-methylpiperazine; 1- phenylpiperazine; 1 -pyrimidylpiperazine; 4-fluorophenylpiperazine; 4- methoxyphenylpiperazine; 4-methylphenylpiperazine; 4- trifluoromethoxyphenylpiperazine; 4-trifluoromethylphenylpiperazine; 1 -(2- pyridyl)-piperazine; 4-fluorophenylpiperazine; 4-methoxyphenylpiperazine; 4- trifluorophenylpiperazine; 1 -tert-butoxycarbonylpiperazine; 1 -tert- butoxycarbonyl perhydrodiazepine; 1-methylpiperazine; 1 -phenylpiperazine; and, 1 -pyrimidylpiperazine and the pharmaceutically acceptable salts thereof.

10. A composition comprising a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9.