WO2000063168A1

WO2000063168A1 - Synthesis of azetidine derivatives

Info

Publication number: WO2000063168A1
Application number: PCT/US1999/008361
Authority: WO
Inventors: Zhengming Chen; Hatmuth C. Kolb; Paul Richardson; Zhi-Min Huang
Original assignee: Coelacanth Chemical Corporation
Priority date: 1999-04-16
Filing date: 1999-04-16
Publication date: 2000-10-26
Also published as: AU3565999A

Abstract

The present invention provides compound having formula (I), useful as building blocks for combinatorial libraries and methods of making such compounds. Also provided is a novel process for synthesizing such compounds. In addition, the present invention includes products made by these processes.

Description

SYNTHESIS OF AZETIDINE DERIVATIVES

BACKGROUND OF THE INVENTION 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 serve as building blocks and methods for generating such compounds. The present invention further relates to a novel process for preparing 3-amino-azetidine derivatives, key intermediates of compounds with well-documented biological properties. The present invention also relates to azetidine compounds made by such a novel process.

Description of the Related Art

Combinatorial chemistry refers to techniques for creating a multiplicity of compounds, refeπed 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 that are, themselves, structurally diverse. A "building block" is a reagent or compound which can combine (i.e., react) with one or more 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.

Many azetidine derived compounds are known in the art to have various biological properties. For instance, the Fluoroquinolone azetidines are widely known as antibacterial agents. See, for example, Friggola, Jordi et al, J. Med. Chem. (1995), 38(7), 1203-15; Friggola, Jordi et al, J. Med. Chem. (1993), 36(7), 801-10; Remuzon, P. et al, J. Med. Chem. (1991), 34(1), 29-37. A few of these compounds are currently undergoing preclinical studies and Phase I trials. Another class of compounds that contains the azetidine backbone is the carbapenem derivatives, which are used primarily for their antibacterial and antibiotic properties. Kawamoto, Isao et al, WO 97/23483; Kawamoto, Isao et al, EP 560613. Anti-viral, and specifically anti-AIDS, peptide mimetics are also prepared by using key azetidine intermediates. Greengrass, C.W. et al, WO 93/19059. Finally, the preparation of 3-azetidinylalkypiperidines or - pyrrolidines as tachykinin antagonists are also synthesized via a 3-amino-azetidine derivative. Mackenzie, A.R. et al, WO 97/25322.

Because 3-amino-azetidines are key intermediates to several biologically active compounds, a facile and efficient process for the preparation of these intermediates is necessary. Chemistry that increases product yields and provides access to a larger number of azetidines is desired.

SUMMARY OF THE INVENTION This invention provides novel compounds of Formula I:

wherein

R, Ri, R₂ are the same or different and represent hydrogen, -C₆ lower alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ alkylcarbonyl, C₃-C₆ cycloalkyl, trifluoromethylcarbonyl; or R, Ri , R₂ are the same or different and represent (CH₂)_n-phenyl or

heteroaryl where n is 0 to 4 and where the phenyl or the heteroaryl is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, Cι-C₆ lower alkyl, Cι-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, Ci- C₆ carboxyalkyl or aryl or heteroaryl carbonyl where each ring portion is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, Cι-C₆ lower alkyl, Cι-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, or Cι-C₆ carboxyalkyl; or Ri and R₂, together with the nitrogen to which they are attached, form a heterocyclic ring of the formula (CH₂)-^

-NH W— R₃

AA wherein m is 1, 2, or 3; W is N, CH, or O, provided that when W is O, R₃ does not exist; and R₃ is hydrogen, Cι-C₆ lower alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C -C₆ alkylcarbonyl, C₃-C₆ cycloalkyl, carboxy, or C₂-C₆ alkoxycarbonyl; or R₃ is aryl or heteroaryl optionally mono-, di-, or trisubstituted with up to three groups independently selected from Cι-C₆ lower alkyl, halogen, trifluoromethyl, hydroxy, C₂-C₆ alkenyl, Cι-C₆ alkoxy, trifluoromethoxy, amino, mono or dialkylamino where each alkyl portion is Cι-C₆ lower alkyl, -CO₂R-} where R is Cι-C₆ lower alkyl, or -(CH₂)_q-O-R₅ where q is 1-6 and R₅ is hydrogen or Cι-C₆ lower alkyl.

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 an acceptable carrier.

The present invention also provides a novel process for the preparation of compounds of Formula I, which in turn are intermediates for the synthesis of biologically active compounds.

In addition, the present invention provides for a product of Formula I made by a novel process.

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 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. 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 R¹-^-, which is formed from the reaction of an electrophilic precursor compound and R^LNH₂, 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, Εthm₂, R'R^ΠNH, 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^N-, R^πS-, R^πO, -SH, respectively, into the member compound. R¹¹ 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^πιR^IVNH, or the anion thereof, wherein R^πι 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^mR^IVN- 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 NH₃ (or NH₂ ^"), H₂O (or OH^"), CI^", Br^", I^", CN^", N₃ ^", and trimethylsilycyanide, 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, -CI, -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, SI₂, 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^VINH, R^VSH, R^vOH, or the anions thereof. R and R^V1 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^VIN-, 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^VIIR^VIIINH, or the anion thereof. R^vπ and R^vπι, 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^VIIINH or its anion and a suitable eletrophilic precursor compound, R^vllR^vmN- 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^V1NH₂, 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 below. 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 prefeπed 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, C₂-C₆ alkylcarbonyl, trifluoromethylcarbonyl, or

(CH₂)_n-phenyl where n is 0 to 4 and where the phenyl is optionally substituted with

halogen, Cι-C₆ lower alkyl, Cι-C₆ carboxy, C₂-C₆ alkylcarbonyl; in addition, Ri and R₂, together with the nitrogen to which each is attached, may form azide or a structure shown below:

In another prefeπed embodiment, the present invention provides a compound of Formula I wherein R is selected from CH₂-phenyl, H, t-butyl,

O O

II II

C^_CF₃ and C-CH₃

In yet another prefeπed embodiment, a compound of Formula I is provided wherein R is CH₂-ρhenyl and wherein Ri, R₂ and the N to which each is attached form azide or a structure selected from:

Yet another prefeπed compound of Formula I is provided wherein R is hydrogen and wherein Ri, 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, R₂ and the N to which each is attached form one of the following structures:

In another prefeπed embodiment of Formula I, R is

O -C-CF₃ and Ri, R₂ and the N to which each is attached form one of the following structures:

In yet another prefeπed embodiment of Formula I, R is

O

II

— C-CH₃ and Rj, R₂ and the N to which each is attached form a structure selected from:

The most prefeπed compounds include the following and their pharmaceutically acceptable salts: 2-methoxyphenylpiperazine; l-(2-pyridyl)- piperazine; 1-pyrimidylpiperazine; 1-phenylpiperazine; 1-methylpiperazine; morpholine; piperidine; pyπolidine; dimethylamine; methylamine; isopropylamine; methally amine; 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. By "alkyl", "lower alkyl", and "Cι-C₆ alkyl" in the present invention is meant a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms (unless stated otherwise; preferably Cι-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. By the term "halogen" in the present invention is meant fluorine, bromine, chlorine, and iodine.

By "alkenyl", "lower alkenyl", and "C₂-C₆ alkenyl" in the present invention is meant 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.

By "alkynyl", "lower alkynyl", and "C₂-C₆ alkynyl" in the present invention is meant means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one triple bond. Typical C₂-C₁₀ alkynyl groups include propynyl, 2-butyn- 1-yl, 3-pentyn-l-yl, and the like.

By the term "cycloalkyl" in the present invention is meant a cyclic hydrocarbyl group such as cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl, and the like.

By "alkoxy", "lower alkoxy", and "Cι-C₆ alkoxy" in the present invention is meant 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. By the term "acyl" in the present invention is meant 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, C]-Cι₀ alkyl (preferably Cι-C₆), Ci-Cio alkoxy (preferably Cι-C₆), hydroxy, carboxy, Ci-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 Cj-do 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, piperazinyhnethyl, and

2-(4-methylpiperazinyl)ethyl.

Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-( 1 -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, andN. 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.

An illustration of the preparation of compounds of the present invention is given in Scheme I and Scheme II. In Scheme I and II, the groups R, Ri and R2 are as defined above for Formula I.

Scheme I

Scheme II The novel methods provided by the instant invention provide for an improved mesylate displacement reaction, an improved debenzylation reaction (R = Bn to R = H), an 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 Scheme III, in which R is lower alkyl or arylalkyl.

t-Bu amine

Scheme III

The synthesis of substituted azetidines by a mesylate displacement is 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.

In one embodiment of the invention, mesylation is carried out in a chlorinated solvent such as methylene chloride, 1,2-dichloroethane or chloroform at low temperature, typically between about -10°C to -70 °C, and prefeπably about -40°C to

minimize the formation of side products. The reaction is carried out in the presence of an organic tertiary base such as triethylamine or diisopropylethylamine. In another embodiment of the invention, the mesylate is used immediately after its formation (within a period of no more than two hours after isolation of the product of the mesylation) to prevent decomposition (the decomposition of the mesylate is less than 20% at the time of displacement). In yet another embodiment of the invention, the displacement reaction is carried out in water thereby providing easy removal of any by-products (a feature of Clickchem™). In addition, the product crashes out of solution in many instances (particularly in the case of aromatic nucleophiles where a slight excess of the mesylate is employed). Furthermore, use of the tert-butyl group as the "R" group (see Scheme III above) on the azetidine nitrogen unexpectedly and surprisingly leads to a cleaner displacement reaction; this simplifies product isolation and purification. The majority of known studies on substituted azetidines have avoided benzyl as the protecting group (i.e. the "R" group in Scheme III above), 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. In a preferred embodiment, the benzyl group is cleaved under high pressure in the presence of a catalyst at lightly elevated temperatures of about between 30°C to 80°C, and preferably at about 55°C to 65°C. Preferably, the catalyst employed is a palladium catalyst such as palladium hydroxide. Acylative dealkylation is also contemplated by the instant invention. The procedure using acetic anhydride is developed by Dave (J. Org. Chem., 1996, 61, 5453), though its use is limited to three substrates due probably to difficulty in isolating the products. The present invention solves certain difficulties associated with the method of Dave. In an embodiment of the invention, a co-solvent is used to increase the solubility of the substrate without the addition of an excess amount of a reactive carboxylic acid anhydride, such as, for example, acetic anhydride. A prefeπed co-solvent is a Lewis acid as, for example, boron trifluoride etherate. This provides for a simplified work-up (i.e. the presence of excess acetic anhydride is very cumbersome) that makes product isolation easier. In a prefeπed embodiment, the work-up includes the filtering of the reaction product through a pad of silica. In yet another embodiment of the invention, the hydrolysis of the amide bond is achieved by using a strong mineral acid in a suitable solvent, such as, for example, ethanol. A prefeπed strong mineral acid is hydrogen chloride gas. These modifications also extend the scope of the process of Dave to a number of new substrates.

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 cuπent 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 by employing a fluorinated carboxylic acid anhydride, as, for example, trifluoroacetic anhydride. Trifluoroacetic anhydride has previously been used to cleave 2,4-dimethoxybenzylamines (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. In an embodiment of the invention, the reaction takes place at lower temperatures of about -10°C to 25°C, and preferably at about 0°C. In another embodiment of the invention, only slightly more than a stoichiometric amount of fluorinated carboxylic acid anhydride is required, preferably in an amount ranging from about 1 molar equivalent to 2 molar equivalents of the N-(t-butyl)-aminoazetidine. An advantage to this process is that the reaction is very rapid (i.e. with the addition of one equivalent of triethylamine, the reaction is complete within one hour). In yet another embodiment of the reaction, amide hydrolysis is also rapid and takes place at room temperature. Other advantages to the reaction is that the work-up is simple and the reaction is very clean, thus simplifying product isolation.

The process set forth in Schemes I and II can be used to form both novel and known 3-amino-azetidine derivatives. In the case of the known azetidines, these compounds are precursors to many biologically active compounds. These agents are synthesized by azetidine intermediates prepared by the process of the present invention. Some of these compounds are cuπently undergoing preclinical studies and Phase I trials. The most widely used compound classes and their biological applications are summarized in Tables 1-4.

Table 1

Fluoroqumolone Azetidines

Representative Compounds of the Class:

Yazaki, A. et al, WO 97/38971; Yazaki, A. et al, WO 97/11068; Yazaki, A. et al, WO 96/12704; Kuramoto, Y. et al, WO 94/27993; Kuramoto, Y. et al, WO 93/13091; Kuramoto, Y. et al, EP 393,400 (1990). Corominas, J.P. et al, EP 388,298 (1990); Corominas, J.P. et al, EP 324,298

(1989). Iwata, M. et al, EP 241,206 (1987).

Table 2

Carbapenem Azetidines

R1, R2 = H, Imidazolyl, formimidoyl

Representative Compounds of the Class:

Kawamoto, I. et al, WO 97/23483; Kawamoto, I. et al, EP 560,613 (1993). Table 3

Antiviral Compounds (Anti-AIDS)

Representative Compounds of the Class:

1 Greengrass, C.W. et al, WO 93/19059. Table 4

Tachykinin (Neurokinin) Antagonists

o,

Representative Compounds of the Class:

Mackenzie, A.R. et al, WO 97/25322. The compounds of Tables 1-4 are prepared using the 3-amino-azetidines synthesized by the improved process of the present invention. One improvement the process of the instant invention has over existing processes is that the yield and the scope of the azetidine preparation are greatly enhanced. Further, the process of the present invention provides access to a larger number of azetidines, which facilitates drug optimization and development.

The 3-amino-azetidines produced by the instant invention can be used to prepare the fluoroquinolone azetidines of Table 1 by displacing a leaving group on the fluoroquinolone nucleus as shown in Scheme IV (See, for example, Friggola, Jordi et al, J. Med. Chem. (1995), 38(7), 1203-15; Friggola, Jordi et al, J. Med. Chem. (1993), 36(7), 801-10; Remuzon, P. et al, J. Med. Chem. (1991), 34(1), 29-37; Yazaki, A. et al, WO 97/38971; Yazaki, A. et al, WO 97/11068; Yazaki, A. et al, WO 96/12704; Kuramoto, Y. et al, WO 94/27993; Kuramoto, Y. et al, WO 93/13091; Kuramoto, Y. et al, EP 393,400 (1990); Corominas, J.P. et al, EP 388,298 (1990); Corominas, J.P. et al, EP 324,298 (1989); Iwata, M. et al, EP 241,206 (1987).

X = H, F, CI, Br, OR₄ Y = C, N

K_]. R₂ = H, lower alkyl, acyl j- R₃ = Aryl, Alkyl, cycloalkyl Z = F, CI

Scheme IV The 3-amino-azetidines produced by the instant invention can be used to prepare the fluoroquinolone azetidines of Table 1 by displacing a leaving group on the fluoroquinolone nucleus as shown in Scheme V (Kawamoto, I. et al, WO 97/23483; Kawamoto, I. et al, EP 560,613 (1993)).

1 Carbonyldπimdazo , MeCN

2 Pi removal

Deprotection

R1, R2 = H, Imidazolyl, formimidoyl PI, P2, P3 - Protecting groups OR = Leaving group

Scheme V Further, the 3-amino-azetidines produced by the instant invention can be used to prepare the antiviral compounds of Table 3 via two amide coupling steps as shown in Scheme VI (Greengrass, C.W. et al, WO 93/19059).

2 Alcohol deprotection

Ar = Ph, p-Cl-Ph P = Protecting group

Scheme VI

Also, the 3-amino-azetidines produced by the instant invention can be used to prepare the tachykinin (neurokinin) antagonist compounds of Table 4 by nucleophilic substitution using the azetidine as the nucleophile, shown in Scheme VII (Mackenzie, A.R. et al, WO 97/25322). Base, MeCN, reflus

Scheme VII

The following nonlimiting examples illustrate the inventors' prefeπed 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. The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.

The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods. Representative examples of methods for preparing intermediates of the invention are set forth below. EXAMPLE 1

Synthesis N-t-butyl-3-hvdroxyazetidine

1. N-ført-butyl-3-trimethylsiloxyazetidine

A solution of t-butylamine (146.3 g, 2 mol) and epichlorohydrin (156 ml, 2 mol) in hexane (1.5 L) is stirred at room temperature for 2 days. The initial clear solution turns cloudy after 48 hrs. Hexamethyldisilazane (211 ml, 1 mol) and CH₃CΝ (500 mL) are added to this mixture, and the resulting solution is refluxed overnight. The solvent is removed in vacuo to give a red brown oil, which is then dissolved in acetonitrile (IL). Triethylamine (303.1 g, 3 mol) is added, and the mixture is refluxed for 3 days (a white solid is observed to precipitate from solution within 24 hrs). After being allowed to cool to room temperature, triethylamine hydrochloride is filtered off, and the solid washed with petroleum ether. Removal of the solvent in vacuo gave a yellow oil, which is 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 nimHg). 2. N-t-butyl-3-hydroxy azetidine

N-t-butyl-O-trimethylsilylazetidine (400 g, 2 mol) is added portionwise to 3Ν Hydrochloric acid solution (733 mL) at room temperature, and the resulting mixture is stiπed at ambient temperature. An exothermic reaction took place. After 1 hour, the pink mixture is extracted once with ether (ca. 500 mL) to remove the silyl ether. A solution of NaOH (100 g) in water (250 mL) is added to the aqueous layer and the resulting white suspension is saturated with K₂CO₃. The crude product is separated, and the aqueous layer is extracted with CH₂C1₂ (500 mL x 2). The organics are 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%).

Example 2

Mesylate Displacement Reactions 1.. 2-methoxy-l-[4-(l-benzylazetidin-3-yl)piperazinyl]benzene

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

(lOOg, O.όlmol) in methylene chloride (700ml) at -40°C is added methanesulfonyl chloride (58ml, 0.75mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is heated to 50°C. TLC analysis after 15 minutes indicates almost complete consumption of the starting mesylate. The reaction is allowed to stir at 50°C for 3 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) is added, and the organic layer is separated. The aqueous is extracted with methylene chloride (2 x 250ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a yellow oil. Purification of the product is 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%) is obtained as a slightly yellow liquid which upon cooling gave a white solid.

2. l-(l-benzylazetidin-3-yl)-4-(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 is added methanesulfonyl chloride (58ml, 0.75mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is heated to 50°C. The reaction is allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) is added, and the organic layer is separated. The aqueous is extracted with methylene chloride (2 x 400ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a yellow oil. Purification of the product is 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%) is obtained as a slightly yellow liquid which upon cooling gave a yellow solid.

3. 2-[4-(l-benzylazetidin-3-yl)piperazinyl]pyrimidine

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

(lOOg, O.όlmol) in methylene chloride (700ml) at -40°C is added methanesulfonyl chloride (58ml, 0.75mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is heated to 50°C. The reaction is allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) is added, and the organic layer is separated. The aqueous is extracted with methylene chloride (2 x 400ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a yellow oil. Purification of the product is 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%) is obtained as a colorless solid.

4. 4-Phenyl-l-(l-benzylazetidin-3-yl)piperazine

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

(lOOg, O.όlmol) in methylene chloride (700ml) at -40°C is added methanesulfonyl chloride (58ml, 0.75mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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 (HOg,

0.68mol) and water (130ml) are added to the crude mesylate, and the reaction is heated to 50°C. The reaction is allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) is added, and the organic layer is separated. The aqueous is extracted with methylene chloride (2 x 400ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as an orange oil. Purification of the product is 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 is noticed in several of the fractions, which contained the product, and this is removed by filtration. The product (104g, 55%) is obtained as a slightly yellow liquid.

5. 4-methyl-l-(l-benzylazetidin-3-yl)piperazine

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

(lOOg, O.όlmol) in methylene chloride (700ml) at -40°C is added methanesulfonyl chloride (58ml, 0.75mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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-methylpiperazine (70ml, 0.63mol) and water (130ml) are added to the crude mesylate, and the reaction is heated to 50°C. The reaction is allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) is added, and the organic layer is separated. The aqueous is extracted with methylene chloride (2 x 500ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a yellow oil. Purification of the product is 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%) is obtained as an orange oil.

6. 4-(l-benzylazetidin-3-yl)morpholine

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

7. l-benzylazetidin-3-ylpiperidine

Immediately, piperidine (182ml, 1.84mol) and water (130ml) are added to the crude mesylate, and the reaction is heated to 50°C. The reaction is allowed to stir at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) is added, and the organic layer is separated. The aqueous is extracted with diethyl ether (2 x 250ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as an orange oil. Purification of the product is 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. Ig, 54%) is obtained as a colorless liquid. 8. l-benzylazetidin-3-ylpyrrolidine

To a solution of N-benzy 1-3 -hydroxy azetidine (20g, 0.12mol) in chloroform (250ml) is added triethylamine (43ml, 0.31mol). The solution is cooled to below -

20°C, and a solution of methanesulfonyl chloride (17ml, 0.22mol) in chloroform

(50ml) is added in a dropwise fashion. Upon completion of the addition, the reaction is poured into saturated sodium bicarbonate solution (300ml). The organic layer is separated, and the aqueous layer is extracted with a further portion of chloroform (50ml). The combined organic extracts are dried over sodium bicarbonate, and the solvent removed in vacuo to afford the crude mesylate.

To the mesylate is added pyπolidine (52ml, O.όmol). The reaction is heated to

55-60°C, and stiπed for 2 hours. After being allowed to cool, the reaction is poured

into saturated sodium bicarbonate solution (200ml) extracted with diethyl ether (2 x 250ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo. The product is placed on the high vacuum lines for 12 hours to remove residual pyrrolidine, after which N-benzyl-3-pyπolidinoazetidine (23.8g, 90%) is obtained as an orange oil, which is used without further purification. 9. dimethyl(l-benzylazetidin-3-yl) amine

To a solution of N-benzy 1-3 -hydroxy azetidine (25g, 0.15mol) in chloroform (250ml) is added triethylamine (54ml, 0.39mol). The solution is cooled to below -

20°C, and a solution of methanesulfonyl chloride (22ml, 0.28mol) in chloroform

(70ml) is added in a dropwise fashion. Upon completion of the addition, the reaction is poured into saturated sodium bicarbonate solution (400ml). The organic layer is separated, and the aqueous layer is extracted with a further portion of chloroform (100ml). The combined organic extracts are dried over sodium bicarbonate, and the solvent removed in vacuo to afford the crude mesylate.

To the mesylate is added aqueous dimethylamine (173ml, 40%, 1.57mol). The

reaction is heated to 55-60°C, and stirred for 12 hours. After being allowed to cool,

solid sodium bicarbonate (lOg) is added, and the reaction is extracted with diethyl ether (3 x 400ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford N-benzyl-3-dimethylaminoazetidine (29g, 99%) as a slightly yellow liquid, which is used without further purification.

10. l-benzylazetidin-3-ylamine

To a solution of N-benzyl-3-hydroxyazetidine (20g, 0.12mol) in methylene chloride (250ml) is added triethylamine (68ml, 0.49mol). The solution is cooled to

below -20°C, and a solution of methanesulfonyl chloride (17ml, 0.22mol) in

methylene chloride (50ml) is added in a dropwise fashion. Upon completion of the addition, the reaction is poured into saturated sodium bicarbonate solution (300ml). The organic layer is separated, and the aqueous layer is extracted with a further portion of methylene chloride (100ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude mesylate.

To the mesylate is added aqueous ammonia (130ml, 2.29mol, 30%). The

reaction is heated to 55-60°C, and stiπed for 12 hours. After being allowed to cool, solid sodium bicarbonate (lOg) is added, and the mixture is extracted with diethyl ether (3 x 250ml). The combined organic extracts are dried over magnesium sulfate,

and the solvent removed in vacuo to give the crude product. Distillation (78-82°C/

lmmHg) affords N-benzyl-3-aminoazetidine (6.8g, 34%) as a colourless liquid.

11. methyl(l-benzylazetidin-3-yl) amine

To a solution of N-benzyl-3-hydroxyazetidine (25g, 0.15mol) in chloroform

(250ml) is added triethylamine (54ml, 0.39mol). The solution is cooled to below -

20°C, and a solution of methanesulfonyl chloride (22ml, 0.28mol) in chloroform

To the mesylate is added aqueous methylamine (180ml, 2.7mol, 40%). The

reaction is heated to 55-60°C, and stiπed for 12 hours. After being allowed to cool,

solid sodium bicarbonate (lOg) is added, and the mixture is extracted with diethyl ether (2 x 400ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to give N-benzyl-3-methylaminoazetidine (ό.Og, 22%) as a slightly yellow liquid. Further purification can be carried out by distillation

(75-78°C/ lmmHg) to afford N-benzyl-3-methylaminoazetidine as a colourless liquid.

12. isopropyl(l-benzylazetidin-3-yl)amine

To a solution of N-benzy 1-3 -hydroxy azetidine (20g, 0.12mol) in methylene chloride (250ml) is added triethylamine (68ml, 0.49mol). The solution is cooled to

below -20°C, and a solution of methanesulfonyl chloride (17ml, 0.22mol) in

methylene chloride (50ml) is added in a dropwise fashion. Upon completion of the addition, the reaction is poured into saturated sodium bicarbonate solution (300ml). The organic layer is separated, and the aqueous layer is extracted with a further portion of methylene chloride (100ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude mesylate. To the mesylate is added triethylamine (45ml, 0.32mol), and isopropylamine

(31ml, 0.48mol). The reaction is heated to 55-60°C, and stiπed for 12 hours. After

being allowed to cool, solid sodium bicarbonate (lOg) is added, and the mixture is extracted with diethyl ether (3 x 250ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to give the crude product.

Distillation (89-98°C/ lmmHg) affords N-benzyl-3-isopropyaminoazetidine (10.27g, 41%) as a colourless liquid.

13. methallyl(l-benzylazetidin-3-yl) amine

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

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

14. 3-(azadiazomvinyl)-l-benzylazetidine

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

Immediately, triethylamine (130ml, 0.92mol), sodium azide (80g, 1.22mol) and water (200ml) are added to the crude mesylate. The reaction is heated gently at 50°C for 12 hours, before being allowed to cool. Solid sodium bicarbonate (lOg) is added, and the reaction is extracted with methylene chloride (2 x 300ml). The combined organic extracts are 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 is 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%).

15. l[l-(t-butyl)azetidin-3-yl]-4-(2-pyridyl)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 is added a solution of methanesulfonyl chloride (60ml, 0.78mol) in methylene chloride (100ml) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is heated to 50°C for 12 hours. After being allowed to cool, solid sodium bicarbonate (10g) is added, and the reaction mixture is extracted with methylene chloride (3 x 500ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product is 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%) is obtained as a colorless solid. 16. l-(t-butyl)azetidin-3-ylpiperazine

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 is added a solution of methanesulfonyl chloride (75ml, 0.97mol) in methylene chloride (150ml) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is heated to 50°C for 12 hours. After being allowed to cool, solid sodium bicarbonate (lOg) is added, and the reaction mixture is extracted with chloroform (3 x 700ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a viscous yellow oil. Purification of the product is 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%) is obtained as a colorless oil. 17. t-butyl4-[l-(t-butyl)azetidin-3-yl]-l,4-diazaperhydroepinecarboxylate

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 is added a solution of methanesulfonyl chloride (75ml, 0.97mol) in methylene chloride (150ml) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is heated to 50°C for 12 hours. After being allowed to cool, the reaction mixture is saturated with potassium carbonate and extracted with methylene chloride. The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a viscous yellow oil. Purification of the product is 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%) is obtained as a slightly yellow solid. 18. l-[l-(t-butyl)azetidin-3-yl]-4-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 is added a solution of methanesulfonyl chloride (72ml, 0.93mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate. The reaction is very exothermic. After being stirred for 90 minutes, TLC analysis indicates complete consumption of the mesylate. The reaction is extracted with chloroform (2 x 500ml), and the combined extracts are dried over magnesium sulfate. The solvent is removed in vacuo, and the compound placed under high vacuum for 30 minutes. The product oil (71g, 43%) is eluted off the gummy solid, and used without any further purification. 19. l-[l-(t-butyl)azetidin-3~yl]-4-phenylpiperazine

To a solution of triethylamine (160ml, 1.15mol) and N-tert-butyl-azetidin-3-ol (lOOg, 0.78mol) in methylene chloride (600ml) at -10°C is added a solution of methanesulfonyl chloride (74ml, 0.94mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate. After being stiπed for 60 minutes, TLC analysis indicates complete consumption of the mesylate, and a solid precipitate is noticed. The reaction is quenched by addition of hexane : diethyl ether (1 : 1, 200ml) and water (100ml). The solid is filtered and washed with hexane : diethyl ether (1 : 1) and water and dried under vacuum. The product (123g, 65%) is obtained as a colorless solid, and used without further purification.

20. 2-{4-[l-(t-butyl)azetidin-3-yl]piperazinyl}pyrimidine

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 is added a solution of methanesulfonyl chloride (51ml, O.όόmol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate. After being stiπed for 12 hours, TLC analysis indicates complete consumption of the mesylate, and a solid precipitate is noticed. The reaction is quenched by addition of water (200ml). The solid is filtered and washed with ether (200ml). After being dried under vacuum, the product (lOOg, 74%) is obtained as a colorless solid, and used without further purification.

21. l-[l-(t-butyl)azetidin-3-ylJ-4-(4-fluorophenyl)piperazine

To a solution of N-t-buty 1-3 -hydroxy azetidine (68 g, 0.53 mol) in 500 ml of CH₂C1₂ with Et₃Ν (58.6g, 0.58 mol), is added dropwise methanesulfonyl chloride

(44.8 ml, 0.58 mol) at - 40°C. The cooling bath is removed after completion of

addition. The resulting mixture is stiπed at ambient temperature for 30 min. Then 300 ml of NaHCO₃ (sat.) is added, and the mixture allowed to stir for 15 min. The organic layer is separated and the water layer is extracted once with CH₂CI₂ (ca. 500 mL). The organics are combined, and evaporated in vacuo while the bath temperature

not exceeding 25°C. The residue (yellow oil) is directly used in the replacement

reaction (1H NMR shows the mesylate is about 90% pure). To this mesylate is added 4-fluorophenylpiperazine (114 g, 0.68 mol) with 300 ml water and 80 g of Et₃N (0.8

mol). The mixture is stirred at 40°C over night. After cooling down, white crystals

crashed out and are filtered and checked by 1H NMR to be 90% pure product with 10% unreacted piperazine. The water layer is extracted with CH₂C1₂ (3 x 300ml). The organics are combined and dried over K₂CO and solvent is 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). 22. l-[l-(t-butyl)azetidin-3-yl]-4-(4-methoxyphenyl)piperazine

To a solution of triethylamine (125.7ml, 0.9mol) and N-tβrt-butyl-azetidin-3- ol (106g, 0.82mol) in methylene chloride (1000ml) at -40°C is added a solution of methanesulfonyl chloride (69.6ml, 0.9mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is heated to 50°C for 12 hours. After being allowed to cool, the reaction mixture is extracted with methylene chloride (3 x 500ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product is 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%) is obtained as a colorless solid. 23. l-[l-(t-butyl)azetidin-3-yl]-4-(4-methylphenyl)piperazine

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 is added a solution of methanesulfonyl chloride (69.6ml, 0.9mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is 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 is extracted with methylene chloride (3 x 500ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product is carried out by passing it through a pad of silica gel eluting the product with 35 : 60 : 5 ; ethyl acetate : hexanes : triethylamine to furnish 41g of product. A total of 121 g product (yield: 55.5%) is obtained as a colorless solid. 24. (4-{4-[l-(t-butyl)azetidin-3-yl]piperazinyl}phenoxy)trifluoromethane

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 is added a solution of methanesulfonyl chloride (46.8ml, O.όlmol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is heated to 50°C for 12 hours. After being allowed to cool, the reaction mixture is extracted with methylene chloride (3 x 500ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product is 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%) is obtained as a colorless solid. 25. l-[l-(t-butyl)azetidin-3-yl]-4-[4-(trifluoromethyl)phenyl]piperazine

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 is added a solution of methanesulfonyl chloride (63.7ml, 0.82mol) in a dropwise fashion. Upon completion of addition, TLC analysis indicates that the reaction is complete. The reaction is 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) are added to the crude mesylate, and the reaction is heated to 50°C for 12 hours. After being allowed to cool, the reaction mixture is extracted with methylene chloride (3 x 500ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the crude product as a slightly yellow solid. Purification of the product is 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%) is obtained as a colorless solid. Example 3

Debenzylation reactions

Azetidin-3-ol

OH

N

I

H In a Pan shaker pressure bottle, the hydrochloride salt of l-benzylazetidine-3- ol (122g, 0.62mol) is dissolved in methanol (IL) and palladium hydroxide (12g, 20% on carbon) is added. The bottle is evacuated, and then pressurized under hydrogen

(40ρsi) and shaken while being heated to 60°C. On reaching the desired temperature, the pressure is increased to όOpsi, and shaking is continued for a further 90 hours (during this time the hydrogen pressure is recharged four times after samples are removed for NMR analysis to monitor the progress of the reaction). The heater is then turned off, and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure is released, the bottle is opened, and the reaction is filtered through celite washing with methanol (2.5L). The solvent is removed in vacuo to afford the crude product as a white solid. Recrystalhsation from ethanol/methyl tert-butyl ether afforded the product (33.2g, 50%) as colorless needles.

l-(4-azetidin-3-ylpiperazinyl)-2-methoxybenzene

In a Parr shaker pressure bottle, the hydrochloride salt of 2-methoxy-l-[4-(l- benzylazetidin-3-yl)piperazinyl]benzene (185g, 0.41mol) is dissolved in methanol (IL) and palladium hydroxide (21g, 20% on carbon) is added. The bottle is evacuated, and then pressurized under hydrogen (40psi) and shaken while being heated to 60°C.

On reaching the desired temperature, the pressure is increased to 60psi, and shaking is continued for a further 48 hours (during this time the hydrogen pressure is recharged twice). The heater is then turned off, and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure is released, the bottle is then opened, and the reaction is 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 are removed by washing the solid with hot methanol, and filtration. Excess methanol is removed by azeotroping the solid obtained with toluene using a Dean-Stark trap. Removal of the toluene gave 62g

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

The water is removed form the aqueous wash in vacuo, and the product is further dried by placing it on the vacuum lines for 12 hours. 58g (42%) of product is obtained as a brown powder. 3. 4-azetidin-3-ylmorpholine

In a Pan shaker pressure bottle, the hydrochloride salt 4-(l-benzylazetidin-3- yl)morpholine (162g, 0.53mol) is dissolved in methanol (IL) and palladium hydroxide (16.2g, 20% on carbon) is added. The bottle is evacuated and then pressurized under hydrogen (40psi) and shaken while being heated to 60°C. On reaching the desired temperature, the pressure is increased to όOpsi, and shaking is continued for a further 110 hours (during this time the hydrogen pressure is recharged four times after samples are removed for NMR analysis to monitor the progress of the reaction). The heater is then turned off and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure is released, the bottle is opened, and the reaction is filtered through celite washing with methanol (3L). The solvent is removed in vacuo to afford the crude product as a white solid. Recrystalhsation 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.

4-azetidin-3-ylpiperidine

In a Pan shaker pressure bottle, the hydrochloride salt l-benzylazetidin-3- ylpiperadine (116g, 0.39mol) is dissolved in methanol (1.15L) and palladium hydroxide (12.2g, 20% on carbon) is added. The bottle is evacuated and then pressurized under hydrogen (40psi) and shaken while being heated to 60°C. On reaching the desired temperature, the pressure is increased to όOpsi and shaking is continued for another 72 hours (during this time the hydrogen pressure is recharged three times after samples are removed for NMR analysis to monitor the progress of the reaction). A further portion of palladium hydroxide (8g) is added, and the reaction heated at 60°C under hydrogen pressure (όOpsi) for another 24 hours. The heater is then turned off and the reaction is allowed to cool to room temperature under hydrogen. After the hydrogen pressure is released, the bottle is opened and the reaction is filtered through celite washing with methanol (2.5L). The solvent is 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. 3-(4-azetidin-3-ylpiperazinyl)propan-l -ol

In a Pan shaker pressure bottle, the hydrochloride salt of 3-[4-(l- benzylazetidin-3-yl)piperazinyl]propan-l-ol (116g, 0.39mol) is dissolved in methanol (1.15L) and palladium hydroxide (12.2g, 20% on carbon) is added. The bottle is evacuated and then pressurized under hydrogen (40psi) and shaken while being heated to 60°C. On reaching the desired temperature, the pressure is increased to όOpsi and shaking is continued for another 72 hours (during this time the hydrogen pressure is recharged three times after samples are removed for NMR analysis to monitor the progress of the reaction). A further portion of palladium hydroxide (2g) is added, and the reaction is heated at 60°C under hydrogen pressure (60psi) for another 24 hours. The heater is then turned off, and the reaction is allowed to cool to room temperature under hydrogen. After the hydrogen pressure is released, the bottle is opened and the reaction is filtered through celite washing with methanol (3L). The solvent is removed in vacuo to afford the crude product as an oily solid, which is slurried with wo-propanol (250ml) and methanol (100ml) and heated to reflux for 15 minutes. After being allowed to cool, the product (54g, 62%) is collected by filtration, washing the solid obtained with iso-propanol. Example 4

I. Acylative dealkylation I

1. l-acetyl-3-[4-(2-pyridyl)piperizinyl]azetidine

To a solution of the vigorously stiπed l[l-(t-butyl)azetidin-3-yl]-4-(2- pyridyl)piperazine (55.3g, 0.20mol) in ether (85ml) at 0°C is added acetic anhydride (110ml, 1.17mol). Upon completion of the addition, boron trifluoride ethereate (8ml) is added in a slow dropwise fashion. The reaction is then heated to reflux for 24 hours. After being allowed to cool, the reflux condenser is replaced by a distillation head, and excess acetic anhydride (ca. 70ml is collected. 45-48°C / 2mmHg) is removed by distillation under reduced pressure. The viscous black residue is 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 is extracted with methylene chloride (3 x 400ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product is 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%) is obtained as a slightly yellow solid. 2. l-acetyl-3-[4-(4-fluorophenyl)piperizinyl] azetidine

To l-[l-(t-butyl)azetidin-3-yl]-4-(4-fluorophenyl)piperazine (105 g, 0.36 mol) in a 500 ml round bottom flask in an ice water bath is added slowly pre-cooled acetic anhydride 200 ml, followed by 10 ml of BF₃ etherate (2M). The mixture is then refluxed over 38 hrs until the starting material is completely consumed. Then about 100 ml of acetic anhydride is distilled out under water pump and the resulting brown oil is poured into 400 ml of ice with 200 ml of 50%KOH. Check pH (pH = 14). The mixture is extracted by CH2CI₂ (500 ml X 3). The organics is dried (K₂CO₃) and solvent is removed. The crude product is column filtered through a short pad of silica gel to give 95 g of product (yield 95%) as an off white solid.

l-acetyl-3-[4-(4-methoxyphenyl)piperizinyl]azetidine

To a solution of the vigorously stiπed l-[l-(t-butyl)azetidin-3-yl]-4-(4- methoxyphenyl)piperazine (123g, 0.46mol) in ether (85ml) at 0°C is added acetic anhydride (210ml, 2.3mol). Upon completion of the addition, boron trifluoride ethereate (10ml) is added in a slow dropwise fashion. The reaction is then heated to reflux for 24 hours. After being allowed to cool down, the reflux condenser is replaced by a distillation head, and excess acetic anhydride (ca. 100 ml, 45-48°C / 2mmHg) is removed by distillation under reduced pressure. The viscous black residue is 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 is extracted with methylene chloride (3 x 600ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product is 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%) is obtained as a slightly yellow solid. 4. l-acetyl-3-[4-(4-methylphenyl)piperizinyl]azetidine

To a solution of the vigorously stiπed l-[l-(t-butyl)azetidin-3-yl]-4-(4- methylphenyl)piperazine (121g, 0.41mol) in ether (85ml) at 0°C is added acetic anhydride (210ml, 2.3mol). Upon completion of the addition, boron trifluoride ethereate (10ml) is added in a slow dropwise fashion. The reaction is then heated to reflux for 24 hours. After being allowed to cool, the reflux condenser is replaced by a distillation head, and excess acetic anhydride (ca. 100 ml, 45-48°C / 2mmHg) is removed by distillation under reduced pressure. The viscous black residue is 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 is extracted with methylene chloride (3 x 400ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product is 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%) is obtained as a slightly yellow solid. l-acetyl-3-[4-(4-trifluoromethylphenyl)piperizinyl]azetidine

To a solution of the vigorously stiπed l-[l-(t-butyl)azetidin-3-yl]-4-(4- trifluoromethylphenyl)piperazine (96g, 0.28mol) in ether (85ml) at 0°C is added acetic anhydride (210ml, 2.3mol). Upon completion of the addition, boron trifluoride ethereate (10ml) is added in a slow dropwise fashion. The reaction is then heated to reflux for 24 hours. After being allowed to cool down, the reflux condenser is replaced by a distillation head, and excess acetic anhydride (ca. 100 ml, 45-48°C / 2mmHg) is removed by distillation under reduced pressure. The viscous black residue is 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 is extracted with methylene chloride (3 x 600ml). The combined organic extracts are dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product is 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%) is obtained as a slightly yellow solid. II. Amide hydrolysis

1. l-azetidin-3yl-4-(2-pyridyl)piperazine

A steady stream of hydrogen chloride gas is bubbled through a stirred suspension of the l-acetyl-3-[4-(2-pyridyl)piperizinyl]azetidine (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 (45 g, 73%) as the hydrochloride salt.

2. l-azetidin-3-y-4-(4-methoxyphenyl)piperazine

A steady stream of hydrogen chloride gas is bubbled through a stirred suspension of the l-acetyl-3-[4-(4-methoxyphenyl)piperizinyl]azetidine (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.

3. l-azetidin-3-y-4-(4-methylphenyl)piperazine

A steady stream of hydrogen chloride gas is bubbled through a stiπed suspension of the l-acetyl-3-[4-(4-methylphenyl)piperizinyl]azetidine (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. l-azetidin-3-y-4-[4-(trifluoromethyl)phenylpiperazine

A steady stream of hydrogen chloride gas is bubbled through a stiπed suspension of the l-acetyl-3-[4-(4-trifluoromethylphenyl)piperizinyl]azetidine (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. l-azetidin-3-y-4-(4-fluorophenyl)piperazine

To l-acetyl-3-[4-(4-f_uorophenyl)piperizinyl]azetidine (95 g, 0.34 mol) in 500 ml of ethanol in a round bottom flask, HCl gas is bubbled in for 10 min. The resulted yellow suspension is refluxed over night. After cooling down, the white solid is filtered off to give 61 g of desired product as a HCl salt (yield: 52%).

Example 5

I. Acylative dealkylation II (for acid sensitive substrates)

1. t-butyl4-[l-(2,2,2-trifluoroacetyl)azetidin-3-yl]piperazinecarboxylate

To a solution of the vigorously stiπed t-butyl4-[l-(t-butyl)azetidin-3- yljpiperazinecarboxylate (49g, O.lόmol) and in methylene chloride (490ml) at 0°C is added trifluoroaceticacetic anhydride (35ml, 0.25mol) in a dropwise fashion. After being stiπed for 4 hours, 1H NMR analysis indicates the reaction to be 60% complete. Triethylamine (10ml) is added, and the reaction stiπed for a further 30 minutes. The reaction is poured into saturated sodium bicarbonate (500ml) and extracted with methylene chloride (500ml). The combined organic extracts are dried over magnesium sulfate. Purification of the product is 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%) is obtained as a colorless solid.

2. t-butyl4-[l-(2,2,2-trifluoroacetyl)azetidin-3-yl]-l,4- diazaperhydroepinecarboxylate

Ot-Bu

To a solution of the vigorously stirred t-butyl4-[l-(t-butyl)azetidin-3-yl]-l,4- diazaperhydroepinecarboxylate (82g, 0.26mol) and triethylamine (40ml, 0.29mol) in methylene chloride (820ml) at 0°C is added trifluoroaceticacetic anhydride (56ml, 0.39mol) in a dropwise fashion. After being stiπed for 3 hours, 1H NMR analysis indicates the reaction to be complete. The reaction is poured into saturated sodium bicarbonate (500ml) and extracted with methylene chloride (500ml). The combined organic extracts are dried over magnesium sulfate. Removal of the solvent in vacuo affords the crude product as an orange solid. Purification of the product is carried out by passing it through a pad of silica gel eluting the product with 50 :50 ethyl acetate : hexanes. The product (72g, 76%) is obtained as a yellow solid. 2,2,2-trifluoroacetyl-l-[3-(4-methylpiperazinyl)azetidinyl]ethan-l- one

To a solution of the vigorously stiπed l-[l-(t-butyl)azetidin-3-yl]-4- methylpiperazine (71g, 0.34mol) and triethylamine (47ml, 0.34mol) in chloroform

(500ml) at 0°C is added trifluoroaceticacetic anhydride (57ml, 0.41 mol) in a dropwise fashion. After being stiπed for 10 minutes, TLC analysis indicates that the starting material is totally consumed. The reaction is poured into saturated sodium bicarbonate

(500ml) and extracted with chloroform (500ml). The combined organic extracts are dried over magnesium sulfate. Removal of the solvent in vacuo affords the product as an orange solid (83g, 98%) which is used without further purification.

4. 2,2,2-trifluoroacetyl-l-[3-(4-phenylpiperazinyl)azetidinyl]ethan-l- one

To a solution of the vigorously stirred l-[l-(t-butyl)azetidin-3-yl]-4- phenylpiperazine (120g, 0.44mol) and triethylamine (12.2ml, 0.09mol) in chloroform (500ml) at 0°C is added trifluoroaceticacetic anhydride (93ml, 0.67mol) in a dropwise fashion. After being stiπed for 1 hour, TLC analysis indicates that the starting material is totally consumed. The reaction is poured into saturated sodium bicarbonate (500ml) and extracted with chloroform (500ml). The combined organic extracts are dried over magnesium sulfate. Removal of the solvent in vacuo gives the crude product. Recrystalhsation from hexanes : ethyl acetate gave the product as a white solid (105g, 76%).

5. 2,2,2-trifluoroacetyl-l-[3-(4-primidin-2- ylpiperazinyl)azetidinyl]ethan-l-one

To a solution of the vigorously stiπed 2-{4-[l-(t-butyl)azetidin-3- yl]piperazinyl}pyrimidine (lOOg, 0.36mol) and triethylamine (10.1ml, 0.07mol) in chloroform (500ml) at 0°C is added trifluoroaceticacetic anhydride (76ml, 0.55mol) in a dropwise fashion. After being stiπed for 10 minutes, TLC analysis indicates that the starting material is totally consumed. The reaction is poured into saturated sodium bicarbonate (500ml) and extracted with chloroform (500ml). The combined organic extracts are 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. 2,2,2-trifluoroacetyl-l-(3-{3-[4-(4- trifluoromethoxy)phenyl]piperazinyl}azetidinyl)ethan-l-one

Fscr^o

To a solution of the vigorously stiπed (4-{4-[l-(t-butyl)azetidin-3- yl]piperazinyl}phenoxy)trifluoromethane (52. Ig, 0.15mol) and in methylene chloride (490ml) at 0°C is added trifluoroaceticacetic anhydride (25.7ml, 0.18mol) in a dropwise fashion. After being stiπed for 4 hours, 1H NMR analysis indicates the reaction to be 60% complete. Triethylamine (10ml) is added and the reaction stiπed for a further 30 minutes. The reaction is poured into saturated sodium bicarbonate (500ml) and extracted with methylene chloride (500ml). The combined organic extracts are dried over magnesium sulfate. The solvent is evaporated to give a yellow solid which is crystallized in ethyl acetate to give the product (47. Ig, 78.1%) as a solid.

II. Trifluoroacetamide hydrolysis

t-butyl 4-azetidin-3-ylpiperazinecarboxylate

To a solution of the t-butyl4-[l-(2,2,2-trifluoroacetyl)azetidin-3- yljpiperazinecarboxylate (29.3g, 0.08mol) in methanol (720ml) and water (70ml) at 0°C is added solid potassium carbonate (60g, 0.43mol). After being allowed to stir for 1 hour, the solvent is removed in vacuo. Chloroform (400ml) is added to the residual solid, and the mixture warmed gently with stirring to break up the solid cake. After 45 minutes, solid potassium carbonate is added, the mixture is filtered, and the solids are washed with chloroform (250ml). Removal of the solvent in vacuo affords the crude product as a slightly green oil. Purification is carried out by filtration through a pad of silica gel eluting the product with 10 : 3 : 1 ethyl acetate : methanol : triethylamine. The product is obtained as a colorless solid (15g, 72%), which becomes slightly yellow on exposure to air.

l-azetidin-3-yl-4-methylpiperazine

To a solution of the 2,2,2-trifluoroacetyl-l-[3-(4- methylpiperazinyl)azetidinyl]ethan-l-one (83. Ig, 0.33mol) in methanol (IL) and water (40ml) at 0°C is added solid potassium carbonate (85g, O.όlmol). The reaction is stiπed vigorously for 45 minutes after which time TLC analysis indicates that the starting material is totally consumed. The reaction is 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 is taken up in ethyl acetate (500ml) and heated to reflux. On cooling, the product (23g, 45%) is separated as a white solid and is isolated by filtration.

3. l-azetidin-3-yl-4-phenylpiperazine

To a solution of the 2,2,2-trifluoroacetyl-l-[3-(4- phenylpiperazinyl)azetidinyl]ethan-l-one (105g, 0.34mol) in methanol (11) and water (40ml) at 0°C is added solid potassium carbonate (88g, 0.63mol). After being allowed to stir for 1 hour, the solvent is removed in vacuo. Chloroform (400ml) is added to the residual solid and the mixture is warmed gently with stirring to break up the solid cake. After 45 minutes, solid potassium carbonate is added, the mixture filtered, and the solids are washed with chloroform (250ml). Removal of the solvent in vacuo affords the crude product as a light yellow solid. Recrystalhsation from hexanes : ethyl acetate gives the product (XX) as a colorless solid. 4. 2-(4-azetidin-3-ylpiperazinyl)pyrimidine

To a solution of the 2,2,2-trifluoroacetyl-l-[3-(4-primidin-2- ylpiperazinyl)azetidinyl]ethan-l-one (88g, 0.28mol) in methanol (11) and water (40ml) at 0°C is added solid potassium carbonate (72g, 0.52mol). After being allowed to stir for 1 hour, the solvent is removed in vacuo. Chloroform (400ml) is added to the residual solid and the mixture is warmed gently with stirring to break up the solid cake. After 45 minutes, solid potassium carbonate is added, the mixture filtered, and the solids washed with chloroform (250ml). Removal of the solvent in vacuo affords the crude product as a white solid. Recrystalhsation from hexanes : .^'-.o-propanol gives the product (XX) as a colorless solid.

5. [4-(4-azetidin-3-ylpiperazinyl)phenoxy]trifluoromethane

A steady stream of hydrogen chloride gas is bubbled through a stiπed suspension of the 2,2,2-trifluoroacetyl-l-(3-{3-[4-(4- trifluoromethoxy)phenyl]piperazinyl}azetidinyl)ethan-l-one (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.

The invention and manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing 3-amino-azetidines, comprising:

(a) reacting an N-arylalkyl-azetidin-3-ol in a chlorinated solvent with methanesulfonylchlori.de in the presence of an organic tertiary base at temperatures ranging from between -10°C to -70°C to form the mesylate;

(b) displacing the mesylate in water with an amine in the presence of a base to form an N-benzyl-3-aminoazetidine; and

(c) deprotecting the N-arylalkyl-3-aminoazetidine with a catalytic amount of catalyst under hydrogen pressure ranging from between 30psi to 70psi to form the 3- amino-azetidine.

2. A process for preparing 3-amino-azetidines, comprising:

(a) reacting an N-(t-butyl)-azetidin-3-ol in a chlorinated solvent with methanesulfonylchloride in the presence of an organic tertiary base to form the mesylate;

(b) displacing the mesylate in water with an amine in the presence of a base at temperatures ranging from between -10°C to -70°C to form an N-(t-butyl)-3- aminoazetidine;

(c) dealkylating the N-(t-butyl)-3-aminoazetidine with a reactive carboxylic acid anhydride in the presence of a Lewis acid to form an N-acyl-3-aminoazetidine; and

(d) hydro lyzing the N-acyl-3-aminoazetidine with a strong mineral acid to form the 3-amino-azetidine.

3. A process for preparing 3-amino-azetidines, comprising:

(a) reacting an N-(t-butyl)-azetidin-3-ol in a chlorinated solvent with methanesulfonylchloride in the presence of an organic tertiary base to form the mesylate; (b) displacing the mesylate in water with an amine in the presence of a base at temperatures ranging from between -10°C to -70°C to form an N-(t-butyl)-3- aminoazetidine;

(c) dealkylating the N-(t-butyl)-3-aminoazetidine with a fluorinated carboxylic acid anhydride at a temperature from about — 10°C to 25°C to form an N-fluoroacyl-3- aminoazetidine; and

(d) hydro lyzing the N-fluoroacyl-3 -aminoazetidine with an inorganic base to form the 3-amino-azetidine.

4. A process according to Claim 1 wherein the mesylate is displaced with the amine before substantial decomposition of the mesylate occurs.

5. A process according to Claim 1 wherein the chlorinated solvent is selected from the group consisting of methylene chloride, 1,2-dichloroethane and chloroform.

6. A process according to Claim 1 wherein the organic tertiary base I triethylamine or diisopropylethylamine.

7. A process according to Claim 1 wherein the N- arylalkyl -azetidin-3-ol is mesylated at a temperature of about -40°C.

8. A process according to Claim 1 wherein the N-arylalkyl-azetidine-3-ol is N-benzyl-azetidin-3-ol.

9. A process according to Claim 8 wherein the N-arylalkyl-3- aminoazetidine is deprotected at a hydrogen pressure of about όOpsi.

10. A process according to Claim 9 wherein the catalyst is palladium hydroxide.

11. A process according to Claim 2 wherein the dealkylation of the N-(t- butyl)-3-aminoazetidine further comprises the purifying of the N-acyl-3- aminoazetidine by passing the N-acyl-3 -aminoazetidine through a pad of silica gel.

12. A process according to Claim 2 wherein the Lewis acid is boron trifluoride etherate.

13. A process according to Claim 2 wherein the mesylate is displaced with the amine before substantial decomposition of the mesylate occurs.

14. A process according to Claim 2 wherein the chlorinated solvent is selected from the group consisting of methylene chloride, 1,2-dichloroethane and chloroform.

15. A process according to Claim 2 wherein the organic tertiary base is triethylamine or diisopropylethylamine.

16. A process according to Claim 2 wherein the N-(t-butyl)-azetidin-3-ol is mesylated at a temperature of about — 40°C.

17. A process according to Claim 2 wherein the reactive carboxylic anhydride is acetic anhydride.

18. A process according to Claim 2 wherein the strong mineral acid is hydrogen chloride.

19. A process according to Claim 3 wherein the mesylate is displaced with the amine before substantial decomposition of the mesylate occurs.

20. A process according to Claim 3 wherein the chlorinated solvent is selected from the group consisting of methylene chloride, 1,2-dichloroethane and chloroform.

21. A process according to Claim 3 wherein the organic tertiary base is triethylamine or diisopropylamine.

22. A process according to Claim 3 wherein the N-(t-butyl)-azetidin-3-ol is mesylated at a temperature of about -40°C.

23. A process according to Claim 3 wherein the N-(t-butyl)- aminoazetidine is dealkylated at a temperature of about 0°C.

24. A process according to Claim 3 wherein the fluorinated carboxylic acid anhydride is trifluoroacetic anhydride.

25. A process according to Claim 3 wherein the trifluoroacetic anhydride is present in an amount ranging from about 1 molar equivalent to 2 molar equivalents of the N-(t-butyl)-aminoazetidine.

26. A product made by the process of Claim 1 having the formula

wherein

R, Ri, R₂ are the same or different and represent hydrogen, Cι-C₆ lower alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ alkylcarbonyl, C₃-C₆ cycloalkyl, trifluoromethylcarbonyl; or

R, Ri, R are the same or different and represent (CH₂)_n -phenyl or -(CH₂)_n- heteroaryl where n is 0 to 4 and where the phenyl or the heteroaryl is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, Cι-C₆ lower alkyl, C]-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, Q-

C₆ carboxyalkyl or aryl or heteroaryl carbonyl where each ring portion is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, Cι-C₆ lower alkyl, Cι-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, or Cι-C₆ carboxyalkyl; or

Ri and R₂, together with the nitrogen to which they are attached, form a heterocyclic ring of the formula f (CH₂)-^ NH W— R,

AA wherein m is 1, 2, or 3;

W is N, CH, or O, provided that when W is O, R₃ does not exist; and R₃ is hydrogen, Cι-C₆ lower alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ alkylcarbonyl, C -C₆ cycloalkyl, carboxy, or C₂-C₆ alkoxy carbonyl; or

R₃ is aryl or heteroaryl optionally mono-, di-, or trisubstituted with up to three groups independently selected from Cι-C₆ lower alkyl, halogen, trifluoromethyl, hydroxy, C₂-C₆ alkenyl, Cι-C₆ alkoxy, trifluoromethoxy, amino, mono or dialkylamino where each alkyl portion is Cι-C₆ lower alkyl, -CO^ where R-i is C]-C₆ lower alkyl, or -(CH )_q-O-R₅ where q is 1-6 and R₅ is hydrogen or Cι-C₆ lower alkyl.

27. A product made by the process of Claim 2 having the formula

^R1 2

wherein

R, Ri, R₂ are the same or different and represent hydrogen, C]-C lower alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C -C₆ alkylcarbonyl, C₃-C₆ cycloalkyl, trifluoromethylcarbonyl; or R, Ri, R₂ are the same or different and represent (CH₂)_n -phenyl or -(CH₂)_n- heteroaryl where n is 0 to 4 and where the phenyl or the heteroaryl is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, C]-C₆ lower alkyl, Cι-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, C - C₆ carboxyalkyl or aryl or heteroaryl carbonyl where each ring portion is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, Cι-C₆ lower alkyl, Cι-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, or Cι-C₆ carboxyalkyl; or Ri and R₂, together with the nitrogen to which they are attached, form a heterocyclic ring of the formula (CH₂)-^ NH W— R₃

wherein m is 1, 2, or 3;

W is N, CH, or O, provided that when W is O, R does not exist; and R₃ is hydrogen, C]-C₆ lower alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ alkylcarbonyl, C -C₆ cycloalkyl, carboxy, or C₂-C alkoxycarbonyl; or R is aryl or heteroaryl optionally mono-, di-, or trisubstituted with up to three groups independently selected from C]-C₆ lower alkyl, halogen, trifluoromethyl, hydroxy, C2-C6 alkenyl, Cι-C₆ alkoxy, trifluoromethoxy, amino, mono or dialkylamino where each alkyl portion is Cι-C₆ lower alkyl, -CO- j, where R₄ is Cι-C₆ lower alkyl, or -(CH₂)_q-O-R₅ where q is 1-6 and R₅ is hydrogen or C C₆ lower alkyl.

28. A product made by the process of Claim 3 having the formula

wherein

R, Rj, R₂ are the same or different and represent hydrogen, Cι-C₆ lower alkyl, C₂-C₆ alkenyl, C2-C₆ alkynyl, C₂-C₆ alkylcarbonyl, C₃-C₆ cycloalkyl, trifluoromethylcarbonyl; or

R, Ri, R₂ are the same or different and represent (CH )_n-phenyl or -(CH₂)_n- heteroaryl where n is 0 to 4 and where the phenyl or the heteroaryl is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, Cι-C₆ lower alkyl, Cι-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, C1- C₆ carboxyalkyl or aryl or heteroaryl carbonyl where each ring portion is optionally mono-, di-, or trisubstituted with up to three groups independently selected from halogen, Cι-C₆ lower alkyl, Cι-C₆ alkoxy, C₂-C₆ alkylcarbonyl, carboxy, or Cι-C₆ carboxyalkyl; or

Ri and R₂, together with the nitrogen to which they are attached, form a heterocyclic ring of the formula

wherein m is 1, 2, or 3;

W is N, CH, or O, provided that when W is O, R does not exist; and R₃ is hydrogen, Cι-C₆ lower alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ alkylcarbonyl, C₃-C₆ cycloalkyl, carboxy, or C₂-C₆ alkoxycarbonyl; or R₃ is aryl or heteroaryl optionally mono-, di-, or trisubstituted with up to three groups independently selected from C]-C₆ lower alkyl, halogen, trifluoromethyl, hydroxy, C₂-C₆ alkenyl, Cι-C₆ alkoxy, trifluoromethoxy, amino, mono or dialkylamino where each alkyl portion is Cι-C₆ lower alkyl, -CO₂R₄ where R_j is Cι-C₆ lower alkyl, or -(CH₂)_q-O-R₅ where q is 1-6 and R₅ is hydrogen or Cι-C₆ lower alkyl.