US006967201B1

(12) United States Patent (10) Patent N0.: US 6,967,201 B1 Briner et al. (45) Date of Patent: *Nov. 22, 2005

(54) BENZOFURYLPIPERAZINES AND (56) References Cited BENZOFURYLHOMOPIPERAZINES: AGONISTS U.S. PATENT DOCUMENTS 5,698,766 A 12/1997 Julius et 211. (75) Inventors: Karin Briner, Indianapolis, IN (US); 6,638,936 B1 * 10/2003 Briner et a1. Joseph Paul Burkhart, Plain?eld, IN (US); Timothy Paul Burkholder, FOREIGN PATENT DOCUMENTS Carmel, IN (US); Brian Eugene EP 0 006 524 A 1/1980 Cunningham, Martinsville, IN (US); EP 0 189 612 A 8/1986 Matthew Joseph Fisher, Mooresville, W0 W0 95 11243 A 4/1995 IN (US); William Harlan Gritton, W0 W0 97 08167 A 3/1997 Zionsville, IN (US); Shawn W0 W0 97 36893 A 10/1997 Christopher Miller, Noblesville, IN (US); J e?'rey Thomas Mullaney, OTHER PUBLICATIONS Indianapolis, IN (US); Matthew Robert Kuipers W. et al: “N4-unsubstituted 1-6 nl-arylpiperaZines Reinhard, Indianapolis, IN (US); as high-affinity 5 -HT1A recept r ligands” Journal of Medici Dennis Charles Thompson, nal Chemistry., vol. 38, No. 11, May 26, 1995, pp. 1942 Indianapolis, IN (US); Leonard Larry 1954, XP002153536 American Chemical Society. Washing Winneroski, Greenwood, IN (US); ton., US ISSN: 0022-2623. Yanping Xu, Fishers, IN (US) * cited by examiner (73) Assignee: Eli Lilly and Company, Indianapolis, Primary Examiner—Emily Bernhardt IN (US) (74) Attorney, Agent, or Firm—R. Craig Tucker (57) ABSTRACT (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. The present invention provides serotonergic benZofurylpip eraZines of Formula I: This patent is subject to a terminal dis claimer.

(21) Appl. No.: 10/031,312 / R4 '\/ / R1 (22) PCT Filed: Jul. 21, 2000 R3 / O

R (86) PCT No.: PCT/ US00/ 19543 § 371 (6X1), Where: (2), (4) Date: May 6, 2002 A is a of formula: (87) PCT Pub. No.2 wo01/09111 H (i) PCT Pub. Date: Feb. 8, 2001 R7 | R6’ N R7’ R6 Related US. Application Data R8 R5’ Provisional application No. 60/146,270, ?led on Jul. (60) R8’ N R5 29, 1999.

(51) Int. Cl.7 ...... A61K 31/496; C07D 405/10 and R, R1, R2, R3, R4, R5, R5’, R6, R6’, R7, R7’, R8, and R8' (52) US. Cl...... 514/254.11; 544/376; 544/231 are as described in the speci?cation. (58) Field of Search ...... 544/376, 231; 514/254.11 9 Claims, No Drawings US 6,967,201 B1 1 2 BENZOFURYLPIPERAZINES AND R6’ is hydrogen or methyl, provided that R6 may be BENZOFURYLHOMOPIPERAZINES: methyl only When R6 is other than hydrogen; or R6 and SEROTONIN AGONISTS R6’, together With the carbon atom to Which they are attached, form a cyclopropyl moiety; This US. national stage application of International R7’ is hydrogen or methyl, provided that R7 may be Application PCT/US00/19543, ?led Jul. 21, 2000, claims methyl only When R7 is other than hydrogen; or R7 and R7’, together With the carbon atom to Which they are priority to US. provisional application Ser. No. 60/146,270, attached, form a cyclopropyl moiety; ?led Jul. 29, 1999. R8’ is hydrogen or methyl, provided that R8 may be The neurotransmitter serotonin (5-hydroXytryptamine, 1O methyl only When R8 is other than hydrogen; or R8 and 5-HT) has a rich pharmacology arising from a heteroge R8’, together With the carbon atom to Which they are neous population of at least seven receptor classes. The attached, form a cyclopropyl moiety; serotonin 5 -HT2 class is further subdivided into at least three R9 is C1—C8 alkyl Where the alkyl chain is optionally subtypes, designated 5-HT2a, 5-HT2b, and 5-HT2C. The substituted With a substituent selected from the group 5-HT2C receptor has been isolated and characterized (Julius, 15 consisting of phenyl and pyridyl; et al., US. Pat. No. 4,985,352), and transgenic mice lacking or pharmaceutically acceptable acid addition salts thereof the 5-HT2C receptor have been reported to exhibit seiZures subject to the folloWing provisos: and an eating disorder resulting in increased consumption of a) When R2, R3, and R4 are all selected from the group food (Julius, et al., US. Pat. No. 5,698,766). Compounds consisting of hydrogen, tri?uoromethyl, cyano, C1—C4 selective for the 5-HT2C receptor Would provide useful alkoXy, or C1—C4 alkyl, neither R6 nor R7 may be therapies for the treatment of seiZure and eating disorders selected from the group consisting of hydrogen and Without the side effects associated With current therapies. C1—C6 alkyl unless: 1. R is halo; The present invention provides compounds of Formula I: 2. R1 is halo or phenyl 25 3. R6’ or R7’ is methyl; or 4. R5 or R8 are other than hydrogen, b) When R, R1, and tWo of R2, R3, and R4 are hydrogen and one of R2, R3, or R4 is selected from the group consisting of ?uoro, chloro, bromo, methyl, or meth oXy, at least one of R5, R6, R7, or R8 must be other than R1 hydrogen; R3 / c) When R1 is bromo or R is methyl, at least one of R2, R3, o and R4 must be other than hydrogen; and R d) no more than tWo of R5, R6, R7, and R8 may be other 35 than hydrogen. This invention also provides a pharmaceutical formula Where: tion Which comprises, in association With a pharmaceuti A is homopiperaZine or a piperaZine of formula: cally acceptable carrier, diluent or eXcipient, a compound of Formula I. 40 The present invention provides a method for increasing activation of the 5-HT2C receptor in mammals comprising administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of For mula I. 45 The present invention also provides a method for treating obesity in mammals comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of Formula I. A further embodiment of this invention is a method for increasing activation of the 5-HT2C receptor for treating a R is hydrogen, halo, tri?uoromethyl or C1—C6 alkyl; variety of disorders Which have been linked to decreased R1 is hydrogen, halo, tri?uoromethyl, phenyl, or C1—C6 neurotransmission of serotonin in mammals. Included alkyl; among these disorders are depression, obesity, bulimia, R2, R3, and R4 are independently hydrogen, halo, diha premenstrual syndrome or late luteal phase syndrome, alco lomethyl, tri?uoromethyl, 1,1-di?uoroethy-1-yl, 55 holism, tobacco abuse, panic disorder, anXiety, post-trau cyano, C1—C4 alkoXy, C1—C4 alkoXycarbonyl, C1—C6 matic syndrome, memory loss, dementia of aging, social alkyl, —C(O)NHR9, or C1—C6 alkyl substituted With a phobia, attention de?cit hyperactivity disorder, disruptive substituent selected from the group consisting of halo, behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic C1—C4 alkoXy and hydroXy. fatigue syndrome, premature ejaculation, erectile dif?culty, R5, R6, R7, and R8 are independently hydrogen, C1—C6 anorexia nervosa, disorders of sleep, autism, anXiety, seiZure alkyl, phenyl, benZyl, hydroXymethyl, halomethyl, disorders, and mutism. Any of these methods employ a dihalomethyl, trihalomethyl, or benZyloXymethyl; compound of Formula I. R5’ is hydrogen or methyl, provided that R5v may be This invention also provides the use of a compound of methyl only When R5 is other than hydrogen; or R5 and 65 Formula I for the manufacture of a medicament for the R5’, together With the carbon atom to Which they are treatment of obesity. Additionally, this invention provides a attached, form a cyclopropyl moiety; pharmaceutical formulation adapted for the treatment of US 6,967,201 B1 3 4 obesity containing a compound of Formula I. Furthermore, substituent on the piperaZine ring is other than hydrogen are this invention includes a method for the treatment of obesity illustrated by the folloWing structures: Which comprises administering an effective amount of a compound of Formula I. The general chemical terms used in the formulae above have their usual meanings. For example, the term “alkyl” includes such groups as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like. The term “alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy, 10 butoxy and the like. The term “acyl” includes such groups as R3_ R2 R3_ R2 formyl, acetyl, propionyl, butyryl, 2-methylpropionyl, and m/ / R1 l/ / R1 the like. The term “halo” includes ?uoro, chloro, bromo and R4 R4 iodo. O / O / 15 The term “C1—C6 alkyl substituted With a substituent R R selected from the group consisting of C1—C4 alkoxy and hydroxy” means a branched or linear alkyl group substituted in the carbon chain With one or tWo substituents indepen H E1 6 H 56 dently selected from hydroxy or C1—C4 alkoxy. \ R \ H The term “C1—C8 alkyl Where the alkyl chain is optionally N N substituted With a substituent selected from the group con sisting of phenyl and pyridyl” means a branched or linear alkyl group Which may be substituted in the carbon chain N\ \ N\ \ With a phenyl or pyridinyl ring. Since the compounds of this invention are amines, they PEER./ / R1 PEER./ / R1 are basic in nature and accordingly react With any of a R4 / R4 / number of inorganic and organic acids to form pharmaceu O O 3O tically acceptable acid addition salts. Since some of the free R R amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition Individual diastereomers, for example those compounds of salts for ease of handling and administration, since the latter the present invention Where tWo substituents on the pipera are routinely solid at room temperature. Acids commonly Zine ring are other than hydrogen, are illustrated by the employed to form such salts are inorganic acids such as folloWing structures: hydrochloric acid, hydrobromic acid, hydroiodic acid, sul furic acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic 40 acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benZoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sul?te, bisul?te, phos phate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyro-phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, mal onate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benZoate, chloroben Zoate, methylbenZoate, dinitrobenZoate, hydroxybenZoate, methoxybenZoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, 55 lactate, [3-hydroxybutyrate, glycollate, tartrate, methane sulfonate, propanesulfonate, naphthalene-l-sulfonate, naph thalene-2-sulfonate, mandelate and the like. Preferred phar maceutically acceptable salts are those formed With hydrochloric acid and fumaric acid. The skilled artisan Will appreciate that certain of the compounds of the present invention have at least one chiral carbon, and may therefore exist as a racemate, as individual enantiomers or diastereomers, and as mixtures of individual enantiomers or diastereomers. For example, individual enantiomers of compounds of the invention Where one US 6,967,201 B1 5 The enantiomers and diastereomers illustrated above are representative of other enantiomers and diasteromeric pairs created by other combinations of non-hydrogen substituents aZ) R4 is tri?uoromethyl; on the piperaZine ring, and are not intended to limit the scope ba) R5 is hydrogen; of the present invention in any Way. Furthermore, the skilled bb) R5 is C1—C4 alkyl; artisan Will appreciate that certain substituents on the ben bc) R5 is methyl; Zofuryl ring of the compounds of the invention introduce additional asymmetric centers into the molecule, creating bd) R6 is hydrogen; additional optical isomers as described above. 1O be) R6 is C1—C4 alkyl; While it is a preferred embodiment of the invention that bf) R6 is methyl; the compounds of the invention exist, are formulated, and bg) R7 is hydrogen; are used as single enantiomers or diastereomers, the present invention also contemplates the compounds of the invention bi) R7 is methyl; existing in racemic form and as mixtures of the individual bj) R8 is hydrogen; enantiomers and diastereomers. The methods and formula tions of the invention also contemplate the use and formu lation of the compounds of the invention in their racemic bl) R8 is methyl; form and as mixtures of the individual enantiomers and bm) R5 and R5’ taken together With the carbon to Which diastereomers. they are attached form a cyclopropyl moiety; The individual enantiomers and diastereomers may be bn) R6 and R6’ taken together With the carbon to Which prepared by chiral chromatography of the racemic or enan they are attached form a cyclopropyl moiety; tiomerically or diastereomerically enriched free amine, or bo) R7 and R7’ taken together With the carbon to Which fractional crystalliZation of salts prepared from racemic or 25 they are attached form a cyclopropyl moiety; enantiomerically or diastereomerically enriched free amine bp) R8 and R8’ taken together With the carbon to Which and a chiral acid. Alternatively, the free amine may be they are attached form a cyclopropyl moiety; reacted With a chiral auxiliary and the enantiomers or bq) The compound is a free base; diastereomers separated by chromatography folloWed by br) The compound is a salt; removal of the chiral auxiliary to regenerate the free amine. Furthermore, separation of enantiomers or diastereomers bs) The compound is the hydrochloride salt; may be performed at any convenient point in the synthesis bt) The compound is the fumarate salt; of the compounds of the invention. The compounds of the bu) The compound is a racemate; invention may also be prepared by the use of chiral synthe 35 bv) The compound is a single enantiomer; ses. bW) The compound is a single diastereomer; While all of the compounds of Formula I are useful bx) A is attached at the 7-position of the benZofuryl S-HTZC agonists, certain classes of the compounds are pre moiety and only one of R2, R3, or R4 is hydrogen; ferred. The folloWing paragraphs describe such preferred 40 by) A is attached at the 7-position of the benZofuryl classes: moiety and all three of R2, R3, and R4 are other than aa) A is a piperaZine of formula (i); hydrogen; ab) A is attached at either the 4- or 7-position of the benZofuran ring; bZ) One of R5, R6, R7, and R8 is other than hydrogen; ac) A is attached at the 4-position of the benZofuran ring; 45 ca) TWo of R5, R6, R7, and R8 are other than hydrogen; ad) A is attached at the 7-position of the benZofuran ring; cb) Ais a piperaZine of formula and it is substituted in ae) R is hydrogen; both the tWo and ?ve positions; af) R is halo; cc) A is a piperaZine of formula and it is substituted in ag) R is C1—C6 alkyl; both the tWo and three positions; ah) R1 is hydrogen; cd) Ais a piperaZine of formula and it is substituted in ai) R1 is halo; the tWo position. aj) R1 is tri?uoromethyl; It Will be understood that the above classes may be com bined to form additional preferred classes. al) R2 is hydrogen; 55 am) R2 is halo; The present invention also provides a method for increas ing activation of the 5-HT2C receptor in mammals by admin istering to a mammal in need of such activation a pharma ap) R2 is tri?uoromethyl; ceutically effective amount of a compound of Formula II. aq) R3 is hydrogen; The preferred mammal is human. ar) R3 is halo; The compounds of the invention are prepared beginning With an appropriately substituted benZofuran as illustrated in the folloWing scheme Where X is bromo, iodo, or tri?uo au) R3 is tri?uoromethyl; 65 romethylsulfonyloxy; PG is a nitrogen protecting group; and av) R4 is hydrogen; the variables R, R1, R2, R3, R4, R5, and R6 are as previously aW) R4 is halo; de?ned: US 6,967,201 B1

| k/V/\/ O R3 R4 HOMOPIPERAZINE

R2 R1 / \N \ \ R \_/ k/VY| O R3 R4 UNSUBSTITUTED/ SYMMETRICAL PIPERAZINE PG \ K 1. l H—NR? N—:r\/\j:giRR. R1 N R5 \ / k/VY 0 IL R3 R4 3-MONO-/3,5-DISUBSTITUTED PIPERAZINE 5 R2 R1 R5 R2 R1 \ \ deprotect /—< \ \ PG—N N—:( \ R H—N N—:r \ R k/V/\/ O \_/ k/V/\/ 0 R3 R4 3 R4 2—MONO-/2,6—DISUBSTITUTED PIPERAZINE; UNSYMMETRICAL 2,5-DISUBSTITUTED

Generally, a benZofuryl bromide, iodide, or tri?ate is reaction is complete. Additional portions of any reagent may reacted With homopiperaZine or an appropriate piperaZine in be added during the course of the reaction as necessary or the presence of an appropriate catalyst and base. Typically, 45 desired. 1—10 equivalents of homopiperaZine or an appropriate pip When homopiperaZine, piperaZine, or a symmetrically eraZine relative to beginning benZofuran are employed. The is reacted With a benZofuran, 3.5—4 coupling is catalyZed With an appropriate metal catalyst, equivalents of the appropriate amine are used to avoid such as nickel or palladium. Palladium catalysts are pre coupling a benZofuran moiety at each available nitrogen. When an unsymmetrically substituted piperaZine is ferred and are either commercially available or may be employed in the coupling to provide, for example, 3-mono generated in situ by combining trisdibenZylideneacetone or 3,5-disubstituted piperaZine products, the least sterically dipalladium or palladium chloride With a phosphine ligand hindered nitrogen reacts selectively, requiring the use of such as racemic 2,2‘-bis(diphenylphosphino)-1,1‘-binaph only 1—1.2 equivalents of the amine. When the desired thyl, tri-o-tolylphosphine, or bis(diphenylphosphino)fer 55 product results from coupling at the most sterically hindered rocene. The ratio of palladium to phosphine ligand is typi nitrogen, for eXample to provide 2-mono- or 2,6-disubsti cally betWeen 1:1 and 1:5. Typically 0.01 to 0.1 equivalents tuted piperaZine products, the least hindered nitrogen must of catalyst are used relative to starting benZofuran. Useful be protected. Nitrogen protecting groups useful for this bases include sodium tert-butoXide, lithium tert-butoXide, reaction are Well knoWn to the skilled artisan. A summary of and potassium tert-butoXide. Typically 1—5 equivalents of such groups may be found in Greene’s Protective Groups in Organic Synthesis, Second Edition, Wiley Interscience. Par base are used relative to starting benZofuran. ticularly useful protecting groups include benZyl and tert The benZofuran, homopiperaZine or appropriate pipera butoXycarbonyl. Once the protected piperaZine has been Zine, catalyst, and base are combined in a suitable solvent. coupled With the benZofuran, the protecting group is Suitable solvents include , benZene, dioXane, and 65 removed by standard methods. The benZyl moiety, for tetrahydrofuran. The mixture is stirred at 20—200° C. under eXample, may be removed by either hydrogenation or treat an inert atmosphere, typically nitrogen or argon, until the ment With 1-chloroethyl chloroformate. The tert-butoXycar US 6,967,201 B1 9 10 bonyl moiety may be removed by treatment With acid, for benZyloXyethylamine under the conditions previously example, tri?uoroacetic acid or hydrogen chloride. described. The skilled artisan Will appreciate that the appro Compounds of the invention may alternatively be pre priately substituted benZyloXyethylamines may be prepared pared as described in the following scheme Where variables from the corresponding amino acid under standard condi R, R1, R2, R3, R4, R5, and R6 are as previously de?ned: tions. The resulting ether is deprotected and the correspond

SyntheticSchemell

Br R —> HZN i/V/n 0

2. reduction

WIn.. 5 R1

The piperaZine ring may be constructed onto the benZo- 55 ing converted to the diamine under standard condi furyl moiety by coupling an appropriate benZofuran, for tions. eXample a bromobenZofuran, With benZophenone imine The diamines prepared by either of these routes is treated under the coupling conditions previously described. The With an appropriate reagent, for eXample bromoacetyl bro resulting adduct is treated With aqueous acid to provide the mide, to prepare the corresponding lactam. Reduction of this corresponding amine. This aminobenZofuran is coupled With 60 lactam under standard hydride reducing conditions, for an appropriate nitrogen-protected amino acid under standard eXample by treatment With borane or lithium aluminum peptide coupling conditions. The resulting amide is reduced hydride, provide the compounds of the present invention. With a hydride reducing agent such as lithium aluminum The requisite benZofuran intermediates are either com hydride, and the corresponding amine deprotected to pro mercially available or may be prepared from an appropri vide a diamine. 65 ately substituted phenol by methods Well knoWn in the art as Alternatively, an appropriately substituted benZofuran, for illustrated in the folloWing scheme Where variables R2, R3, eXample bromobenZofuran, is coupled With an appropriate and R12 are as previously de?ned: US 6,967,201 B1 11 12

SynthetiLSchemelIl O(alkyl) OH O(alkyl) 0 R12 Br R12 ( 1k 1) R2 R12 O a y Q R2 \ O(alkyl) R2_f_\ \ acid Br_f_\ /\ \ k/\¢\/| base k/\?\/| k/| / O R3 Br R3 Br R3

/ Br acid base

_ OH _ R12 .1\ \ CH0 O/\/ OH R m / R12 R12 {\7 (\ \ \ / 03 R B r R2—:k/V/ —>heat R2—:k/v/ —>reductive Workup R3 Br R3 Br R2 f\ \

BrT / OH _ R3 \¢\Rl2 O _

A solution of an appropriately substituted phenol in a chromatography, distillation, or crystallization. The o-al suitable solvent, typically dimethylformamide, is treated lylphenol is then treated With an excess of oZone in an With a base, to generate the corresponding phenoxide. Bases appropriate solvent, dichloromethane and methanol are use useful for this reaction include hydride sources, such as 40 ful solvents for this step. The reaction mixture is then purged sodium or potassium hydride, or carbonates, such as sodium of oZone and the oZonide is treated under reducing condi or potassium carbonate. The phenoxide solution is then tions, typically by treatment With triphenylphosphine or reacted With a chloro- or bromoacetaldehyde Which is pro- dimethylsul?de, to provide the corresponding phenylacetal tected as a cyclic or dialkyl acetal. Bromoacetaldehyde 45 dehyde. The skilled artisan Will appreciate that the orienta diethyl acetal is particularly useful for this reaction. The tion of the aldehyde With the respect to the phenolic phenoxyacetaldehyde acetal prepared by this procedure is hydroxyl group gives rise to the formation of a cyclic reacted With a source of acid in a suitable solvent to provide hemiaeetal which exists in some equilibrium mixture with the desired benZofuran. Suitable solvents include aromatic the free hydroxyaldehyde A Solution of this equilibrium Solvents Such as toluene, Xylene, benZene, and halobenzenes 50 mixture in a suitable solvent, such as toluene, is treated With such as chlorobenZene. Suitable~ acids include concentrated a Catalytic amount of an appropriate acid, Such as Sulfuric sulfuric acid, polyphosphoric acid, and acidic resins such as acid, to provide the desired benzofuran Amberlyst 15TM. . . . . _ _ _ _ _ The skilled artisan Will appreciate that benZofurans sub Alternatively, the phenoxide SOlIlIIOII'IS treated With an 55 Stituted in the 2_ and/Or 3_posi?on may be prepared by allyl bromide or allyl chloride to provide, after standard ------_ _ _ _ _ modi?cation of the chemistry described in Synthetic Scheme isolation and puri?cation procedures, the corresponding . . . . . III. For example, the phenol may be alkylated With a suitable allyl ether. ThlS puri?ed ether is heated at a temperature ...... haloketone and then cycliZed to provide a substituted ben sufficient to effect an ortho-Claisen rearrangement to pro- _ _ - - - - - Zofuran. Alternatively, the benZofuran moiety may be sub vide the corresponding o-allylphenol. It is critical that the 60 _ d _ h _ _ _ _ _ h allyl ether employed in this rearrangement is substantially Smute _m t e 2' or 3'p0sm0n at any Convemem pom? m t 6 free of residual dimethylformamide. The skilled artisan Will synthesls of the Compounds Of_the present mvennon by appreciate that, depending upon the location and nature of methods known to those Sklned 1n the art' the R2 and R3 substituents, the rearrangement can provide a The requisite benZofurans may also be prepared from an mixture of tWo isomeric products. These isomers may be 65 appropriately substituted phenol as illustrated in the folloW separated at this stage or later in the synthetic sequence as ing scheme Where variables R2, R3, and R12 are as previ is convenient or desired. The separation may be effected by ously de?ned: US 6,967,201 B1 13 14 peptide coupling conditions to provide the corresponding dipeptide. This dipeptide is N-deprotected and heated to mmsmmmy provide the corresponding dilactam. This dilactam is N reduced under standard hydride reducing conditions, for R2 ( W R2 5 example With lithium aluminum hydride, to provide the corresponding N-benZylated piperaZine. The N-benZyl ?/? N" \/N KT/? group is removed by either catalytic hydrogenation or by R3T —Br LN\/ R3T —BY treatment With 1-chloroethyl chloroformate to provide the /\/\ OH acid / / OH corresponding piperaZine. The benZyl group may be R12 R12 10 removed either prior or subsequent to coupling With an CHO appropriate benZofuran depending upon the speci?c cou pling orientation desired as described supra. 1_ (PhECHZBOBT The skilled artisan Will appreciate that the racemic N-tert lbase butoXycarbonyl alanine and N-benZyl glycine ethyl ester 15 displayed in Synthetic Scheme V are illustrative, and are not R2 intended to limit the scope of the invention in any Way. The ?/? amino acids employed in this synthetic scheme are dictated R3—: —Br by the speci?c substituted piperaZine desired. Furthermore, k/ / the skilled artisan Will appreciate that not all substituents are R12 / 2O compatible With the reaction conditions employed to prepare 0 the compounds of the invention. Those substituents incom patible With these conditions may be introduced at a more convenient point in the synthesis, or may be prepared by A mixture of an appropriate phenol and heXamethylenetet- functional group transformations Well knoWn to one of ramine are treated With an appropriate acid, such as tri?uo- 25 ordinary skill in the art. Furthermore, many of the com roacetic acid, to provide upon aqueous Workup the corre- pounds of the present invention, While useful 5-HT2C ago sponding o-formylphenol. This o-formylphenol is then nists in their oWn right, are useful intermediates to prepare treated With (bromomethyl)triphenylphosphonium bromide other compounds of the invention. Those compounds of the folloWed by an appropriate base such as potassium tert- invention bearing an ester functionality, for eXample, may be butoXide to provide the desired benZofuran. 3O hydrolyZed under standard conditions to provide the corre The requisite are either commercially avail- sponding carboXylic acids. These acids may then be reacted able or may be prepared by methods Well knoWn in the art. With amines under standard peptide coupling conditions to One such approach is illustrated in the folloWing scheme provide the corresponding amides. Alternatively, the esters Where R5 is as previously de?ned: may be reduced to provide the corresponding .

Syntheticichemel Yf$w @VNQKA YTAYQAKV

H | | N N reduce \K ] debenzylate \[ j <— N N | H

65 An appropriate N-protected amino acid is coupled With an Furthermore, alkoXy groups may be cleaved to provide the N-benZylated carboXy-protected amino acid under standard corresponding phenols, and primary amines may be diaZo US 6,967,201 B1 15 16 tiZed and displaced to provide the corresponding haloge Preparation II nated compounds. Furthermore, an alcohol or aldehyde or ketone may be converted to the corresponding mono?uoro 4-methoxy-7-bromobenZofuran or di?uoro derivative by reaction With diethylaminosulfur tri?uoride at any convenient point on the synthesis of the 2-bromo-5-methoxyphenol and 4-bromo-5-methoxyphenol compounds of the present invention. A solution of 40.0 gm (322.2 mMol) 3-methoxyphenol in The following Preparations and Examples are illustrative 1 L acetonitrile Was cooled to 0° C. under a nitrogen of methods useful for the synthesis of the compounds of the atmosphere. To this cooled solution Was added a solution of present invention. 57.35 gm (322.2 mMol) N-bromosuccinimide in 500 mL 10 acetonitrile dropWise at a rate to maintain the temperature of Preparation I the reaction mixture at 0° C. (approximately 2 hours). The reaction mixture Was stirred at 0° C. for about 1 hour after 5 -?uoro -7-bromobenZofuran the addition Was complete and Was then concentrated under reduced pressure. The residue Was treated With carbon 15 tetrachloride and the solid Which formed Was removed by 2-(2-bromo-4-?uorophenoxy)acetaldehyde Diethyl Acetal ?ltration. The ?ltrate Was concentrated under reduced pres To a solution of 20 gm (105 mMol) 2-bromo-4-?uorophe sure to provide a mixture of bromination isomers as a red oil. nol in 211 mL dimethylformamide Were added 15.8 mL (105 This oil Was subjected to silica gel chromatography, mMol) bromoacetaldehyde diethyl acetal folloWed by 14.5 eluting With a gradient system of hexane containing from gm (105 mMol) anhydrous potassium carbonate. This mix 0—30% ethyl acetate. Fractions containing the fastest eluting ture Was then heated at re?ux for about 18 hours under a compound Were combined and concentrated under reduced nitrogen atmosphere. The reaction mixture Was then con pressure to provide 18.1 gm (28%) of 2-bromo-5-methox centrated under reduced pressure and the resulting residue yphenol as a clear liquid. partitioned betWeen 200 mL of ethyl acetate and 200 mL 1N 25 1H-NMR(CDCl3): 6 7.31 (d, 1H), 6.6 (d, 1H), 6.41 (dd, sodium hydroxide. The phases Were separated and the ethyl 1H), 5.5 (s, 1H), 3.77 (s, 3H). Fractions containing the later eluting components Were acetate phase Was Washed With 200 mL of Water, giving rise combined and concentrated under reduced pressure. This to an emulsion. An additional 100 mL ethyl acetate and 20 residue Was subjected to silica gel chromatography, eluting mL of Water Were added to the emulsion. The separated ethyl With dichloromethane. Fractions containing substantially acetate phase and emulsion Were removed and saved. The pure 4-bromo-5-methoxyphenol Were combined and con ethyl acetate phase Was Washed again With 200 mL of Water. centrated under reduced pressure to provide 24.1 gm (37%) This neW emulsion Was combined With the original emulsion of a White crystalline solid (m.p.=68—69° C.). and aqueous phase. The mixture Was partitioned betWeen 1H-NMR(CDCl3): 6 7.34 (d, 1H), 6.45 (d, 1H), 6.33 (dd, 700 mL ethyl acetate and 780 mL of Water. The emulsion 1H), 4.9 (br s, 1H), 3.85 (s, 3H). and aqueous layer (1600 mL) Were removed. The organic phase Was dried over magnesium sulfate and concentrated 2-(2-bromo-5-methoxyphenoxy)acetaldehyde Diethyl under reduced pressure to provide 26.4 gm (82%) of the Acetal desired material as an amber oil. The reserved emulsion and A mixture of 16.0 gm (78.8 mmol) 2-bromo-5-methox yphenol, 10.9 gm (78.8 mMol) potassium carbonate, and aqueous phase Was Washed With 1 L of toluene. The phases 40 Were separated and organic phase Was dried over magne 15.5 gm (78.8 mMol) bromoacetaldehyde diethyl acetal in 300 mL dimethylformamide Was heated at 142° C. for 16 sium sulfate and concentrated under reduced pressure to hours. The reaction mixture Was then cooled to room tem provide an additional 4.67 gm of the desired compound as perature and diluted With 100 mL 2N sodium hydroxide an amber oil. Total recovery of desired product Was 31.1 gm folloWed by 500 mL ethyl acetate. This mixture Was Washed (96.7%). 45 tWice With 1 L of Water. The combined aqueous Washes Were CycliZation extracted tWice With 300 mL portions of ethyl acetate. All A mixture of 109.4 gm Amberlyst-15 in 707 mL chlo organic phases Were combined, Washed With lt of Water, Washed With 1 L of saturated aqueous sodium chloride, dried robenZene Was heated at re?ux to remove Water by aZeo over magnesium sulfate and concentrated under reduced tropic distillation. Distillate Was removed until the volume remaining in the pot Was about 500 mL. To this mixture Was pressure to provide the desired compound as a dark amber oil. then added dropWise over 2 hours a solution of 109.4 gm (356 mMol) 2-(2-bromo-4-?uorophenoxy)acetaldehyde CycliZation diethyl acetal in 4060 mL chlorobenZene. The mixture Was A mixture of 17 gm polyphosphoric acid in 500 mL stirred at re?ux With constant Water removal. When no more 55 chlorobenZene Was heated to 80° C. With stirring. To this Water Was observed in the aZeotrope distillate, the reaction mixture Was added dropWise over 30 minutes a solution of mixture Was cooled to room temperature. The ?lter cake Was 16 gm (50.13 mMol) 2-(2-bromo-5-methoxyphenoxy)ac Washed With 400 mL dichloromethane and the combined etaldehyde diethyl acetal in 100 mL chlorobenZene. The ?ltrates Were concentrated under reduced pressure to pro resulting mixture Was stirred for 5 hours at 80° C. and 2 vide 102 gm of a colorless oil. This oil Was diluted With 500 hours at 120° C. The reaction mixture Was cooled to room mL hexane and subjected to silica gel chromatography, temperature and the chlorobenZene solution Was decanted eluting With hexane. Fractions containing the desired prod from the polyphosphoric acid phase. The remaining residue uct Were combined and concentrated under reduced pressure Was Washed With ?ve 200 mL portions of diethyl ether. All to provide 39.6 gm (52%) of the title compound. of the organic phases Were combined and concentrated 1H-NMR(CDCl3): 6 7.75 (d, J=2.1 HZ, 1H), 7.27 (dd, 65 under reduced pressure to provide a dark amber oil. This oil JH,H= 2.5 HZ, JH,F=8.8 HZ, 1H), 7.25 (dd, JH,H=2.5 HZ, Was subjected to silica gel chromatography, eluting With a JH,F= 8.3 HZ, 1H), 6.85 (d, J=2.2 HZ, 1H). gradient of hexane containing from 0—5% ethyl acetate. US 6,967,201 B1 17 18 Fractions containing product Were combined and concen Preparation V trated under reduced pressure to provide 11.3 gm (99%) of the title compound as a White, crystalline solid 5 -bromobenZofuran (m.p.=60—62° C.). EA: Calculated for C9H7BrO2: Theory: C, 47.61; H, 3.11. Beginning With 10 gm (57.8 mMol) 4-bromophenol, 4.2 gm (38%) of the title compound Were prepared essentially Found: C, 47.40; H, 3.37. by the procedure described in Preparation IV. EA: Calculated for C8H5BrO: Theory: C, 48.77; H, 2.56. Preparation III Found: C, 48.51; H, 2.46. 10 5 -bromo-6-methoxybenZofuran Preparation VI

Beginning With 23 gm (113.3 mMol) 4-bromo-5-methox 7-bromobenZofuran yphenol, 16.2 gm of the title compound Were prepared as a White crystalline solid essentially by the procedure of Prepa Beginning With 10 gm (57.8 mMol) 2-bromophenol, 5 gm ration II. (45%) of the title compound Were prepared essentially by the procedure described in Preparation IV. Preparation IV EA: Calculated for C8H5BrO: Theory: C, 48.77; H, 2.56. Found: C, 49.02; H, 2.82. 4-bromobenZofuran and 6-bromobenZofuran Preparation VII

2-(3-bromophenoxy)acetaldehyde Diethyl Acetal 5 -methoxy-7-bromobenZofuran A solution of 10 gm (57.8 mMol) 3-bromophenol in 25 mL dimethylformamide Was added dropWise to a mixture of 25 2-bromo-4-methoxyphenol 2.8 gm (70 mMol) sodium hydride (60% suspension in A solution of 2.6 mL (100 mmol) bromine in 10 mL mineral oil) in 30 mL dimethylformamide. The reaction carbon disul?de Was added dropWise over 30 minutes to a mixture Was stirred for one hour after the addition Was solution of 12.4 gm (100 mMol) 4-methoxyphenol in 20 mL complete. To the reaction mixture Was then added 9.7 mL carbon disul?de at 0° C. After 30 minutes an additional 1 mL (64.5 mMol) bromoacetaldehyde diethyl acetal and the of bromine in 10 mL carbon disul?de are added dropWise. resulting mixture Was stirred at 153° C. for 2 hours. The The reaction mixture Was then concentrated under reduced reaction mixture Was then alloWed to cool to room tempera pressure and the residue Was dissolved in diethyl ether. This ture and Was diluted With 300 mL diethyl ether. This mixture solution Was Washed sequentially With 100 mL Water and Was then Washed With tWo 150 ml portions of Water, Washed 100 mL saturated aqueous sodium chloride, dried over 35 magnesium sulfate and concentrated under reduced pres With 50 mL saturated aqueous sodium chloride, dried over sure. The residue Was subjected to silica gel chromatogra magesium sulfate and concentrated under reduced pressure phy, eluting With a gradient of hexane containing from 0 to to provide about 17 gm of the desired compound. 20% ethyl acetate. Fractions containing product Were com 1H-NMR(CDCl3): 6 7.15—7.05 (m, 2H), 6.85 (dd, 1H), bined and concentrated under reduced pressure to provide 4.8 (t, 1H), 3.95 (d, 2H), 3.8—3.55 (m, 4H), 1.25 (t, 6H). 11.6 gm (57%) of the desired compound as a crystalline CycliZation solid. 1H-NMR(CDCl3): 6 7.0 (d, 1H), 6.95 (d, 1H), 6.8 (dd, A mixture of 17 gm (57.8 mMol) 2-(3-bromophenoxy) 1H), 5.15 (s, 1H), 3.75 (s, 3H). acetaldehyde diethyl acetal and 17.5 gm polyphosphoric Beginning With 11.5 gm (56.9 mMol) 2-bromo-4-meth acid in 400 mL chlorobenZene Was heated to 80° C. for 2 oxyphenol, 4.5 gm (35%) of the title compound Were hours. The reaction mixture Was cooled to room temperature prepared essentially by the procedure described in Prepara and the chlorobenZene Was decanted from the polyphospho tion IV. ric acid. The polyphosphoric acid Was Washed With tWo 150 EA: Calculated for C9H7BrO2: Theory: C, 47.61; H, 3.11. mL portions of diethyl ether. All or the organic phases Were Found: C, 47.79; H, 3.13. combined and concentrated under reduced pressure. The residue Was redissolved in diethyl ether and the organic Preparation VIII phases Were Washed With saturated aqueous sodium bicar bonate, Water, and saturated aqueous sodium chloride, dried 6-methoxy-7-bromobenZofuran over magnesium sulfate and concentrated under reduced pressure. The residual oil Was subjected to silica gel chro matography, eluting With hexane. 2-bromo-3-methoxyphenol Fractions containing the faster eluting isomer Were com Asolution of 22 gm (177.4 mMol) 3-methoxyphenol in 30 bined and concentrated under reduced pressure to provide mL dihydropyran Was added dropWise to a solution of 100 1.7 gm (15%) 4-bromobenZofuran. mg (0.525 mmol) p-toluenesulfonic acid monohydrate in 10 mL dihydropyran While cooling in an ice/Water bath. After EA: Calculated for C8H5BrO: Theory: C, 48.77; H, 2.56. stirring for 1 hour the reaction mixture Was diluted With 300 Found: C, 48.89; H, 2.72. mL diethyl ether and then Washed sequentially With 100 mL Fractions containing the sloWer eluting isomer Were com 0.1 N sodium hydroxide and 100 mL saturated aqueous bined and concentrated under reduced pressure to provide sodium chloride. The remaining organic phase Was dried 2.5 gm (22%) 6-bromobenZofuran. 65 over magnesium sulfate and concentrated under reduced EA: Calculated for C8H5BrO: Theory: C, 48.77; H, 2.56. pressure. The resulting oil Was distilled. The fraction dis Found: C, 48.89; H, 2.67. tilling at 110—130° C. Was collected and then partitioned US 6,967,201 B1 19 20 between 5 N sodium hydroxide and diethyl ether. The Preparation XI organic phase Was separated, Washed sequentially With Water and saturated aqueous sodium chloride, dried over 6-?uoro-7-bromobenZofuran magnesium sulfate and concentrated under reduced pressure to provide 27.1 gm (73%) of tetrahydropyran-2-yl 3-meth- 5 Beginning With 7.5 gm (39.3 mMol) 2-bromo-3-?uo oxyphenyl ether. rophenol, 10.83 gm (90%) 2-(2-bromo-3-?uorophenoxy) 1H-NMR(CDCl3): 6 7.18 (t, 1H), 6.65—6.60 (m, 2H), 6.50 acetaldehyde diethyl acetal Was prepared essentially as (dd, 1H), 5.4 (t, 1H), 3.95—3.90 (m, 1H), 3.80 (s, 3H), described in Preparation IV. 3.62—3.55 (m, 1H), 2.0—1.6 (m, 6H). Beginning With 5.0 gm (16.3 mMol) of 2-(2-bromo-3 10 ?uorophenoxy)acetaldehyde diethyl acetal, 2.2 gm (63%) of 33 mL (52.8 mmol) n-butyllithium (1.6 M in hexane) the title compound Were prepared essentially as described in Were added dropWise to a solution 10 gm (48.1 mMol) Preparation IV. tetrahydropyran-2-yl 3-methoxyphenyl ether in 100 mL tetrahydrofura over 15 minutes. After stirring for 2.5 hours Preparation XII at room temperature, the reaction mixture Was cooled to 0° 15 C. and then 4.6 mL (53.2 mMol) 1,2-dibromoethane Were 5 -chloro -7-bromobenZofuran added dropWise. The reaction mixture Was then alloWed to stir at room temperature for about 14 hours. The reaction Beginning With 25 gm (120.5 mmol) 2-bromo-4-chlo mixture Was then diluted With 50 mL 1 N hydrochloric acid rophenol, 41.16 gm crude 2-(2-bromo-4-chlorophenoxy) and Was stirred for 1 hour. The aqueous phase Was extracted acetaldehyde diethyl acetal Was prepared essentially as With three 100 mL portions of diethyl ether. The organic described in Preparation IV. A sample of this crude material phases Were combined and extracted Well With 5 N sodium Was subjected to silica gel chromatography to provide an hydroxide. These basic aqueous extracts Were combined and analytical sample. cooled in an ice/Water bath. The pH of this aqueous solution EA: Calculated for C12H16BrClO3: Theory: C, 44.54; H, Was adjusted to about 1 With 5 N hydrochloric acid and then 4.98. Found: C, 44.75; H, 4.97. extracted With three 100 mL portions of diethyl ether. These Beginning With 20 gm (61.8 mMol) of 2-(2-bromo-4 ether extracts Were combined and Washed With saturated chlorophenoxy)acetaldehyde diethyl acetal, 4.48 gm (31%) of the title compound Were prepared as a crystalline solid aqueous sodium chloride, dried over magnesium sulfate and essentially as described in Preparation I. concentrated under reduced pressure. The resulting residue 3O EA: Calculated for C8H4BrClO: Theory: C, 41.51; H, Was subjected to silica gel chromatography, eluting With a 1.74. Found: C, 41.67; H, 1.78. gradient of hexane containing from 0 to 10% ethyl acetate. Fractions containing the desired compound Were combined Preparation XIII and concentrated under reduced pressure to provide 2.91 gm (30%) of a residue Which crystalliZed upon standing. 4,5 -di?uoro-7-bromobenZofuran EA: Calculated for C7H7BrO2: Theory: C, 41.41; H, 3.48. Found: C, 41.81; H, 3.46. Beginning With 5 gm (23.9 mMol) 2-bromo-4,5-di?uo Beginning With 6.9 gm (34 mmol) 2-bromo-3-methox rophenol, 7.05 gm (91%) 2-(2-bromo-4,5-di?uorophenoxy) yphenol, 3.2 gm (41%) of the title compound Were prepared acetaldehyde diethyl acetal Were prepared essentially as as a White ?uffy solid essentially by the procedure described described in Preparation IV. in Preparation IV. EA: Calculated for C12H15BrF2O3: Theory: C, 44.33; H, 4.65. Found: C, 44.34; H, 4.41. High Resolution MS: Calculated for C9H7BrO2: Theory: Beginning With 6.60 gm (20.3 mmol) of 2-(2-bromo-4, 225.9629. Found: 225.9626. 5-di?uorophenoxy)acetaldehyde diethyl acetal, 0.42 gm 45 (9%) of the title compound Were prepared as a crystalline Preparation IX solid essentially as described in Preparation I. EA: Calculated for C8H3BrF2O: Theory: C, 41.24; H, 4-?uoro-7-bromobenZofuran 1.30. Found: C, 41.20; H, 1.51. Beginning With 5 gm (26 mMol) 2-bromo-5-?uorophenol 50 Preparation XIV and 6.5 gm (39 mMol) bromoacetaldehyde ethylene glycol acetal, 3.3 gm (59%) of the title compound Were prepared 3-methyl-5-?uoro-7-bromobenZofuran essentially by the procedure described in Preparation IV. EA: Calculated for C8H4BrFO: Theory: C, 44.69; H, 1.88. 55 1-(2-bromo-4-?uorophenoxy)-2-propanone Found: C, 44.44; H, 1.91. A mixture of 1.9 gm (10 mMol) 2-bromo-4-?uorophenol, 0.92 gm (10 mMol) chloroacetone, 0.1 gm potassium iodide, Preparation X and 1.4 gm (10 mmol) potassium carbonate in 100 mL tetrahydrofuran Was heated at re?ux for 4 hours. The mix 5 -bromo -7-?uorobenZofuran 60 ture Was concentrated under reduced pressure and the resi due partitioned betWeen dichloromethane and 1 N sodium Beginning With 20.5 gm (108 mMol) 2-?uoro-4-bro hydroxide. The phases Were separated and the aqueous mophenol, 3.0 gm (13%) of the title compound Were pre phase extracted Well With dichloromethane. The organic pared essentially by the procedure described in Preparation phases Were combined, Washed With 1 N sodium hydroxide, I dried over sodium sulfate and concentrated under reduced 1H-NMR(CDCl3): 6 7.65 (d, J=2.4 HZ, 1H), 7.50 (d, J=1.5 pressure. The residual Was subjected to silica gel chroma HZ, 1H), 7.19 (dd, JH=1.5 HZ, JF=8.3 HZ, 1H), 6.76 (m, 1H). tography, eluting With hexane containing 20% ethyl acetate. US 6,967,201 B1 21 22 Fractions containing product Were combined and concen addition of dilute sulfuric acid. The phases Were separated trated under reduced pressure to provide 2.7 gm (100%) of and the aqueous phase Was extracted With tWo 150 mL the desired compound as a White solid. portions of diethyl ether. The organic phases Were combined, Washed With 50 mL saturated aqueous sodium chloride, CycliZation dried over magnesium sulfate and concentrated under Beginning With 2.7 gm (10 mmol) 1-(2-bromo-4-?uo reduced pressure. The residual solid Was dissolved in 200 rophenoxy)-2-propanone and 15 gm polyphosphoric acid, mL ethanol to Which Were added 4.8 gm (85.5 mMoL) 2.03 gm (81%) of the title compound Were prepared as a potassium hydroxide. The resulting suspension Was Warmed yellow crystalline solid essentially as described in Prepara on a steam bath for 1 hour. The suspension Was then cooled tion II. 10 to room temperature. After about 18 hours the mixture Was Preparation XV ?ltered and dried under reduced pressure to provide 14.1 gm (98%) of the desired compound as an orange solid. 2-methyl-5 -?uoro-7-bromobenZofuran 13C-NMR(DMSO-d6): 6 160.3, 159.8, 154.0, 143.9, 129.7, 122.2, 117.7, 108.0, 103.8. 15 5 -nitro-7-bromobenZofuran-2-carboxylic Acid Ethyl 2-(2-bromo-4-?uorophenoxy)propionate A mixture of 11.5 gm (35.5 mMol) potassium 5-nitro-7 A mixture of 15 gm (78.5 mMol) 2-bromo-4-?uorophe bromobenZofuran-2-carboxylate and 36 gm DoWex nol, 11.2 mL (86.4 mMol) ethyl 2-bromopropionate, and 13 50WX8-200 resin in 1.6 L methanol Was stirred for 1 hour gm (94.2 mMol) potassium carbonate Was heated at re?ux at room temperature. The mixture Was ?ltered and the ?ltrate for 3 hours. At this point 0.1 gm potassium iodide Were concentrated under reduced pressure. The residue Was added and re?ux continued for another 2 hours. The reaction diluted With about 80 mL of methanol and heated on the mixture Was partitioned betWeen Water and ethyl acetate. steam bath With stirring. The mixture Was cooled to room The phases Were separated and the aqueous phase Was temperature and ?ltered. The residual solid Was dried under extracted Well With ethyl acetate. The organic phases Were vacuum to provide 6.7 gm (66%) of the desired compound 25 combined, Washed With saturated aqueous sodium chloride, as a gold solid. dried over sodium sulfate, and concentrated under reduced m.p.=257° C. (dec.) pressure. The residue Was subjected to silica gel chroma MS(FD): m/e=285, 287 (M+) tography, eluting With hexane containing 5% ethyl acetate. EA: Calculated for C9H4NO5Br: Theory: C, 37.79; H, Fractions containing product Were combined and concen 1.41; N, 4.90. Found: C, 37.81; H, 1.55; N, 4.77. trated under reduced pressure to provide 19.8 gm (87%) of the desired compound as a clear oil. Decarboxylation A sonicated mixture of 0.42 gm (1.47 mMol) 5-nitro-7 2-(2-bromo-4-?uorophenoxy)propionaldehyde bromobenZofuran-2-carboxylic acid and 0.085 gm copper A solution of 19.4 gm (66.7 mmol) ethyl 2-(2-bromo-4 poWder in 10 mL freshly distilled quinoline Was heated at ?uorophenoxy)propionate in 400 mL toluene Was cooled to 35 185° C. under nitrogen for 7 minutes. The reaction mixture —78° C. at Which point 100 mL (100 mMol) diisobutylalu Was cooled to room temperature and ?ltered. The solid minum hydride (1 M in toluene) Were added dropWise over recovered Was Washed With tWo 20 mL portions of dichlo 35 minutes. The reaction mixture Was stirred at —78° C. for romethane and these Washes Were combined With the ?ltrate. an additional 20 minutes after the addition Was complete and The ?ltrate Was then diluted With 70 mL dichloromethane then the reaction Was quenched by the addition of methanol. 40 and Was Washed sequentially With tWo 100 mL portions of The reaction mixture Was Warmed to room temperature and 1 N hydrochloric acid, and 50 mL 4:1 saturated aqueous then treated With saturated aqueous sodium potassium car sodium chloride:5 N sodium hydroxide. The remaining bonate. The mixture Was stirred for 30 minutes and Was then organics Were dried over sodium sulfate and concentrated extracted Well With ethyl acetate. The organic phases Were under reduced pressure. The residue Was subjected to silica combined, dried over sodium sulfate, and concentrated 45 gel chromatography, eluting With hexane containing 10% under reduced pressure to provide 16.9 gm of crude desired ethyl acetate. Fractions containing product Were combined compound. and concentrated under reduced pressure. The residual solid CycliZation Was crystalliZed from hexane to provide 0.15 gm (42%) of Beginning With 16.5 gm of the crude aldehyde, 5.2 gm the title compound as ?ne, light orange needles. (34% for the reduction and cycliZation) of the title com pound Were prepared essentially as described in Preparation MS(FD): m/e=241, 243 (M+) II. EA: Calculated for C8H4NO3Br: Theory: C, 39.70; H, 1.67; N, 5.79. Found: C, 40.05; H, 2.03; N, 5.67. Preparation XVI 55 Preparation XVII 5 -nitro-7-bromobenZofuran 3-tri?uoromethyl-5 -?uoro -7-bromobenZofuran

Potassium 5-nitro-7-bromobenZofuran-2-carboxylate A solution of 2.10 gm (16.7 mmol) 1-tri?uoromethyl A mixture of 11.0 gm (44.7 mMol) 2-hydroxy-3-bromo prop-1-en-3-ol, 3.19 gm (16.7 mMol) 2-bro and 4.81 gm 5-nitrobenZaldehyde, 5.56 gm (40.24 mmol) potassium car (18.4 mMol) triphenylphosphine in 25 mL dichloromethane bonate, and 8.0 mL (46.95 mMol) diethyl bromomalonate in Was cooled to 0° C. and then 2.9 mL (18.4 mMol) diethyl 55 mL 2-butanone Was heated at re?ux for 5 hours. The aZodicarboxylate Were added. The reaction mixture Was reaction mixture Was cooled to room temperature and con stirred for 1 hour at room temperature and then the reaction centrated under reduced pressure. The residue Was parti 65 mixture Was directly subjected to ?ash silica gel chroma tioned betWeen 450 mL diethyl ether and 250 mL Water and tography, eluting With 20:1 hexane:ethyl acetate. Fractions the aqueous phase Was adjusted to pH of about 1 by the containing product Were combined and concentrated under US 6,967,201 B1 23 24 reduced pressure to provide 6 gm of crude 1-(1-tri?uorom Preparation XXII ethylprop-1-en-3-yloxy)-2-bromo-4-?uorobenZene. 1.0 gm (3.34 mMol) 1-(1-tri?uoromethylprop-1-en-3 4-chloro-5-?uoro-7-bromobenZofuran yloxy)-2-bromo-4-?uorobenZene Was heated at 250° C. for 3 hours. The reaction mixture, containing primarily 2-(3 Bromination tri?uoromethylprop-1-en-3-yl)-4-?uoro-6-bromophenol, A mixture of 5 gm (34.1 mMmol) 3-chloro-4-?uorophe Was diluted With dichloromethane and the solution cooled to nol and 1.76 mL (34.1 mMol) bromine in 20 mL carbon —78° C. This solution Was then treated With excess oZone disul?de Was stirred at room temperature for 18 hours. The reaction mixture Was concentrated under reduced pressure and Was stirred at —78° C. until the 2-(3-tri?uoromethyl and the residue Was dissolved in dichloromethane, Washed prop-1-en-3-yl)-4-?uoro-6-bromophenol Was consumed as With Water, dried over sodium sulfate and concentrated measured by thin layer chromatography. At this point the under reduced pressure to provide a mixture of 2-bromo-4 oZone Was purged from the reaction With oxygen and then ?uoro-5-chlorophenol and 2-bromo-3-chloro-4-?uorophe 0.88 gm (3.34 mMol) triphenylphosphine Were added. The nol. 15 mixture Was stored at —20° C. for about 64 hours. The Ether Formation reaction mixture Was then concentrated under reduced pres This mixture of bromination isomers Was combined With sure and the residue subjected to ?ash silica gel chromatog 12 gm allyl bromide and 13.6 gm potassium carbonate in 90 raphy, eluting With hexane containing 10% ethyl acetate. mL dimethylformamide. After stirring at room temperature Fractions containing the desired compound Were combined for 2.5 hours, the mixture Was partitioned betWeen dichlo and concentrated under reduced pressure to provide 2-hy romethane and Water. The organic phases Were combined, droxy-3-tri?uoromethyl-5-?uoro-7-bromo-2,3-dihydroben dried over sodium sulfate and concentrated under reduced Zofuran. A solution of this dihydrobenZofuran in 10 mL pressure to provide 9.7 gm of a mixture of allyl ether toluene Was treated With 4 drops of sulfuric acid and Was isomers. stirred at re?ux for 10 minutes. The reaction mixture Was 25 cooled to room temperature and Was then Washed With Rearrangement/OZonolysis/Dehydration saturated aqueous sodium bicarbonate. The organic phase The mixture of allyl ethers Was reacted as described in Preparation XVII to provide 0.49 gm of the title compound Was separated and concentrated under reduced pressure. The as a White crystalline solid. residue Was subjected to ?ash silica gel chromatography, eluting With hexane. Fractions containing product Were 1H-NMR(300 MHZ, CDCl3): 6 7.73 (d, J=2.1 HZ, 1H); combined and concentrated under reduced pressure to pro 7.29 (d, J=8.8 HZ, 1H); 6.92 (d, J=2.1 HZ, 1H). vide the title compound. Preparation XXIII Preparation XVIII 35 4-tri?uoromethyl-7-bromobenZofuran and 5 -methoxycarbonyl-7-bromobenZofuran 6-tri?uoromethyl-7-bromobenZofuran

Beginning With methyl 3-bromo-4-allyloxybenZoate, the 4-Tri?uoromethylphenol Was brominated essentially as title compound Was prepared essentially as described in 40 described in Preparation XXII to provide a 58:12:30 mixture Preparation XVII. of 2-bromo-5-tri?uoromethylphenol:2-bromo-3-tri?uorom ethylphenol: 4-bromo-3-tri?uoromethylphenol. The Preparation XIX 4-bromo-3-tri?uoromethylphenol Was separated from the other tWo isomers by silica gel chromatography. The remain 45 ing mixture of isomers Was then alkylated to provide a 3-ethyl-5 -?uoro -7-bromobenZofuran mixture of 2-bromo-5-tri?uorophenyl allyl ether and 2-bromo-3-tri?uoromethylphenylallyl ether Which Was then Beginning With pent-2-en-1-yl 2-bromo-4-?uorophenyl separated by chromatography. ether, the title compound Was prepared essentially as The 2-bromo-5-tri?uoromethylphenyl allyl ether Was described in Preparation XVII. converted to 4-tri?uoromethyl-7-bromobenZofuran essen tially as described in Preparation XXII. Preparation XX 1H-NMR(300 MHZ, CDCl3): 6 7.81 (d, J=2.0 HZ, 1H); 7.55 (d, J=8.3 HZ, 1H); 7.41 (d, J=8.3 HZ, 1H); 7.03 (m, 1H). 3-isopropyl-5-?uoro-7-bromobenZofuran The 2-bromo-3-tri?uoromethylphenyl allyl ether Was 55 converted to 6-tri?uoromethyl-7-bromobenZofuran essen Beginning With 4-methylpent-2-en-1-yl 2-bromo-4-?uo tially as described in Preparation XXII. rophenyl ether, the title compound Was prepared essentially 1H-NMR(300 MHZ, CDCl3): 6 7.83 (d, J=1.9 HZ, 1H); as described in Preparation XVII. 7.61 (d, J=8.3 HZ, 1H); 7.57 (d, J=8.3 HZ, 1H); 6.91 (d, J: 1.9 HZ, 1H). Preparation XXI Preparation XXIV 3,4-dimethyl-5 -?uoro -7-bromobenZofuran 5-tri?uoromethyl-7-bromobenZofuran

Beginning With but-2-en-1-yl 2-bromo-4-?uoro-5-meth 65 Beginning With 5-tri?uoromethylphenol, the title com ylphenyl ether, the title compound Was prepared essentially pound Was prepared essentially as described in Preparation as described in Preparation XVII. XXII. US 6,967,201 B1 25 26 Preparation XXV mixture Was ?ltered and the ?ltrate concentrated under reduced pressure. The residue Was subjected to silica gel 4,5 ,6-tri?uoro-7-bromobenZofuran chromatography, eluting With hexane. Fractions containing product Were combined and concentrated under reduced Beginning With 3,4,5-tri?uorophenol, the title compound 5 pressure to provide 3.9 gm (53%) of the title compound as Was prepared essentially as described in Preparation XXII. a White solid. m.p.=46.5—48° C. Preparation XXVI

10 Preparation XXVIII 4,6-dimethyl-5 -chloro-7-bromobenZofuran 5 -hydroxymethyl-7-bromobenZofuran Beginning With 3,5-dimethyl-4-chlorophenol, the title compound Was prepared essentially as described in Prepa A solution of 0.63 gm (2.46 mmol) 5-methoxycarbonyl ration XXII. 15 7-bromobenZofuran in 10 mL toluene Was cooled to —78° C. When material precipitated, 5 mL dichloromethane Were Preparation XXVII added to effect solution. To this solution Were then sloWly added 1.5 mL (8.6 mmol) diisobutylaluminum hydride and Alternate Synthesis of the reaction mixture Was alloWed to Warm gradually to room 4,5-di?uoro-7-bromobenZofuran temperature. After 10 minutes the reaction Was quenched by the addition of methanol folloWed by 1.5 gm sodium ?uoride 2-bromo-4,5-di?uorophenyl Allyl Ether and 50 mL Water and then Rochelle’s salt solution. The mixture Was diluted With additional dichloromethane and A mixture of 79.4 gm (0.38 mole) 2-bromo-4,5-di?uo Was stirred vigorously for about 1 hour. The phases Were 25 rophenol and 79 gm (0.57 mole) potassium carbonate in 200 separated and the aqueous phase extracted Well With ethyl mL dimethylformamide Was stirred at room temperature for acetate. The organic phases Were combined and concen 30 minutes. At this point 33 mL (0.38 mMol) allyl bromide trated under reduced pressure. The residue Was crystalliZed Were added and the resulting mixture Was stirred for 18 from hexane and dichloromethane to provide 0.46 gm (82%) hours at room temperature. The reaction mixture Was then of the title compound as a White crystalline solid. diluted With diethyl ether and Washed With Water folloWed by saturated aqueous sodium chloride. The remaining organ Preparation XXIX ics Were dried over magnesium sulfate and concentrated under reduced pressure to provide 90 gm (96%) of the 5 -methoxymethyl-7-bromobenZofuran desired compound. 35 2-allyl-3,4-di?uoro-6-bromophenol A solution of 0.372 gm (0.40 mMol) 5-hydroxymethyl 15 gm (60.5 mmol) 2-bromo-4,5 di?uorophenyl allyl 7-bromobenZofuran in tetrahydrofuran Was added to a mix ether Was heated at 200° C. for 2 hours under a nitrogen ture of 1.80 mmol sodium hydride (60% suspension in mineral oil) in 2 mL tetrahydrofuran. After stirring at room atmosphere. The reaction mixture Was cooled to room 40 temperature and ?ltered through a pad of celite. The celite temperature for 1 hour, 204 pL iodomethane Were added and pad Was Washed With 500 mL hexane and the ?ltrate stirring Was continued for 2.5 hours. The reaction mixture concentrated under reduced pressure. The residue Was sub Was quenched by the addition of Water and the resulting jected to ?ash silica gel chromatography, eluting With hex mixture Was extracted Well With ethyl acetate. The organic ane. Fractions containing product Were combined and con 45 phase Was concentrated under reduced pressure to provide a centrated under reduced pressure to provide 9.7 gm (65%) of nearly quantitative yield of the title compound. the desired compound. Preparation XXX (2-hydroxy-3-bromo-5,6-di?uorophenyl)acetaldehyde A solution of 7.8 gm (31.45 mMol) 2-allyl-3,4-di?uoro 5 -carboxy-7-bromobenZofuran 6-bromophenol in 100 mL dichloromethane and 20 mL methanol Was cooled to —78° C. and Was then saturated With A solution of 0.52 gm (2.03 mMol) 5-methoxycarbonyl oZone. After 20 minutes the reaction mixture Was purged 7-bromobenZofuran and 0.41 gm (10.13 mMol) sodium With nitrogen for 10 minutes and Was then treated With 5 mL hydroxide in 4 mL ethanol Was stirred at room temperature dimethylsul?de. The reaction mixture Was alloWed to Warm 55 until all of the starting material had been consumed. The gradually to room temperature. After 15 hours the reaction reaction mixture Was concentrated under reduced pressure mixture Was concentrated under reduced pressure to provide the title compound. and the residue dissolved in Water. This solution Was then made basic by the addition of 1N sodium hydroxide and Was CycliZation extracted Well With ethyl acetate. The remaining aqueous A mixture of 7.5 gm Amberlyst 15TM resin in 150 mL phase Was made acidic (pH about 2) by treatment With chlorobenZene Was heated at 160° C. and the solvent dis potassium hydrogen sulfate and the resulting solid removed tilled to remove Water. The reaction mixture Was cooled to by ?ltration. The aqueous phase Was extracted Well With 120° C. and then a solution of 31.45 mMol (2-hydroxy-3 ethyl acetate and the organics Were combined and concen bromo-5,6-di?uorophenyl)acetaldehyde in chlorobenZene 65 trated under reduced pressure to provide 0.40 gm (82%) of Was added dropWise. The temperature Was again increased 5-carboxy-7-bromobenZofuran as an off-White solid. to 160° C. and solvent distilled. After 1.5 hours, the reaction US 6,967,201 B1 27 28 Preparation XXXI Preparation XXXII

4-bromo-5-?uoro-, and 5 -?uoro-6-bromobenZofuran Alternate Synthesis of 4-chloro-5-?uoro-7-bromobenZofuran O-acetyl 3-bromo-4-?uorophenol A solution of 1.09 gm (5 mMol) 3-bromo-4-?uoroac A mixture of 90.4 gm (0.40 mole) 2-bromo-4-?uoro-5 etophenone and 3.45 gm (20 mMol) m-chloroperbenZoic chlorophenol (containing 10% 2-bromo-3-chloro-4-?uo acid (70%) in 15 mL dichloromethane Was heated at re?ux rophenol) and 64 gm (0.45 mole) hexamethylenetetramine for 18 hours. An additional 3.45 gm m-chloroperbenZoic Was cooled in an ice bath. To this cooled mixture Were added acid Were added and re?ux continued for about 12 hours. At 306 mL tri?uoroacetic acid. After stirring at about 0° C. for this point an additional 1.4 gm m-chloroperbenZoic acid 15 minutes, the reaction mixture Was heated at re?ux for 1.5 Were added and re?ux continued for 18 hours. The reaction hours. The reaction mixture Was then cooled in an ice bath mixture Was cooled to room temperature and Was then and treated With 439 mL of Water folloWed by 220 mL 50% sulfuric acid. The reaction mixture Was stirred Without diluted With 50 mL diethyl ether. The resulting mixture Was 15 cooled to 0° C. and Was then treated With 15 mL 20% cooling for tWo hours. The reaction mixture Was then diluted aqueous sodium thiosulfate. The resulting slurry Was stirred With 500 mL Water and the resulting solid collected by for about 1 hour and then the phases separated. The organic ?ltration. The solid Was Washed With Water until the Wash phase Was Washed sequentially With 3><20 mL 20% aqueous Was neutral (pH about 7). The solid Was dried under reduced sodium thiosulfate folloWed by 3><20 mL saturated aqueous pressure and Was then subjected to silica gel chromatogra sodium chloride. The organic phase Was then dried over phy, eluting With a gradient of hexane containing from 0—2% sodium sulfate and concentrated under reduced pressure. ethyl acetate. Fractions containing the desired compound The residue Was subjected to silica gel chromatography, Were combined and concentrated under reduced pressure to eluting With 10:1 hexane:diethyl ether. Fractions containing provide 57 gm (62%) 2-hydroxy-3-bromo-5-?uoro-6-chlo robenZaldehyde. product Were combined and concentrated under reduced 25 pressure to provide 68% of the desired compound. A suspension of 49.2 gm (0.19 mole) 2-hydroxy-3 bromo-5-?uoro-6-chlorobenZaldehyde and 127 gm (0.29 3-bromo-4-?uorophenol mole) (bromomethyl)triphenylphosphonium bromide in 230 Asolution of 0.80 gm (3.43 mMol) O-acetyl 3-bromo-4 mL tetrahydrofuran Was cooled to 0° C. under a nitrogen ?uorophenol in 10 mL 6% diisopropylethylamine in metha atmosphere. To this Were added dropWise 330 mL (0.33 nol Was stirred at room temperature for 8 hours. The reaction mole) potassium tert-butoxide (1M in tetrahydrofuran) over mixture Was concentrated under reduced pressure at 0° C. to 3 hours. An additional 90 mL (0.09 mole) potassium tert provide the desired compound. butoxide (1M in tetrahydrofuran) Were then added to react 3-bromo-4-?uorophenyl Allyl Ether remaining starting material. The reaction mixture Was 35 diluted With 700 mL of hexane and the resulting precipitate Amixture of 0.65 gm (3.43 mMol) 3-bromo-4-?uorophe removed by ?ltration. The recovered solid Was slurried in nol, 0.60 mL (6.86 mMol) allyl bromide, and 0.71 gm (5.15 300 mL hexane and ?ltered 4 times. The combined ?ltrates mMol) potassium carbonate in 6 mL acetone Was stirred at Were Washed With 2x500 mL Water folloWed by 500 mL re?ux for 13 hours. The reaction mixture Was concentrated saturated aqueous sodium chloride. The remaining organics under reduced pressure and the residue subjected to silica 40 Were dried over sodium sulfate and concentrated under gel chromatography, eluting With hexane. Fractions contain reduced pressure to provide a residual solid. This solid Was ing product Were combined and concentrated under reduced slurried and ?ltered With 4><300 mL diethyl ether to remove pressure to provide 61% of the desired compound. triphenylphosphine oxide. The ?ltrates Were concentrated Claisen Rearrangement and the residue subjected to silica gel chromatography, eluting With hexane. Fractions containing product Were 3-bromo-4-?uorophenyl allyl ether Was placed in a sealed 45 tube and Was deoxygenated by bubbling nitrogen through combined and concentrated under reduced pressure to pro vide 40 gm (83%) of the title compound as a White solid. the liquid. The tube Was sealed and then heated at 230° C. for 3 hours. After cooling to room temperature, the mixture is subjected to silica gel chromatography, eluting With 8:1 Preparation XXXIII hexane:diethyl ether. The faster eluting product isomer Was 2-allyl-4-?uoro-5-bromophenol. The sloWer eluting isomer 2(S)-methyl-5(S)-methylpiperaZine Was 2-allyl-3-bromo-4-?uorophenol. The isomers Were iso lated in a ratio of 3:2 respectively. To a suspension of 2.7 gm (19 mmol) cyclo(L-Alanine L-Alanine) in 95 mL tetrahydrofuran Were added 115 mL 4-bromo-5-?uorobenZofuran 55 (115 mmol) borane(1 M in tetrahydrofuran) over 25 min Beginning With 3 gm (13 mMol) 2-allyl-3-bromo-4-?uo utes. The reaction mixture Was stirred for one hour at room rophenol, the title compound Was prepared in 98% yield temperature and then at re?ux for three hours. The reaction essentially by the procedure described in Preparation XXVII mixture Was then alloWed to cool to room temperature. With the exception that the cycliZation/dehydration step Was While cooling in an ice bath, the reaction mixture Was performed using sulfuric acid in toluene. treated With 100 mL 1M hydrochloric acid over 10 minutes. The resulting mixture Was concentrated under reduced pres 5-?uoro-6-bromobenZofuran sure and the residual oil dissolved in 30 mL methanol Beginning With 3.5 gm (15 mMol) 2-allyl-4-?uoro-5 folloWed by 25 mL 2M hydrogen chloride in diethyl ether. bromophenol, the title compound Was prepared in 90% yield After heating at 60° C. for 1 hour, the resulting suspension essentially by the procedure described in Preparation XXXI 65 Was concentrated under reduced pressure. The residue Was With the exception that the cycliZation/dehydration step Was suspended in diethyl ether and stirred at room temperature performed using sulfuric acid in toluene. for 1 hour. The crystalline precipitate Was ?ltered and dried US 6,967,201 B1 29 30 under reduced pressure at room temperature for 15 hours to Preparation XXXV provide 3.28 gm (92%) 2(S)-methyl-5(S)-methylpiperaZine dihydrochloride. 1 -benZyl-3(S)-isopropylpiperaZine A portion (0.48 gm) of the dihydrochloride salt Was loaded on an SCX ion exchange column (10 gm). The N-benZyl-N-[N‘-tert-butoxycarbonyl-(S)-valinyl]glycine column Was Washed With 100 mL 1:1 dichloromethane: Ethyl Ester methanol. The title compound Was eluted With 7:3 dichlo romethane containing 2M ammoniazmethanol. Fractions A solution of 6.18 gm (28.5 mMol) (S)-N-tert-butoxy containing product Were combined and concentrated under carbonylvaline, 3.85 gm (28.5 mMol) 1-hydroxybenZotria Zole, and 4.95 mL (28.5 mMol) diisopropylethylamine in reduced pressure to provide 0.25 gm (73%) of the title 10 compound. 100 mL dichloromethane Was cooled to 0° C. To this solution Was added a solution of 5.46 gm (28.5 mMol) Preparation XXXIV 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro chloride in 75 mL dichloromethane over 10 minutes. The reaction mixture Was stirred for 25 minutes and then a 1 -benZyl-3,3-ethylidenepiperaZine 15 solution of 5.0 gm (25.9 mMol) N-benZyl glycine ethyl ester in 25 mL dichloromethane Was added over 10 minutes. The N-benZyl-N-[N‘-tert-butoxycarbonyl 1-amino- 1 -cyclopro reaction mixture Was alloWed to Warm gradually to room panecarbonyl]glycine Ethyl Ester temperature and Was stirred over night. The reaction mixture To a solution of 1.36 gm (6.8 mmol) N-tert-butoxycar Was concentrated under reduced pressure and the residue bonyl 1-amino-1-cyclopropanecarboxylic acid, 1.26 mL subjected to silica gel chromatography, eluting With dichlo (13.5 mMol) N-benZylglycine ethyl ester, and 2.35 mL (13.5 romethane containing from 0—3% methanol. Fractions con mMol) diisopropylethylamine in 36 mL Were taining product Were combined and concentrated under added 2.57 gm (6.8 mMol) o-(7-aZabenZotriaZol-1-yl)-N,N, reduced pressure to provide 7.1 gm (70%) of the desired N‘,N‘-tetramethyluronium hexa?uorophosphate. The result 25 dipeptide. ing mixture Was stirred at room temperature over night and Was then diluted With 70 mL dichloromethane. The reaction N-benZyl-N-[(S)-valinyl]glycine Ethyl Ester mixture Was Washed sequentially With 2><50 mL 1M hydro A mixture of 5.82 gm (14.8 mMol) N-benZyl-N-[N‘-tert chloric acid, 2><35 mL 2N sodium hydroxide, and 50 mL butoxycarbonyl-(S)-valinyl] glycine ethyl ester in 20 mL 4N saturated aqueous sodium chloride. The remaining organics hydrogen chloride in dioxane Was stirred at room tempera Were dried over magnesium sulfate concentrated under ture under a nitrogen atmosphere over night. The reaction reduced pressure. The residue Was treated With 65 mL mixture Was concentrated under reduced pressure and the diethyl ether and the resulting slurry ?ltered to provide 2.08 residue partitioned betWeen dichloromethane and saturated gm (82%) of the desired dipeptide. aqueous sodium bicarbonate. The aqueous phase Was extracted again With dichloromethane. The combined 1-benZyl-2,5-dioxo-3,3-ethylidenepiperaZine 35 organic phases Were dried over magnesium sulfate and 200 mL ethanol Was cooled in an ice bath and stirred concentrated under reduced pressure to provide 4.2 gm mechanically as 8.0 gm (102 mMol) acetyl chloride Were (97%) of the desired compound as a yelloW oil. added over 5 minutes. The mixture Was stirred for 30 minutes at 0—5° C. and then a slurry of 3.84 gm (10.2 mmol) 1-benZyl-2,5-dioxo-3(S)-isopropylpiperaZine of the dipeptide in 50 mL ethanol Was added. The mixture 40 A solution of 4.2 gm (14.4 Mol) N-benZyl-N-[(S)-valinyl] Was stirred at 0° C. for 30 minutes and then at room glycine ethyl ester and 1.2 mL (0.98 mMol) pyridine in 85 temperature overnight. The reaction mixture Was concen mL toluene Was heated at re?ux for 3 hours. The reaction trated under reduced pressure and the residue dissolved in mixture Was then concentrated under reduced pressure to dichloromethane. This solution Was Washed sequentially provide 3.4 gm (96%) of the desired compound as an oily With 2><75 mL saturated aqueous sodium bicarbonate and 50 45 solid. mL saturated aqueous sodium chloride. The remaining 1-benZyl-3(S)-isopropylpiperaZine organics Were dried over sodium sulfate and concentrated To 100 mL tetrahydrofuran cooled to 0° C. Were added 9 under reduced pressure. The residue Was treated With 20 mL diethyl ether and the resulting slurry ?ltered and dried to mL (8.9 mMol) lithium aluminum hydride (1.0 M in tet provide 1.97 gm (83%) of the desired bislactam. rahydrofuran) dropWise. To this Was added dropWise a solution of 1.0 gm (4.06 mmol) 1-benZyl-2,5-dioxo-3(S) Reduction isopropylpiperaZine in 50 mL dichloromethane over 30 To a slurry of 0.70 gm (3 mMol) of the bislactam in 6 mL minutes. The reaction mixture Was then heated at re?ux over tetrahydrofuran Were added 12.2 mL (12.2 mmol) borane night. The reaction mixture Was then cooled to 0° C. and Was (1M in tetrahydrofuran) over 20 minutes at room tempera 55 stirred vigorously While being treated sequentially With 1 ture under a nitrogen atmosphere. The reaction mixture Was mL Water, 1 mL 5N sodium hydroxide, 2 mL Water, and 5 stirred at 60° C. overnight. After cooling to room tempera gm sodium sulfate. After stirring for 30 minutes the reaction ture, the reaction mixture Was carefully treated With 2 mL mixture Was ?ltered and the ?lter cake Washed With dichlo methanol and then concentrated under reduced pressure. The romethane. The ?ltrate Was concentrated under reduced residue Was treated With 20 mL methanol and 10 mL 1M pressure and the yelloW Waxy solid residue Was subjected to hydrogen chloride in diethyl ether at 60° C. for 45 minutes, silica gel chromatography, eluting With dichloromethane and Was then concentrated under reduced pressure. The containing 0—3% methanol. Fractions containing product residue Was passed through a SCX ion exchange column (10 Were combined and concentrated under reduced pressure to gm), eluting With 7:3 dichloromethane:2M ammonia in provide 0.38 gm (42%) of the title compound. methanol. Fractions containing product Were combined and 65 Other substituted piperaZines may be prepared essentially concentrated under reduced pressure to provide 0.46 gm as described in Preparation XXXV by substituting an appro (74%) of the title compound. priate amino acid for valine. US 6,967,201 B1 31 32 Preparation XXXVI from 0—100% acetone). Fractions containing product Were combined and concentrated under reduced pressure to pro 2(S)-(benZyloxymethyl)piperaZine vide 8.8 gm (84%) of the corresponding R,S-bislactam. A solution of 7.0 gm (30.1 mmol) R,S-bislactam in 150 A solution of 0.30 gm (1.01 mMol) 1-benZyl-2(S)-(ben mL tetrahydrofuran Was cooled to 0° C. To this solution Was Zyloxymethyl)piperaZine in 20 mL 1,2-dichloroethane Was added dropWise 300 mL 1M borane in tetrahydrofuran. The cooled to 00 C. To this solution Were added 1.09 mL (10.1 reaction mixture Was stirred at room temperature for 50 mMol) 1-chloroethyl chloroformate and the resulting mix minutes and then an additional 300 mL tetrahydrofuran Were ture Was heated at 80° C. for 4 hours. The reaction mixture added. This mixture Was stirred at re?ux for 5 hours and Was Was then cooled again to 00 C. and an additional 2.18 mL 10 then cooled to 0° C. This cooled solution Was treated (20.2 mMol) 1-chloroethyl chloroformate Were added. The carefully With 150 mL methanol and Was then stirred at 0° reaction mixture Was heated at re?ux overnight and Was then C. for 30 minutes and then at room temperature for 30 concentrated under reduced pressure. The residue Was dis minutes. The mixture Was again cooled to 0° C. and then 5 solved in 40 mL methanol and heated at re?ux for 2 hours. mL concentrated hydrochloric acid Were added. After 20 The mixture Was concentrated under reduced pressure and 15 minutes at room temperature, the reaction mixture Was the residue subjected to silica gel chromatography, eluting concentrated under reduced pressure. The residue Was dis With dichloromethane containing 0—10% methanol and 0.1% solved in 300 mL diethyl ether and this solution Was Washed ammonium hydroxide. Fractions containing the desired sequentially With 5N aqueous sodium hydroxide and satu product Were combined and concentrated under reduced rated aqueous sodium chloride. The ether layer Was dried pressure to provide 0.17 gm (81%) of the title compound. 20 over sodium sulfate and concentrated under reduced pres Preparation XXXVII sure to provide 5.9 gm (96%) of the title compound. 2(S)- Preparation XXXIX 25 A mixture of 0.32 gm (1.2 mMol) 1-benZyl-3(S)-ben 1 -(N- [(triphenyl)methyl] amino) -2-amino -2-methylprop ane ZylpiperaZine and 0.06 gm 20% palladium(II) hydroxide on carbon in 50 mL methanol Was hydrogenated at room A solution of 10 mL (95.4 mMol) 1,2-diamino-2-meth temperature over night at an initial hydrogen pressure of 50 ylpropane and 20 mL (144 mMol) triethylamine in 300 mL psi. The reaction mixture Was ?ltered, the solid Washed 30 dichloromethane Was cooled to 0° C. To this solution Was With methanol, and the ?ltrate concentrated under reduced added a solution of 26 gm (93.3 mMol) (triphenyl)methyl pressure to provide 0.10 gm (50%) of the title compound. chloride in 50 mL dichloromethane. The resulting mixture Was stirred at room temperature for about 18 hours. The Preparation XXXVIII reaction mixture Was Washed With saturated aqueous sodium 35 bicarbonate, dried over magnesium sulfate, and concen 1 -benZyl-2(S)-methyl-5 (R) -methylpiperaZine trated under reduced pressure. The residue Was subjected to silica gel chromatography, eluting With ethyl acetate con To a solution of 32.4 gm (171 mMol) N-tert-butoxycar taining from 0—10% methanol. Fractions containing product bonyl D-alanine, 171 mMol N-benZyl L-alanine methyl Were combined and concentrated under reduced pressure to ester, and 59.6 mL (342 mMol) diisopropylethylamine in 40 provide 16.0 gm (52%) of the desired compound as a White 925 mL chloroform Were added 65 gm (171 mMol) O-(7 solid. aZabenZotriaZol-1-yl)-N,N,N‘,N‘-tetramethyluronium hexa?uorophosphate. The resulting mixture Was stirred for General Procedure I about 66 hours at room temperature. The reaction mixture Was then Washed sequentially With 3><500 mL 1N hydro 45 Coupling of a PiperaZine or HomopiperaZine to a chloric acid, 2><500 mL 1N sodium hydroxide, and 100 mL BenZofuran saturated aqueous sodium chloride. The remaining organic phase Was dried over magnesium sulfate and concentrated One equivalent of an appropriately substituted benZofuran under reduced pressure. The residual yelloW oil Was sub is dissolved in anhydrous toluene under nitrogen. The solu jected to silica gel chromatography, eluting With a gradient 50 tion is treated With 4 equivalents of piperaZine, 1.4 equiva of diethyl ether containing from 50—20% hexane. Fractions lents of sodium tert-butoxide, 0.15 equivalents racemic containing product Were combined and concentrated under 2,2‘-bis(diphenylphosphino)-1,1‘-binaphthyl (BINAP), and reduced pressure to provide 16.4 gm (26%) of the corre 0.05 equivalents tris(dibenZylideneacetone)dipalladium sponding dipeptide (9:1 mixture of R,S and R,R diastere (Pd2(dba)3). The reaction is evacuated and purged With omers). 55 nitrogen, and then heated at about 100° C. for about 5 hours. A solution of this dipeptide mixture in 100 mL methanol The reaction is cooled to room temperature, poured into Was added to a solution prepared by adding 32 mL (450 ether, and ?ltered through celite. The ?ltrate is concentrated mMol) acetyl chloride to 200 mL methanol at 0—5° C. The under reduced pressure, and the residue subjected to silica resulting mixture Was stirred at room temperature for 2.5 gel chromatography, eluting With a step gradient of 3% hours and Was then concentrated under reduced pressure to 60 methanol in dichloromethane, 10% methanol in dichlo provide a White foam. The residue Was dissolved in dichlo romethane, and then With 9:1:0.1 dichloromethanezmetha romethane and Was then Washed With 150 mL saturated nol:ammonium hydroxide. Fractions containing the product aqueous sodium bicarbonate folloWed by 100 mL saturated are combined and concentrated under reduced pressure to aqueous sodium chloride. The remaining organic phase Was provide the desired benZofurylpiperaZine. The benofurylpip dried over sodium sulfate and concentrated under reduced 65 eraZine is then optionally treated With a pharamceutically pressure. The residue Was subjected to silica gel chroma acceptable acid if desired. The compounds of EXAMPLES tography, eluting With a gradient of ethyl acetate containing 1—8 Were prepared essentially as described in this procedure. US 6,967,201 B1 33 34 EXAMPLE 1 EXAMPLE 8

1-(4,5-di?uorobenZofur-7-yl)piperaZine Fumarate 1-(5 -?uorobenZofur-7-yl)homopiperaZine Hydrochloride Beginning With 4,5 -di?uoro-7-bromobenZofuran and pip eraZine, the title compound Was prepared as described. Beginning With 5-?uoro-7-bromobenZofuran and homopiperaZine, the title compound Was prepared as EA: Calculated for C12H12N2OF2—C4H4O4: C, 54.24; H, described. 4.55; N, 7.91. Found: C, 53.95; H, 4.37; N, 7.71. EA: Calculated for C13H15N2OF—HCl: C, 57.67; H, 5.96; N, 10.35. Found: C, 57.73; H, 5.94; N, 10.07. EXAMPLE 2 General Procedure II 1 -(4,6-di?uorobenZofur-7-yl)piperaZine Hydrochloride Coupling of a 1-tert-ButoXycarbonylpiperaZine to a 15 BenZofuran Beginning With 4,6-di?uoro-7-bromobenZofuran and pip One equivalent of an appropriately substituted benZofuran eraZine, the title compound Was prepared as described. is dissolved in anhydrous toluene under nitrogen. The solu MS: m/e=239(M+H) tion is treated With 1.2 equivalents of N-tert-butoXycarbon ylpiperaZine, 1.4 equivalents of sodium tert-butoXide, 0.1 EXAMPLE 3 equivalents tri(o-tolyl)phosphine, and 0.05 equivalents tris (dibenZylideneacetone)dipalladium (Pd2(dba)3). The reac 1 -(4-?uoro-5-chlorobenZofur-7-yl)piperaZine tion is evacuated and purged With nitrogen, and then heated fumarate at about 100° C. for about 5 hours. The reaction is cooled to 25 room temperature and ?ltered through a celite pad. The pad Beginning With 4-?uoro-5-chloro-7-bromobenZofuran is Washed With dichloromethane and the ?ltrate Washed With Water. The organic phase is dried over magnesium sulfate, and piperaZine, the title compound Was prepared as concentrated under reduced pressure, and the residue sub described. jected to silica gel chromatography, eluting With 20% ethyl acetate in heXane. The residue from this chromatography is EXAMPLE 4 again subjected to silica gel chromatography, eluting With 10% ethyl acetate in heXane. Fractions containing the 1-tert 1 -(4-chloro-5-?uorobenZofur-7-yl)piperaZine butoXycarbonyl-4-benZofurylpiperaZine are combined and Hydrochloride concentrated under reduced pressure. 35 The 1-tert-butoXycarbonyl moiety is removed by treat Beginning With 4-chloro-5-?uoro-7-bromobenZofuran ment With either hydrogen chloride in dioXane or neat and piperaZine, the title compound Was prepared as tri?uoroacetic acid. The resulting benofurylpiperaZine is described. then optionally treated With a pharmaceutically acceptable acid if desired. The compounds of EXAMPLES 9—25 Were MS: m/e=255, 257(M+H) 40 prepared essentially as described in this procedure. EXAMPLE 5 EXAMPLE 9 1 -(5-?uorobenZofur-5 -yl)piperaZine Hydrochloride 1-(3-phenylbenZofur-7-yl)piperaZine OXalate 45 Beginning With 5-?uoro-4-bromobenZofuran and pipera Beginning With 3-phenyl-7-bromobenZofuran and 1-tert Zine, the title compound Was prepared as described. butoXycarbonylpiperaZine, the title compound Was prepared as described.

EXAMPLE 6 EXAMPLE 10 1-(5-?uorobenZofur-6-yl)piperaZine Hydrochloride 1-(3-ethylbenZofur-7-yl)piperaZine OXalate Beginning With 3-ethyl-7-bromobenZofuran and 1-tert Beginning With 5-?uoro-6-bromobenZofuran and pipera butoXycarbonylpiperaZine, the title compound Was prepared Zine, the title compound Was prepared as described. as described. MS: m/e=221(M+H) EXAMPLE 11 EXAMPLE 7 1 -(4,6-dimethyl-5 -chlorobenZofur-7-yl)piperaZine 1 -(5-?uorobenZofur-7-yl) -2,6-dimethylpiperaZine Hydrochloride OXalate Beginning With 4,6-dimethyl-5-chloro-7-bromobenZofu Beginning With 7-bromobenZofuran and 2,6-dimethylpip 65 ran and 1-tert-butoXycarbonylpiperaZine, the title compound eraZine, the title compound Was prepared as described. Was prepared as described. US 6,967,201 B1 35 36 EXAMPLE 12 EXAMPLE 19 1-(4-rnethyl-5 -?uorobenZofur-7-yl)piperaZine 1 -(5-(rnethoxyrnethyl)benZofur-7-yl)piperaZine Oxalate Oxalate Beginning With 4-rnethyl-5-?uoro-7-brornobenZofuran Beginning With 5-(rnethoxyrnethyl)-7-brornobenZofuran and 1-tert-butoxycarbonylpiperaZine, the title compound and 1-tert-butoxycarbonylpiperaZine, the title compound Was prepared as described. Was prepared as described.

EXAMPLE 13 EXAMPLE 20 1-(3 -ethyl-4,6-dirnethyl-5 -chlorobenZofur-7-yl)pip 1-(4,5,6-tri?uorobenZofur-7-yl)piperaZine Oxalate eraZine Oxalate 15 Beginning With 4,5,6-tri?uoro-7-brornobenZofuran and Beginning With 3-ethyl-4,6-dirnethyl-5-chloro-7-bro 1-tert-butoxycarbonylpiperaZine, the title compound Was rnobenZofuran and 1-tert-butoxycarbonylpiperaZine, the title prepared as described. compound Was prepared as described.

EXAMPLE 21 EXAMPLE 14 1 -(3-rnethyl-4,5 ,6-tri?uorobenZofur-7-yl)piperaZine 1 -(3-isopropyl-5-?uorobenZofur-7-yl)piperaZine Oxalate Oxalate 25 Beginning With 3-rnethyl-4,5,6-tri?uoro-7-brornobenZo Beginning With 3-isopropyl-5-?uoro-7-brornobenZofuran furan and 1-tert-butoxycarbonylpiperaZine, the title corn and 1-tert-butoxycarbonylpiperaZine, the title compound pound Was prepared as described. Was prepared as described.

EXAMPLE 22 EXAMPLE 15 1 -(3 -tri?uorornethyl-5 -?uorobenZofur-7-yl)pipera 1 -(3-pentyl-5-?uorobenZofur-7-yl)piperaZine Zine Oxalate Oxalate Beginning With 3-tri?uorornethyl-5-?uoro-7-brornoben 35 Beginning With 3-pentyl-5-?uoro-7-brornobenZofuran Zofuran and 1-tert-butoxycarbonylpiperaZine, the title corn and 1-tert-butoxycarbonylpiperaZine, the title compound pound Was prepared as described. Was prepared as described. EXAMPLE 23 40 EXAMPLE 16 1-(4-rnethyl-5-?uorobenZofur-7-yl)piperaZine 1-(5,6-di?uorobenZofur-7-yl)piperaZine Oxalate Oxalate Beginning With 4-rnethyl-5-?uoro-7-brornobenZofuran Beginning With 5,6-di?uoro-7-brornobenZofuran and 45 1-tert-butoxycarbonylpiperaZine, the title compound Was and 1-tert-butoxycarbonylpiperaZine, the title compound prepared as described. Was prepared as described.

EXAMPLE 24 EXAMPLE 17 1-(5 -?uoro-6-rnethylbenZofur-7-yl)piperaZine 1 -(5 -rnethoxycarbonylbenZofur-7-yl)piperaZine Hydrochloride Oxalate Beginning With 5-?uoro-6-rnethyl-7-brornobenZofuran Beginning With 5-rnethoxycarbonyl-7-brornobenZofuran 55 and 1-tert-butoxycarbonylpiperaZine, the title compound and 1-tert-butoxycarbonylpiperaZine, the title compound Was prepared as described. Was prepared as described.

EXAMPLE 25 EXAMPLE 18 1 -(4-chloro -5 -rnethoxycarbonylbenZofur-7-yl)pip 1-(4,6-dichlorobenZofur-7-yl)piperaZine Oxalate eraZine Oxalate

Beginning With 4,6-dichloro-7-brornobenZofuran and Beginning With 4-chloro-5-rnethoxycarbonyl-7-bro 1-tert-butoxycarbonylpiperaZine, the title compound Was 65 rnobenZofuran and 1-tert-butoxycarbonylpiperaZine, the title prepared as described. compound Was prepared as described. MS: rn/e=271(M+H) US 6,967,201 B1 37 38 General Procedure III tion is treated With 1.2 equivalents of a 2-substituted pip eraZine, 1.4 equivalents of sodium tert-butoXide, 0.04—0.15 Coupling of 2(S)-Methyl-5(S)-MethylpiperaZine to equivalents racernic 2,2‘-bis(diphenylphosphino)-1,1‘-bi a BenZofuran naphthyl (BINAP), and 0.02—0.05 equivalents tris(diben Zylideneacetone)dipalladiurn (Pd2(dba)3). The reaction is One equivalent of an appropriately substituted benZofuran evacuated and purged With nitrogen, and then heated at is dissolved in anhydrous toluene under nitrogen. The solu about 100° C. for about 5 hours. The reaction is cooled to tion is treated With 1.4 equivalents of sodium tert-butoXide, room temperature and stirred for about 15 hours. The 0.04 equivalents racernic 2,2‘-bis(diphenylphosphino)-1,1 reaction mixture is then poured into ether and ?ltered binaphthyl (BINAP), and 0.02 equivalents tris(dibenZylide 10 through celite. The ?ltrate is concentrated under reduced neacetone)dipalladiurn (Pd2(dba)3). To this solution is then pressure, and the residue subjected to silica gel chromatog added a concentrated solution of 3.5 equivalents of 2(5) rnethyl-5-(S)-rnethylpiperaZine in dichlorornethane. The raphy, eluting With a step gradient of 3% methanol in reaction is evacuated and purged With nitrogen, and then dichlorornethane, 6% methanol in dichlorornethane, and heated at about 100° C. for about 2.5h. The reaction is 15 9:1:0.1 dichlorornethane:rnethanol:—arnrnoniurn hydrox cooled to room temperature, poured into ether, and ?ltered ide. Fractions containing the product are combined and through celite. The ?ltrate is concentrated under reduced concentrated under reduced pressure to provide the desired pressure, and the residue subjected to silica gel chromatog benZofurylpiperaZine. The benofurylpiperaZine is then raphy eluting With 95:5 dichlorornethane containing 2M optionally treated With a pharrnaceutically acceptable acid if arnrnonia:rnethanol. Fractions containing the product are 20 desired. The compounds of EXAMPLES 29—48 Were pre combined and concentrated under reduced pressure to pro pared essentially as described in this procedure. vide the desired benZofurylpiperaZine. The benofurylpipera Zine is then optionally treated With a pharrnaceutically EXAMPLE 29 acceptable acid if desired. The compounds of EXAMPLES 26—28 Were prepared essentially as described in this proce 25 1-(5 -?uorobenZofur-7-yl)-3(S)-rnethylpiperaZine dure. Hydrochloride

EXAMPLE 26 Beginning With 5-?uoro-7-brornobenZofuran and 2(5) rnethylpiperaZine, the title compound Was prepared as 1-(4-?uoro -5 -chlorobenZofur-7-yl)-2(S)-rnethyl-5 30 described. (S)-rnethylpiperaZine Furnarate EA: Calculated for C13H15N2OF—HCl: C, 57.67; H, 5.96; N, 10.35. Found: C, 57.84; H, 5.81; N, 10.13. Beginning With 4-?uoro-5-chloro-7-brornobenZofuran and 2(S)-rnethyl-5(S)-rnethylpiperaZine, the title compound [a]D=—26.9° (c=1.03, rnethanol) Was prepared as described. 35 EA: Calculated for C14H16N2OclF—C4H4O4: C, 54.21; EXAMPLE 30 H, 5.05; N, 7.02. Found: C, 54.05; H, 5.08; N, 6.80. 1-(7-?uorobenZofur-5-yl)-3(S)-rnethylpiperaZine EXAMPLE 27 Hydrochloride 40 1-(4-chloro -5 -?uorobenZofur-7-yl)-2(S)-rnethyl-5 Beginning With 5-brorno-7-?uorobenZofuran and 2(5) (S)-rnethylpiperaZine Furnarate rnethylpiperaZine, the title compound Was prepared as described. Beginning With 4-chloro-5-?uoro-7-brornobenZofuran HRMS: Calculated for C13H15N2OF: 235.1247. Found: and 2(S)-rnethyl-5(S)-rnethylpiperaZine, the title compound 45 235.1243. Was prepared as described. EA: Calculated for C14H16N2OclF—C4H4O4: C, 54.21; EXAMPLE 31 H, 5.05; N, 7.02. Found: C, 54.50; H, 4.86; N, 6.80. 1-(5 -?uorobenZofur-7-yl)-3(S)-benZyloXyrnethylpip EXAMPLE 28 50 eraZine Furnarate

1 -(5 -?uorobenZofur-7-yl)-2(S)-rnethyl-5(S)-rneth Beginning With 5-?uoro-7-brornobenZofuran and 2(5) ylpiperaZine Furnarate benZyloXyrnethylpiperaZine, the title compound Was pre pared as described. Beginning With 5-?uoro-7-brornobenZofuran and 2(S)rne 55 thyl-5(S)-rnethylpiperaZine, the title compound Was pre MS: rn/e=341(M+H) pared as described. EA: Calculated for C14H17N2OF—C4H4O4: C, 59.33; H, EXAMPLE 32 5.81; N, 7.69. Found: C, 59.44; H, 5.91; N, 7.46. 60 1 -(4,5 -di?uorobenZofur-7-yl) -3(S) -rnethylpiperaZine General Procedure IV Furnarate Preparation of Beginning With 4,5-di?uoro-7-brornobenZofuran and 1 -(BenZofuryl) -3-Substituted-PiperaZines 2(S)-rnethylpiperaZine, the title compound Was prepared as 65 described. One equivalent of an appropriately substituted benZofuran EA: Calculated for C13H14N2OF2—C4H4O4: C, 55.44; H, is dissolved in anhydrous toluene under nitrogen. The solu 4.93; N, 7.61. Found: C, 55.48; H, 4.90; N, 7.51.