AU716479B2

AU716479B2 - Optically active 3-(1-(alkylamino) alkyl pyrrolidines

Info

Publication number: AU716479B2
Application number: AU79961/98A
Authority: AU
Inventors: Thomas J Fleck; William W. Mcwhorter; Bruce A. Pearlman
Original assignee: Pharmacia and Upjohn Co; Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1993-05-06
Filing date: 1998-08-13
Publication date: 2000-02-24
Anticipated expiration: 2014-05-03
Also published as: AU7996198A

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: 0 04 0* 0 *0t0 0@ 0 0 0.00 0 Name of Applicant: Pharmacia Upjohn Company Actual Inventor(s): William W. McWhorter Thomas J. Fleck Bruce A. Pearlman Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: OPTICALLY ACTIVE 3-(1-(ALKYLAMINO))ALKYL PYRROLIDINES Our Ref 539399 POF Code: 1459/285890 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): N 010, -1- I -la- OPTICALLY ACTIVE 3-(1-ALKYLAMINO))ALKYL PYRROLIDINES FIELD OF THE INVENTION This patent application is a divisional from parent application 68189/94, the entire contents of which is incorporated herein by reference.

This method allows the convenient, large scale preparation for compounds, possibly used as intermediates of quinolones, in high optical purity and good yield. Previously published methods lack adequate stereoselectivity for large scale preparation or are impractical for large scale preparation.

BACKGROUND OF THE INVENTION The quinolonecarboxylic acid based antibacterial agents such as norfloxacin and ciprofloxacin, now used clinically, exhibit potent antibacterial activity. Efforts to synthesize or discover a quinolone based antibacterial compound exhibiting maximum antibacterial properties and minimum toxic side effects continue. Many investigators have focused their efforts on developing quinolones with aminoalkyl pyrrolidinyl moieties attached to the 7 position of the quinolone.

Within the chiral environment of living organisms, individual stereoisomers of biologically active compounds are often known to have unique properties relative to their related stereoisomers. In vitro and in vivo studies of quinolone derivatives with various aminoalkyl pyrrolidinyl 7 position side chains have shown that the activity of these compounds can be strongly influenced by the stereochemical positions of the atoms in the side chain. European Patent Application Publication 0,443,498 Al, published 28 August 1991, discloses an aminoalkyl pyrrolidinyl 7 positon side chain quinolones hving 2 asymmetric carbon atoms on a 3-amino-4-methylpyrrolidine ring attached to the 7 position of a quinolone. Two of the four possible stereochemical isomers were two to six times more active than the other two stereoisomers. United States patent number 5,157,128, issued 20 October 1992, (Hagen) describes the effect of stereospecific alkylation at the l'-aminoethyl position of a 3pyrrolodine substituent also substituted at the 7 position of a quinolone. Hagen reported that the R- (1,1-dialkylated-l-aminomethyl)pyrrolidine, when coupled at the 7 position of a quinolone leads to S* antibacterial agents with improved activity and safety.

This invention relates to a process for the synthesis of various optically active amino pyrrolidinyl stereoisomers, or enantiomers, that may be attached to quinolonecarboxylic acids or naphthyridones. The process disclosed by the procedures and examples herein allow the synthesis of these side chains in a more efficient manner than any previously disclosed method of synthesis. Novel intermediates are also disclosed.

INFORMATION DISCLOSURE Kokai Patent Application No. Hei 3 (1991)-72476, discloses the preparation of similar compounds using a less selective method synthesis. Another less selective method of synthesis is provided in the Journal of Heterocyclic Chemistry, Vol. 29, No. 6, pp. 1481-98 C:\WINWORD\MICHELLESPECIES\68l89A94.DOC -2- (1992), also mentioned below. US 5,157,128 issued 20 October, 1992, (Hagen), discloses optically pure isomers of 7-(3-(1,1-dialkylmethyl- -amino)- -pyrrolidinyl quinolones and naphthyridones and their method of manufacture. Guanti, Giuseppe, et al. in Tetrahedron Letter, Vol. 28, No. 37, pp 4335-4338 (1987) discuss a stereocontrolled synthesis of hydroxyethyl)-2-azetidinones through trimethylsilyl trifluoromethanesulphonate catalyzed condensation of silyl ketene acetal. Estermann and Seebach, Helvetica Chimica Acta, Vol. 71 pp. 1824-39 (1988) discloses diastereoselective alkylation of N-protected 3-aminobutanoic acid esters at the 2 position. Seebach and Esterman, Tetrahedron Letters, Vol.28, No. 27 pp. 3310- 3106 (1987) add additional discussion concerning alkylation of benzaldehyde to give enantiomerically pure 3-aminobutanoic acid derivatives. Furukawa et. al., Chemical Pharmaceutical Bulletin, Vol. 27. pp. 2223-6 at 6 (1979) discloses the use of Pearlman's reagent, 10% palladium hydroxide on charcoal, to hydrogenolytically remove benzyl groups from amines. The protection of the amino group with protecting groups such as carboxy benzyl are disclosed in Helvetica Chimica Acta, Vol. 66, Fasc. 2, Nr. 38, p. 461 (1983). Davies, in 15 both Tetrahedron:Asymmetry, Vol. 2, No. 3, pp. 183-186 (1991) and in commercial literature, see, "Chiral Lithium Organoamide Technology Available," from Oxford Asymmetry Limited, Oxfordshire, UK. (Lithium Link), discloses the use of lithium organoamides in stereoselective Michael additions to crotonate esters. Orsini et. al., Synthetic Communications, Vol. 12, No. 14, pp. 1147-54 (1982) and Davis et. al., Journal of the American Chemical Society, Vol. 109, No.

20 11, pp. 3370-7 (1987) provide examples of the preparation of the starting materials used in this method. The reduction of amides and urethanes to amines using lithium aluminium hydride is well known and there are many examples of this transformation in the chemical literature: for an example, see Journal of Heterocyclic Chemistry, Vol. 29, No. 6, pp. 1481-98 (1992). All the references provided above incorporated by reference into this document.

25 SUMMARY OF THE INVENTION This invention relates to processes for the synthesis of various optically active amino pyrrolidinyl stereoisomers, or enantiomers, that may be attached to quinolonecarboxylic acids or naphthyridones or other appropriate compounds. Processes and essential intermediates are disclosed for the synthesis of compounds represented by the structure shown in figure BG 5 below.

NH

R

2

NH

R

Figure BG -3where R 50 is is 1 -Cg)alkyl, (C 3 -Cg)cycloalkyl, (C 1 -Cg)alkyl-(C 3 -Cg)cycloalkyl,

(C

6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-C

12 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6

-C

12 aryl),(C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl, where R 2 is (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1 -Cs)alkyl-(C 3 -Cg)cycloalkyl,

(C

6

-C

12 aryl), (C 1 -Cg)alkyl-(C 6

-C

12 aryl),(C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; where R 6 is H, (C 1 -Cs)alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3 -Cg)cycloalkyl,

(C

6

-C

12 aryl), (C 1 -Cg)alkyl-(C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; Depending upon the starting materials used, compounds represented by the structure shown by figure BG 5 may have one of either of the two steriochemical arrangments shown by the structures below, figure BGS_ 1 50,5 -NH NH *R 5 R 2 2 R NH R NH 20 R6 R 6 Figure BG5-1 or, if the starting materials are a racemic mixture, the reaction may produce a 1:1 ratio of the combination of products shown in Figure BG 5 i.e. a racemic mixture.

This invention discloses two separate and distinct but related procedures for preparing 25 the various enantiomers. Both procedures are significant advances in the art. The first group of procedures are described under the various reactions labeled as CHART A and CHART B reactions. The second major group of reactions are described under the various reactions labeled as CHART C, CHART D, CHART E and CHART F reactions.

The reactions from CHART A and CHART B are summarized below. This part of the invention comprises a series of reactions beginning with subjecting a compound or compounds represented by the structure shown in figure AGO, below, 0 R 2 A W Figure AGO -4- -N and W is Cl, Br, -SR 2 or figure to right,

L

to treatment with R 3 XLi where R 3 is (CI-C 8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )allcyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C 1

-C

8 )allcyl-(C 6

-C

1 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl, and where Xis0, NH, S, to obtain a compound represented by the structure shown in figure AGl(a), below 0

X

Figure AG 1 (a) which is then reacted with a compound represented by the deprotonated form of the structure formed in figure AGIl), below, or its appropriate isomer, 12 NH R 1 0 14 Figure AG I R1 where R12 is (C 6

-C

12 aryl), or the aryl is substituted with one to three of the following groups,

R

13 is H, (C 1

-C

8 )alkyl. (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-C

1 2 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl, where R 14 is 1

-C

8 alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl,

(C

6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-CI

2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (Ci-C 3 alkoxy, halogen, trifluoromethyl; to produce the compounds represented by the structures shown in figure AG 2 below, H R12 S H R 13 R 2

R

3 R X R12 2 L R 13 N

O

R2

X

R 3 Figure

AG

2 the compounds of figure AG 2 are then deprotected under hydrogenolysis conditions with a reducing agent such as Pearlman's catalyst, 10 percent palladium hydroxide on charcoal, to obtain the compounds, represented by the structures shown in figure AG 3 below,

S

H

2 0

H

2 N O 2 /R 3 R X 20 Figure AG 3 the compounds represented by the structure shown in figure AG 3 are then used according to the procedures described the reactions of CHART B to produce the desired compounds.

The reactions of CHART B comprises, using starting materials represented by the structure shown in figure BG- 1 which are the same compounds represented by figure AG 3 below, HN O

I

H2N 0 "Ij X 'llR Figure

BG

0 -1 where R 2 and R 3 is (C 1 -Cg)alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3 Cg)cycloalkyl, (C 6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-C

12 aryl),(C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; X is O, NH, S reacting those starting materials with a compound represented by the structure in figure BG-R 1 below, 0 R1 z Figure BG-RL where R 1 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-C

12 aryl), -O-(C 1 8 alkyl), -O-(C3-8 cycloalkyl), -O-(C 1 8 alkyl)(C 3 -8 cycloalkyl), -O-(C 6 -12 aryl), -O-(C 1 -8 alkyl)-aryl, or the aryl or alkyl is substituted with one to three of the following groups, (C 6

-C

12 aryl),(C 1

-C

3 )alkyl, (CI-C 3 alkoxy, halogen, trifluoromethyl, Z is Cl, N 3 S- (C 6

-C

12 )aryl, O CEN

II

*,CR 1 or ON=C Ar in a suitable organic solvent to yield a compound or compounds represented by the structure shown in figure BG- 1 below, 0 1 1 2 A NH 0 Figure BGl-1 R R, R 3 R 3 R

R

the compounds represented by BG 1 are dissolved in a suitable solvent, to which is added a compound represented by figure GRX, below, 7 N-M Figure GRX R8 where R 7 and R8 are defined independently and are (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1 C8)alkyl-(C6-C12)aryl; M is Li, Na, or K, the resulting dianion is then reacted with a compound represented by the structure shown in figure GYX, Figure GYX where, R 4

R

5 and R 6 are defined independently and are H, (C 1

-C

8 )alkyl, (C 3 -C8)cycloalkyl,

(C

1

-C

8 )alkyl-(C 3

-C

8 )cycloalcyl, (C 6

-CI

2 aryl), (C 1

-C

8 )alkyl-(C 6

-CI

2 aryl), (C 1

-C

3 )alkyl,

(C

1

-C

3 alkoxy, halogen, trifluoromethyl; Y is halogen, -OTs, -OMs, or OTf to produce a compound or compounds represented by figure BG 2 1 C.

C

S.

C

C.

CC.

C C C. S S

C

S

0 RA N H R HRAKNH 0Figure

BG

2 1

~R

the compound or compounds represented by the structures in figure BG 2 1 are then used according to the process described below for the preparation of a compound or compounds 25 represented by the structures on the left side, or the right side of figure BG4_ 1 below, or, if the starting materials are a racemic mixture, the reaction may produce a mixed ratio of compounds represented on both sides of the figure BG4_ 1 below, R

NH

R

R9 NHFigure BG4- 1 R 2 R N where 11 50 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-CI

-C

12 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl.

When R, is -O-(C 1 8 alkyl), -0-(C 3 8 cycloalkyl), -O-(CI- 8 alkyl)(C 3 -8 cycloalkyl), -0-(C 6 2 aryl), -O-(C 1 8 alkyl)-aryl, then reduction with LAH, DIBAL or Borane will always produce

R

5 0 is H.

where R 2 is (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl,

(C

6

-C

1 2 aryl), (C 1

-C

8 )alkyl-(C 6

-C

-CI

2 aryl),(C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl;

(C

6

-C

1 2 aryl, where R 6 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl,

(C

6

-C

1 2 aryl), (C 1

-C

8 )alkyl-(C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (CI-C 3 alkoxy, halogen, trifluoromethyl; where R 9 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, 15 (C 6

-CI

2 aryl), (C 1

-C

8 )alkyl-(C 6 -Cl 2 aryl), or the aryl or alkyl is substituted with one to three ~of the following groups, (C 6

-C

12 aryl), (C 1 Caly,-(-C)lkyhogn trifluoromethyl; comprising treating a compound or compounds represented by figure BG 3 1 with a reducing agent such as with LiAlH 4 DIBAL or Borane in a suitable solvent such as THF preceeded by 20 the following process, a process for preparing a compound or compounds represented by figure BG 3 1 0 0 Figure BG 3 1 N a A N 0 R

R

RIN -R 92N -R9

R

6 where R 1 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (CI-C 8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6 -Cl 2 aryl), -O-(CI- 8 alkyl), -O-(C 3 8 cycloalkyl), -O-(Ci- 8 alkyl)(C 3 8 cycloalkyl), -0-(C 6 -12 aryl), -0-(C 1 8 alkyl)-aryl, or the aryl or alkyl is substituted with one to three of the following groups, (C 6

-CI

2 aryl),(C 1

-C

3 )alkyl, (Cl-C 3 alkoxy, halogen, trifluoromethyl, where R 2 is (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl,

(C

6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6 -Cl 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6

-CI

2 aryl),(C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; where R6is H, (Cl-C 8 )alkyl, (C 3

-C

8 )cycloalkyl, (Cl-C 8 )allcyl-(C 3

-C

8 )cycloalkyl,

(C

6

-CI

2 aryl), (CI-C 8 )alkyl-(C 6

-CI

2 aryl), (CI-C 3 )alkyl, (Cl-C 3 alkoxy, halogen, trifluoromethyl; where R 9 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (CI-C 8 )alkyl-(C 3

-C

8 )cycloalkyl,

(C

6

-CI

2 aryl), (C 1

-C

8 )alkyl-(C 6

-CI

2 aryl), (CI-C 3 )alkyl, (CI-C 3 alkoxy, halogen, trifluoromethyl; which comprises subjecting to ozonolysis a compound or compounds represented by figure BG 2

I

0 0 RIIkNH 0 A N Figure BG 2 1 5R 2

R-R

*FR 6

R

6

R

5 R 5 R where R 3 is -W 8 alkyl, (C 3

-C

8 )cycloalkyl, (Cl-C 8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-CI

2 aryl), (C 1

-C

8 )alkyl-(C 6

-CI

2 aryl), or the aryl or alkyl. is substituted with one to three of the following groups, (C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl,

R

4

R

5 and R6are defined previously, X is0, NH,or S, followed by reaction with R 9

-NH

2 under reducing conditions, such as with sodium cyano borohydride, sodium triacetoxy borohydride or sodium borohydride, (in order of preference) at 0o0-5&C, or a cool temperature to control heat, to produce the desired compounds.

The invention also comprises the reactions of CHARTS C and D, summarized below.

The process for the preparation of a compound or of compounds represented by the structures on the left side, or the right side of figure CG 3 below, or, if the starting materials are a racemic mixture, the reaction may produce a mixed ratio of compounds represented on both sides of the figure CG 3 below, R21

R

21 H H>R2 R22 H HR2 R22 N O N O R2 X R R2 X R 3 Figure

CG

3 which comprises, a series of reactions, beginning with an appropriate optically active amine represented by figure CG-R 1 below, R20 N N N- H H

S

S.Figure

CG-R

1 20 15 where R is (C 1

-C

8 )alkyl, (C 3 -Cg)cycloalkyl, (C 1 -Cg)alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-C

1 2 aryl), (C 1

-C

3 )alkyl, (Cl-C 3 alkoxy, halogen, trifluoromethyl, is condensed with a carbonyl compound, such as one represented by the structure shown in Figure CG-R 2 below, S 20 R21 0 'R22 Figure

CG-R

2 where R21 and R 22 are defined independently and are H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, 25 (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalcyl, (C 6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-C

1 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C6-C 12 aryl), (C 1

-C

3 )alkyl,

(C

1

-C

3 alkoxy, halogen, trifluoromethyl; under reducing conditions using NaBH 4 or a similar suitable boron hydride reducing agent in a suitable solvent such as THF to obtain compounds represented by the structures shown in figure CG 1 below, R20 R 21

R

20

R

21 SH R22 H R22 N N N N N H H Figure

CG

1 (b) compounds represented by the deprotonated form of figures CG1(b), above, then undergoes a Michael Addition reaction with a compound represented by the structure shown in Figure CG1(a), below, A compound represented by the structures shown in CGI(a), below, 0 R2 R3 Figure CGI(a) where, R 2 and R 3 are independently, lower alkyl, alkylaryl, or optionally substituted aryl, then deprotonation is carried out with an appropriate base such as n-BuLi, to produce compounds, after coupling, represented by the structures shown in figure CG 2 below, 20 R 2 1

R

2 1 SHJ..R22 HL R 22 fN o nr N O X RX R2 X R2 Figure CG 2 the carbon nitrogen bonds are hydrogenolytically cleaved with an appropriate reducing agent such as Pearlman's catalyst, 20 percent palladium hydroxide on charcoal, in an appropriate solvent, such as EtOH, to obtain the desired compounds. Products of the reactions of CHART C are then used in the reactions of CHART D, summarized below. Note that the compounds 20 represented by figure CG 3 are the same as those represented by figure DG 0 The process for the preparation of a compound or the compounds represented by the structures on the left side, or the right side of figure DG 7 below, or, if the starting materials are a racemic mixture, the reaction may produce a mixed ratio of compounds represented on both sides of the figure DG7, below, 25 R21 R 22

R

2 1

R

22 H NH H N H R2N-H \R 6 R 6 Figure DG7 which comprises a series of reactions, the reactions beginning with a compound represented by the structures in figures DGO, below, -12- R21

R

2 1 H H R22 H H I R22

R

3 z R 3 R2 RAx R Figure DGo where R 2 and R 3 are defined independently and are lower alkyl, alkylaryl, or optionally substituted aryl; where R 21 and R 22 are defined independently and are H, (C 1 -Cs)alkyl, (C 3 Cg)cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C 1 -Cs)alkyl-(C 6

-C

12 aryl),

(C

1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; and where X is O, NH, S; are dissolved in a suitable organic solvent such as tetrahydrofuran, and then added, in a cool temperature to control exothermic formations under an inert atmosphere, such as between a temperature of -50 0 C and 0°C in a nitrogen atmosphere, to a solution of a compound of the description in figure GRX, dissolved in a suitable organic solvent,

R

7

N-M

R

8 20 Figure GRX where R 7 and R 8 are defined independently and are (C 1

-C

8 )alkyl, (C 3 -Cg)cycloalkyl, (C 1

C

8 )alkyl-(C 6

-C

12 )aryl; where M is Li, Na, or K; and the resulting anion or dianion is then reacted with a compound represented by the structure shown in figure DG-R 2 below,

R

6 R4 25 y

R

Figure DG-R 2 where R 4

R

5 and R 6 are independent and are H, alkyl, alkylaryl, or optionally substituted aryl, and where Y is halogen, -OTs, -OMs, or -OTf; to obtain a compound represented by the structures shown in figure DG 1 below.

-13- R2 R2H R 6 H H 4R 5 R R

RR

Figure

DG

1 the compounds represented by the structures shown in figure DGI are subjected to an established method of ozonolysis, such as bubbling 03 from an ozone generator, such as a Welsbach ozonator, through the reaction mixture in an appropriate solvent, such as water or methanol, followed by reduction of the intermediate ozonide with an appropriate boron hydride *'reducing agent such as NaBH 4 or LiBH 4 to obtain a compound represented by the structures shown in figure DG 2 below,

R

2 1

R

22

R

2 1 R22 Rr q R6 R2'4 H R6

H

appropriate amine base, such as triethylamine, and an activating agent, such as methanesulfonyl chloride in a solvent such as tetrahydrofuran or toluene to obtain a compound represented by the 25 structures shown in figure DG below, R21 R22 R21 R22 H OH H OH H H H OMs H OMs Figure

DG

3 where Ms is mesylate, the compounds represented by the structures shown in figure DG 3 are treated in an appropriate solvent such as toluene or THF with an amine represented by the structure shown in figure DG-R 1 below,

H

N-R9

H

Figure

DG-R

1 where R 9 is H, (C 1 -Cs)alkyl, (C 3 -Cg)cycloalkyl, (C 1 -Cg)alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-C

1 2 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; to obtain a compound represented by the structures shown in figure DG 4 below,

R

21 R22 R 2 1 R2 015 H R 9 H N R9

H

Figure DG 4 the compounds represented by the structures shown in figure DG 4 undergo thermal isomerization to give a compound represented by the structures shown in figure DG 5 below,

R

2 R21 1 H 2 2

R

21 R22 NH

NH

o N-R 9 R2 N-R 25 N S*R R Figure DG the compounds represented by the structures shown in figure DG 5 are treated with a suitable reducing agent such as LiAH 4 DIBAL or borane in a suitable solvent such as THF to obtain a compound represented by the structures shown in figure DG 6 below,

R

21

R

2 1

R

S R2 -R 9

R

2

N-R

9 4rD 6

R

Figure DG 6 when R 9 is a protective group, where, for example, an alkylaryl is connected to the nitrogen atom with one carbon atom between the nitrogen and the aryl, then the compounds represented by the structures shown in figure DG 6 may be hydrogenolytically cleaved with, for example, percent palladium hydroxide on charcoal, H 2 to obtain the desired compound or compounds.

Another series of reactions, similar to those in CHART C and CHART D are also claimed in this invention, those are from the reactions of CHART E and CHART F, below.

Also claimed is a process for the preparation of compounds represented by the structures on the left side, or the right side of figure FG 6 below, or, if the starting materials are a racemic mixture, the reaction may produce a mixed ratio of compounds represented on both sides of the figure FG 6 below, R24 R 2 4 H

H

H 4NH H NH 15 -,R9 -R 9 Figure FG 6 which comprises a series of reactions, the reactions beginning with a compound represented by the structures in figures EG-R 1 below, 20 R20 R 20 N-H N N

N

I I II I H

H

Figure EG-R 1 25 where R 20 is (C 1

-C

8 )alkyl, (C 3 -C)cycloalkyl, (C 1 -C)alkyl-(C 3 -Cg)cycloalkyl, (C 6

-C

12 aryl), (C 1 -Cg)alkyl-(C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; is condensed with a compound represented by the structure shown in figure EG-R 2 below, 0 U J R23 R2 0 R23 Figure

EG-R

2 where R 23 is (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3 -Cg)cycloalkyl, (C 6

-C

12 aryl), (C 1 -Cs)alkyl-(C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; where R 24 is H, (C 1 -Cs)alkyl, (C 3 -Cg)cycloalkyl, (C 1 -Cg)alkyl-(C 3

-C

8 )cycloalkyl,

-(C

6

-C

1 2 aryl), (C 1

-C

8 )alkyl-(C 6

-C

1 2 aryl), (C 1

-C

3 )alkyl, (Ci-C 3 alkoxy, halogen, trifluoromethyl; to obtain a compound represented by the structures shown in Figure EGl(b') below, R20

R

20 N R2 4 N R2 4 I H

H

Figure EG 1 which is treated with an appropriate reducing agent such as LiAlH 4 DIBAL or Borane in a suitable solvent such as THF to obtain compounds represented by the structures shown in figure EGl(b), below.

20 H S: H R24 J H R24 fc N f N H H Figure EGI(b) the compounds represented by the structures shown in EGI(a), below,

X

Figure EGl(a) !where R 2 are R 3 are independently, lower alkyl, arlkylaryl, or optionally substituted aryl, then undergoes a Michael Addition reaction with a compound represented by the deprotonated form of the structures shown in figure EGI(b), (the deprotonation is carried out with an appropriate base such as n-BuLi) to produce compounds, after coupling, represented by the structures shown in figure EG2, below, H R 20

H

H R24 R24 SX R 3 2 J

R

R2 R2 Figure

EG

2 the compounds represented by the structures shown in figure EG 2 have carbon nitrogen bonds that are hydrogenolytically cleaved with an appropriate reducing agent such as Pearlman's -17catalyst, 20 percent palladium hydroxide on charcoal, in an appropriate solvent, such as EtOH, to obtain the compounds represented by the structures shown in figure EG 3 same figure as FG

O

below, H H H Hj R24 H H .R24 N O N 0 R2

R

3 7 2

R

3 X R3 Figure EG 3 Figure FG 0 where R R 3

R

24 and X are defined above); is dissolved in a suitable organic solvent such as tetrahydrofuran, and added, in a cool temperature to control exothermic formations under an inert atmosphere, such as, between a temperature of -50 0 C and 0°C in a nitrogen atmosphere, to i 1 a solution of a compound represented by the structures shown in figure GRX, below, *Figure GRX where R 7 and R 8 are defined independently and are (C1-Cs)alkyl (C3-C8)cycloalkyl (Cl- Cs)alkyl-(C6-C12)aryl; and M is Li, Na, or K; the resulting anion or dianion is then reacted with a compound represented by the structures 20 shown in figure FG-R 2 below,

R

6

^N-M

15

R

5 Figure GRX where R 4 R and R are defined independentl and are H, -(C-Calkyl, (C 3 -C)cycloalkylaryl, or optionally substituted aryl,

C

8 )alkyl-(C 6

-C

1 2 )aryl; and M is Li, Na, or K; and wheresulting anion or dianion is then reacted witho obtain a compound represented by the structures structures shown in figure FG-R below, H R 24 H R 2 4 R "~'RR6 R2

R

R4 R R4 R

R

Figure FG-R 2 where R 4

R

5 and R 6 are independent and are H, alkyl, alkylaryl, or optionally substituted aryl, and where Y is halogen, -OTs, -OMs, or -OTf; to obtain a compound represented by the structures shown in figure FG 1 below, H R 24 H R 24 R2 R 6 R2'+h R6 H

H

R4 R4 R Figure

FG

1 -18the compounds represented by the structures shown in figure FG 1 are subjected to an established method of ozonolysis, such as bubbling 03 from an ozone generator, such as a Welsbach ozonator, through the reaction mixture in an appropriate solvent such as water or methanol, followed by treatment of the intermediate ozonide with an appropriate boron hydride reducing agent such as NaBH 4 or LiBH 4 to obtain a compound represented by the structures shown in figure FG 2 below, H R 24 H R 24 R2 R6 R2 H R6 H H H OH H OH Figure FG 2 the compounds represented by the structures shown in figure FG 2 are treated with an appropriate amine base, such as triethylamine, and methanesulfonyl chloride in a solvent such as 15 tetrahydrofuran or toluene to obtain a compound represented by the structures shown in figure

FG

3 below, H R 24 H R 24 H O H' O 20 R2' "H R 6 R2 H R6 H H H H OMs H OMs Figure FG 3 the compound or compounds represented by the structures shown in figure FG 3 where Ms is mesylate, are treated in an appropriate solvent such as toluene or THF with an amine represented by the structure shown in figure FG-R 1 below,

H

N-R

9

H

Figure FG-R 1 where R 9 is H, (C 1 -Cg)alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C 1 -Cs)alkyl-(C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; to -19obtain a compound represented by the structures shown in figure FG 4 below, H R 24 H R 24

R

2 H R 6 R2H "R 6

H

H N-R 9 H N-R 9 H

H

Figure

FG

4 the compounds represented by the structures shown in figure FG 4 thermally isomerizes to give a compound represented by the structures shown in figure FG 5 below, R24 R 24

HAH

H NH 0 NH 0 15 i 2 N-R 9 *R2 R2 so Figure FG the compound or compounds represented by the structures shown in figure FG 5 are treated with a suitable reducing agent such as LiAlH 4 DIBAL or Borane in a suitable solvent such as THF to obtain the desired compounds.

These reactions and processes are of course designed to be used with specific reactants 0 to produce specific products same of these specific reactions and products are described more 0 completely herein.

DETAILED DESCRIPTON OF THE INVENTION The compounds of this invention are identified by both descriptive names and by reference to structures shown in appropriate charts and text. In appropriate situations, the proper stereochemistry, an important aspect of this invention is also represented in the charts.

The compounds and processes of this invention may be divided into two groups. The four groups are described in CHARTs A, and B. Within each group the reactions are shown as steps. CHARTs AG and BG are generic charts, various substituted R groups are indicated. The steps from CHARTs AG and BG are generic steps that describe reactions that are specified to the degree needed to enable one ordinarily skilled in the art to practice the invention. Following the general procedures for each group are one or more detailed preparations and examples that describe precisely how to prepare specific compounds of this invention. CHART AXI thus describes the experimental steps for one specific reaction sequence described in CHART AG 19aand BX1 shows a specific reaction from CHART BG. Note that the generic charts as well as the specific reactions show the stereochemistry of the compounds. The specific procedures are to be construed as merely illustrative, and do not impose limitations upon the general reaction schemes in any manner whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants as well as to reaction conditions and techniques.

a S* 4* *a* *e o** WN C:WINWORK\WENDY\TYPING\6f9T OC 20 Throughout the description and claims of this specification, the word "canprise" and ;variations- of the word, such as "ccmprising" and '"caprises", is not intended to exclude other additives,.

conponents, integers or steps.

DEFINITIONS

The following words or abbreviations are used to describe this invention. The definitions and examples provided below are intended to provide guidance and illustration for procedures and methods described herein but are not intended to impose limitations upon the subject matter described.

10 Variables defined.

In this document the parenthetical term (Cn-Cm) is inclusive such that a compound of

(CI-C

8 would include compounds of one to 8 carbons and their isomeric forms. The various carbon moieties are defined as follows: Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl, etc.

Lower alkyl refers to alkyl compounds that includes 1 to 8 carbons, C 1

C

8 and their isomeric forms.

Alkoxy, as represented by -OR x when R x is a (C 1 -Cg) alkyl, refers to an alkyl radical which is attached to the remainder of the molecule by oxygen and includes branched or unbranched forms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy, t-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexoxy, n-heptoxy, isoheptoxy, and noctoxy.

Aryl refers to aromatic hydrocarbon radicals that contain 6 to 12 carbon atoms such as phenyl, a-naphthyl, B-naphthyl, m-methylphenyl, p-trifluoromethylphenyl and the like. The aryl groups can also be substituted with one to three of any of the following groups: C 1

-C

3 alkoxy,

C-C

3 alkyl, trifluoromethyl, halogen.

Alkylaryl refers to an alkyl, as defined above, attached to an aryl, as defined above. A moiety expressed as "lower alkylaryl" could also be expressed as "(Ci-Cg)alkylaryl" the alkyl portion would be attached to the molecule of interest. Benzyl for example would be an unsubstituted C alkylaryl.

Aryloxy refers to an aryl radical, as described above, which is attached to the remainder of the molecule by oxygen.

Arylalkoxy refers to an aryl radical, as described above, which is attached to an alkyl, as -21described above, which is attached to the remainder of the molecule by oxygen.

Cycloalkyl refers to a radical of a saturated cyclic hydrocarbon containing 3 to carbon atoms, (C 3

-C

10 )cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. The term also includes alkyl-substituted cycloalkyl, such as 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3 diethylcyclopropyl, 2butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,2-dimethylcyclopentyl.

Cycloalkoxy refers to a cycloalkyl, as described above, which is attached to the remainder of the molecule by oxygen.

Halogen or Halo refers to the halogens which include fluorine, chlorine, bromine and iodide.

Constants defined.

BnO is benzyloxy. DIBAL is Diisobutyl Aluminum Hydride. Borane may refer to any borane, BH 3 and related reagents such as diborane, B 2

H

6 Boron hydride reducing agents are exemplified by such reagents as LiBH 4 and NaBH 4 OC is degree Centigrade. Celite or Celite S 15 Pad is commercially available filter aid. Et20 is diethyl ether. EtOAc is ethyl acetate. g is gram. H 2 is hydrogen gas. Hx is hexane. HCI Hydrochloric acid. i-Pr 2 NH is diisopropylamine. L is liter. LAH or LiAlH 4 is Lithium Aluminum Hydride. LDA is Lithium Diisopropyl Amide. M is Molar. Mol. is mole. mg is milligram. MgSO 4 is Magnesium Sulphate. min. is minute. mL is milliliter. mM is milliMole. Ms is mesylate. N is Normality of solution, where appropriate. N is Nitrogen atom where appropriate, N 2 is nitrogen gas or atmosphere. N 3 is azide or azido or azido carboxy compound. NMR is Nuclear Magnetic Resonance. NaOH is Sodium Hydroxide. NaCNBH 3 is Sodium Cyano Borohydride. O is Oxygen. OEt is ethoxy. -OMs is methylsulfonate or mesylate. -OTf is i trifluoromethylsulfonate or triflate. -OTs is p-toluenesulfonate or tosylate. "Pearlman's" catalyst is 10 percent Paladium Hydroxide on charcoal. psi is pounds per square inch. n-BuLi is n-Butyllithium. RT or R.T. is room temperature. S is Sulphur. S-aryl is a thioaryl compound. SiO 2 is Silica gel. Strong hydride reducing agents are exemplified by such reagents as DIBAL, LAH, and Borane. t-BuOH is tertiary butyl alcohol. THF is tetrahydrofuran.

"Welsbach ozonator" is an example of an ozone generating device. Any suitable ozone generating device may be used in the operation of this invention.

Temperature and atmosphere considerations. Many reactions in this invention are performed under cooler conditions to better cope with heat generated during the reaction (exothermic formations). The deprotonation reactions are typical of this type of exothermic reaction. These deprotonation reactions are usually run at 0 to -50 OC, this is the preferred range using the reactants used here. This is not to say that the reaction must be run at this range, indeed, many of the deprotection reactions could be run anywhere from room temperature down to below -100 0 C. When the atmosphere is described it is intended to provide a preferred method of running the reaction. The Michael Addition reactions, among others, have fewer side reactions when they are run under an atmosphere that excludes water. Thus reactions run under nitrogen gas could also be run under argon gas or other suitable inert or nonreactive gases that would operate to exclude side reactions with water. The Michael Addition reactions also have greater selectivity when they are run at lower temperatures. Thus the preferred range for a Michael Addition is about -70 to -80 0 C, but this reaction can be run from room temperature to below -100 0 C, but the selectivity declines appreciably at highter temperatures.

The best mode of performing the reactions appears to be according to the procedures found in CHARTS E and CHARTS F.

THE REACTIONS AND COMPOUNDS OF THE CHARTS The reactions of this invention are grouped in varous CHARTS. The CHARTS are logical groupings of sequential reactions. The word CHART indicates the written procedures, including what is commonly known in the art and obvious variants thereof, as well as the S: 15 specific flow charts containing images or drawings suggesting chemical structures. Sometimes the product of the reactions in one CHART will be used as the starting material for the reaction in another CHART. In this manner CHARTS A and B are related, CHARTS C and D are related, and CHARTS E and F are related. CHARTS A, C and E describe three different procedures for making similar compounds, as do CHARTS B, D, and E. The CHARTS are named sequentially by the letters A-E, the letter in the CHART indicates the CHART shows a general scheme, with structures containing variables. The letter in the name of the CHART indicates it is a specific reaction with X meaning an specific embodiment or eXample.

Thus CHART AG shows generically how to make many compounds, the products of this CHART could be used as starting material for CHART BG and representational embodiments are shown in CHARTS AX1, AX2, BX1, BX2, etc.

THE REACTIONS AND COMPOUNDS OF CHART A CHART AG shows the general reaction scheme and the major reaction Steps of the reactions involved in the synthesis of the compounds of CHART A. CHART AX1 shows a specific reaction scheme for a single specific compound that is generally described in CHART A. The final compounds produced by the descriptions for CHART A are used as the starting materials for the reactions of CHART B. A description of the Steps and procedures from the compounds and reactions shown in CHARTs AG and AX1 appear below, followed by CHART AG and CHART AX1. The reactions and compounds of CHART B follows this section.

THE STEPS OF CHART AG The starting materials utilized to prepare the compounds of this invention are either available commercially or can be prepared by the following methods.

-23- Step AG 0 AGI(a).

A compound represented by the structure shown in figure AG 0 below 0 ~R 21 Figure

AG

0 where R 2 is (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-CI

2 aryl), (C 1

-C

8 )alkyl-(C 6

-CI

2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, ((2 6

-C

12 aryl),(Cl-C 3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; and Wis Cl,Br, -SR or is treated with R 3 XLi ~**where R 3 is (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), 1 C)aklC 6

C

-CI

2 aryl), (Cl-C 3 )allcyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; and Xis 0, NH, S, to obtain a compound represented by the structure shown in figure AGI(a). below 0 0* 3 Figure AG 1 a Step amnide aldehyde AGI 1 b.

An appropriate optically active amine and an appropriate aldehyde, below, are reacted under reducing conditions using NaB H 4 or a similar suitable boron hydride reducing agent to produce the compound represented by the structure shown in figure AG 1 below, j R 13

NH

2 R R 14 12 ~Figure AG I I 1 -24where R 12 is (C 6

-C

12 aryl), or the aryl is substituted with one to three of the following groups,

(C

1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl;

R

13 is H, (Cl-C 8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

C

12 aryl), (CI-C 8 )alkyl-(C 6

-CI

-C

12 aryl), (Cl-C 3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl, where R 14 is 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl,

(C

6

-CI

2 aryl), (Cl-C 8 )alkyl-(C 6

-CI

2 aryl), (C 1

-C

3 )aJlcyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl.

Stev 2. AGl(a) AGl(b) AG 2 A compound represented by the structure shown in figure AGl(a) is reacted with a compound represented by the deprotonated form of the structure shown in figure AG 1 Deprotonation is carried out with an appropriate base such as n-BuLi, 15 to produce the compounds represented by the structures shown in figure AG 2 below, 14 a...14 R R1 H R&13 ~.~R1 N 0N 0

R

3 2 R3R2

R

Figure

AG

2 Step 3. AG 2 -4 AG 3 Since R 12 is aryl, the nitrogen may be deprotected. The carbon nitrogen bonds are hydrogenolytically cleaved with an appropriate reducing agent such as Pearlman's catalyst, percent paladium. hydroxide on charcoal, to obtain the compounds represented by the structure shown in figure AG 3 below.

H

2 N H 2 0 R R 3 R21) A X-1R3 Figure

AG

3 Compounds represented by the structure shown in figure AG 3 can then be used in the reactions of CHART B.

EXAMPLES FROM CHART A CHART AX1 The specific procedures and examples described below, shown in CHART AX1 are to be construed as merely illustrative of the procedure described above, and do not impose limitations upon the general reaction schemes in any manner whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants as well as to reaction conditions and techniques.

Step Preparation of t-butyl crotonate.

0 O The starting materials for this step are commercially available. Shown above is Crotyl chloride and the product t-butyl crotonate.

A solution of t-BuOH (0.50 mol, 37.1 g, 47.8 mls) in THF (500 mis) is cooled to 5 0

C;

15 then over a 30 minute period n-BuLi (0.56 mol., 350 ml, 1.6 M) is added to the solution. The resulting mixture is stirred for 40 minutes at room temperature. Crotyl chloride (0.50 mol., 52.3 g, 47.9 mis) in THF (250 mls) is added to the reaction mixture at room temperature over a minute period. The resulting mixture is heated under reflux for 50 minutes. The reaction mixture is cooled to 0°C and ice-water (800 mis) is added. The layers are separated and the aqueous layer is extracted with Et20 (3 x 600 mis). The organic phases are combined, dried over Na 2

SO

4 filtered and concentrated by rotary evaporation to give a red oil. Distillation 0 C, 22 mm) yields t-butyl crotonate: 1 H NMR (300 MHz, CDC13) 8 1.46 9H), 1.83 (dd, J is 6.9, 1.7 Hz, 3H), 5.74 (dq, J is 15.5, 1.7 Hz, 1H), 6.85 (dq, J is 15.5, 6.9 Hz, 1H).

Step Preparation of S-benzyl-a-methylbenzylamine.

I

NH2

H

A N N S y S-a-methylbenzylamine (40 g, 0.33 mol.) and benzaldehyde (35.5 g, 0.33 mol.) are combined in toluene (500 mis). The reaction mixture is refluxed until a constant amount of

H

2 0 (5.2 ml) collects in a Dean-Stark trap. The reaction mixture is concentrated by rotary evaporation to yield a light yellow liquid (89.2 g) which is dissolved in ethanol (350 ml).

NaBH 4 (12.5 g, 0.33 mol.) is added portion-wise to the reaction mixture over a one hour period.

The reaction mixture is stirred at room temperature for one hour and then cooled to 0°C. 2N -26- HC1 is added dropwise over a 2-hour period to the cold reaction mixture. The reaction mixture is concentrated by rotary evaporation and the residue is partitioned between EtOAc (200 ml) and

H

2 0 (100 ml). The layers are separated and the aqueous layer is back-extracted with EtOAc (2 x 100 mis). The organic layers are combined, dried over MgSO 4 and concentrated by rotary evaporation to yield a light yellow oil. Distillation (115 0 C, 0.75 mm Hg) yields S-benzyl-amethylbenzylamine: 1 H NMR (300 MHz, CDC13) 8 1.37 J is 6.6 Hz, 3H), 3.60 J is 13.1 Hz, 1H), 3.66 J is 13.1 Hz, 1H), 3.81 J is 6.6 Hz, 1H), 7.23 7.36 Step 2. Preparation of t-butyl (S,S)-3-((N-benzyl)(N-methylbenzyl))aminobutyrate.

methylbenzylamine (53.5 g, 0.25 mol.) in THF (400 mls) at o°C under N 2 The reaction mixture is stirred for 15 minutes and then cooled to -780C. t-Butyl crotonate (18.0 g, 0.13 mmol) dissolved in THF (150 ml) is added via canula to the -780C reaction mixture over a minute period. Twenty minutes after the last of the t-Butyl crotonate is added, the reaction mixture is quenched with saturated aqueous NH4C1 (100 mis), then saturated aqueous NaCl (300 I H mls) is added. The layers are separated and the aqueous layer is extracted with ether (2 x 200 ml). The combined organic layers are washed with brine (100 mls), dried over MgSO 4 filtered and concentrated by rotary evaporation. The crude oil (72.72 g) is taken up in hexane (500 mls) and washed with 10% aqueous citric acid (buffered to pH 4, 100 ml portions) until all of the secondary amine is extracted from the organic phase. The organic phase is dried over MgSO 4 filtered and concentrated to yield t-butyl (S,S)-3-((N-benzyl)(N-methylbenzyl))aminobutyrate: 1H NMR (300 MHz, CDC13) 8 1.09 J is 6.7 Hz, 3H), 1.31 J is 6.9 Hz, 3H), 1.37 9H), 2.00 (dd, J is 14.1, 9.1 Hz, 1H), 2.23 (dd, J is 14.1, 4.7 Hz, 1H), 3.41 1H), 3.60 J is 15.0 Hz, 1H), 3.74 J is 15.0 Hz, 1H), 3.87 J is 7.0 Hz, 1H), 7.19 7.40 Ste 3. Preparation of t-butyl (S)-3-aminobutyrate.

o t-butyl (S,S)-3-((N-benzyl)(N-methylbenzyl))aminobutyrate (36.5 g, 0.103 mel.) is dissolved in MeOH (500 mis). Pearlman's catalyst (5.25 g) is added and the reaction vessel is pressurized to 30 psi of H 2 After shaking for 24 hours, the reaction mixture is filtered through celite. The methanol is removed by distillation. The crude product is distilled (29 mm, 96 0 C) to yield S-t-butyl-o-aminobutyrate: 1 H NMR (300 MHz, CDCl 3 8 1.17 J is 6.5 Hz, 3H), 1.45 9H), 2.38 (dd, J is 16.0, 8.2 Hz, 1H), 2.32 (broad s, 2H), 2.29 (dd, J is 16.0, 4.7 Hz, 1H), 3.39 1H). [a]2 5 is +19.50 (c 1.65, MeOH).

CHART AX2. Using the procedures above, a more preferred starting material is to substitute ethyl crotonate for t-butyl crotonate, see step Then, following the above procedures, prepare ethyl (S,S)-3-((N-benzyl)(N-methylbenzyl))aminobutyrate, 1H NMR (300MHz, CDCL 3 8 1.14 J is 7, 3H), 1.16 J is 7, 3H), 1.34 J is 7, 3H), 2.10 goo*i (dd, J is 14, 8, 1H), 2.35 (dd, J is 14, 6, 1H), 3.43 (ddq, J is 6, 8, 7, 1H), 3.68 J is 15, 1H), S. 3.73 J is 15, 1H), 3.89 J is 7, 1H), 3.92 (dq, J is 11, 7, 1H), 4.02 (dq, J is 11, 7, 1H); in step 2 instead of t-butyl (S,S)-3-((N-benzyl)(N-methylbenzyl))aminobutyrate and 15 finally, in step 3, prepare ethyl (S)-3-aminobutyrate instead of t-butyl (S)-3-aminobutyrate.

CHARTAX3. Using the procedures above only starting with methyl crotonate, methyl (S)-3-aminobutyrate has also been prepared. The ethyl (S)-3-aminobutyrate is slightly preferred over the methyl (S)-3-aminobutyrate. The ethyl (S)-3-aminobutyrate shown as one example in the reactions of CHARTB, the compound is shown in CHARTBX1.

THE REACTIONS AND COMPOUNDS OF CHART B CHART B shows the general reaction scheme and the major reaction Steps of the reactions involved in the synthesis of the compounds of CHART B. CHART BG shows the general reaction scheme and the 5 reaction Steps of the compounds of CHART B. CHART BX1 shows a specific reaction scheme for a single specific compound that is generally described in CHART BG. A description of the Steps and procedures from the compounds and reactions shown in CHART BG appears below. Specific examples, with detailed procedures, follow the general steps in the example section for the compounds of CHART B. Following a description of the steps are the CHARTS BG and BX1.

THE STEPS IN CHART BG Step 1. BG BG 1 Refer to the procedures described in CHART A to obtain the starting materials for this reaction. The compound or compouds represented by the structures shown in figure BG 0 below,

H

2 N 0 9 x /1R3

H

2 N 0

S

&c S S. S S S. S S S, S S 5*

S

Figure BG 0 1 where R 2 and R 3 is (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl,

(C

6

-CI

2 aryl), (C 1

-C

8 )alkyl-(C 6

-C

12 aryl),(C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; and X is 0, NH, S are reacted with a compound represented by the structure in figure BG-R 1 below, 0 Figure

BG-R

1 where R 1 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloallyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-CI

2 aryl), (C 1

-C

8 )alkyl-(C 6

-C

12 aryl), -O-(C 1 8 alkyl), -O-(C 3 8 cycloalkyl), -O-(Cl 1 8 alkyl)(C 3 8 cycloalkyl), -0-(C 6 1 2 aryl), -0-(CI- 8 alkyl)-aryl, or the aryl or alkyl is substituted with one to 20 three of the following groups, (C6-C 12 aryl),(C 1

-C

3 )allyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl, and Z is Cl, N 3 S-aryl, 0 I I oKR -0 H C-N Ar in a suitable organic solvent to yield a compound or compounds represented by the structures shown in figure BGI-I, below, ANH 0 R

R

3 x /I 0 1 NHFigure

BGI

1 Z- xI/

R

Step 2, BGI BG 2 To a solution of the compounds represented by the structure shown in figure BGi in a suitable organic solvent such as tetrahydrofuran, between a temperature of -45 0 C (-78 0 under a nitrogen atmosphere is added a compound of the following general description, figure GRX, below.

7

N-M

R

8 Figure GRX where R 7 and R 8 are are defined independently and are (C 1

-C

8 )alkyl, (C 3 -Cs)cycloalkyl,

(C

1 -Cs)alkyl-(C 6

-C

12 )aryl; and M is Li, Na, or K; The resulting dianion is then reacted with a compound represented by the structure shown in figure GYX, below, R. 6

*R

4

Y

R

Figure GYX where R 4

R

5 and R 6 are defined independently and are H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl,

(C

1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

1 2 aryl), (CI-Cg)alkyl-(C 6

-C

12 aryl), (C 1

-C

3 )alkyl,

(C

1

-C

3 alkoxy, halogen, trifluoromethyl; and Y is halogen, OTs, OMs, OTf to obtain a compound or compounds represented by the structures shown in figure BG 2 below.

0 0

II

R

1 NH O R NH 0 25 R2 X-R 3

R

2

X-R

3 R2R 6

R

5 R4

R

5

R

4 Figure BG2-1 Step 3. BG 2 -4 BG 3

BG

2 is subjected to an established method of ozonolysis, such as bubbling 03 from an ozone generator, such as a Welsbach ozonator, through the reaction mixture, followed by treatment of the intermediate carbonyl compound with R 9

-NH

2 under reducing conditions, such as with sodium cyano borohydride, sodium triacetoxy borohydride or sodium borohydride, (in order of preference) at 00-50C, or a cool temperature to control heat, to obtain a compound or compounds represented by the structures shown in figure BG 3 1 below, 0 0 NH O 1 NH 0 R2 9 9R2 9 N -R N -R R6 Figure BG 3 -16 where R 9 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

1 2 aryl), (C 1

-C

8 )alkyl-(C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl.

Step 4. BG 3

BG

4

BG

3 is reduced by LAH, DIBAL, Borane, etc. to obtain the compound or compounds represented by the structures shown in figure BG 4 below, R R 9 2 29 9 R N -R 2 N -R R6 R 6 Figure BG4-1 where R 50 is H, (C 1 -Cg)alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

C

12 aryl), (C 1 -C)alkyl-(C 6

C

'C

1 2 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl.

When R 1 is -O-(C 1 -8 alkyl), -O-(C 3 8 cycloalkyl), -Q-(C 1 8 alkyl)(C 3 8 cycloalkyl), -O-(C6- 12 aryl), -Q-(C 1 8 alkyl)-aryl, then reduction with LAH, DIBAL or Borane will always produce

R

50 is H.

SteD 5. BG 4

BG

5 When it is desired to make R 9 a protective group, where for example an alkylaryl is connected to the nitrogen atom with one carbon atom between the nitrogen and the aryl, that is where aryl is bound to the first carbon in the alkyl side chain, then this deprotection step 5 may be used. For example, if R 9 is benzyl, figure BG 4 could be hydrogenolytically cleaved with 10 percent paladium hydroxide on charcoal, H2; to obtain a compound represented by the structure shown in figure BG 5 below.

SNH

R

2

NH

R

6 Figure BG Depending upon the starting materials used, compounds represented by the structure shown by figure BG 5 may have one of either of the two steriochemical arrangments shown by the structures below, figure BG 5 -1, NH 5

N

R R 2 15R 2NH

RNH

0@ a. or, if the starting materials are a racemic mixture, the reaction may produce a 1:1 ratio of the a.

ester shown in chart, ethyl ester used below) are to be construed as merely illustrative, and do not impose limitations upon the general reaction schemes in any manner whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants as well as to reaction conditions and techniques. The actual NMR data provided below each step was obtained from the racemic mixture. The specific enantiomer shown in the steps below by using the appropriate starting materials. Although the ethyl ester is shown in the steps below, the t-butyl ester could also be used as is shown in CHART BXI.

Ste. e. Preparation of Ethyl (S)-3-carboxybenzylaminobutyrate.

H

2 N 0 BnO 2_OBnO NH 0 OEt OEt 3 5 f On ntN Cool a a solution of ethyl 3-aminobutyrate (20 g, 153 mmol.) in pyridine (55 ml), to 0 0 C and add benzyl chloroformate (32.6 ml, 39.0 g, 229 mmol) over a 45 minute period. Stir the resulting reaction mixture at room temperature under N 2 for 20 hours. Partition the reaction mixture between ethyl ether and 2% H 2

SO

4 Separate the layers. The organic layer is washed with 2% H 2

SO

4 5% NaHC03 and brine. The organic layer was dried over MgSO 4 filtered and concentrated to yield ethyl 3-carboxybenzylamino butyrate: 1H NMR (300 MHz, CDC13) 8 1.24 J is 6.7 Hz, 3H), 1.25 J is 7.1 Hz, 3H), 2.52 J is 5.6 Hz, 2H), 4.12 1H), 4.14 J is 7.1 Hz, 2H), 5.09 2H), 5.24 (broad s, 1H), 7.31 7.38 Step 2. Preparation of Ethyl (S,S)-2-(1'-(carboxybenzylamino)ethyl)-4pentenoate.

0 0 BnO NH BnO NH O(S)Et SOEt To a solution of i-Pr 2 NH (2.93 ml, 20.88 mmol) in tetrahydrofuran (20 ml) at -30 0

C

and under a nitrogen atmosphere add 1.6M n-BuLi (11.5 ml, 18.37 mmol). The resulting solution of LDA was allowed to warm to -10 0 C over 50 min. and was then cooled to -55 0

C.

Ethyl (S)-3-carboxybenzylaminobutyrate (2.0 ml, 8.35 mmol), in solution in tetrahydrofuran ml) at room temperature, is added during a 5 minute period to the -55 0 C solution of LDA. The temperature may rise to -48 0 C during this addition. The reaction is cooled to -56 0 C and tetrahydrofuran (20 ml) is added over 3 minutes to the reaction mixture. After 30 minutes allylbromide (2.89 ml, 33.40 mmol) is added during a 3 minute period to the -45 0 C reaction mixture. The reaction mixture is maintained at -45 0 C for 20 minutes and is then allowed to warm to room temperature during a 12 hour period. The reaction mixture is combined with saturated aqueous NH 4 Cl (100 mls) and is extracted with CH 2 C1 2 (5 x 100 mls). The combined organic extracts are dried over MgSO 4 filtered and concentrated by rotary evaporation. The resulting crude oil is chromatographed (SiO 2 5:1 Hx EtOAc) to yield ethyl (carboxybenzylamino)ethyl]-4-pentenoate: 1 H NMR (300 MHz, CDC13) 8 1.17 J is 6.8 Hz, 3H), 1.25 J is 7.1 Hz, 3H), 2.29 (ddd, J is 14.0, 7.0, 7.0 Hz, 1H), 2.40 (ddd, J is 14.0, Hz, 1H), 2.53 1H), 3.97 1H), 4.14 J is 7.1 Hz, 2H), 5.03 J is 10 Hz, 1H), 5.06 J is 16 Hz, 1H), 5.09 2H), 5.57 (broad d, J is 9 Hz, 1H), 5.74 (ddd, J is 16, 10, 7 Hz, 1H), 7.30 7.37 Step 3. Preparation of (S,S)-1-benzyl-2-oxo-3-(l'- (carboxybenzylamino)ethyl)pyrrolidine.

0 BnO NH o BnO NH OEt 0 Ethyl (S,S)-2-[1'-(carboxybenzylamino)ethyl]-4-pentenoate (2.19 g, 7.18 mmol) is dissolved in MeOH (50 ml) and the resulting solution cooled to -78 0 C. 03, from a Welsbach ozonator set at the standard settings, is bubbled through the reaction mixture until starting material can no longer be detected by thin-layer chromatography (2:1 hexane EtOAc).

Dimethyl sulfide (5 ml) is added to the reaction mixture which is allowed to warm to room temperature and is then concentrated by rotary evaporation. The crude aldehyde is dissolved in methanol (25 ml) and tetrahydrofuran (25 ml) and the resulting solution is cooled to 0°C under a nitrogen atmosphere. Benzyl amine (4.06 ml, 37.15 mmol) followed by acetic acid (4.68 ml, S81.73 mmol) is added to the reaction mixture which is then stirred at 0°C for 12 min.

NaCNBH 3 (0.95 g, 14.86 mmol) is added to the reaction mixture which is allowed to warm to room temperature and continuously stirred for a 24 hour period. The reaction mixture is adjusted to pH 9 with IN NaOH and the resulting mixture is partitioned between EtOAc and 20 water. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over MgSO 4 filtered and then concentrated by rotary evaporation. The crude product is purified by chromatography (1:1 hexane EtOAc) to give (S,S)-l-benzyl-2-oxo- 3-[1'(carboxybenzylamino)ethyl] pyrrolidine: 1 H NMR (300 MHz, CDC13) 8 1.30 J is 7 Hz, 13H), 1.77 (ddd, J is 16, 12, 9 Hz, 1H), 2.04 1H), 2.59 (ddd, J is 9, 9, 4 Hz, 1H), 3.04 3.09 2H), 3.95 1H), 4.34 2H), 5.01 2H), 5.11 (broad s, 1H), 7.10 7.28 Step 4. Preparation of (R,S)-l-benzyl-3-[1'-(methylamino)ethyl]pyrrolidine.

o nN (S,S)-1-benzyl-2-oxo-3-[1'-(carboxybenzylamino)ethyl]pyrrolidine (0.51 g, 1.44 mmol) is dissolved in tetrahydrofuran (20 ml) under a N 2 atmosphere. LAH (0.32 g, 8.43 mmol) is added and the reaction mixture is refluxed for 12 hours. The reaction mixture is cooled to 0°C, diluted with Et 2 O and quenched with 15% aqueous NaOH. The resulting mixture is filtered through a celite pad which is then washed carefully with Et20. The filtrate is washed with -34aqueous NaOH and the aqueous layer extracted with Et 2 O. The combined Et20 layers are dried over MgSO 4 filtered and concentrated under a stream of N 2 to give crude (R,S)-l-benzyl-3-[l'- (methylamino)ethyl]pyrrolidine: 1 H NMR (300 MHz, CDC13) 8 1.04 J is 6 Hz, 3H), 1.52 1H), 1.93 1H), 2.17 1H), 2.25 (dd, J is 16, 8 Hz, 1H), 2.37 3H), 2.33 2.49 (m, 2H), 2.56 (dd, J is 15, 8 Hz, 1H), 2.77 (dd, J is 8, 8 Hz, 1H), 3.58 J is 12.8 Hz, 1H), 3.60 J is 12.8 Hz, 1H), 7.23 7.36 5H). This crude material is suitable for use in Step Step 5. Preparation of '-(methylamino)ethyl]pyrrolidine.

NH NH *N

NH

(R,S)-l-benzyl-3-[ '-(methylamino)ethyl]pyrrolidine (0.51 g of crude product) is dissolved in MeOH (10 ml) under a N 2 atmosphere, Pearlman's catalyst and ammonium formate 15 (0.89 g, 14.11 mmol) are then added. The reaction mixture is refluxed for 12 hours. The i reaction mixture is then diluted with CH 2 Cl 2 :MeOH and filtered through a celite pad. The filtrate is washed with 15% aqueous NaOH:brine and the aqueous layer is back extracted with CH 2 C1 2 The combined organic layers are dried over MgSO 4 filtered and S" concentrated under a stream of N 2 to give crude (R,S)-3-[l'-(methylamino)ethyl]pyrrolidine: 1

H

NMR (300 MHz, CDC13) 8 1.05 J is 6.3 Hz, 3H), 1.43 (ddd, J is 17, 12, 9 Hz, 1H), 1.87 1H), 2.02 (dd, J is 16, 8 Hz, 1H), 2.38 3H), 2.41 1H), 2.61 (broad s, 2H), 2.65 (dd, J is 11, 8 Hz, 1H), 2.91-3.00 2H), 3.13 (dd, J is 11, 8 Hz, 1H). This material is suitable for use in various reactions including but not limited to the synthesis of quinolones.

THE REACTIONS AND COMPOUNDS OF CHART C-G The procedures below refer to CHART C-G.

Step 1(b) Formation of CGl(b). An appropriate optically active amine, such as a compound represented by the structures shown in Figure CG-R 1 below,

R

20 I I I SH

H

Figure CG-R 1 where R 20 is (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (Ci-C 8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-C

1 2 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl,, is 35 condensed with a carbonyl compound, such as one represented by the structure shown in Figure

CG-R

2 below, Figure

CG-R

2 where R 21and R 22are defined independently and are H, (Cl-0 8 )alkyl, (03-

Q

8 )cycloalkyl, (Ci-C8)alkyl-(C 3

-C

8 )CYCloalkyl,

-(C

6 -Cl 2 aryl), (Cl-C 8 )alkyl-(0C 6

C

12 aryl), or the aryl or alkyl is substituted with one to three of the following groups,

(C

6

-O

12 aryl), -(Cl-0 3 )alkyl, -(0 1

-C

3 )alkoxy, halogen, trifluoromethyl; under reducing conditions using NaBH 4 or a similar suitable boron hydride reducing agent in a suitable solvent such as THIF to obtain compounds represented by the ::structures shown in figure CGl(b) below,

R

20

R

20

R

2 H

H*

H

Figure CGI(b) SteD 2 CGl(a) CGj(b) 0G 2 A compound represented by the structures shown in CGi(a), below, 0 253 Figure CGI(a) where, R 2 and R 3 are defined independently, and are (C 1 -0 8 )alkyl, (03- C8)cycloalkyl, (C1-C8)alkyl(C 3

-C

8 )cycloalkyl, (C.-Cl 2 aryl), (0 1 -0 8 )alkyl, (06-

C

(C

6 -Cl 2 aryl), (0 1

-C

3 )alkyl, (CI-C 3 )alkoxy, halogen, trifluoromethyl; -36undergoes a Michael Addition reaction, between 0 and -1000C temperature, but preferably at -70 to -80 0 C, with a compound represented by the deprotonated, form of the structures shown in figure CG(b). Deprotonation is performed between 0 and -100C, but preferably between -30 to -500C, with an appropriate base such as n-BuLi, to produce compounds, after coupling, represented by the structures shown in figure CG 2 below,

R

20 21

R

20

R

21 10 H R 22 H R 22 N 0 t 0 R 3 K R 3

X

R

2

R

2 Figure CG 2 Step 3 CG 2

CG

3 Since the amine nitrogen of structures CG 2 has a 15 benzyl substituent, this nitrogen may be deprotected. The carbon nitrogen bonds are hydrogenolytically cleaved with an appropriate reducing agent such as Pearlman's catalyst, 20 percent palladium hydroxide on charcoal, in an appropriate solvent, such as EtOH, to obtain the compounds represented by the structures shown in figure CGa.

20

R

21 H\H R2 H NH R 3 0 R3 ,J R

R

2 X

R

2

X

Figure CG 3 Compounds represented by the structures shown in figure CG 3 are then used as starting materials for the reactions of CHARTS D.

THE REACTIONS AND COMPOUNDS OF CHART D-G.

The procedures below refer to CHART D-G.

Step 1. DGo DGI. Refer to the procedures described in CHART C to obtain the starting materials for this reaction. The compounds represented by the structures in figure DGo, below, -37-

R

2 1

R

21 H H R22 H H R 22

MJ

N 0

R

3

R

3 R X R R2 x Figure DGo (Where R 21 and R 22 are defined independently and are H, (C 1

-C

8 )alkyl, (C3-

C

8 )cycloalkyl, (C 1 -Cs)alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C1-C 8 )alkyl-(C 6

C

(C

6

-C

12 aryl), (Cl-C 3 )alkyl, (Cl-C 3 )alkoxy, halogen, trifluoromethyl. Where R 2 S. and R 3 are defined independently and are (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (Ci-C 8 )alkyl-(C 3

-C

8 )cycloalkyl, (CCaryl), (C-C 8 )alkyl, (C 6

-C

12 aryl), or the 15 aryl or the alkyl is substituted with one to three of the following groups, (C6-

C

12 aryl), (C-C 3 )alkyl, (C 1

-C

3 )alkoxy, halogen, trifluoromethyl; are dissolved in a suitable organic solvent such as tetrahydrofuran, and then added, between a temperature of -50 0 C and 0°C, preferably around -30 or -40 0 C, in a nitrogen atmosphere, to a solution of a compound of the description in figure GRX, S 20 dissolved in a suitable organic solvent.

7

R

8 Figure GRX (Where R 7 and R 8 are defined independently and are (C 1

-C

8 )alkyl, (C 3 Ca)cycloalkyl,

(C

1 -Cs)alkyl-(C 6

-C

12 )aryl; where M is Li, Na, or K) Note that the compounds represented by the figure GRX contain R groups, R 7 and R that are not incorporated into the desired compounds, figure GRX represents a compound that only acts as a base. This use of the compounds of Figure GRX applies to all the reactions of this invention. The resulting anion or dianion is then reacted with a compound represented by the structure shown in figure GYX, below, 37a

R

6 R4 y

R

Figure GYX Where R 4

R

5 and R 6 are independent and are H, (C 1

-C

8 )alkyl, (C 3

C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

1 2 aryl); (Ci-C 8 )alkyl-(C 6

C

(C

6

-C

12 aryl), (C 1

-C

3 )alkyl, (Ci-C 3 )alkoxy, halogen, trifluoromethyl and where Y is halogen, -OTs, -OMs, or -OTf.) to obtain a compound represented by the structures shown in figure DG 1 below.

R

21 R22 R21 R H*N O

H

RT" 6 RH R 6 R R 4 5 4 R R R R R Figure DG, Step 2. DG 1

DG

2

DG

1 is subjected to an established method of ozonolysis, such as bubbling 03 from an ozone generator, such as a Welsbach ozonator, through the reaction mixture in an appropriate solvent, such as water or methanol, followed by reduction of the intermediate ozonide with an appropriate boron hydride reducing agent such as NaBH 4 or LiBH 4 to obtain a compound represented by the structures shown in figure DG 2 below,

R

21

R

22

R

2 1

R

2 2 0 0 Figure DG 2 37b Step 3. DG 2 DG3. DG 2 is treated with an appropriate amine base, such as triethylamine, and an activating agent, such as methanesulfonyl chloride in a solvent such as tetrahydrofuran or toluene to obtain a compound represented by the strucutres shown in figure -38-

DG

3 where Ms is mesylate, below.

R

2 1

R

22

R

2 1 R22 H' N H N R R R2 H R 6 H H H OMs H OMs Figure DG 3 Step 4. DG 3 -4 DG4. DG 3 is treated in an appropriate solvent such as toluene or THF with an amine represented by the structure shown in figure DG-R 1 below,

H

SN-R9

H

Figure DG-R 1 15 (where R 9 is defined previously) to obtain a compound represented by the structures shown in figure DG 4 below.

R

21 R22 R 2 1 R22 HO

HO

20 R2T R 6

R

2 H R6 H "C 'C H N- R 9 H N- R 9 H

H

Figure DG4 Step 5. DG 4

DG

5 In the same reaction vessel as step 4, above, DG 4 thermally isomerizes to give a compound represented by the structures shown in figure DG5 below.

R

21 H21 R 22

R

21 R22 H NH 0 H NH 0 R2N-R 9 R2 A N-R 9 R6 R6 Figure DG Step 6. DG 5 4 DG 6

DG

5 is treated with a suitable reducing agent such as LiAlH 4 DIBAL or Borane in a suitable solvent such as THF to obtain a compound or compounds -39represented by the structures shown in figure DG 6 below.

S R22

R

2 1 R22 H NH H NH R2 R 9 R2N -R 9

R

6

R

6 Figure

DG

6 Step 7. DG 6

DG

7 When R 9 is a C 1

-C

6 alkyl the reaction stops, and if R9 is an alkylaryl that is connected to the nitrogen atom with more than one carbon atom between the nitrogen and aryl, the reaction will also stop. When it is desired to make R 9 a protective group, where for example an alkylaryl is connected to the nitrogen atom with one carbon atom between the nitrogen and the aryl, that is where the aryl is bound to the first carbon atom in the alkyl side chain, then this deprotection step 7 may be used. For example if R 9 is benzyl, figure DG 6 could be hydrogenolytically cleaved with 20 percent palladium hydroxide on charcoal; to obtain a compound represented by the structures shown in figure DG 7 below, R R 2 2 R21 R2 *H NH H NH -H R -H R2 2 '4 R6 R 6 Figure

DG

7 o Depending upon the starting materials used, compounds represented by the structures on the left side of the figures or the right side of the figures or, if the starting materials are a racemic mixture, the reaction may produce a 1:1 ratio of compounds represented on both sides of the figure DG 7 i.e. a racemic mixture.

EXAMPLES OF COMPOUNDS FROM CHART D-G.

Using appropriate starting materials using the procedures shown in CHART D can be used to make the following compounds: 3-(l'-(S)-benzylamino)ethyl)pyrrolidine and 3-(l'-(S)-methylamino)ethyl)pyrrolidine.

3-(1'-(S)-benzylamino)ethyl)pyrrolidine and 3-(1 '-(S)-ethylamino)ethyl)pyrrolidine.

THE REACTIONS AND COMPOUNDS OF CHART E-G The procedures below, which are the more preferred procedures, refer to CHART E-G.

Step l(a) Formation of EGl(b'). A compound represented by the structures shown in Figure EG-R 1 below, N

N

I I I H

H

Figure

EG-R

1 (where R 20 is (C 1 -C8)alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6 -Cl 2 aryl), (C 1

-C

8 )alkyl-(C 6

-C

12 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl,), is condensed with a compound represented by the structure shown in figure EG-R 2 below, 0 R23 Figure EG-R 2 (where R 23 is (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )allyl-(C 3

-C

8 )cycloalkyl, (C 6

-C

12 aryl), (C 1

-C

8 )alkyl-(C 6

-C

12 aryl), (C 1 -C)alyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; where R 24 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3

-C

8 )cycloalkyl,

-(C

6

C

12 aryl), (C 1 -C)alkyl-(C-C 12 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6

-C

1 2 aryl), (C 1

-C

3 )alkyl, (C 1

-C

3 alkoxy, halogen, trifluoromethyl; to obtain a compound represented by the structures shown in Figure EGIb) below, S N) R 24 N R24 I H

H

Figure EG I Step 1(b) EGl(b.) EGI(b). EG1~b) is treated with an appropriate reducing agent such as LiAlH 4 DIBAL or Borane in a suitable solvent such as THE to obtain compounds -41 represented by the structures shown in figure EG(b), below.

R

20 H

R

2 0 H R20 0 a a

C

Figure EGi(b) Step 2 EG1(a) EG(b) EG 2 A compound represented by the structures shown in EGI(a), below, 0 2 R3 R x R Figure EGi(a) where, R 2 and R 3 are defined independently, and are -(C-Cs)alkyl, -(C3- Cs)cycloalkyl, -(Ci-Cs)alkyl-(C 3 -Cs)cycloalkyl,

-(C

6

-C

12 aryl), -(C-C 8 )alkyl(C 6

C

12 aryl), or the aryl or the alkyl is substituted with one to three of the following groups, (C 6

-C

12 aryl), (C-C 3 )alkyl, (C,-C 3 )alkoxy, halogen, trifluoromethyl, undergoes a Michael Addition reaction with a compound represented by the deprotonated form of the structures shown in figure Deprotonation is carried out with an appropriate base such as n-BuLi, to produce compounds, after coupling, represented by the structures shown in figure EG 2 below.

N 0 R x1-1RR

H

-H H R24 N 0 R2 X R Figure

EG

2 -42- Step 3 EG 2

EG

3 Since the amine nitrogen of structures EG 2 has a benzyl substituent, this nitrogen may be deprotected. The carbon nitrogen bonds are hydrogenolytically cleaved with an appropriate reducing agent such as Pearlman's catalyst, 20 percent palladium hydroxide on charcoal, in an appropriate solvent, such as EtOH, to obtain the compounds represented by the structures shown in figure EG 3 H H H HH R24 H H R24 N o N 0

::R

3

R

3 Figure EG 3 The compounds represented by the structures shown in figure EG 3 are The procedures below refer to CHART FG.

Sten I FGo FG 1 Refer to the procedures described in CHART E to obtain the starting materials for this reaction. The compounds represented by the structures shown in figure FG, below H

H

H NHi R24 H H R24 Nt 0 N R2 X R3 R2 X R3

R

3 Figure FGo (Where R 24 is H, (C 1

-C

8 )alkyl, (C 3

-C

8 )cycloalkyl, (C 1

-C

8 )alkyl-(C 3 C)cycloalkyl, (C 6

-C

12 aryl), (C-C )alkyl-(C6-C12aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6

-C

12 aryl), (C,-C 3 )alkyl,

(C

1

-C

3 )alkoxy, halogen, trifluoromethyl;, and where X is O, NH, or S; and where 42a R 2 and R 3 are defined independently, and are (0 1 -Ca)alkyl, (0 3 -Ca)cycloalkyl,- -(Cl-C 8 )alkyl-(C 3

-C

8 )cycloalkyl, (C 6 -Cl 2 aryl), (Cj-C 8 )alkyl(C 6

-C

12 aryl), or the aryl or the alkyl is substituted with one to three of the following groups, (C 6 -Cl 2 aryl),- -(Cl-C 3 )alkyl, (C 1

-C

3 )alkoxy, halogen, trifluoromethyl are dissolved in a suitable organic solvent such as tetrahydrofuran, and added, between a temperature of 5000 and OQ, in an inert atmosphere or an atmosphere without water, preferably about -300C or -400C, in a nitrogen atmosphere; to a solution of a compound represented by the structures shown in figure FG-Rj, below.

H

Fiur N-R (WeeR sH (C-8ccoly, (lC)ly-C3C)ylakl *(C1ay) -(a.)ly-C-1ay) rtearlo ly ssbtttdwt n 155 Figure FG-R (Where R is (Cl-0)alkyl,-(C 3

-C

8 )cycloalkyl, -(C-0 8 ayl -(Cl-C 8 )clalkyl, 6

C

2 rl,-0- 8 akl( 6

C

1 2 aryl), or the aryl or alkyl is substituted with onetohrefteflowngous othe f h floin rop,--(0 6

-O

1 2 aryl), -(C 1

-C

3 )alkyl, (C-C 3 )alkoxy,haoetilrmty, -43and where Y is halogen, -OTs, -OMs, or -OTf) to obtain a compound represented by the structures shown in figure FG 1 below, H R 24 H R 24 H- O H R2" 'H R 6 R2 f H R6

H

R4 R5 R4 Figure

FG

1 Step 2. FG 1

FG

2

FG

1 is subjected to an established method of ozonolysis, such as bubbling 03 from an ozone generator, such as a Welsbach ozonator, through the reaction mixture in an appropriate solvent such as water or methanol, followed by treatment of the 15 intermediate ozonide with an appropriate boron hydride reducing agent such as NaBH 4 or LiBH 4 to obtain a compound represented by the structures shown in figure FG 2 below.

H R 24 H R 24 H 0 H N 0 R" "1H R6 R2 H R6 H

H

H OH H OH Figure

FG

2 Step 3. FG 2 -4 FG 3

FG

2 is treated with an appropriate amine base, such as triethylamine, and methanesulfonyl chloride in a solvent such as tetrahydrofuran or toluene to obtain a compound represented by the structures shown in figure FG 3 where Ms is mesylate, below.

H R 24 H R 24 O O0 H N H

N

R2' "H R6 R2 H R6 H H H OMs H OMs Figure

FG

3 Step 4. FG 3

FG

4

FG

3 is treated in an appropriate solvent such as toluene or THF with an amine represented by the structure shown in figure FG-R 1 below,

H

N-R

9

H

Figure FG-R 1 (where R 9 is defined earlier) to obtain a compound represented by the structures shown in figure

FG

4 below, H R 24 H R 24 H-X< H 0 N^ R6 NZf H R R R 6 R2R 6 4 H 7 H H N-R 9 H N-R 9

I

H H Figure FG 4 Step 5. FG 4

FG

5 In the same reaction vessel as step 4 above, FG 4 thermally isomerizes to give a compound represented by the structures shown in figure FG 5 below, 9* R24 R24 H.

H

2 0 H NH 0 H NH 0 R2*

N-R

9 W A N-R 9 6 R R Soo S" Figure FG Step 6. FG 5

FG

6

FG

5 is treated with a suitable reducing agent such as LiAlH 4 DIBAL or Borane in a suitable solvent such as THF to obtain a compound represented by the structures shown in figure FG 6 below, R24 R24 H H N H:>4NH H NH 9 3" N-R9 R2 V Q N-R 9 R2

RR

Figure FG 6 Step 7. FG 6

FG

7 When R 9 is a C 1

-C

6 alkyl the reaction stops, and if R9 is an alkylaryl that is connected to the nitrogen atom with more than one carbon atom between the nitrogen and aryl, the reaction will also stop. When it is desired to make R 9 a protective group, where for example an alkylaryl is connected to the nitrogen atom with one carbon atom between the nitrogen and the aryl, that is where the aryl is bound to the first carbon in the alkyl side chain, then this deprotection step 7 may be used. For example if R 9 is benzyl, figure FG 6 could be hydrogenolytically cleaved with 20 percent palladium hydroxide on charcoal; to obtain a compound represented by the structures shown in figure FG 7 below, R24 R24 H> NH H NH R2 H R2 H

R

6

R

Figure FG 7 i Depending upon the starting materials used, compounds represented by the structures on the left side of the figures or the right side of the figures or, if the starting materials are a racemic 15 mixture, the reaction may produce a 1:1 ratio of compounds represented on both sides of the figure FG 7 i.e. a racemic mixture.

EXAMPLES OF COMPOUNDS FROM CHART E CHART EX1 The specific prodecures and examples described below, shown in CHART EX1 are to be construed as merely illustrative of the procedures described above, and do not impose S' 20 limitation upon the general reaction schemes in any manner whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants as well as to reaction conditions and techniques.

Step l(a) of CHART EX1. Synthesis of N-Formyl-N-(S)-l-phenylethylamine, EXll(b). Add (S)-(-)-phenylethylamine (940g) and ethyl formate (1.83kg) to a 5000 ml. flask. Heat the 25 solution to reflux and stir overnight. Remove the excess ethyl formate in vacuo leaving 1.15 kg of N-formyl-(S)-l-phenylethylamine. 13 CNMR (CDCl 3 ppm 8) 21.80, 47.61, 126.11, 127.42, 128.66, 142.73, 160.60.

STEP l(b) of CHART EX1. Synthesis of N-Methyl-N-(S)-l-phenylethylamine, EXl(b). Add powdered LiAlH 4 (50g) and THF (500 mL) to a 3000 ml flask. Then add a solution of Nformyl-N-(S)-l-phenylethylamine (EXll(b), 100g in THF (500mL) dropwise into the LiAlH 4 solution. Heat the solution to reflux and stir 5 hours. After reflux, cool the solution to 5 0

C

and slowly quench the reaction with 10% NaOH (500mL), then extract the product with MTBE (1 x 2L). Remove the solvent in vacuo, and purify the product by distillation to yield of N-methyl-N-(S)-l-phenylethylamine. 13 CNMR (CDCl 3 ppm 8) 24.15, 34.76, 60.49, 126.84, 127.14, 128.65, 145.64.

Step 2 of CHART EX1. Synthesis of 3-(N-Methyl-N-(S)-l'-phenylethylamino)butyric acid, 2-methylpropyl ester, EX1 2 Add N-methyl-N-(S)-l-phenylethylamine (EXllb, 3 90.0g, 2.88 mol, l.leq) and THF (14L) to a 22 L flask. Cool this solution to -5 0 C and add n-buLi (1.80L, 2,88 mol,) over a period of 30 min. maintaining the internal reaction temperature below 0°C.

The solution is stirred at 0°C for 30 min. and then cooled to -78 0 C. A pre-cooled, to -40 0

C,

solution of isobutyl crotonate (372g) in THF (3.0L) is added at a rate such that the internal reaction temperature does not exceed -70 0 C. After the addition is complete, the reaction is stirred at -75 0 C for 30 min. The reaction is quenched with saturated NH 4 Cl until the pH is between about 9 to 11. The organic phase is separated and the solvent is removed in vacuo.

The product is redissolved in EtOAc (1.5L) and the resulting solution is filtered. The EtOAc is distilled off and MeOH (1.OL) and 37% HCI (210 mL) are added. MTBE (5L) is added to crystallize the amine hydrochloride salt of the 2-methylpropyl ester of 3-(N-methyl-N-(S)-l'phenylethylamino)butyric acid. The crystalline amine hydrochloride salt is dissolved in CH 2 Cl 2 (2.5L) and water (1.OL) is added. A 10% NaOH solution is used to adjust the pH to between about 9 to 11. The organic layer is separated and the solvent is removed in vacuo to yield 290g 15 of 3-(N-methyl-N-(S)-l'-phenylethylamino)butyric acid, 2-methylpropyl ester.

13 CNMR (CDC13, ppm 8) 14.70, 19.39, 21.97, 27.95, 32.31, 39.25, 51.43, 62.36, 70.70, 126.91, 127.40, 128.47, 146.45, 173.06.

Step 3 of CHART EX1. Synthesis of 3-(N-Methylamino)butyric acid, 2-methylpropyl ester, EX1 3 Add 20wt% Pd(OH) 2 on carbon (5.0g) to a 4L Parr shaker, followed by ethanol and 3- 20 (N-methyl-N-(S)-l'-phenylethylamino)butyric acid, 2-methylpropyl ester (EX1 2 Pressurize the Parr shaker to 70 atm with H 2 No further H 2 uptake after 1.5 hours indicates the reaction is complete. When the reaction is complete, filter off the catalyst and remove the solvent in vacuo to yield 65g (100%) of 3-(N-methylamino)butyric acid, 2-methylpropyl ester. 13

CNMR

(CDCI

3 ppm 8) 16.56, 19.05, 27.60, 30.32, 37.47, 52.23, 71.42, 169.81.

25 EXAMPLES OF COMPOUNDS FROM CHART F CHART FX1 The specific prodecures and examples described below, shown in CHART FX1 are to be construed as merely illustrative of the procedures described above, and do not impose limitation upon the general reaction schemes in any manner whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants as well as to reaction conditions and techniques.

Step 1 of CHART FX1. Synthesis of 3-[(S)-2'-propenyl]-2-(S)-methyl-N-methylazetidinone, FX1 1 Add diisopropylamine (83.4g) and THF (1.5L) to a 5 ml flask. This solution is cooled to -10 0 C, and 1.6M n-BuLi (515mL, 825mmol) is added at a rate such that the internal temperature does not exceed 0°C. After 30 min, cool the solution to -40 0 C, and add the 2methylpropyl ester of 3-(N-methylamino)butyric acid (EX1 3 65g). After 30 minutes stirring add the allyl bromide (91g) and stir an additional 30 minutes, then quench with saturated NH 4

CI

(350mL). The organic layer is separated, and the solvent is removed in vacuo. Purification by silica gel chromatography (33% EtOAc:heptane) yields 42g of 3-[(S)-2'-propenyl]-2-(S)methyl-N-methylazetidinone. 13 CNMR (CDC1 3 PPM 8) 17.15, 25.80, 32.16, 54.46, 56.44, 116.57, 134.60, 169.12.

Step~ 2 of CHART FX1. Synthesis of 3-[(S)-2'-hydroxyethyl]-2-(S)-methyl-Nmethylazetidinone, FX 2 Add 3-[(S)-2'-propenyl]-2-(S)-methyl-N-methylazetidinone

(FX

1 23 1g) and H 2 0 (3.OL) to a 5L flask. Cool the solution to 0 0 C then pass ozone through the solution for 8 hours. Slowly quench the ozonide intermediate with NaBH 4 (50g) while maintaining the internal temperature <10 0 C. Bring the aqueous layer to near saturation with 1kg NaCl, and then extract the product with CH 2 C1 2 (4 X 2L). After solvent removal, the material is purified by silica gel chromatography MeOH:EtQAc) to yield 160g of hydroxyethyl]-2-(S)-methyl-N-methylazetidinone. 1 3 CNR (CDCl 3 ppm 8) 17.38, 26.44, 31.63, 55.56, 56.02, 61.32, 170.61.

****Step 3 of CHART FX1. Synthesis of 3-[(S)-2'-methanesulfonylethyll-2-(S)-methyl-Nmethylazetidinone, FX1 3 Add 3-[(S)-2'-hydroxyethyl]-2-(S)-methyl-N-methylazetidinone (FX1 2 1 100g), THF (1 OL), and triethylainine (920g) to a 2L flask. The solution is cooled to 0 C and methanesulfonyl chloride (84.0g) is added over 20 min maintaining the internal reaction temperature about or less than -25 0 C. After the white precipitate of triethylaminehydrochioride is filtered off, the solution of 3-[(S)-2'-methanesulfonylethyl]-2-(S)- 20 methyl-N-methylazetidinone in THF is used directly in the next step, but it can be isolated as a yellow oil. 13 CNMR (CDCl 3 PPM 8) 17.39, 26.41, 28.37, 37.48, 54.21, 55.77, 68.44, 168.89.

Steps 4 and 5 of CHART FX1. Synthesis of 3-[(S)-2'-N-benzylaxninoethyl]-2-(S)-methyl-Nmethylazetidinone, FX1 4 and 3-[1 '-[(S)-methylamino]ethyl]-N-benzylpyrrolidinone, FX1 5

A

solution of benzylamine (223g) in THF (1.OL) is heated to reflux. A solution of methanesulfonylethyl]-2-(S)-methyl-N-methylazetidinone (FX1 3 1.4kg) is dripped into the refluxing benzylaxnine solution from an addition funnel over 10 min. Reflux in THF is continued for 1 6h until the 3-I(S)-2'-methanesulfonylethylI-2-(S)-methyl-N-methylazetidinone, which is initially converted to 3-[(S)-2'-N-benzylarninoethylI-2-(S)-methyl-N-methylazetidinone, is exhausted. The 3-[(S)-2'-N-benzylaininoethyl]-2-(S)-methyl-N-methylazetidinone thermally rearranges to 3-f 1'-[(S)-methylamino]ethyl]-N-benzylpyrrolidinone under the reaction conditions.

Removal of the THF by distillation, replacement with toluene and continued reflux completes the transformation of 3-[(S)-2'-N-benzylaminoethy1]-2-(S)-methyl-Nmethylazetidinone to 3-fl '-[(S)-methylamino]ethyl]-N-benzylpyrrolidinone. After solvent removal, purification by silica gel chromatography (15% MeOH:EtOAc w/ 1% NH 4 OH) yielded 1 13g of 3-fl '-f(S)-methylaniinolethyl]-N-benzylpyrrolidinone. 1 3 CNR (CDC1 3 ppm 8) 16.21, 20.71, 33.52, 44.68, 45.31, 46.45, 56.29, 127.41, 127.94, 128.52, 136.25, 175.51. Note that 3-I(S)-2'-N-benzylaininoethyl]-2-(S)-methyl-N-methylazetidinone, FX1 4 was made and isolated by an alternate route. 13 CNMR (CDCI 3 PPM 8) 17.56, 26.25, 28.95, 47.50, 54.06, 55.66, 56.32, 127.15, 128.32, 128.60, 140.37, 170.07.

Step 6 of CHART FX1. Synthesis of 3-[1 '-[(S)-methylamino]ethyl]-N-benzylpyrrolidine, FX1 6 Add a lM solution of LiAlH 4 (392mL, 43lmmol) to a 2L flask. Heat the solution to reflux and add a solution of 3-[1 '-II(S)-methylaminolethyl]-N-benzylpyrrolidinone (FX1 5 100g) in THF (100mb) is over 10 min. After stirring for 30 mini, cool the solution to -30 0 C and quench slowly with 10% NaOH (183g). A 50% citric acid solution is added until a pH of 9 is obtained. The product is extracted with EtOAc (2 x IL), and the solvent is removed in vacuo to give 70g of 3-[1 '-jI(S)-methylaminolethyl]-N-benzylpyrrolidine. 13 CNMR (CDCl 3

PPM

8) 17.81, 27.94, 34.09, 44.04, 54.40, 58.04, 59.28, 61.01, 127.09, 128.43, 129.04, 139.45.

Step 7 of CHART FX. Synthesis of 3-[1 '-[(S)-methylaminolethyllbenzylpyrrolidine, FX1 7 Add 20 wt% Pd(OH) 2 on carbon (12.0g) to a 3L autoclave followed by methanol and 3-[l :::.methylamino]ethyll-N-benzylpyrrolidine (FX 6 1 12g) The autoclave, is pressurized to 70 atm with H 2 and heated to 650C2. No H 2 uptake after 18 hours indicates thle reaction is complete.

:The catalyst is filtered off, and the solvent is removed in vacuo, to yield 70g (100%) of 34[1'- [(S)-methylamino]ethyl]benzylpyfrolidine. 13 CNMR (CDC1 3 ppm 8) 17.85, 29.37, 33.70, 45.89, 46.76, 50.34, 58.44.

CHART AG 0 R 2N

(AGO)

Step l(a)

NH

2 0 12 R 14

NH

2 a a a a. a.

a Step INb) 0 4k R 13

R

14

R

2R 13 'I H (AGl(b)) 14 R

R

9-1 R 12 0

R

Step 14

R

1 2 H4-R13 N 0 R 2X 1

H

2 N 0 3 R 2

X*

Step 3

(AG

2

(AG

3 R 1 R 12 A H)LR13 NN 0 R 2 R3

H

2 N 0 R3 See Chart

B

See CliB CHART AMi 0 Step 1 (a) ethyl crotonate 0 a a Step 2

'NH

2 Step 1 (b) 0 S-ethyl-3-((N-benzyl)(S-Nmediylbenzyl))aniinobutyrate 0\ Step 3 ethyl (S)-3-aminobutyrate

H

2

N

CHART BG (page 1)

H

2 N 0

H

2 N 0

R

2 X

R

(AG

3 is BG 0 from CHART A)

(BGO)

Step 1 a a. a a a a. a *ba.

a a a.

a a a a a a *aaa..

RKNH 0

R

2 3 .0 R1'K NH 0

(BG

1

Y

R4 Step 2 0

R'K

(BG

2

R

9

-NH

2 Step 3 (Continued next page) CHART BG (page 2)

R

9

-NH

2 Step 3 00 R IL>JH 0R~IN 2_ R 9N- N-R 6(BG 3 6 R

R

I Step 4

'-NH

RH RN

R

9 (BG 4 -R9 0 6. N-R 6 R96 Step 50 NH50 NH R H NH R 2 NH (BG 5

RN

6

P

6

DR

CHART BX1 (page 1)

H

2 N 0 Step 1 0* a. a a a a 9* *a a ethyl (S)-3-carboxybenzylaminobutyrate IStep 2 ethyl Step 3 -54- CHART BXI (page 2) IStep 3 olN

S

S S S. S S S 5555 S S S. S SSS5

S

*555**

S

(S -benzyl-2-oxo-3-[l' 1 robenzylamino)ethyllpyrrolidine ifStep 4 (R,S)-l1-benzyl-3-[ 1'-(methylamidno)ethyllpyrrolidine Step

NH

'-(methylamino)ethyllpyrrolidine CHART CG 3 1 1

NH

2 a a.

a a a. a.

a.

a a a a. a a a a a STEP 1 (b) 20 R 21

N

I 22 o <R 22 STEP 1 1

R

N JR22 H (C431(b)) STEP 2 21 Y 0 Ro2

(CG)

3 3 R 2X

R

R 20 21 Ni H 2 -R 22 R 2

AI

R 1 1STEP 3 R21

H

2 22 H RA2 H N 0 0 3 2R SEE CHART OG SECATD SEE CHART DG -56- CHART DG 21 R 22 H

N

0 3 2 x- (DGO is 0G 3 from CHART CG)

(DG

0 R4 STEP 1 21

R

N 0 21

R

H N

(DG

1 b** R 4' IR5 4 1 1 STEP 2 (DG 2 R 22 H <N 0 R2 H r', STEP 3 CHART DG (Continued) MsOH STEP 3

XR

(DG

3 H <N 0 2 i H 6 R c R HCm 9* S S a. S a S

S.

SS

*5 C 55 S S *5

S

-9 a a

R

9

-NH

2 STEP 4 21

R

(DG

4 "H 6 H N-

R

STEP

R

H <N

H

(DG 5 STEP 6 R 22

NH-

H N RR

N-P

CHART DG (Continued) STEP 6 21 R 22R

RR

(DG 6 21 R 22 2 R N-R 9 R 6 0

I*

S S 0050

SS

I. S 0* OS 0

IS

SI..

I

if.

0 S

SI

0e S. S S S

SS

a 50*5

IS

I I

S

STEP 7 (DG 7 22 R 2 2 R e

N-H

CHART EG R 20

NH,

23 o STEP l(a R 0o N H STEP 1(b) 0 x

R

3 (EG 1 (a)

NH

2 R23 0 l+ R 24 STEP 1(a) R 0 11 N NR 24

NH

S STEP 1 (b)

R

>HIL 24

H

H HL.R 24 R 24 H N- 2 2 f 0 R 3 (EGl(b)) STEP 2 (EG 2 STEP 3 (EG 3 R2 24 f 0 2/ SEE CHART FG SECATF SEE CHART FG CHART EX

NH

2 0 H3C

H

3 STEP 1 (a)

H

OH

2

OH

3 (EXi l(a)) isobutyi crotonate N. H

S.

S. (EXll1(b)) STEP I1(b)

H

(EX1l1(b)) STEP 2 (EX1 2 STEP 3 HhH 0CH

H

3 C0

OH

3

H

3 C0

OH

3 (EX13i SEE CHART FX1 CHART FG H 24 H

R

0 R 2 A X

R

I

2 (FG 0 is EG 3 rmCHART EG) (FG 0 3

H

H.L 24 0 R 24 3

Y

R

5 R4 STEP 1 0.0.0: (FG1) R 4 STEP 2 4, (FG 2 R6 H OH H R24 H>/XN 0 2 H R 6 H

OH

4, STEP 3 -62- CHART FG (Continued) MsOH STEP 3 (FG 3 H R N 0 2 H R 6 R H R H~ Oms

R

9

-NH

2 STEP 4 H -6

(FG

4 R9

H

STEP (FG 5 H R H X<N' 0 2 R N-R 9 STEP 6 -63- CHART FG (Continued) STEP 6 H A 24 H x

NH

2N A 6 (FG 6 H

A

24 H N 2 A N-A 9 S.

SS.S

S

S* SQ

S

STEP 7 (PG7) H A H XN A oed

N-H

A 6

I-H

A 6 -64- CHART FX HV (FXI H N

H-

3 C 0~H

OH

3 I STEP 1 0is EXi from CHART EXi) FX1 0 .Br (EXi 1

S

5

S

as SS5 S H

H

H xN 1- 3

C

STEP 2

H

3

C""

(FX12) STEP 3 CHART FX (Continued) MsOH STEP 3

H

3

C

H m FX1 3)

S

STEP 4

H

N9 N0

H

3 0 H e FX1 4 STEP H H H x N H0

H

3

CN

(FX1 STEP 6 -66- CHART FX (Continued) STEP 6

H

3

C

(FX1 6 *fee.

STEP 7 H

H

H xN'H

H

3 0 N-H FX1 7

Claims

2. The process for the preparation of a compound or compounds represented by the structures on the left side, or the right side of figure I3G4 1 below. or, if the starting materials are a racemic mixture, the reaction may produce a mixed ratio of compounds represented on both sides of the figure BG 4 1 below, R 29 R 6 N HFigure BG4- 1 29 R N -R 9 where R 30 is H. (C 1 .Cg)alkyl. (CI-C 8 )cycloalkyl. (Ci.C 8 )alkvl.((- ICscycloalkyl. (C 6 C 12 aryl). -(C 1 -C 8 )alkyl-(C 6 -C 1 aryl). or the aryl or alkyl is substituted with one to three of the following groups. (C 6 -CI 2 auyl). (C 1 .)alkyl, (C 1 -Cj) alkoxy. halogen. tnifluoromethyl. When R' is -O-(C 1 8 alkyl), -0-C 8 ccakl.-(C., 8 aky)~ cvcloalkyl). -0-(C 6 1 aryl). -O-(C 1 4 8 alkyl)-aryl, then reduction with LAW. DIBAL or Borane will always produce R 50 is H. where R 2 is 1 -CS)alkyl. (C.1-C 8 )cycloalkyl. (C 1 -Cgalkvl-(C 1 -CgkvcloalkvI. (C 6 -C 1 2 arvl)- (C 1 -C 8 )alkyl-(C 6 -CI 2 aryl). or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -CI 2 aryl).(C,-CI)alkyl, (C 1 -Cl) alkoxy. halogen. triflunromethyl. where R 6 is H, (C 1 -C 8 )alkyl. (C 1 j-C 8 )c%-cloalkyl. 1 -CgalkyIl-(C 1 -C 8 )cycloalkvl1. (C 6 -CI 2 atyl), (C 1 -C 8 )lkyl-( 6 C. aryl), or the aryl or alkyl is substituted with one to three of the follo~ing groups. (C 6 -C 1 aryl). (C 1 -C 1 ,)alkyl. (C 1 -Cl'i alkoxv. halogen. 12 trifluoromethy 4 where R 9 is H, (C 1 -CS)alkyl. (C 3 -CS)cycloalkyl, (C 1 -Cslalkyl-(CI-CS~cycloalkvl. (C6-C 12 aryl), (CI-Cg)alkl-(C 6 -C 1 2 aryl), or thie aryl or alkyl is substituted with one to three of the following groups. (C 6 .C 1 2 aryl), (CI'C 3 )alkyl, (C 1 -C 1 alkoxy. halogen. trifluoromethyl; which comprises treating a compound or compounds represented by figure BG 3 1 0 0 Figure BG.%. 1 ANH 0 1 A'kNH 0 R R 11 IN-R N -R R6 p with a reducing agent. such as with LiAlH 4 DIBAL or Boranc in a suitable solvent such as THF. to produce the desired compounds. where R' is H. -(C 1 -C 8 )alkyl. (C 3 -C 8 )cycloalkyl. (C 1 -C 8 )alkYl-(C 3 -CS)cycloalkyl, (C 6 -C 12 aryl). (C 1 -CS)alkyl.(C 6 -CI2 aryl). -O-(C 1 8 alkyl)., O-(C 3 .g cycloalkyl), -O-(C 1 8 alkyl)(C 3 8 cycloalkyl). -0-(C 6 2 ay) -0-(C 1 8 alkylh-aryl. or the aryl or alkyl is substituted with one to thme of the following groups, (C 6 -C 1 .2 aryl)-(C 1 C 3 )alkyl. (C 1 -C 3 alkoxy. halogen, trifluoromethyl. When R' is -0-(C 1 8 alkyl). -0-(C3- 8 cycloalkyl). -0-(C 1 8 alkyl)(C 3 8 cycloalkyl). -0-(C 6 12 aryl). -O-(C 1 8 alkyl)-aryl. then reduction with LAH, DIBAL or Borane will always produce R 50 is H. (Chart B. step 4)
3. The process, of claim 2, for the preparation of a compound or compounds represented by the structures on the left side. or the right side of figure BG 4 1 below, or. if the starting matcria% arc a racemir mixture, the reaction may produce a mixed ratio of compounds represented on both sides of the figure BG 4 1 below, H5NH Figure BG 4 1 N -R 9 R N R R 6 R where R 50 is H, (C 1 .C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl.(C 3 -C 8 )cycloalkyl, (C 6 C 12 aryl), (C 1 -C 8 )alkyl.(C 6 -C 1 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -CI 2 aryl). (C 1 -C 3 )alkyl, (C 1 -C 3 alkoxy, halogen, trifluoromcthyl. When R 1 is -O-(Cl* 8 alkyl), 'O-(C 3 8 cycloalkyl), -O-(C 1 8 alkyl)(C 3 8 cycloalkyl), .0-(C 6 12 :15 aryl), -O-(C 1 .g alkyl)-aryl. then reduction with LAH, DIBAL or Borane will always produce R 50 is H. where R7 is (C 1 .C 8 )alkyl, (C 3 .C 8 )cycloalkyl, (C 1 -C 8 )alkyl-(C 3 -C 8 )cycloalkyl, (C 6 -C 12 aryl), (C 1 .C 8 )alkyl.(C 6 -CI 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -C 12 aryl),(C 1 -C 3 )alkyl, (C 1 -C 3 alkoxy, t;slogen, trifluoromethyl; where R 6 is H, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 .CI)alkyl-(C 3 -C 8 )cycloalkyl, (C 6 -CI 2 aryl), (C 1 -Cg)alkyl-(C 6 -C 1 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, -C 6 C 2 aryl). (C 1 -C 3 alkyl, (C 1 -C 3 alkoxy, halogen, trifluoromethyl; where R 9 is H, (C 1 -Cg)alkyl. (C 3 -Cg)cycloalkyl, (C 1 -C 8 )alkyl.(C 3 -C 8 )cycloalkyl. (C 6 -C 1 2 aryl). (CI-C 8 )alkyl-(C 6 -CI 2 aryl). or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -CI 2 aryl), (C 1 .C 3 )alkyl, (C 1 -C 3 alkoxy, halogen, trifluoromethyl; comprising the process of clam 2, preceeded by the following process, a process for preparing a compound or compounds represented by figure BG 3 1 0 0 Figure BG 3 1 .JNH 0 RIANH 0 RR R29 R 2 N -R N -R wihere R' is 1 -C 8 )alkyl. (C 3 -C 1 S)cycloalkyl. (C 1 -Cg)alkyl-(C 3 1-Cg)cycloalk~l, 6 -CI 2 aryl). 1 -C 8 )alkyl-(C 6 .C 1 2 aryl). -O-(C 1 8 alkyl). -O-(C 3 8 cycloalkyl), *O-(Cl.g alkylX(C.1, cycloalkyl). -0-(C 6 -12 aryl), -0-(C 18 alkyl)-aryl, or the aryl or alkyl is substituted with onlC to three of the following groups, (C 6 *C 12 aryl).(C 1 -C.I)alkyl, (C 1 -C 1 alkoxy, halogen, trifluoromethyl, where R2is 1 -Cg)alkyl, (C 3 -C 8 )cycloalkyl. 1 -Cg)alkyI-(C- 1 -C 8 )cycloatlkyl, (C 6 -CI 2 aryl), (C 1 -C 8 )alkyl-(C 6 -C 1 2 axyl), or thc aryl or alkyl is substituted with one to three of the following groups, (C 6 -C 12 aryl),(C 1 -C 3 I)alkyl, (C 1 -C 3 alkoxy. halogen. trifluoromcthyl; where R 6 is H, (C 1 -C 8 )alkyl, (C 3 .C8)cycloalkyl, (C 1 -C 8 )alkyl-(C.1-CI)cycloalkyI. (C 6 -CI 2 aryl), (C 1 -C 8 )alkyl-(C 6 -CI 2 aryl). or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -C 12 aryl), (C 1 .C 3 )alkyl, (C 1 -C 3 alkoxy. halogen. trifluoromethyl; :~.where R 9 is H, 1 .Cg)alkyl, (C 3 .Cg)cycloalkyl, (C 1 .C 8 )alkyl-(C 3 -C 8 )cycloalkyl. (C 6 -CI 2 aryl). (CI-CB)alkyl.(C 6 .C 1 2 aryl). or the aryl or alkyl is substituted with one to three of the following groups, o-(C 6 -CI 2 aryl), (C 1 .C 3 )alkyl, (C 1 -C 3 alkoxy, halogen. trifluoromethyl; which comprises subjecting to ozonolysis a compound or compounds represented by figure BO 2 *2 0 0 Figure BG 21 R2X-11 3 J -R R F RAI R 5 RA where R 3 is 1 -C 8 )alkyl, o-(C 3 -Cg)cycloalkyl, (C 1 .Cg)alkyl-(C 3 -C 8 )cycloalkyl, (C 6 -C 1 2 aryl), (C 1 .C 8 )alkyl.(C 6 .C 12 aryl), or the aryl or alkyl is substituted with one to three of the following groups, o.(C 6 -C 1 2 aryl), (C 1 -C 3 )alkyl, (C 1 .C 3 alkoxy. halogen, trifluoromethyl; R 4 R 5 and R 6 are defined independently and are H, (C 1 -C 8 )alkyl, (C 3 C 8 )cycloalkyl, (C 1 -Cg)alkyl-(C 3 -C 8 )cycloalkyl, (C 6 -C 1 2 aryl), (C 1 -C 8 )alkyl-(C 6 -C 1 2 aryl). or the aryl or alkyl is substituted with one to three of the following groups, (C 6 "C 12 aryl), (C 1 .C 3 )alkyl- (CI-C 3 alkoxy, halogen, trifluoromethyl. X isO0.NH.or S. followed by reaction with R 9 -NH 2 under reducing conditions, such as with sodium cyano -72- borohydride, sodium triacetoxy borohydride or sodium borohydride, (in order of preference) at 00-50 0 C. or a cool temperature to control hcat, to produce the desired compounds. (Chart BC]. step 3) (Chart B, St ep 4 preceeded by Stcp 3)
4. The process, of claim 3, for the preparation of a compound or compounds represented by the structures on the left side, or the right side of figure 13G 5 1, below, or, if the starting materials are a racemic mixture, the reaction may produce a mixed ratio of comipounds represented on both sides of thc figure BG 5 1 below, 59<.H5 N H Figure BGi 51 R R 2 2 NH R NH where R 50 is H, (C 1 -CS)&lkyl, (C 3 -Cg)cycloalkyl, (C 1 .Cg)alkyl-(C 3 -C 8 )cycloulkyl, (C 6 C 12 aryl), (C 1 -Cg)alkyl-(C 6 -CI 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -C 1 2 aryl). (C 1 -C 3 )alkyl, (C 1 -C 3 alkoxy, halogen, trifluoromethyl. where R 2 and R 3 is (C 1 -Cg)alkyl, (C 3 -Cg)cycloalkyl, (C 1 .C 8 )alkyl.(C 3 20 C 8 )cYC1oalkyl, (C 6 -C 12 aryl), (C 1 .C 8 )alkyl.(C 6 .CI 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -CI 2 aryl),(C 1 -C 3 )alkyl, (C 1 -C 3 alkoxy, halogen, trifluoromethyl. where R 6 is H. (C 1 -Cg)alkyl,.(C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl.(C 3 -C 8 )cycloa!kyl,.--- (C 6 -C 12 aryl). (C 1 -C 8 )alkyl-(C 6 -CI 2 azyl), or the aryl or alkyl is substituted with one to three of the following groups, 6 -C 1 2 aryl), (C 1 -C 3 )alkyl, (C 1 .C 3 alkoxy, halogen, trifluoromethyl: which comprises, using starting materials represented by the structure shown in figure BOO.,, below, H1 2 N 0 H 2 N 0 Figure BG 0 1 I ~R 3 kx R 3 X is 0, NH, S reacting those starting materials with a compound represented by the structure in figure BG-R 1 below, -73- 0 R Zz Figure BG-RI where R 1 is H, (C 1 -Cg)alkyl (C 3 -C 8 )cycloalkyl, -(C-C 8 )alkyl-(C 1 -C 8 )cycloalkyl. (C 6 -CI2 aryl), (CI -CBlkyl-(C6-CI2 aryl), -0-(Cl.g alkyl). (C3.8 cycloalkyl). -0-(CIlIg alkyl)(C3.8 cycloalkyl), -0-(C 6 -12 aryl), -O-(C 1 8 alkyl)-aryl, or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -C 12 aryl),(C 1 -C3)a!kyl, (C 1 -C 3 alkoxy, halogen, trifluoromethyl, Z is Cl, N3, S' (C 6 -CI 2 )aryl, 0 or II H CEN 0- R 0 Ar in a suitable organic solvent to yield a compound or compounds represented by the structure shown in figure BG 1 I. below, 0 1ANH 0 R ANH 0 Figure BG 1 3 R 2 x 2 x x x the compounds represented by BG 1 are dissolved in a suitable solvent, to which is added a compound represented by figure GRX, below, N- Figure GRX R 8 Where R 7 and R 8 are defined independentiy and are (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl (C 1 C 8 )alkyl-(C 6 .C 1 2 )aryl; M is Li, Na, or K; the resulting dianion is then reacted with a compound represented by the structure shown in -74- figure GYX, R6 R4 Y R 5 Figure GYX where, R 4 R 5 and R 6 independently are H, (CI-C 8 )alkyl. (CI -CR)alkyl (C 6 -C 1 2 )aryl, or the aryl is substituted with one to three of any of the following groups: (C 6 -C 1 2 aryl. C 1 -C3 alkoxy, C 1 -C 3 alkyl, trifluoromethyl, fluoro, chloro, or bromo, but not hydroxy. Y is halogen. -OTs, OMs, or OTf to produce a compound or cornpowaids represented by figure BG 2 1 9 9 9* 9* 9
9. 9 9990 9 9 9999 9* 9. 9 9. 0 0999 0 9. *9 9 9 9 RA KNH 0 R 2 X-R 3 RO R5 A 4 0 Ar<K NH 0 Figure BG 2 1 X-e A 5 R 4 the compound or compounds represented by the structures in figure BG 2 1 are then used according to the process described in claim 3 to create the compound or compounds represented by figure BG 4 1 R 2 -R A I Figure BG 4 1 R N-A where R 9 is H, (C 1 .Cg)alkyl, (C 3 -Cg)cycloalkyl, (C 3 -'C)alkyl-(C 3 -C 8 )cycloalkyl. (C 6 -C 1 2 aryl), (C 1 .C 8 )alkyl-(C 6 -CI 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -CI 2 aryl), (C 1 -C 3 )alkyl, (C 1 -C 3 alkoxy, halogen. trifluoromethyl; the compound represented by figure BG 4 may be then treated with an appropriate reducing agent such as Pearlman's catalyst. 10-20 perctnt palladium hydroxide on charcoal, only where the aryl is bound to the first carbon in the alkyl side chain, to produce the desired compounds. (Chart B Steps 5. The process, of claim 4, for the preparation of a compound or compounds represented by the structures on the left side, or the right side of figure BG 5 1 below, or, if the starting materials are' a racemnic mixture, the reaction may produce a mixed ratio of compounds represented on both sides of the figure BG 5 1 below, R5G' H R NH Figure BG 51 R 2 00** 2 :1 6i 6 wher R 50 is H 1 -Cg)alkyl, (C 3 .Cg)cycloalkyl, (C 1 -C 8 )alkyl-(C 3 -Cg)cycloalkyl, (C 6 C 1 aryl), (C 1 -Cg)alkyl-(C 6 -C 1 2 aryl), or the aryl or alkyl is substituted with one to thre of the following groups, (C 6 -C 12 aryl), (C 1 -C 3 )alkyl, (C 1 -C 3 alkoxy, halogen, trifluoromethyl. where R 2 is 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl-(C 3 -C 8 )cycloalkyl, 20 (C 6 -CI 2 aryl)- (C 3 -CS)alkyl.(C 6 -C 1 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -C 12 aryl), (C 1 .C 3 )alkyl., (C 1 -C 3 alkoxy, halogen. :trifluorornethyl; where R 6 is H. 1 -C 8 )alcyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl-(C 3 .Cg)cycloalkyl. (C 6 -C 12 W7y1). (CI-C 8 )alkyl-(C 6 -CI 2 aryl). or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -CI 2 aryl), (C 1 -C 3 )alkyl, (C 1 -C 3 alkoxy, halogen, trifluoromethyl; which comprises a series of reactions beginning with subjecting a compound or compounds represented by the structure shown in figure AGO, below. 0 R 2 W Figure AGO N- N and W is Cl, Br, -SR 2 or figure to right, 1J to treatment with R 3 XLi where R3 is (C 1 -C 8 )alkyl, -(C 3 'C 8 )cycloalkyl, (C 1 -C 8 )alkyl-(C 3 -C 8 )cycloalkyl. -(C 6 .C 12 aryl), (CI-C 8 )alkyl-(C 6 -C 1 2 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -C 1 2 aryl), (CI-C 3 )alkyI, (C 1 -C 3 alkoxy. halogen-?trifluoromcthyl; and X is O NH, S, to obtain a compound represented by the structure shown in figure AGI(a), below 0 3 *.RFigure AGI(a) which is then reacted with a compound represented by the deprotonated form of the structure formed in figure AG below, or its appropriate isomer, 14 12 RR 13l~R1 NH 2 04 Figure AG I R 14 R 12 where R 12 is (C 6 -CI 2 aryl), or the aryl is substituted with one to three of the following groups. (C 1 -C 3 )alkyl, (CI-C 3 alkoxy, halogen, trifluoromethyl; R 13 is H, (C 1 -CS)alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl*(C 3 -C 8 )cycloalkyl, (C 6 C 12 aryl), (C 1 -C 8 )alkyl-(C 6 -C 12 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -CI 2 aryl), (C 1 -C 3 )alkyl, (C 1 -C 3 alkoxy, halogen, trifluoromethyl, where R 1 4 is (CI-C 8 )alkyl, (C 3 -CB)cycloalkyl, (C 1 -C 8 )alkyl-(C 3 -C 8 )cycloalkyl, (C 6 -C 1 2 aryl), (C 1 -Cg)alkyl-(C 6 -C 12 aryl). or the aryl or alkyl is substituted with one to three of the following groups. (C 6 -CI 2 aryl). (C 1 -CI)alkyI. (C]-C 1 alkoxy. halogen. trifluoromethyl; to produce the compounds represented by the structures shown in figure below, 14 1R1 R 13 3 2 3 C2 F0tR X R X Figure AG 2 the compounds of figure AG 2 are then deprotected under hydrogenolysis conditions with a reducing agent such as Pearlman's catalyst, 10 percent palladium hydroxide on charcoal, to obtain the compounds. represented by the structures shown in figure AGI. below. isH 2 N oH 2 N 0 R 2 X 3 R2 Xi\F 20 Figure AG 3 the compounds represented by the structure shown in figure AG., are used according to the procedures described in claim 4, to produce the desired compounds represented by figure BG 5 1 6. A process of claim 1 for the preparation of (SS)-l-benzyl.2-oxo-3.(l'- (carboxybenzylamidno)ethyl)pyrrolidine, shown below, 78 v-hich comprises subjecting ethyl I .tcarboxybcnzylamlno)cthvil 4-peflteloatC. bclow. S a *SS to o7nnolysis, followed by reaction with benzylamine. under reducing conditions. such as with sodium cya~no borohydride, sodium triacetoxy borohydride or sodium borohydride. (in order of preference) at 00-500C. or cool temperature to control heat, to produce the desired compounds'. (Char BXI step 3) 7. A process of claim 2 for the preparation of (R.SI-l-benzyl-3-l'- (methylamidno)ethyl)pyrrolidine, shown below, a S .5 *5S5 S. S. S S. S. a S S which comprises miating (S,S)-lI-benzyl-2-oxo 1'.(carboxybenzylanino)cthyl)pyTrolidilc, shown below. 0 with a reducing agent. such as with such as LiAIH 4 DIBAL or Borane in a suitable solvent suchasTHF. at 0' 50*C, or a cool epraueto control heat, to prodiice the desired compounds (Chart BXI step 4) 8. The process of claim 6 followed by the process described in claim 7 for preparing I1. -79. bcnzyl-3-(1'- methylamino)ethyl )pyrrolidine. shown below, (Chart BXI, step 3 4) 9. A process of claim 4 for the preparation of (RS)-3-(I'-(mcthylamino)ethyl)pyrrolidinc, shown below, *r 9. which comprises, using starting material represented by the structure shown below. H 2 N 0 and reacting this compound with the structure below, in THF in the presence of 1 M KHC0 3 to produce ethyl (S)-3-carboxybcnzylaminobutyrate. shown below, 0 0 0 Ok N H 0 which is added to a suitable solvent, then adding Lithium Diisopropyl Amide, reacting the resulting diianion with allylbromide to produce ethyl '-(carboxybenzylamino)ethyl)-4- pcntenoate. shown below. S S S. S S S S. S *5 S S S ethyl (S.S)-2-(P-(carboxyhenxlamino)cthyl)4-.pcntenoatc, is then treated according to the process of claim 8 to produce (RS)-l-bcnzyl-3-(1 '-(methylaminokthyl)pyrrolidine. shown below. NH (R.S)-l-benzyl.3-(l '-(methylamino)ethyl)pyrrolidine is then hydrogenolytically cleaved with an 20 appropriate reducing agent. such as Pearlman's catalyst. 10-20 percent palladium hydroxide on charcoal in an appropriate solvent such as EtoH to produce the desired compounds. (Chart BXl steps 2, 3. 4. A process of claim 5 for the preparation of (RS)-3-(I'-(methylamino)ethyl)pyrrolidine. shown below, NH NH which comprises subjecting ethyl crotonate to treatment with the lithium amide prepared from (S)-((l-phenyl)ethyl)(benzyl)amine. shown below. to produce ethyl (S.S)-3-(((l'-phenyl)ethyl)(benzyl ))aminobutyrate. shown below. S.. be C CC C. *r C Ce.. C C C 15 O which is deprotected with a reducing agent such as Pearlman's catalyst. 10-20 percent palladium hydroxide on charcoal, in an appropriate solvent, such as EtOH, to obtain ethyl aminobutyrate, shown below. H 2 ,N 0 which is then reacted with benzyl choloroformate. to produce ethyl(S)-3- carboxybenzylaminobutyrate, which is then treated according to the process described in claim 9. (Chart AXI step 1. 2. 3 and chart BXI step 1. 2. 3. 4,
11. A compound or compounds represented by the structures shown in figure BG3- 1 shown -82- below, 0 0 Figure BG 3 N H 0 1 H 0 RR/ R 2 9 .9 N -R N N-R R 6 R 6 where R 1 is H. -CS)alk)vI, (CI-C 8 )cvcloalkyl. 1 -C,~alkvI-(CI-C 8 )cv.cloalk%,I, -C 1 cycloalkyl). ar1).) *O-(CI. 8 alkvi)-aryl. or the aryl or alkyl is substituted with one to three of the following groups, (C 1 aryl).(C 1 -C3)alkyl, alkoxy. halogen. trifluoromethyl. where R 2 is I-Cg)alkyl, (C 3 -C 8 )cycloalkyl. (C;-CSalky1.(C3-C 8 )cycloalkyI. (C 6 -CI 2 aryl). (Cl-C 8 )alkyl.(C 6 -C 12 aryl). or the aryl or alkyl is substituted with one to hre of the following groups. (C 6 -C 12 aryl). (C 1 -C 3 )a&kyl, (CI-C 1 j) alkoxy. halogen. trifluoromethyl; .9*where R6 is (CI-C 8 )alkyl. (C 3 -C 8 )cycloalk-yi. (C 1 -C)akvl-(CI-C 8 )cvcloalkyl, (C 6 -C 12 l-C 8 )alkyl-(C 6 -C 12 aryl). or the aryl or alkyl is substituted with one to three of the following groups. (C 6 12 aryl). (C 1 -C 3 )alkyl,. -(C 1 -C 3 I) alkoxy. halogen. trifluoromethyl. where R 9 is H. -(C 1 -C 8 )alkl, (C 3 -C 8 )cycloalkyl. (C 1 -C 8 )alkyl-(C 3 -C 8 )cycloalkyl, a*l) C 8aky9C- (C 6 -C 1 2 arl. -C-C 8 )ly-C- 1 aryl). or the aryl or alkyl is substituted with one to thre of the following groups, (C 6 -C 12 aryl), (C 1 -C 3 )alkyl. (C 1 ulkoxy. halogen. trifluoromethyl.
12. A compound of claim I I that is I -benzyl-2-oxo-3.( I' (carboxybenzylanhinokethyl)pyrrolidine. shown below, 83
13. A compound rcprcscntcd by the structure or structures shown in figure Mi. 1 sow N H 5 N I [IF ure-R.G.I R 292 9 R N -R N P 6 6 whecre R' 0 is H, (C 1 -C8)alkyl. (C3-Cg)cycloalkyl. (C 1 .Cx)alkyl-(C3-C)cycloalk'. 1C C 12 aryl), (C 1 -C 8 )alkyl-(C 6 -C 12 aryl), or the aryl or alkyl is suhstitutcd with one to threc of thc following groups. (C 6 -C 1 2 aryl),(C 1 -C 3 )alkyl, (C 1 alkoxy. halogcn, Lrifluoromrcthyl, where R 2 is (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C_'alkyl-(C 3 -C 8 )cycloalkyl. (C 6 -C 12 aryl), (C 1 -C 8 )alkyl-(C 6 -C 1 2 aryl, or the aryl or alkyl is substituted with one to the of the following groups, (C 6 -CI 2 (CI-C 3 )alkyl, (C-C 3 aoXhlgn where R 6 is H, (C 1 -Cg)ialkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl-(C 3 -C 8 )cycloalkyl. (C 6 -C 1 2 aryl), (C 1 -C,)alkyl-(C 6 -C 12 az-yl), or the aryl or alkyl is substituted with onc to three of the following groups, (C 6 -C 1 2 aryl), (C 1 -C 3 )alkyl, (C 1 -C 3 alkoxy. halugen. ON'*2 trifluoromethyl;, 4. 9* where R, is H4, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl. (C 1 -C 8 )alkyl-( C)cy'cloalkyl. (C 6 C 1 2 aryl), (C 1 -Cg)alkyl-(C 6 -C 12 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C 6 -C 1 2 aryl), (C 1 -C)lkl (C 1 -C 3 alkoxy. halogen, trifluoromethyl, except that when R 5 'I is H or C alkyl, then at least one of eteR 2 6' 9 1-8 eihe R or R or R shall not also be H or C 1 8 alkyl.
14. A compound of claim 13 that is I -bcnzyl-3-( I -(mcthylamino)cthyl)pyrTolidine. shown below, N NHN DATED: 30 December 1999 PHILLIPS ORMONDE FITZPATRICK Attorneys for: PHARMACIA UPJOHN COMPANY