Ethyl nipecotate

Enantiopure (R)- and (S)-nipecotic acid (Nip) derivatives 64 were obtained following classical resolution of ethyl nipecotate with either enantiomer of tartaric acid and successive recrystallization of the corresponding salts [153, 154, 156] or by resolution of racemic nipecotic acid with enantiomerically pure camphorsul-fonic acid [154]. N-Boc protected pyrrolidine-3-carboxylic acid (PCA) 65 for the synthesis of homo-ohgomers [155] was prepared by GeUman from trans-4-hydroxy-L-prohne according to a known procedure [157]. 

The drug candidate 1 was prepared from chiral cyclopentanol 10 as shown in Scheme 7.3. Reaction of 10 with racemic imidate 17, prepared from the corresponding racemic benzylic alcohol, in the presence of catalytic TfOH furnished a 1 1 mixture of diastereomers 18 and 19 which were only separated from one another by careful and tedious chromatography. Reduction of ester 18 with LiBH4 and subsequent Swern oxidation gave aldehyde 20 in 68% yield. Reductive animation of 20 with (R)-ethyl nipecotate L-tartrate salt 21 and NaBH(OAc)3 and subsequent saponification of the ester moiety yielded drug candidate 1. 

Chiral ethyl nipecotate L-tartrate salt 21 was not available on a large scale. 

The completion of the synthesis of 1 required installation of the (R)-nipecotic moiety. The original method used (R)-ethyl nipecotate L-tartrate 21, which was commercially available, but the availability of this intermediate on multi-kilogram scale required long lead times and cost was a major factor. In addition, it was also discovered that saponification of the ethyl ester in the final stages of the synthesis, as shown in Scheme 7.3, was accompanied by small amounts of epimerization at the carboxylic acid center of 1, resulting in diastereomeric contamination of the final product. 

Ethyl nipecotate, e249 Ethyl oleate, e230 Ethyl oxirane, e3... 

Ethyl nicotinate, e215 Ethyl nipecotate, e205 Ethyl oleate, el 89... 

Methyl-2-bromothiophene Ethyl nipecotate Nipecotic acid ethyl ester Sodium hydroxide... 

This compound was without further purification used for coupling with ethyl nipecotate. 

With most methyl esters, hydrazinolysis occurs at room temperature however, resin-bound methyl 3-aminobenzoate, ethyl nipecotate, and proHne methyl esters require heating (45-50 °C) for 7-8 h. 

FIGURE 9.1 The structure of ethyl nipecotate, including the numbering of the relevant atoms for the assignment of the H and CNMR spectra. 

Consider the molecule ethyl nipecotate (Figure 9.1). After we draw the molecule and number the atoms whose resonances we will assign, we can make a table with seven columns for the NMR data and another table with five columns for the NMR data (Tables 9.1 and 9.2). 

Table 9.1 Format for table to contain predicted and observed NMR shifts (5), integrals (int), and multiplicities (mult) for ethyl nipecotate. pred d = predicted, obs d = observed, d = doublet, q = quartet. ...

Figure 9.3 shows the gCOSY spectrum of ethyl nipecotate. The gCOSY spectrum contains the 1-D spectrum along its diagonal and... 

We have now assigned all of the resonances of ethyl nipecotate, and we leave as an exercise the identification of the cross peaks between the resonances from the H4 s and H5 s. 

Now we are ready to examine the actual 1-D spectrum of ethyl nipecotate (Figure 9.4). On the basis of its downfreld position and... 

I FIGURE 9.5 The 2-D HMQC NMRspectrum of ethyl nipecotate in CDCI3,... 

Ethyl nipecotate contains only one nonprotonated carbon site. Because of this lack of multiple nonprotonated carbon sites, it fails to serve as a useful example for illustrating the power of the 2-D heteronuclear multiple bond correlation (HMBC) experiment in assigning the resonances from nonprotonated C s. As a general rule, a molecule with few nonprotonated carbons will rarely require data from the HMBC experiment. 

Scheme 6.46. Chemoselective preparation of tertiary amines, (a) Utilization of a REM resin to synthesize multiply substituted tertiary amines. R and R = Me, (CH2)2Ph, tetrahydroisoquinoline, ethyl Isonipecotate, ethyl nipecotate R = allyl, 4-NO2-C6H4. (b) Selective quaternizatlon of diamines to yield tertiary amines. R = CHPh2, CONHPh R = Me, allyl.

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