Beating the hydrogen bond: First selective and high-yielding N-acylation process for an α,β-diaminoalcohol

Article abstract of DOI:10.1021/op0601464

The first selective and high-yielding N-acylation of an α,β-diaminoalcohol is reported, as well as the first use as N-acylation agent of a 5-mercaptobenzothiazolyl thioester of an α,β-unsaturated carboxylic acid. Other conventional coupling methods (acid

Full text of DOI:10.1021/op0601464

Organic Process Research & Development 2006, 10, 1184−1191
Beating the Hydrogen Bond: First Selective and High-Yielding N-Acylation
Process for an r,â-Diaminoalcohol
Thomas Storz,* Peter Dittmar, Dominique Grimler, and Maria Testa
Process R&D, Chemical & Analytical DeVelopment, NoVartis Pharma AG, CH-4002 Basel, Switzerland
Heiko Potgeter and Didier Chappel
Analytical R&D, Chemical & Analytical DeVelopment, NoVartis Pharma AG, CH-4002 Basel, Switzerland
Otto Hartmann, Daniel Niederer, and Martin Tru¨by
Pilot Plant Operations, Chemical & Analytical DeVelopment, NoVartis Pharma AG, CH-4002 Basel, Switzerland
Abstract:
While there is certainly ample precedence for selective
N-acylations of simple R- and â-aminoalcohols,11 to our
astonishment, we found very little published material on the
N-acylation of R,â-diaminoalcohols: Charlton et al.12 had
reported the N-acylation of diaminoalcohols A and B by a
benzoic acid carbonyl imidazolide in the presence of tri-
ethylamine; Naylor et al.13 synthesized the amide D from
the cyclic diaminoalcohol C; and Chandrakumar et al.14
obtained the amino acid amide F from the diaminoalcohol
E (Scheme 1). To the best of our knowledge, these are the
only reported examples of this reaction type to date.15 They
all appear to proceed in mediocre to poor yield (18-42%,
Scheme 1).
The first selective and high-yielding N-acylation of an r,â-
diaminoalcohol is reported, as well as the first use as N-acylation
agent of a S-mercaptobenzothiazolyl thioester of an r,â-
unsaturated carboxylic acid. Other conventional coupling
methods (acid chloride, uronium salt, carbonyl diimidazole,
phosphonium salt) gave low yields respectively difficult to purify
mixtures of N- and O,N-diacylated product (4b), due to the
unusually high reactivity of the primary hydroxyl group caused
by an intramolecular hydrogen bond to the dialkylamino moiety
in the â-position. Both the cinnamic thioester preparation and
the coupling step were safely and reproducibly scaled up to a
chromatography-free process in the pilot plant.
Our goal was to find a reproducible, high-yielding, and
selective method for the N-acylation of this type of diami-
noalcohol.
Introduction
Vicinal diaminoalcohols as well as 1,2- and 1,3-aminoal-
cohols and their derivatives are among the most widely used
structural motives in active pharmaceuticals ingredients,
agrochemicals, and chiral auxiliaries alike.1-8 For one of our
development projects,9 we were faced with the seemingly
simple challenge of attaching a substituted cinnamic acid
side chain9 to the primary amino group of the R,â-diamino
alcohol 110 (Figure 1).
Results and Discussion
Our starting material, the chiral diaminoalcohol dihydro-
chloride 1, was conveniently obtained from the N,O-
isopropylidene-, N-BOC-protected aminoalcohol precursor
216 by simultaneous N,O-deprotection with a small excess
of concentrated, aqueous hydrochloric acid in n-butyl acetate.
(11) For instance, see: (a) Smeets, J. W. H.; Weber, P. G. PCT Int. Appl. 1993
WO 9320038. (b) Eckstein, M.; Cegla, M.; Gajewczyk, L. Pol. J. Chem.
1984, 58, 607. (c) Sakurai, K.; Ishida, K.; Ogura, M. Eur. Pat. Appl. EP
835864 19980415. (d) Bouzoubaa, M.; Leclerc, G.; Ehrhardt, J. D.;
Andermann, G. Bull. Soc. Chim. Fr. 1985, 1230. (e) Gotor, V. Org. Process
Res. DeV. 2002, 6, 420. (f) Ranu, B. C.; Dutta, P.; Sarkar, A. J. Chem.
Soc., Perkin Trans. 1 2000, 2223. (g) Morcuende, A.; Ors, M.; Valverde,
S.; Herradon, B. J. Org. Chem. 1996, 61, 5264. (h) Kunieda, T.; Higuchi,
T.; Abe, Y.; Hirobe, M. Tetrahedron Lett. 1980, 21, 3065. (i) Hanessian,
S.; Patil, G. Tetrahedron Lett. 1978, 19, 1035.
(12) Vicker, N.; Burgess, L.; Chuckowree, I. S.; Dodd, R.; Folkes, A. J.; Hardick,
D. J.; Hancox, T. C.; Miller, W.; Milton, J.; Sohal, S.; Wang, S.; Wren, S.
P.; Charlton, P. A.; Dangerfield, W.; Liddle, C.; Mistry, P.; Stewart, A. J.;
Denny, W. A. J. Med. Chem. 2002, 45, 721.
(13) Naylor, A.; Judd, D. B.; Lloyd, J. E.; Scopes, D. I. C.; Hayes, A. G.; Birch,
P. J. J. Med. Chem. 1993, 36, 2075.
* To whom correspondence should be addressed. Amgen Inc., One Amgen
Center Drive, P.O. Box, Thousand Oaks, CA 91320-1799, U.S.A. E-mail:
tstorz@amgen.com.
(1) Katz, S. J.; Bergmeier, S. C. Tetrahedron Lett. 2002, 43, 557.
(2) Rozzell, J. D. Applied Biocatalysis in Specialty Chemicals and Pharma-
ceuticals; ACS Symposium Series No. 776; American Chemical Society:
Washington, DC, 2001; pp 191-199.
(3) Mulzer, J. In StereoselectiVe Synthesis; Ottow, E., Schoellkopf, K., Schulz,
B.-G., Eds.; Springer-Verlag: Germany, 1993; pp 37-61.
(4) Bartoli, G.; Cupone, G.; Dalpozzo, R.; De Nino, A.; Maiuolo, L.; Procopio,
A.; Tagarelli, A. Tetrahedron Lett. 2002, 43, 7441.
(5) Vicario, J. L.; Badia, D.; Carrillo, L.; Reyes, E.; Etxebarria, J. Curr. Org.
Chem. 2005, 9, 219.
(6) Ishizuka, T. Yakugaku Zasshi 1997, 117, 339.
(7) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.; Stuermer,
R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788.
(8) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(9) Expert Opin. Ther. Pat. 2002, 12, 1741.
(10) Howe, T.; Bhalay, G.; Le Grand, M.; Storz, T. PCT Int. Appl. 2002, WO
0204420; U.S. Patent 6,670,379, 2003.
(14) Chandrakumar, N. S.; Yonan, P. K.; Stapelfeld, A.; Savage, M.; Rorbacher,
E.; Contreras, P. C.; Hammond, D. J. Med. Chem. 1992, 35, 223.
(15) SciFinder, Beilstein and various reaction database (RXLBRO, MDL)
searches, August 2006.
(16) Obtained via reductive amination of (R)-Garner’s aldehyde17 with 4-(4-
chlorobenzoyl)-piperidine,18 isolated as dibenzoyl(hemi)-L-tartaric acid salt.10
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10.1021/op0601464 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/27/2006

Figure 1. Diaminoalcohol 1.
Scheme 1. Reported diaminoalcohol N-acylations to date
Scheme 2. Synthesis of diaminoalcohol 1
Under these conditions, the dihydrochloride of 1 precipitates
in near quantitative yield and excellent purity, whereas the
dibenzoyl tartaric acid remains behind exclusively in the
butyl acetate mother liquor, obviating the need for additional
purification of 1. This deprotection scaled up very well in
the pilot plant (Scheme 2).19
Early discovery stage coupling studies of the diaminoal-
cohol 1 with 3′-cyano-6′-methoxy-cinnamic acid 310 employ-
ing different activating agents (via acid chloride, carbodi-
imides, CDI, various uronium, and phosphonium reagents)
had shown unsatisfactory yields and selectivities (data not
shown). For a quick initial multigram scale-up, a uronium
salt coupling procedure was used (Scheme 3).24
The unsatisfactory throughput on a 10-g scale (43%) was
well in line with the poor yields seen in the few known
examples (vide supra, Scheme 1). However, upon scaling
up from 10 g to 70 g, the yield dropped even further, as
extensive chromatographic purification was needed to re-
move unwanted N,O-diacyl side product25 4b and upgrade
(20) Dondoni, A.; Perrone, D. Tetrahedron Lett. 1997, 38, 499.
(21) Qiao, L.; Kozikowski, A. P.; Olivera, A.; Spiegel, S. Bioorg. Med. Chem.
Lett. 1998, 8, 711.
(22) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998,
120, 5597.
(23) Gordon, K.; Bolger, M.; Khan, N.; Balasubramanian, S. Tetrahedron Lett.
2000, 41, 8621.
(24) Before the introduction of the dibenzoyl-hemi(L)tartaric acid salt isolation
for the precursor 2, on discovery chemistry stage, the aminoalcohol 1 was
made via a different process (data not shown), hence the lower ee for 1.
(17) Garner, P.; Park, J. M. Org. Synth. 1992, 70, 18.
(18) Helsley, G. C.; Gardner, B. A.; Strupczewski, J. T. Ger. Offen. 1977, DE
2708913.
(19) This constitutes a less hazardous, more practical, and cheaper (n-butylacetate
vs dioxane, aq HCl vs HCl-gas and TFA) deprotection protocol than the
HCl(gas)/dioxane or TFA/CH2Cl2 conditions often used (see refs 20-23)
and might be of general usefulness for the deprotection of N-BOC-,
N-isopropylidene-protected water soluble amines. It also enabled potential
recycling of the chiral auxiliary acid (not investigated further at this stage).
Vol. 10, No. 6, 2006 / Organic Process Research & Development
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Scheme 3. TBTU-coupling of diaminoalcohol 1 with acid 3
Scheme 4. Synthesis of cinnamic thioester 5
the quality of 4 to the desired level. It became clear that for
further scale-up, a higher-yielding, more selective and robust
coupling method was urgently needed.
event, synthesis of the desired thioester was best ac-
complished by reaction of 3 with bis(2-mercaptobenzothia-
zolyl)disulfide37 [(BThS)2] in the presence of triphenylphos-
phine and N-methylmorpholine (Scheme 4).26
The cinnamic thioester 510,40 conveniently precipitated as
a stable, crystalline solid from the reaction mixture and was
isolated by a simple filtration step in good yield and excellent
purity in the pilot plant without any trace of the 1,4-addition
product. Since R,â-unsaturated acids obtained via transition
metal-catalyzed cross-coupling reactions often contain trace
metal impurities, this sequence is especially gratifying since
the 2-mercaptobenzothiazole liberated in situ acts as a
transition/heavy metal scavenger.41
Mercaptobenzothiazolyl-2-thioesters of substituted acetic
acids have been used very successfully for N-acylations of
not only sensitive API intermediates, mostly in the area of
â-lactam antibiotics26-28 but also for ACE inhibitors,29
â-lactones,30 and quinolone antibiotics.31 However, thioesters
of R,â-unsaturated acids such as N-acylating agents have not
been reported,15 perhaps because it was felt that 1,4-addition
of the liberated thiol to the unsaturated carbonyl group would
be a side reaction difficult to overcome in those systems.32
We wanted to investigate the mercaptobenzothiazolyl-2-
thioester of the cinnamic acid 3 as a potentially more
selective36 reaction partner for the aminoalcohol 1. In the
Considering that thiazolidin-2-thione is known to react
with activated carboxylic acids to a thionoamide instead of
a thioester42,43 and 2-mercaptobenzothiazole has been re-
ported to give a mixture of thionoamide and thioester with
(25) All attempts to selectively hydrolyse the N,O-diacyl product back to the
desired N-acyl product were unsuccessful and led to decomposition.
(26) Defossa, E.; Fischer, G.; Gerlach, U.; Hoerlein, R.; Isert, D.; Krass, N.;
Lattrell, R.; Stache, U.; Wollmann, T.; Liebigs Ann. Chem. 1996, 1743.
(27) Wei, C. C.; Bartkovitz, D.; West, K. F. J. Org. Chem. 1992, 57, 4027.
(28) Tsubouchi, H.; Tsuji, K.; Yasumura, K.; Tada, N.; Nishitani, S.; Minami-
kawa, J.; Ishikawa, H. Tetrahedron: Asymmetry 1994, 5, 441.
(29) Prasad, K. K.; Chen, K. M. U.S. Patent 4,847,384, 1989.
(30) Rao, M. N.; Holkar, A. G.; Ayyangar, N. R. Chem. Commun. 1991, 1007.
(31) Li, J.; Lu, R.; Yang, A.; Zhang, J. Heterocycl. Commun. 2004, 10, 447.
(32) High yielding 1,4-additions of 2-mercaptobenzothiazole to Michael acceptors
such as 4-vinylpyridines,33 S-vinyl-sulfimines,34 and acrylates/acrylamide35
have been reported.
(33) Katritzky, A. R.; Takahashi, I.; Marson, C. M. J. Org. Chem. 1986, 51,
4914.
(34) Yamamoto, T.; Okawara, M. Chem. Lett. 1975, 581.
(35) Anan’eva, K. V.; Rozhkova, N. K. Khim. Geterotsikl. Soedin. 1986, 554.
(36) S-Benzoyl-2-mercaptobenzothiazole has been reported to give exclusively
the N-benzoylation product with 2-amino-1-propanol: Lee, J. H.; Kim, J.
D. Bull. Korean Chem. Soc. 1997, 18, 442.
(37) Mercaptobis(benzothiazolyl)disulfide (CAS Reg. No. 120-78-5) is a very
cheap bulk chemical produced on a multiton scale (used as vulcanization
additive in the rubber industry38). For the use of this disulfide in the in situ
generation of a mercaptobenzothiazol-2-yl-thioester-Ti-enolate en route to
â-lactams, see ref 39.
(38) Freytag, H.; Kempermann, T.; Fromandi, G. French Patent FR 1455518,
1966.
(39) Sharma, S. D.; Kanwar, S. Synlett 2004, 2824.
(40) Prior to our study, only a single account on the preparation of a
2-mercaptobenzothiazolylcinnamic acid thioester via a different method
appeared in the literature: Moharram and Assad reported the synthesis of
the 4-nitro- and 4-chlorocinnamic thioesters of 2-mercaptobenzothiazole in
45 and 60% yield, respectively, by reacting the corresponding cinnamic
acid chloride with the sodium salt of 2-mercaptobenzothiazole in benzene
(only elemental analysis and mp given; no NMR, IR, or crystal structure
data reported; hence thione structure can not be excluded): Moharram, H.
H.; Asaad, F. M. Egypt. J. Chem. 1989, 32, 367.
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Figure 2. Thioester-thion equilibrium of 5.
acetic anhydride,44 we characterized thioester 5 carefully. In
the solid state, 5 exists exclusively as the thioester, whereas,
in solution, a slow equilibration toward the thermodynami-
cally more stable44 thionoamide takes place (Figure 2).45
Not surprisingly,48 this equilibrium did not have any
bearing on the subsequent N-acylation process (vide infra).
While a solution of the thioester 5 in EtOH (rt and 40 °C)
failed to show any signs of transacylation to ethanol up to
48 h of reaction time, a solvent screening for the coupling
reaction revealed a puzzling finding: even with this relatively
unreactive and usually N-selective36 thioester, considerable
amounts of the N,O-diacyl product 4b were formed; in ethyl
acetate and pyridine, exclusive formation of 4b was observed
(Table 1)!
Table 1. Solvent screening coupling 1 + 5
4
4b
thioester
[A%
[A%
solvent (equiv) base (equiv) T [°C]/t [h]a HPLC] HPLC]
EtOAc
THF
pyridine
DMSO
1.1
1.1
1.3
1.4
NMM (2.0) 2-25, 7
21.6
11.5
8.7
NMM (2.0) 25-43, 17
82
(none)
0-2, 3.5
NMM (1.5) 25, 120
91.9
1.3
a Reaction stopped after time given in table and analyzed by HPLC.
and 1,4-61 aminoalcohols. While the impact of this phenom-
enon on enzyme mechanisms is well recognized in biology
(Serine esterase model),63 surprisingly few reports probe the
practical consequences for synthetic organic transforma-
tions: an early study of Yoshida et al. from 197264 on the
O-benzoylation of 2-dimethyl- and 2-diethylamino-1-ethanols
At this point we suspected that our results, taken with
the equally disappointing (18-41%) yields in the few
examples known (vide supra, Scheme 112-14), pointed to an
intramolecular N-acceptor hydrogen bond in these systems,
which would be expected to greatly enhance the nucleophi-
licity of the primary hydroxyl group and favor the formation
of the N,O-diacyl side product 4b (Figure 3).
(49) Mulla, S. T.; Jose, C. I.; J. Chem. Soc., Faraday Trans. I 1986, 82, 691.
(50) Prabhumirashi, L. S.; Jose, C. I. J. Chem. Soc., Faraday Trans. II 1975,
71, 1545.
(51) Chitale, S. M.; Jose, C. I. J. Chem. Soc., Faraday Trans. I 1986, 82, 663.
(52) In polar solvents such as alcohols or DMSO, intramolecular hydrogen bonds
usually collapse or are much weaker, as hydrogen bonds to the solvent
dominate; see: (a) Singelenberg, F. A. J.; Lutz, E. T. G.; van der Maas, J.
H.; Jalsovszky, G. J. Mol. Structure 1991, 245, 173. (b) Kramer, R.; Lang,
R.; Brzezinski, B.; Zundel, G. J. Chem. Soc. Faraday Trans. I 1990, 86,
627. (c) Sasanuma, Y.; Hattori, S.; Imazu, S.; Ikeda, S.; Kaizuka, T.; Iijima,
T.; Sawanobori, M.; Azam, M. A.; Law, R. V.; Steinke, J. H. G.
Macromolecules 2004, 37, 9169.
Intramolecular hydrogen bonding has been recognized62
as the dominating noncovalent interaction in 1,2-,59 1,3-,60
(41) 2-Mercaptobenzothiazole readily forms complexes with many transition
metals; see: Wang, B.; Ma, H.; Yang, S. Transition Met. Chem. (London)
1995, 20, 391. A 2-mercaptobenzothiazole clay (a) and poly(vinylene)
polymer (b) have been proposed as matrices for sorption of heavy metals:
(a) Dias Filho, N. L.; Gushikem, Y.; Polito, W. L. Anal. Chim. Acta 1995,
306, 167. (b) Antokolskaya, I. I.; Volf, L. A.; Danilova, E. Y.; Emets, L.
V.; Myasoedova, G. V.; Naumenko, E. A.; Sawin, S. B.; Trutneva, L. M.;
Shvoeva, O. P.; Shcherbinina, N. I. Russian Patent SU 1015651, 1992.
(42) Nagao, Y.; Kawabata, K.; Seno, K.; Fujita, E. J. Chem. Soc., Perkin Trans.
I 1980, 2470.
(53) On a relative price scale, the coupling reagent pair PPh3/(BThS)2 ranges
among the most economic choices (chloroformates/imidoyl chlorides/
carbodiimides):
(43) Nagao, Y.; Inoue, T.; Fujita, E.; Terada, S.; Shiro, M. J. Org. Chem. 1983,
48, 132.
(44) Nishio, T.; Shiwa, K. Heterocycles 2004, 62, 313.
(45) By the same token, the R-amino acid benzothiazole thioesters reported by
Singh et al.46 were most likely the corresponding thione isomers by virtue
of the reported 13C NMR data (δ 203-204 ppm more characteristic of
thiocarbonyl than of thioester- or ester-carbonyl47). The thioester is the
kinetic product, and the thione, the thermodynamic product44; we observed
that the rate of equilibration increases with the solvent polarity (fastest in
pyridine, slowest in chloroform).
(46) Singh, G. P.; Godbole, H. M.; Nehate, S. P.; Mahajan, P. R. Synth. Commun.
2005, 35, 243.
(47) Pretsch, E.; Simon, W.; Seibl, J.; Clerc, T. Spectral Data for Structure
Determination of Organic Compounds, 2nd ed.; Springer-Verlag: Berlin,
1989; C203.
(54) Above 240 °C, an exothermic decomposition sets in from the melt liberating
∼ -115 kJ/kg. In the wetcake, a dynamic DSC reveals that exothermic
decomposition may set in earlier (-175 kJ/kg, at ∼160 °C).
(55) In an experiment where the cinnamic acid was added all in one portion, the
observed ∆Tmax was e15 °C.
(56) At ∼200 °C, the melt exhibits exothermic decomposition (-255 ( 15 kJ/
kg), most likely related to acrylic polymerization since the cinnamic acid 3
shows the same type of behavior in the dynamic DSC above the melting
point (226-228 °C): decomposition around ∼250 °C, -274 kJ/kg.
(57) In more polar solvents, such as DMSO and pyridine, a gradual equilibration
to the thione sets in (slow emergence of second set of signals).
(48) N-Acylthiazolidin-2-thiones have been reported to undergo facile transa-
midation with primary and secondary amines; see: (a) Nagao, Y.; Seno,
K.; Miyasaka, T.; Fujita, E. Chem. Lett. 1980, 159. (b) Joyeau, R.; Brown,
E. Bull. Soc. Chim. Fr. 1982, 391.
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Figure 3. Postulated intramolecular hydrogen bond in 4.
Figure 4. IR (CH2Cl2) of 4 (left, in CH2Cl2) and of 3-diethylamino-1-propanol (right, in C2Cl4)49 in the O-H stretching region.
found significant rate increases in cases where intramolecar
hydrogen bonding was strong; similar observations were later
reported for the O-acylation rates of dimethylaminoalcohols
of varying chain lengths with N-acetylimidazole (De Clercq
et al.65) and hexanoic acid (Bach et al.66), whereas Hine et
al.67,68 investigated o-(dimethylaminomethyl)benzyl alcohol
as a serine esterase model and demonstrated its effectiveness
as a nucleophilic catalyst for the hydrolysis of p-nitrophenyl
acetate.
In fact, dilute solution IR spectra of the aminoalcohol 4
(free base) confirmed our hypothesis (Figure 4). In keeping
with the findings of Jose and Mulla49 on the hydrogen
bonding behavior of 3-diethylamino-1-propanol and similar
aminoalcohols, the relative population of intramolecularly
hydrogen-bonded species versus free species in 4 was found
to be much larger as typically observed for â-alkoxy50 or
â-halogeno51 alcohols (cf. Figures 3 and 4).
(58) Above 170 °C, a slow exothermic decomposition sets in from the melt,
liberating ∼ -110 kJ/kg.
(59) For 2-aminoalcohols, see: (a) Casy, A. F.; Hassan, M. M. A. Can. J. Chem.
1969, 47, 1587. (b) De Roos, A. M.; Bakker, G. A. Recl. TraV. Chim. Pays-
Bas 1962, 81, 219. (c) Shergina, N. I.; Kashik, T. V.; Kositsyna, EÄ . I.;
Dmitrieva, Z. T.; Trofimov, B. A. IzV. Akad. Nauk SSSR, Ser. Khim. 1969,
2703. (d) Houriet, R.; Ru¨fenacht, H.; Carrupt, P.-A.; Vogel, P.; Tichy, M.
J. Am. Chem. Soc. 1983, 105, 3417. (e) Ma´te´-Divo´, M.; Barcza, L. ACH-
Models in Chemistry 1994, 131, 769.
(60) For 3-aminoalcohols, see: (a) De Roos, A. M.; Bakker, G. A. Recl. TraV.
Chim. Pays-Bas 1962, 81, 219. (b) Ma´te´-Divo´, M.; Barcza, L. ACH-Models
in Chemistry 1994, 131, 769. (c) Przeslawska, M.; Melikowa, S. M.;
Lipkowski, P.; Koll, A. Vib. Spectrosc. 1999, 20, 69. (d) Bartoli, G.; Grilli,
S.; Lunazzi, L.; Massaccesi, M.; Mazzanti, A.; Rinaldi, S. J. Org. Chem.
2002, 67, 2659. (e) Koll, A.; Karpfen, A.; Wolschann, P. J. Mol. Struct.
2006, 790, 55.
(61) For 4-aminoalcohols, see: (a) De Roos, A. M.; Bakker, G. A. Recl. TraV.
Chim. Pays-Bas 1962, 81, 219. (b) Delacroix, O.; Andriamihaja, B.; Picart-
Goetgheluck, S.; Brocard, J. Tetrahedron 2004, 60, 1549.
Based on this finding, we decided to further investigate
the coupling reaction in a hydrogen bond donor solvent, i.e.,
an alcohol.52 Furthermore, we speculated that, by only
partially neutralizing the acid in the aminoalcohol dihydro-
chloride 1, the crucial N-acceptor hydrogen bond believed
to be responsible for hydroxyl group activation should
collapse both in the starting material and in the product
(Figure 5), thereby minimizing the formation of the unwanted
N,O-diacylated side product 4b.
Table 2 summarizes the experiments that confirmed our
hypothesis; in the finalized coupling process (Table 2, entry
5), only 1 equiv of base was used (Scheme 5).
The coupling scaled up very well in the pilot plant; after
salt formation and the final polish recrystallization from
(62) Bergmann et al. were the first to recognize this intramolecular interaction
during their study of N-alkyl-substituted 2-aminoalkanols: Bergmann, E.
D.; Gil-Av, E.; Pinchas, S. J. Am. Chem. Soc. 1953, 75, 68.
(63) In several key metabolic enzymes (including acetylcholine esterase and
R-chymotrypsin), the enzyme mechanism involves attack onto a substrate
carbonyl by a serine hydroxyl group activated by a hydrogen bond to an
imidazole from a histidine residue; see: (a) Hartely, B. S. Annu. ReV.
Biochem. 1960, 29, 45. (b) Zeffren, E., Hall, P. L., Eds. The study of enzyme
mechanisms; Wiley-Interscience: New York, 1973; Chapter 9. (c) Scheiner,
S.; Lipscomb, W. N. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 432. (d) Naray-
Szabo, G. THEOCHEM 2000, 500, 157.
(64) Yoshida, J.; Ichimura, K. Bull. Chem. Soc. Jpn. 1972, 45, 3215.
(65) Madder, A.; De Clercq, P. J.; Maskill, H. J. Chem. Soc., Perkin Trans. II
1997, 851.
(66) Breitenlechner, S.; Bach, T. Z. Naturforsch. 2006, 61b, 583.
(67) Hine, J.; Khan, M. N. J. Am. Chem. Soc. 1977, 99, 3847.
(68) Hine, J.; Khan, M. N. Indian J. Chem. 1992, 31B, 427.
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Figure 5. Monohydrochloride reverses the crucial N-H-O hydrogen bond in starting material and product: from acceptor to
donor.
1
Table 2. Screening of base amount
thioester T [°C]/
determined on a Bu¨chi apparatus. H NMR spectra were
recorded at 400 MHz, and 13C NMR spectra were recorded
at 100 MHz on a Bruker DPX 400/500 instrument. Assign-
ments were confirmed by the appropriate 2D NMR experi-
ments. IR spectra were measured on a Bruker IFS660
spectrometer. Exact mass determinations were performed on
a Micromass QtoF Ultima API instrument (a soln of 0.1%
caffeine was used for lock mass correction). For reaction
monitoring, a Hewlett-Packard Series 1050 HPLC system
with either a SymmetryShield RP-18 or YMC ODS-AQ
column (150 mm × 3 mm, 3 µm particle size) was used
(0.01 M (NH4)2HPO4 or KH2PO4-CH3CN gradient). The
enantiomeric purities of 1, 2, and 4 were determined at λ )
245 nm on a Hewlett-Packard Series 1050 or 1100 HPLC
system using a Chiralpak AD column (Daicel, 250 mm ×
4.6 mm, 10 µm particle size); mobile phase: n-hexane/
isopropanol/diethylamine 20:80:0.1, isocratic.
4
N,O-diacyl
solvent (equiv) base (equiv) t [h]a [A% HPLC] [A% HPLC]
iPrOH 1.1
NMM (2.0) 2-25, 8
NMM (4.0) 50, 8
NMM (2.0) 36, 24
NMM (1.25) 45, 27
73.1
92.1
94.4
96.0
97.7
0.9 (+16.5% 1)
EtOH
EtOH
EtOH
EtOH
1.1
1.1
1.1
4.7
2.4
0.9
0.3
1.05 NMM (1.0) 45, 24
a Reaction stopped after time given in table and analyzed by HPLC.
ethanol, we obtained 3.8 kg (76% overall yield [lab: 79%]
from 1) of the tartrate 4 in previously unattainable purity
(>98% HPLC 4b: <0.2%, >99% ee), effectively more than
tripling the overall yield of the discovery route and eliminat-
ing all chromatographic purifications. The thioester activation
in combination with the alcoholic solvent and substoichio-
metric (0.5 equiv) base proved crucial for success. Attempts
to extend these coupling conditions to other activation
methods (acid chloride, CDI, DIC) met with failure due to
increased side product formation with these coupling agents
in alcoholic solvents.
(2S)-2-Amino-3-(4-(4′-chlorobenzoyl)piperidin-1-yl)-1-
propanol Dihydrochloride (1).10 To a suspension of the
dibenzoyl-hemi(L)tartrate 210 (75.0 g, 60.86 mmol) in n-
butylacetate (750 mL) was slowly added concd aq (32%)
hydrochloric acid (35.8 mL, 0.3645 mol) at 20-22 °C. The
resulting thin white suspension was stirred at 20-25 °C for
an additional 2.5 h, when HPLC showed completeness of
the deprotection reaction. The suspension was cooled to 0-2
°C, stirred at this temperature for 90 min, and filtered. The
filter cake was washed with ice-cold n-butyl acetate (4 ×
50 mL), and the colorless filtercake was dried at 45-50 °C
under a vacuum overnight to give 1 as a white, crystalline
solid (44.8 g, 99% yield) [Pilot Plant: 6.3 kg, 93%]. HPLC
[265 nm] 98.1% [Pilot Plant: 98.8%], 97% ee [Pilot Plant:
>99% ee], mp (DSC) 239-240 °C, DSC [dry product]
(dynamic): no exotherm up to 235 °C,54 DSC (isotherm,
100 °C, 24 h): no exotherm observed [dynamic DSC of
stressed sample: no significant changes vs DSC of fresh
Conclusions
The first robust, selective, and high-yielding process for
kilogram-scale, chromatography-free preparation of an R-N-
acyl-R,â-diaminoalcohol (4) has been developed. We propose
this novel and economic53 coupling procedure using the S-2-
mercaptobenzothiazolylester in an alcoholic solvent with
half-stoichiometric base as a selective and efficient N-
acylation method for R-aminoalcohols with an alkylamino
substituent in the â-position, as in those systems the
activation of the hydroxyl group by intramolecular N-
acceptor-hydrogen bonding is expected to be a general
phenomenon.49,60,64-66 Furthermore, we demonstrated the first
use of a S-mercaptobenzothiazolyl thioester of an R,â-
unsaturated (cinnamic) ester as N-acylating agent and found
that 1,4-addition of the liberated mercaptane is not a limiting
side reaction for this coupling system.
1
sample]. H NMR (400 MHz, DMSO) δ 1.95-2.12 (m, 4
H, 2 × NsCH2sCH2 (piperidine)), 3.05-3.90 (br m, 10
H, 3 × NsCH2 (piperidine), H3N+sCH, HOsCH2, CHs
CdO), 5.62 (br s, 1 H, OsH, exch. with NaOD), 7.62/8.03
(AA′BB′, 4 H, 4-ClsPh), 8.65 (br s, 3 H, H3N+, exch. with
NaOD), 10.78 (br s, 1 H, HN+ (piperidine), exch. with
NaOD). 13C NMR (100 MHz, DMSO) δ: 26.3, 26.4, 41.0,
48.5, 52.4, 53.9, 57.0, 60.4, 129.9, 131.2, 134.6, 139.3, 200.8.
Experimental Section
Starting materials, reagents, and solvents were obtained
from commercial suppliers and were used without further
purification. All the melting points are uncorrected and
Vol. 10, No. 6, 2006 / Organic Process Research & Development
•
1189

Scheme 5. Optimized coupling of diaminoalcohol 1 with thioester 5
IR (neat, FT-IR microscope, cm-1): 3543m, 3314s, 2981s,
2956s, 2933s, 2888s, 2759m, 2676sh, 2623m/s, 2496s,
2411sh, 1681ss, 1589m/s, 1464m/s, 1434m, 1308m, 1281m,
1217m, 1153w, 1093m, 1052m, 1012w, 939m, 846m.
Elemental analysis calcd. for C15H23Cl3N2O2 (369.72): C,
48.73%; H, 6.27%; N, 7.58%. Found: C, 48.85%; H, 6.11%;
N, 7.57%.
mide (L)-Tartrate (4).10 To a suspension of the dihydro-
chloride 1 (9.24 g, 25 mmol) in ethanol abs (250 mL) at
20-22 °C was added N-methylmorpholine (2.76 mL, 25
mmol). Under vigorous stirring, the temperature of the white
suspension was slowly increased to 45 °C over a 30 min
period. The first aliquot of thioester 5 (4.40 g, 12.5 mmol)
was added (washed powder addition funnel with 20 mL
ethanol abs). The yellow, thin suspension was stirred
vigorously at 45 °C. In process, controls were taken in 2.5
h intervals. As soon as the HPLC showed no more increase
in 4, the second aliquot of the thioester 5 was added (4.40
g, 12.5 mmol), and stirring was continued until HPLC
indicated g98% conversion of 1 (typically after 22-24 h).
The yellowish suspension was then cooled to 20-22 °C,
N-methylmorpholine (2.76 mL, 25 mmol) was added, and
the mixture was filtered over a glass frit (medium porosity).
The filter residue was washed with ethanol abs (15 mL),
and the yellowish filtrate was evaporated to a small volume.
After a solvent switch to methylene chloride, the clear
solution (300 mL) was washed at 20-22 °C with 10% aq
sodium carbonate (2 × 100 mL), 10% aq sodium chloride
(100 mL), and water (100 mL). The acidity of the combined
aq phases was adjusted to pH 11 by addition of solid sodium
carbonate, and the aq phases were extracted with methylene
chloride (100 mL). The combined organic phases were
filtered over celite and reduced to a small volume. After a
solvent switch to ethanol, the clear solution (130 mL) was
heated to 55 °C. Under vigorous stirring, a solution of (L)-
tartaric acid (4.50 g, 30 mmol) in ethanol abs (100 mL) was
added over a 15 min period. The mixture was quickly heated
to 70 °C and stirred until a clear, homogeneous solution
formed (∼30 min). Over a 1.5 h period, the solution was
slowly cooled to 0 °C and stirred at this temperature for 45
min. The solid was filtered off and washed with cold ethanol
abs (20 mL). The wetcake was suspended in ethanol abs (200
mL) and heated to reflux under stirring. More ethanol abs
was slowly added until a clear solution formed (total
volume: 610 mL). The hot solution was filtered, and the
clear, yellowish filtrate was concentrated under reduced
pressure (300 mbar, 65-67 °C) to 60% of the original
volume. The concentrate was cooled to 30 °C over a 1.5 h
period (seeded with 100 mg of 4 at 60 °C) and then to 0 °C
over a 2 h period and stirred at 0-2 °C for 1.5 h. The
suspension was filtered, and the filter cake was washed with
ice-cold ethanol abs (20 mL) and dried at 45-50 °C under
a vacuum overnight to afford recrystallized 4 as an off-white,
crystalline solid (12.43 g, 79% yield from 1) [Pilot Plant:
(E)-3-(5-Cyano-2-methoxyphenyl)thioacrylicAcidS-Ben-
zothiazol-2-yl-thioester (5).10 A suspension of triphenylphos-
phine (28.4 g, 0.108 mol) and bis(2,2′-benzothiazolyl)-
disulfide (36.0 g, 0.108 mol) in methylene chloride (540 mL)
was stirred vigorously under a nitrogen atmosphere for 1.5
h at 20-22 °C. To the resulting thin, caramel suspension
was added 5-cyano-2-methoxyphenylacrylic acid 310 (20.0
g, 98.4 mmol, [46 ppm Pd]) in four equal portions over a 1
h 20 min period. Under these conditions, the reaction is
nearly addition controlled and only very weakly exothermic
(temp rises by ∼3-4 °C after each addition and then drops
back to ambient temp over an ∼20 min period).55 After the
last addition, the yellow suspension was stirred for an
additional 45 min. N-Methylmorpholine (10.82 mL, 98.4
mmol) was added, and stirring was continued for another
hour, when HPLC showed g99%. The suspension was
cooled to 0-4 °C, stirred for 30 min at 0-4 °C, and filtered.
The filter cake was washed with ice-cold methylene chloride
(1 × 60 mL), and the yellowish filtercake was dried at 35
°C under a vacuum overnight to afford 5 as a slightly
yellowish, crystalline solid (26.95 g, 78% yield) [Pilot
Plant: 3.0 kg, 68%], HPLC [265 nm]: 97.3% [Pilot Plant:
95.3%], Pd e 1 ppm, mp 183-185 °C. DSC [dry product]
(dynamic): no exotherm up to 185 °C.56 DSC (isotherm,
100 °C, 24 h): no exotherm observed [dynamic DSC of
stressed sample: no significant changes vs DSC of fresh
sample]. 1H NMR (400 MHz, CDCl3) δ 4.03 (s, 3 H, OCH3),
3
7.0 (d, 1 H, CHd, Jtrans ) 16.0 Hz), 7.06 (d, 1 H, CHarom
3
[OMe(CN)Ph], J ) 8.4 Hz), 7.48-7.58 (m, 2 H, CHarom
3
[BTh]), 7.73 (d, 1 H, CHarom [OMe(CN)Ph], J ) 8.4 Hz),
7.88 (s, 1 H, CHarom [OMe(CN)Ph]), 7.95-8.12 (m, 2 H,
3
CHarom [BTh]), 8.03 (d, 1 H, CHd, Jtrans ) 16.0 Hz). 13C
NMR (100 MHz, CDCl3) δ 56.7, 105.3, 112.5, 118.6, 121.6,
123.6, 124.1, 126.0, 126.1, 126.8, 127.8, 133.9, 136.5, 137.3,
139.7, 151.9, 158.2 (NdCsS), 162.1, 185.1 (CdO).57
Elemental analysis calcd. for C18H12N2O2S2 (352.43): C,
61.34%; H, 3.43%; N, 7.95%; S, 18.20%. Found: C, 61.12%;
H, 3.65%; N, 7.63%; S, 17.87%.
(E)-N-{(S)-1-[4-(4-Chlorobenzoyl)-piperidin-1-yl-meth-
yl]-2-hydroxyethyl}-3-(5-cyano-2-methoxyphenyl)acryla-
1190
•
Vol. 10, No. 6, 2006 / Organic Process Research & Development

3.85 kg, 77%], HPLC [245 nm]: 98% [Pilot Plant: 98%]
(residual N,O-diacyl product: <0.3% [245 nm], residual
2-mercaptobenzothiazole: <60 ppm), >99% ee [Pilot Plant:
>99% ee]. Mp 165-166 °C. DSC (dynamic): no exotherm
up to 160 °C;58 DSC (isotherm, 130 °C, 12 h): no exotherm
observed [dynamic DSC of stressed sample: no significant
changes vs DSC of fresh sample]. Salt stoichiometry
titrations (NaOH + HClO4): 1:1 salt (tartrate). For NMR-
spectrum analysis, a small sample was freebased (10% Na2-
CH2 (piperidine)), 43.6 (CHsCdO), 49.5 (HNsCH), 53.78/
53.84 (2 × NsCH2 (piperidine)), 57.2 (NsCH2sCH), 59.9
(OCH3), 62.9 (CH2sOH), 104.1 (Cipso arom. (cyanophenyl)),
113.7 (CHarom), 119.7 (CtN), 125.7 (dCsCipso arom.), 126.6
(OdCsCd), 129.8 (2 × CHarom (chlorophenyl)), 131.0 (2
× CHarom (chlorophenyl)), 132.5 (dCsCipso), 133.0 (CHarom),
135.2, 135.5 (2 × Cipso (chlorophenyl), 138.9 (CHarom), 161.5
(Cipso (methoxyphenyl)), 165.4 (HNsCdO), 202.5 (4-ClPhs
CdO). IR [free base] (KBr, cm-1) 3433w/br, 3387m, 3354m,
2945w, 2926w, 2225m, 1664ss, 1623m, 1601s, 1588m,
1527s, 1495s, 1462w, 1267ss, 1208w, 1092m, 1015w, 974m/
s, 821m. HR-MS [free base]: exact mass calculated for
C26H28ClN3O4 × H+, 482.1841; found, 482.1842.
1
CO3/CH2Cl2). H NMR (400 MHz, DMSO) [free base] δ
1H NMR (400 MHz, DMSO) δ 1.50-1.82 (m, 4 H, 2 ×
NsCH2sCH2 (piperidine)), 2.11-2.23 and 2.89-3.01 (2 m,
4 H, 2 × NsCH2 (piperidine), 2.40, 2.50 (2 dd, 2 H, Ns
CH2sCHsN, J ) 7.0 Hz, J ) 12.5 Hz), 3.35-3.41 (m, 1
H, CHsCdO), 3.45-3.53 (br m, 2 H, CH2sOH, collapses
to AB-system with D2O), 3.98 (s, 3 H, OCH3), 3.98-4.08
(m, 1 H, HNsCH), 4.82 (br s, 1 H, OsH, exchanged with
D2O), 6.88 (d, 1 H, HsCdC, Jtrans ) 15.9 Hz), 7.27 (d, 1
Acknowledgment
We are grateful to Mr. Michael Haller for skillful technical
assistance and to Dr. Jacques Wiss for DSC measurements.
Drs. Thomas Allmendinger and Ching-Pong Mak are thanked
for their continued support and encouragement.
H, HsCarom, J ) 8.7 Hz), 7.56 (d, 1 H, HsCdC, Jtrans
)
15.9 Hz), 7.61 (AA′-system, 2 H, HsCarom [chlorophenyl]),
7.83-7.90 (m, 2 H, HsCarom + HsNsCdO, collapses to
a simpler m [1 H] with D2O), 7.96-8.03 (m, 3 H, HsCarom).
13C NMR (100 MHz, DMSO) [free base] δ 29.3 (NsCH2s
Received for review July 23, 2006.
OP0601464
Vol. 10, No. 6, 2006 / Organic Process Research & Development
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1191