Process development of the synthetic route to (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine

Article abstract of DOI:10.1021/op010068e

The optically active (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine (1) is the amine moiety of a novel and potent dopamine (D₂ and D₃) and 5-HT₃ receptors antagonist AS-8112, which is a clinical candidate expected to be abroad antiemetic agent. Process development of an effective synthetic route to the optically active amine 1 from N-Cbz- and N-Ts-L-serine methyl esters was undertaken. In two potential scale-up processes, the route from N-Ts-L-serine methyl ester (21) was chosen because of its better overall yield (>30% yield for seven steps) and handling. The optically active amine 1 with high purity (>99.5% ee)was prepared via the reaction of the key intermediate N-Ts-aziridine 23 with EtNH₂ and successive LiAlH₄ reduction without racemization. Moderate scale-up synthesis of the amine 1 and AS-8112 by condensation of 1 and 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid is described.

Full text of DOI:10.1021/op010068e

Organic Process Research & Development 2002, 6, 28−35
Process Development of the Synthetic Route to
(R)-6-Amino-1-ethyl-4-methylhexahydro-1,4-diazepine
Yoshimi Hirokawa,* Tamaki Horikawa, Hideto Noguchi, Katsuhisa Yamamoto, and Shiro Kato
DiscoVery Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Enoki 33-94, Suita, Osaka 564-0053, Japan
Abstract:
The optically active (R)-6-amino-1-ethyl-4-methylhexahydro-
1,4-diazepine (1) is the amine moiety of a novel and potent
dopamine (D2 and D3) and 5-HT3 receptors antagonist AS-8112,
which is a clinical candidate expected to be a broad antiemetic
agent. Process development of an effective synthetic route to
the optically active amine 1 from N-Cbz- and N-Ts-
methyl esters was undertaken. In two potential scale-up
processes, the route from N-Ts- -serine methyl ester (21) was
L-serine
L
chosen because of its better overall yield (>30% yield for seven
steps) and handling. The optically active amine 1 with high
purity (>99.5% ee) was prepared via the reaction of the key
intermediate N-Ts-aziridine 23 with EtNH2 and successive
LiAlH4 reduction without racemization. Moderate scale-up
synthesis of the amine 1 and AS-8112 by condensation of 1 and
5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid
is described.
Figure 1.
Introduction
was selected as a promising clinical candidate.4-6 The
production of a large amount of AS-8112 was required for
development needs of toxicology, formulation, and pharma-
cology. To meet these production requirements, process
development of a scalable synthetic route to the amine
moiety, (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diaz-
epine (1), and the carboxylic acid part, 5-bromo-2-methoxy-
6-methylaminopyridine-3-carboxylic acid,7 of AS-8112 was
essential. This work describes an efficient synthetic route to
optically active 1 from L-serine methyl ester hydrochloride
(10).
Potent and selective 5-HT3 receptor antagonists are known
to be effective for the control of chemotherapy- or radiation-
induced nausea and vomiting.1 On the other hand, selective
dopamine D2 receptor antagonists have been shown to be
effective for the treatment of symptoms of chronic upper
gastrointestinal distress and for the prevention of nausea and
vomiting resulting from a variety of causes.2a,b Thus, dual
inhibitors at 5-HT3 and dopamine D2 receptors are expected
to be broad antiemetic agents. In the course of our studies
on the structure-activity relationships of a potent and
selective 5-HT3 receptor antagonist DAT-582,3 novel benz-
amides with an alkyl group at the 1- and 4-nitrogen atoms
in the 6-aminohexahydro-1,4-diazepine ring of the amine
moiety were found to show dopamine D2 receptor inhibitory
activity along with a potent 5-HT3 receptor inhibitory activity
and to cause only weak central nervous system depression
and extrapyramidal syndromes.4 Finally, AS-8112, (R)-5-
bromo-N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-
methoxy-6-methylaminopyridine-3-carboxamide difumarate,
Results and Discussion
Synthesis of (R)-6-Amino-1-ethyl-4-methylhexahydro-
1,4-diazepine (1) from N-Benzyloxycarbonyl-l-serine Meth-
yl Ester. We have reported the several synthetic methods
of the structurally novel hexahydro-1,4-diazepine derivatives
2. The reaction of the ethylendiamines 3 with the activated
C3 components 4-9 gave 2 in low overall yield, but that
with 1,3-dichloroacetone was unsuccessful. In addition,
attempts at resolution of 2 (R ) Me, R1 ) Et, X ) NH2, Y
) H) into its enantiomers using various resolving agents also
failed (Scheme 1).8
* Corresponding author. Telephone: +81-06-6337-5902. Fax: +81-06-6338-
7656. E-mail: yoshimi-hirokawa@dainippon-pharm.co.jp.
(1) King, F. D.; Jones, B. J.; Sanger, G. J. 5-Hydroxytryptamine-3 Receptor
Antagonists; CRC Press Inc.: Boca Raton, 1994.
(2) (a) Brogden, R. N.; Carmine, A. A.; Heel, R. C.; Speight, T. H.; Avery, G.
S. Drugs 1982, 24, 360. (b) Davis, R. H.; Clench, M. H.; Mathiae, J. R.
Dig. Dis. Sci. 1988, 33, 1505.
On the other hand, we previously reported the other
synthetic method of (R)-6-amino-1-methyl-4-(3-methylbenz-
(3) Harada, H.; Morie, T.; Hirokawa, Y.; Yoshida, N.; Kato, S. Chem. Pharm.
Bull. 1995, 43, 1364.
(4) Hirokawa, Y.; Yoshida, N.; Kato, S. Bioorg. Med. Chem. Lett. 1998, 8,
1551.
(5) Kato, S.; Fujiwara, I.; Yoshida, N. Med. Res. ReV. 1999, 19, 25.
(6) Yoshikawa, T.; Yoshida, N.; Oka, M. Br. J. Pharmacol. 2001, 133, 253.
(7) Hirokawa, Y.; Horikawa, T.; Kato, S. Chem. Pharm. Bull. 2000, 48, 151.
28
•
Vol. 6, No. 1, 2002 / Organic Process Research & Development
10.1021/op010068e CCC: $22.00 © 2002 American Chemical Society and The Royal Society of Chemistry
Published on Web 01/04/2002

Scheme 1
Scheme 3
Scheme 4
Scheme 2
yl)hexahydro-1,4-diazepine, which is the amine moiety of
DAT-582, from 10, through the N-Cbz-amide 11 and the
2,3-diaminopropanes 12 and 13 (Scheme 2).9 As in this
synthesis the nucleophilic substitution reaction of 13 with
1.04 mol equiv of 3-methylbenzylamine gave the corre-
sponding 1-(3-methylbenzyl)aminopropane derivative in only
27% yield (see Scheme 2); reaction of 13 with EtNH2 was
investigated. The process of this reaction was optimized using
ca. 5 mol equiv of 70% aqueous EtNH2 solution in EtOH,
and (S)-2-Cbz-amino-3-(N-Boc-N-methyl)amino-1-ethylami-
nopropane (14) was obtained in 95% yield. Acid hydrolysis
of 14 produced the 1,2,3-trisubstituted aminopropane 15.
Cyclization of 15 into the hexahydro-1,4-diazepine ring was
carried out as described before.10 Namely, 15 was treated
with glyoxal in the presence of BH3‚Et3N complex or NaBH3-
CN directly to give 6-Cbz-amino-1-ethyl-4-methylhexahydro-
1,4-diazepine (16) in 66% yield. Hydrogenolysis of 16 over
Pd/C afforded the desired optically active (R)-6-aminodiaz-
epine 1 in quantitative yield (Scheme 3). This compound
was identified with the sample obtained from (R)-6-amino-
1-methyl-4-(3-methylbenzyl)hexahydro-1,4-diazepine,11 on
1
the basis of H NMR comparison.
On the other hand, reaction of 14 with ethyl bromoacetate
gave the aminoacetate 17 in 87% yield. After deprotection
of Boc group of 17, intramolecular cyclization of the resultant
aminoacetate 18 into the hexahydro-1,4-diazepin-3-one ring
via the corresponding aminoacetic acid 19 was examined.
Unfortunately, alkaline hydrolysis of 18 did not give the
aminoacetic acid 19. Treatment of 18 with NaOEt in EtOH
at room temperature produced the hexahydro-1,4-diazepin-
3-one 20 as crystals in 44% yield. Finally, borane reduction
of 20 gave the hexahydro-1,4-diazepine 16 in 51% yield
(Scheme 4).
Although a sequence of this process from L-serine methyl
ester with Cbz group was sufficient for small-scale synthesis
of 1, it was inefficient for the preparation of large amounts.
Particularly, borane reduction of 11 to 12 on kilogram-scale
caused a considerable decrease in yield (<30%). Our interest
(8) (a) Kato, S.; Harada, H.; Morie, T. J. Heterocycl. Chem. 1995, 32, 637. (b)
Harada, H.; Hirokawa, Y.; Morie, T.; Kato, S. Heterocycles 1995, 41, 363.
(c) Harada, H.; Morie, T.; Hirokawa, Y.; Kato, S. Chem. Pharm. Bull. 1996,
44, 2205.
(9) Harada, H.; Morie, T.; Kato, S. Chem. Pharm. Bull. 1998, 46, 1160.
(10) Harada, H.; Morie, T.; Suzuki, T.; Yoshida, T.; Kato, S. Tetrahedron 1998,
54, 10671.
(11) Hirokawa, Y.; Morie, T.; Yamazaki, H.; Yoshida, N.; Kato, S. Bioorg. Med.
Chem. Lett. 1998, 8, 619.
Vol. 6, No. 1, 2002 / Organic Process Research & Development
•
29

Table 1. Reaction conditions for amidation of 21
Scheme 5
Scheme 6
optical
purity
of 22c
(% ee)
reaction
solventb temperature time (h)
run
reagenta (equiv)
1
2
3
4
5
6
7
8
MeNH2‚HCl (1.1) + Et3N MeOH
rt
rt
20
2
4
2
1
4
1.5
4
no reaction
89
d
95
43
76
91
98
40% aq NH2Me (5)
40% aq NH2Me (5)
40% aq NH2Me (5)
40% aq NH2Me (5)
40% aq NH2Me (3)
40% aq NH2Me (5)
40% aq NH2Me (5)
MeOH
MeOH
MeOH
MeOH
MeOH
THF
ca. -5 °C
ca. 5 °C
reflux
rt
rt
THF
ca. 5 °C
a 1.0 g (3.7 mmol) of N-(p-toluenesulfonyl)-L-serine methyl ester (21) with
98% ee was used. b 5 mL was used. c Measured by HPLC analysis of the crude
reaction mixture without work-up. Product was not isolated. d 21 did not react
under these conditions.
has then focused on the discovery of an alternative synthetic
route which could eventually be used for the manufacture
of the optically active amine 1.
Large-Scale Synthesis of (R)-6-Amino-1-ethyl-4-me-
thylhexahydro-1,4-diazepine (1) from N-(p-Toluenesul-
fonyl)-l-serine Methyl Ester (21). To improve the yield in
reduction of the amide functionality, the N-protecting group
of L-serine methyl ester was changed from a Cbz group into
a Ts group. This change did not affect the reduction
conditions. Treatment of L-serine methyl ester hydrochloride
(10, >99.5% ee) with TsCl in the presence of Et3N gave
N-Ts-L-serine methyl ester (21)12 in a quantitative yield
without racemization. The reaction conditions for the prepa-
ration of the N-methylcarboxamide 22 from 21 were then
examined (Table 1). Reaction of 21 with 1.1 mol equiv of
MeNH2 generated by MeNH2‚HCl and Et3N in MeOH as a
solvent did not proceed (run 1). On the other hand, in the
reaction with 5 mol equiv of 40% aqueous MeNH2 solution
in MeOH at room temperature, 21 reacted smoothly (2 h)
and the target product 22 was produced although slight
racemization was detected by HPLC (89% ee, run 2). Several
recrystallizations of 22 with 89% ee from AcOEt did not
cause any increase in enantiomeric excess. To obtain
optically pure 22, details of the reaction conditions were
examined (runs 3-8). Reaction of 21 at lower temperature
(ca. -5 °C) needed longer time (4 h) to proceed completely
(run 3). At ca. 5 °C, the reaction smoothly proceeded (2 h)
giving 22 with 95% ee (run 4). Although the reaction of 21
under reflux temperature was fast, it resulted in considerable
racemization (43% ee, run 5). A decrease in mol equivalency
(5 to 3) of MeNH2 needed longer reaction time (4 h) and
reduced enantiomeric excess (89% to 76% ee, run 6). In a
similar reaction in THF instead of MeOH at room temper-
ature, 21 reacted completely after 1.5 h affording 22 with
91% ee (run 7). Finally, a similar reaction in run 7 at ca. 5
°C provided 22 with 98% ee (run 8). Compound 22 did not
racemize in THF under reflux temperature in the presence
of 5.0 mol equiv of 40% aqueous MeNH2 solution. Among
the reaction conditions studies, we selected the reaction under
ice-cooling in THF (run 8) as the best condition. A large-
scale synthesis of 22 without isolation of 21 starting from
10 gave a similar result to that described above, and 22 with
ca. 99% ee was obtained in 80% yield as crystals (Scheme
5).
We previously reported that Mitsunobu-type reaction of
N-Ts-ethanolamine derivative prepared from N2-Ts-L-aspar-
agine occurred in an intramolecular cyclization fashion to
afford the corresponding activated N-Ts-aziridine derivative
in a good yield without racemization and formed the
dehydroalanine13 as a by-product.14 Mitsunobu-type reaction
of 22 with 84% ee at lower temperature (<5 °C) gave the
N-Ts-aziridine derivative 23 in a good yield without forma-
tion of methyl 2-Ts-aminoacrylate (24). However, when the
inner temperature was elevated to >0 °C, 24 was formed.
Addition of 24 to EtNH2 resulted in racemization of 25. Thus,
a Mitsunobu-type reaction was performed at <-5 °C to
avoid racemization. The exothermic Mitsunobu-type reaction
could be easily controlled by the rate of addition of
diisopropyl azodicarboxylate. Without isolation of the opti-
cally active N-Ts-aziridine 23, the THF solution was treated
with 2.0 mol equiv of 70% aqueous EtNH2 solution at room
temperature for 4 h to provide the C3-N aziridine ring-
opened product 25 as crystals. In this reaction, the formation
of the C2-N aziridine ring-opened product and racemization
were not detected by HPLC. Fortunately, a single recrystal-
lization of the crude product 25 from AcOEt gave the
enantiomerically pure 25 (>99.5% ee) in 56% yield in two
steps. When 22 with 95% ee was used as a starting material,
the yield of 25 was elevated to 70% (Scheme 6).
The optically active aziridine 23 was obtained from the
nonactivated N-tritylaziridine derivative 26 via 27 in a
manner similar to that described in our previous report
(Scheme 7).10
Reduction of the amide functionality of 25 with several
reductants (BH3‚THF complex, LiAlH4, sodium bis(2-
methoxyethoxy)aluminum hydride, DIBALH) was next
examined. Reaction of 25 with LiAlH4 and DIBALH
provided the desired 1,2,3-trisubstituted amine derivative 28
in good yield, although the reaction with DIBALH needed
a longer time (ca. 3 d). As a result, LiAlH4 was selected as
(13) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D.,
Jr.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(12) Stoll, A.; Petrzilka, Th. HelV. Chim. Acta 1952, 35, 589.
(14) Kato, S.; Harada, H.; Morie, T. J. Heterocycl. Chem. 1997, 34, 1460.
30
•
Vol. 6, No. 1, 2002 / Organic Process Research & Development

Scheme 7
Scheme 9
Scheme 8
â-D-glucopyranosyl isothiocyanate (30), respectively (Scheme
9).
Preparation of AS-8112. Condensation of 5-bromo-2-
methoxy-6-methylaminopyridine-3-carboxylic acid7 with 1
prepared above using acid anhydride method in AcOEt
proceeded smoothly, and the desired free base of AS-8112
was obtained in good yield. The free base of AS-8112 was
converted into the corresponding difumarate (AS-8112)
without serious problems (see Scheme 8).
the best reductant of 25. Treatment of 25 with LiAlH4 at ca.
10 °C followed by careful decomposition of excess LiAlH4
using saturated aqueous Rochelle salt (potassium sodium
tartarate tetrahydrate) solution gave the 1,2,3-trisubstituted
aminopropane derivative (the free base of 28) as a water-
soluble pale yellow oil. The oil was then converted into the
crystalline dihydrochloride 28 in 87% yield. It is worth noting
that in the reduction of 25 no racemization was detected by
chiral HPLC and that in the work-up water use must be
strictly limited due to the complete solubility of the free base
of 28 in H2O. Cyclization of the 1,2,3-trisubstituted amino-
propane 28 into the hexahydro-1,4-diazepine ring was carried
out according to our previously described method.10 Reaction
of 28 with 40% aqueous glyoxal solution in the presence of
BH3‚Et3N complex, BH3‚Me3N complex, or NaBH3CN
directly gave the target (R)-1-ethyl-4-methyl-6-(p-toluene-
sulfonylamino)hexahydro-1,4-diazepine (29) as a pale yellow
oil in quantitative yield. The oil was used in the next step
without further purification. Finally, we examined the
detosylation of 29 using HI,15 HBr in AcOH,16 aqueous HBr
solution,17 aqueous HBr solution/P,18 and sodium bis(2-
methoxyethoxy)aluminum hydride.19 As a result, a solution
of 29 in aqueous HBr solution was vigorously heated to
reflux for 3 h, and the crude oil was distilled to produce
(R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine (1) as
a considerably water-soluble pale yellow oil in 77% yield
in >99.5% ee (Scheme 8).
Summary
Effective and convergent process for a large-scale prepa-
ration of the optically active amine, (R)-6-amino-1-ethyl-4-
methylhexahydro-1,4-diazepine (1) was examined. Synthesis
of 1 by a sequence containing (1) methylamidation of N-Ts-
L-serine methyl ester (21) obtained from the commercially
available L-serine methyl ester hydrochloride (10), (2)
formation of the aziridine derivative using Mitsunobu-type
reaction, (3) nucleophilic substitution reaction with EtNH2,
(4) reduction with LiAlH4, (5) reductive cyclization into the
hexahydro-1,4-diazepine ring, and (6) deprotection of N-Ts
group was accomplished. Although the step for the reaction
of 21 with methylamine caused a slight decrease of enan-
tiomeric excess, fortunately, a single recrystallization of the
aziridine-opened product 25 gave this compound in an
optically pure form. Amine 1 which is considerably soluble
in water and is highly pure (>99.5% ee) was prepared in
seven steps from 10 in >30% overall yield. This synthetic
process, thus devised, could dispense with chromatographic
purification and required neither expensive reagents nor
special equipment. Therefore, it should be practical enough
to be operated on an industrial scale. AS-8112, which is a
clinical candidate expected to be a broad antiemetic agent,
was prepared from 1 and the corresponding pyridine-3-
carboxylic acid using acid anhydride method in good yield.
The enantiomeric excess of 1 was measured by the 1-[(R)-
1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl]-3-(2,3,4,6-
tetra-O-acetyl-â-D-glucopyranosyl)thiourea (31). Compound
31 and 1-[(S)-1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl]-
3-(2,3,4,6-tetra-O-acetyl-â-D-glucopyranosyl)thiourea (32)
were prepared by treatment of 1 and (S)-6-amino-1-ethyl-
4-methylhexahydro-1,4-diazepine with 2,3,4,6-tetra-O-acetyl-
Experimental Section
General Procedures. All melting points were determined
on a Yanagimoto micromelting point apparatus without
correction. IR spectra were recorded on a Shimadzu FTIR-
8200PC spectrometer with KBr disks. Atmospheric pressure
chemical ionization and secondary ion mass spectra were
obtained on a Hitachi M-1000 spectrometer. 1H NMR spectra
were recorded on a Varian Gemini-200 (200 MHz) or a
JEOL JNM-LA300 (300 MHz) spectrometer using dilute
solution in CDCl3 unless otherwise stated. Chemical shifts
(15) (a) Portoghese, P. S.; Mikhail, A. A. J. Org. Chem. 1966, 31, 105. (b) Sturm,
P. A.; Henry, D. W.; Thompson, P. E.; Ziegler, J. B.; McCall, J. W. J.
Med. Chem. 1974, 17, 481.
(16) Jordis, U.; Sauter, F.; Siddigi, S. M.; Ku¨enburg, B.; Bhattacharya, K.
Synthesis 1990, 925.
(17) Compagnone, R. S.; Rapoport, H. J. Org. Chem. 1986, 51, 1713.
(18) Poduska, K.; Rudinger, J.; Sorm, F. Collect. Czech. Chem. Commun. 1959,
24, 1993.
(19) Gold, E. H.; Babad, E. J. Org. Chem. 1972, 37, 2208.
Vol. 6, No. 1, 2002 / Organic Process Research & Development
•
31

are expressed as δ (ppm) values from Me4Si as an internal
standard. Optical rotations were measured at 589 nm with a
Jasco P-1020 digital polarimeter. Organic extracts were dried
over anhydrous MgSO4. The solvents were evaporated under
reduced pressure.
analytical sample was obtained by conversion to the ox-
alate: mp 142-144 °C (EtOH). Anal. Calcd for C16H25N3O2‚
2C2H2O4‚0.25H2O: C, 50.47: H, 6.25: N, 8.83. Found: C,
50.55: H, 6.44: N, 8.66.
(b) 1.0 M BH3‚THF complex (33 mL, 33 mmol) was
added dropwise to a solution of 20 (3.4 g, 11 mmol) in THF
(34 mL) at ca. 5 °C. The mixture was stirred at room
temperature for 18 h. After addition of 2N aqueous HCl
solution (17 mL, 34 mmol), the whole was heated to reflux
for 1 h and cooled to room temperature. The reaction mixture
was concentrated to dryness, and the resulting aqueous
solution was washed with AcOEt, basified with solid K2-
CO3(s), and extracted with CHCl3 (100 mL × 3). The extract
was concentrated, and the residue was chromatographed on
silica gel with CHCl3/MeOH ) 30/1 to give 1.8 g (51%) of
16 as a pale yellow oil. The resulting 16 was identified with
(S)-2-Benzyloxycarbonylamino-3-(N-tert-butoxycarb-
onyl-N-methylamino)amino-1-ethylaminopropane (14).
Methanesulfonyl chloride (3.8 g, 33 mmol) was added
dropwise to a mixture of (R)-2-benzyloxycarbonylamino-3-
[N-(tert-butoxycarbonyl)-N-methyl]amino-1-propanol9 (9.3 g,
28 mmol), Et3N (4.2 g, 42 mmol), DMAP (0.19 g, 1.6 mmol),
and CH2Cl2 (100 mL) at ca. 5 °C. The mixture was stirred
at the same temperature for 0.5 h, washed with water, and
concentrated to dryness. The oily residue including (R)-2-
benzyloxycarbonylamino-3-[N-(tert-butoxycarbonyl)-N-me-
thyl]amino-1-methanesulfonyloxypropane (13) was dissolved
in EtOH (50 mL), and then 70% aqueous EtNH2 solution
(8.8 g, 137 mmol) was added. The solution was heated to
reflux for 2 h and cooled to room temperature. The volatiles
were evaporated, and the residue was diluted with 25%
aqueous K2CO3 solution and extracted with CHCl3. The
extract was concentrated to dryness to afford 9.5 g (95%)
of crude 14 as a viscous oil. 1H NMR δ 1.06 (t, 3H, J ) 7.1
Hz, CH2Me), 1.43 (s, 9H, CMe3), 2.5-2.7 (m, 2H), 2.73
(dd, 1H, J ) 3.9 Hz, 11.2 Hz), 2.88 (s, 3H, NMe), 3.2-3.4
(m, 3H), 3.87 (m, 1H), 5.09 (s, 2H, CH2Ph), 7.2-7.4 (m,
5H, Ph); MS m/z 366 (MH+).
(R)-2-Benzyloxycarbonylamino-1-(ethylamino)-3-me-
thylaminopropane (15). A mixture of 14 (7.2 g, 20 mmol),
EtOH (25 mL), and 30% HCl in EtOH (25 mL) was stirred
at room temperature for 3 h. After evaporation of the solvent,
the residue was dissolved in 25% aqueous K2CO3 solution
and extracted with CHCl3. The extract was concentrated to
dryness to give 5.0 g (96%) of 15 as an oil. An analytical
sample was obtained by conversion to the fumarate: mp
156-157 °C (EtOH); 1H NMR (DMSO-d6) δ 1.06 (t, 3H, J
) 7.1 Hz, CH2Me), 2.39 (s, 3H, NMe), 2.6-2.9 (m, 6H),
3.86 (m, 1H), 5.02 (s, 2H, CH2Ph), 6.45 (s, 2H, fumaric acid),
7.2-7.4 (m, 5H, Ph), 7.61 (m, 1H, NH); MS m/z 266 (MH+).
Anal. Calcd for C14H23N3O2‚C4H4O4: C, 56.68: H, 7.14:
N, 11.02. Found: C, 56.48: H, 7.19: N, 10.95.
1
the sample obtained above, on the basis of HPLC and H
NMR comparison.
Ethyl (S)-N-{2-Benzyloxycarbonylamino-3-[N-(tert-
butoxycarbonyl)-N-methyl]amino-1-propyl}-N-ethyl-
aminoacetate (17). A mixture of 14 (10.0 g, 27 mmol), ethyl
bromoacetate (5.5 g, 33 mmol), K2CO3 (11.3 g, 82 mmol),
and methyl ethyl ketone (150 mL) was heated to reflux for
4 h and cooled to room temperature. The reaction mixture
was concentrated to dryness, and the residue was dissolved
in H2O (200 mL) and CHCl3 (100 mL). The organic layer
was separated and washed with brine. The solvent was dried
over anhydrous MgSO4 and evaporated. The oily residue was
chromatographed on silica gel with CHCl3/AcOEt ) 9/1 to
1
give 10.8 g (87%) of 17 as a colorless oil. H NMR δ 1.01
(t, 3H, J ) 7.1 Hz, NCH2Me), 1.25 (t, 3H, J ) 7.1 Hz,
OCH2Me), 1.43 (s, 9H, CMe3), 2.5-2.8 (m, 4H), 2.89 (s,
3H, NMe), 3.33 (s, 2H, NCH2CO), 3.2-3.7 (m, 2H), 3.79
(m, 1H, 6-H), 4.14 (q, 2H, J ) 7.1 Hz, CH2Me), 5.09 (s,
2H, CH2Ph), 5.84 (br, 1H, NH), 7.25-7.4 (m, 5H, Ph); MS
m/z 452 (MH+).
Ethyl (R)-N-(2-Benzyloxycarbonylamino-3-methylamino-
1-propyl)-N-ethylaminoacetate (18). A mixture of 17 (16.2
g, 36 mmol) and 10% HCl in EtOH (150 mL) was stirred at
room temperature for 18 h. After evaporation of the volatiles,
the residue was dissolved in H2O (200 mL). The aqueous
solution was then washed with AcOEt (100 mL), basified
with K2CO3(s), and extracted with CHCl3 (200 mL × 2).
The extract was washed with brine and concentrated to
dryness to give 11.4 g (90%) of 18 as a brown oil, which
(R)-6-Benzyloxycarbonylamino-1-ethyl-4-methylhexahy-
dro-1,4-diazepine (16). (a) 40% aqueous glyoxal solution
(32.7 g, 0.23 mol) and BH3‚Et3N complex (82.2 g, 0.71 mol)
were added successively to a solution of 15 (46.0 g, 0.17
mol) in MeOH (460 mL) at ca. 5 °C. The mixture was stirred
at room temperature for 24 h. After addition of 10% aqueous
HCl solution (500 mL) at ca. 5 °C, the whole was heated to
reflux for 1 h and cooled to room temperature. The mixture
was concentrated, and the resulting aqueous solution was
washed with AcOEt (200 mL × 2), basified with K2CO3(s),
and extracted with CHCl3. The extract was concentrated to
dryness, and the oily residue was chromatographed on silica
gel with CHCl3/MeOH ) 30/1 to afford 33.5 g (66%) of 16
1
was used in the next step without further purification. H
NMR δ 1.01 (t, 3H, J ) 7.1 Hz, NCH2Me), 1.25 (t, 3H, J )
7.1 Hz, OCH2Me), 2.42 (s, 3H, NMe), 2.62 (q, 2H, J ) 7.1
Hz, CH2Me), 2.55-2.8 (m, 4H), 3.03 (s, 2H, CH2CO), 3.76
(m, 1H, 6-H), 4.15 (q, 2H, J ) 7.1 Hz, CH2Me), 5.10 (s,
2H, CH2Ph), 5.65 (br, 1H, NH), 7.25-7.45 (m, 5H, Ph);
MS m/z 352 (MH+).
(S)-6-Benzyloxycarbonylamino-1-ethyl-4-methylhexahy-
dro-1,4-diazepin-3-one (20). NaOEt (4.5 g, 66 mmol) was
added to a solution of 18 (25.0 g, 71 mmol) in EtOH (250
mL) at ca. 5 °C, and the mixture was stirred at room
temperature for 6 h. After acidification with 30% aqueous
HCl solution, the mixture was concentrated. The aqueous
1
as a pale yellow oil. H NMR δ 1.01 (t, 3H, J ) 7.0 Hz,
NCH2Me), 2.34 (s, 3H, NMe), 2.3-2.85 (m, 10H), 3.82 (m,
1H, 6-CH), 5.10 (s, 2H, CH2Ph), 5.86 (br d, 1H, J ) 10 Hz,
NH), 7.25-7.4 (m, 5H, Ph); MS m/z 292 (MH+). An
32
•
Vol. 6, No. 1, 2002 / Organic Process Research & Development

solution was then washed with AcOEt (100 mL × 2),
basified with NaHCO3(s), and extracted with AcOEt (200
mL × 2). The extract was washed with brine and concen-
trated to dryness. The residue was chromatographed on silica
gel with CHCl3/MeOH ) 30/1 to give a solid, which was
recrystallized from Et2O to afford 9.6 g (44%) of 20 as a
colorless prism: mp 85-87 °C. [R]27D ) -11.9° (c ) 1.07,
11.77. Found: C, 48.47; H, 5.98; N, 10.42; S, 11.61. Chiral
HPLC [column, CHIRALCEL OD (Daicel Chemical Indus-
tries, Ltd., Japan); 4.6 mm φ × 250 mm; eluent, hexane/
i-PrOH/CF3CO2H ) 90/10/0.2; flow rate, 0.8 mL/min;
column temperature, 25 °C; detection, 254 nm]; the retention
times of 22 and its enantiomer were 24.9 and 29.2 min,
respectively.
1
MeOH). H NMR δ 1.00 (t, 3H, J ) 7 Hz, CH2Me), 2.61
(S)-N-Methyl-1-(p-toluenesulfonyl)aziridine-2-carboxa-
mide (23). To a solution of (S)-N-methyl-1-tritylaziridine-
2-carboxamide10 (26, 10.0 g, 29 mmol) in a mixture of CHCl3
(30 mL) and MeOH (30 mL) was added dropwise CF3CO2H
(20 mL) kept at 0 °C. The mixture was stirred for 5 h at <5
°C and kept at ca. 5 °C overnight. The solvent was
evaporated <40 °C, and the white solid was dissolved in a
mixture of AcOEt (40 mL) and ice-water (50 mL). The
aqueous layer containing (S)-N-methylaziridine-2-carboxa-
mide trifluoroacetate (27) was separated and basified with
NaHCO3(s) (9.8 g, 0.12 mol). After successive addition of
CH2Cl2 (50 mL) and 1,4-dioxane (100 mL), TsCl (4.5 g, 24
mmol) was added portionwise under ice-cooling. The mixture
was stirred at the same temperature for 5 h, and the volatiles
were evaporated. The resulting precipitate was collected by
filtration to give a wet white solid, which was dissolved in
CHCl3. The solution was washed with brine, dried over
anhydrous MgSO4, and evaporated to give 4.7 g (63%) of
23, which was recrystallized from acetone to afford pure 23
(q, 2H, J ) 7 Hz, CH2Me), 2.69 (dd, 1H, J ) 12 Hz, 3 Hz,
5-CH2), 2.88 (s, 3H, NMe), 2.92 (m, 1H, 5-CH2), 3.18 (d,
1H, J ) 14 Hz, 2-CH2), 3.39 (dd, 1H, J ) 14 Hz, 1.5 Hz,
2-CH2), 3.62-3.46 (m, 2H), 3.9 (m, 1H, 6-CH), 5.08 (d,
1H, J ) 12 Hz, CH2Ph), 5.12 (d, 1H, J ) 12 Hz, CH2Ph),
5.4 (br d, 1H, J ) 7.5 Hz, NH), 7.3-7.4 (m, 5H, Ph); MS
m/z 306 (MH+), 198 (M+ - OCH2Ph); IR 3281, 2955, 1713,
1620, 1541, 1288, 1234, 1030 cm-1. Anal. Calcd for
C16H23N3O3: C, 62.93: H, 7.59: N, 13.76. Found: C, 62.73;
H, 7.61; N, 13.73.
(S)-3-Hydroxy-N-methyl-2-(p-toluenesulfonyl)amino-
propionamide (22). To a suspension of L-serine methyl ester
hydrochloride (10, 500 g, 3.2 mol, >99.5% ee) in CHCl3
(2500 mL) was added dropwise Et3N (683 g, 6.8 mol) at
<-5 °C. The mixture was cooled to ca. -20 °C, and TsCl
(613 g, 3.2 mol) was added portionwise at <-12 °C. The
whole was warmed to ca. 10 °C, stirred at the same
temperature for 1.5 h, and poured into ice-water. After
addition of 35% aqueous HCl solution (150 mL), the
resulting crystals were collected by filtration to give N-(p-
toluenesulfonyl)-L-serine methyl ester (21) as a solid, which
was used in the next step without further purification. A
portion of the crude 21 was purified by recrystallization from
as a colorless crystal: mp 144-145.5 °C. [R]27 ) -63.4°
D
1
(c ) 1.05, MeOH). H NMR δ 2.38 (d, 1H, J ) 4 Hz,
3-CH2), 2.48 (s, 3H, C6H4Me), 2.73 (d, 1H, J ) 6 Hz,
3-CH2), 2.75 (d, J ) 5 Hz, NHMe), 3.28 (dd, 1H, J ) 4 Hz,
7 Hz, 2-CH), 6.3 (br, 1H), 7.39 (d, 2H, J ) 7 Hz, arom H),
7.81 (d, 2H, J ) 7 Hz, arom H); MS m/z 255 (MH+); IR
3248, 3096, 1682, 1651, 1574, 1342, 1323, 1157 cm-1. Anal.
Calcd for C11H14N2O3S: C, 51.95: H, 5.55: N, 11.02; S,
12.61. Found: C, 52.00; H, 5.58; N, 11.02; S, 12.48.
(S)-3-Ethylamino-N-methyl-2-(p-toluenesulfonyl)ami-
nopropionamide (25). Diisopropyl azodicarboxylate (892
g, 4.4 mol) was added dropwise to a solution of 22 (1200 g,
4.4 mol, 84% ee) and Ph3P (1150 g, 4.4 mol) in THF (7000
mL) kept at <-5 °C. The reaction mixture was stirred at
the same temperature for 0.5 h. Then, 70% aqueous EtNH2
solution (567 g, 8.8 mol) was added dropwise at -5 °C to
the solution containing (S)-N-methyl-1-(p-toluenesulfonyl)-
aziridine-2-carboxamide (23), and the mixture was stirred
at room temperature for 4 h. After concentration of the
reaction mixture, the oily residue was dissolved in CHCl3
(4000 mL). Cold (ca. 10 °C) aqueous citric acid solution
[citric acid (700 g, 3.6 mol)/H2O (2500 mL)] was added to
the solution at 5 °C, and the mixture was stirred at room
temperature for 3 h. The aqueous solution was separated and
basified with 48% aqueous NaOH solution. K2CO3(s) (about
1500 g) was added, and the mixture was extracted with
CHCl3 (3000 mL + 200 mL). The combined extract was
concentrated to dryness to give 1080 g of a white solid, which
was recrystallized from AcOEt/hexane to afford 734 g (56%,
AcOEt: mp 90-91 °C [Lit.12 92-93 °C (Et2O)]. [R]27
)
D
-11.3° (c ) 1.52, MeOH). 1H NMR δ 2.42 (s, 3H, C6H4Me),
3.62 (s, 3H, CO2Me), 3.88 (d, 2H, J ) 5.0 Hz, CH2OH),
3.98 (m, 1H), 5.61 (d, 1H, J ) 7.5 Hz, NH), 7.31 (d, 2H, J
) 7.5 Hz, arom H), 7.75 (d, 2H, J ) 7.5 Hz, arom H); MS
m/z 274 (MH+); IR 3491, 3273, 1749, 1331, 1165 cm-1.
Anal. Calcd for C11H15NO5S: C, 48.34: H, 5.53: N, 5.12;
S, 11.73. Found: C, 48.31; H, 5.60; N, 5.17; S, 11.63. Chiral
HPLC [column, CHIRALCEL AS (Daicel Chemical Indus-
tries, Ltd., Japan); 4.6 mm φ × 250 mm; eluent, hexane/i-
PrOH/Et2NH ) 60/40/0.2; flow rate, 1.0 mL/min; column
temperature, 25 °C; detection, 254 nm]; the retention times
of 21 and its enantiomer were 10.0 and 8.2 min, respectively.
To a solution of 21 thus obtained in THF (2500 mL) was
added dropwise 40% aqueous MeNH2 solution (1245 g, 16
mol) at ca. 5 °C. The mixture was stirred at the same
temperature for 2 h and concentrated. After addition of ice-
water, the resulting precipitate was collected by filtration and
recrystallized from AcOEt to give 697 g (80%, ca. 99% ee)
of 22 as a crystal: mp 113-115 °C. [R]27 ) -31.2° (c )
D
1
1.18, MeOH). H NMR δ 2.42 (s, 3H, C6H4Me), 2.77 (d,
3H, J ) 5.0 Hz, NHMe), 3.33 (dd, 1H, J ) 5.0 Hz, 11.0
Hz, CH2OH), 3.73 (m, 1H), 3.90 (dd, 1H, J ) 3.5 Hz, 11.0
Hz, CH2OH), 6.07 (br, 1H, NHMe), 6.92 (br, 1H), 7.32 (d,
2H, J ) 9.0 Hz, arom H), 7.76 (d, 2H, J ) 7.5 Hz, arom
H); MS m/z 273 (MH+); IR 1659, 1331, 1163 cm-1. Anal.
Calcd for C11H16N2O4S: C, 48.52: H, 5.92: N, 10.29; S,
>99.5% ee) of 25: mp 123-124.5 °C. [R]27 ) -10.9°
D
1
(c ) 1.06, MeOH). H NMR δ 1.00 (t, 3H, J ) 7.5 Hz,
NCH2Me), 2.25-2.65 (m, 2H), 2.44 (s, 3H, C6H4Me), 2.78
Vol. 6, No. 1, 2002 / Organic Process Research & Development
•
33

1
(d, 3H, J ) 5.0 Hz, NHMe), 3.11 (dd, 1H, J ) 5.0 Hz, 12.5
Hz, CH2N), 3.50 (m, 1H), 3.53 (dd, 1H, J ) 5.0 Hz, 7.5 Hz,
CH2N), 7.32 (d, 2H, J ) 9.0 Hz, arom H), 7.45 (br, 1H),
7.75 (d, 2H, J ) 7.5 Hz, arom H); MS m/z 300 (MH+); IR
3337, 3242, 1651, 1329, 1165 cm-1. Anal. Calcd for
C13H21N3O3S: C, 52.15: H, 7.07: N, 14.04; S, 10.71.
Found: C, 52.06; H, 7.15; N, 13.93; S, 10.56. Chiral HPLC
[column, SUMICHIRAL OA-4900 (Sumika Chemical Analy-
sis Service, Ltd., Japan); 4.6 mm φ × 250 mm; eluent,
hexane/CH2Cl2/EtOH ) 60/30/10; flow rate, 1.0 mL/min;
column temperature, room temperature; detection, 254 nm];
the retention times of 25 and its enantiomer were 10.6 and
17.8 min, respectively.
(R)-1-Ethylamino-3-methylamino-2-(p-toluenesulfon-
yl)aminopropane Dihydrochloride (28). To a suspension
of LiAlH4 (pellet, 256 g, 6.7 mol) in anhydrous THF (6000
mL) was added portionwise 25 (920 g, 3.1 mol) at ca. 10
°C. The reaction mixture was stirred at ca. 20 °C for 18 h.
Aqueous Rochelle salt solution [potassium sodium tartarate
tetrahydrate (1380 g)/H2O (920 mL)] was carefully added
dropwise to the reaction mixture at ca. 5 °C. After addition
of AcOEt (8000 mL) and Celite (2000 g), the mixture was
stirred at room temperature for 3 h. The insoluble materials
were filtered off and washed with AcOEt. The combined
organic layer was dried over anhydrous MgSO4 and con-
centrated to dryness to leave a pale yellow oil, which was
dissolved in a mixture of i-PrOH (1000 mL) and acetone
(1500 mL). HCl ( 20%, 1404 g) in i-PrOH was added at ca.
5 °C, and the solution was allowed to stand at 10 °C
overnight. The resulting precipitate was collected by filtra-
tion, washed with acetone, and dried to give 955 g (87%,
purification. H NMR δ 0.97 (t, 3H, J ) 7.5 Hz, CH2Me),
2.25 (s, 3H, C6H4Me), 2.42 (s, 3H, Me), 2.3-2.85 (m, 10H),
3.45 (m, 1H), 7.29 (d, 2H, J ) 8.4 Hz, arom H), 7.76 (d,
2H, J ) 8.4 Hz, arom H); MS m/z 311 (MH+).
(R)-6-Amino-1-ethyl-4-methylhexahydro-1,4-diaze-
pine (1). (a) A mixture of crude 29 (173 g) and 48% aqueous
HBr solution (1000 mL) was vigorously heated to reflux for
3 h and cooled to room temperature. The aqueous solution
was washed with CHCl3 (400 mL × 2) and basified with
48% aqueous NaOH solution. After addition of K2CO3(s)
(200 g), the mixture was extracted with CHCl3 (700 mL ×
3). The extract was concentrated to dryness to give ca. 90 g
of 1 as an yellow oil, which was distilled to afford 67.8 g
(77%, >99.5% ee) of 1 as a colorless oil: bp 85-102 °C/
5-18 Torr. [R]27D ) -2.0° (c ) 2.65, MeOH). 1H NMR δ
1.04 (t, 3H, J ) 7.0 Hz, CH2Me), 2.38 (s, 3H, Me), 2.3-2.9
(m, 10H), 3.05 (m, 1H); MS m/z 158 (MH+). C8H19N3‚
0.1H2O: C, 60.41: H, 12.17: N, 26.42. Found: C, 60.60;
H, 12.06; N, 26.11.
Compound 1 (3.0 mg) was dissolved in 0.2% Et3N in CH3-
CN solution (0.2 mL in 100 mL; 0.6 mL). To the solution
(100 µL) was added successively H2O (50 µL) and 0.2%
2,3,4,6-tetra-O-acetyl-â-D-glucopyranosyl isothiocyanate (30)
in CH3CN solution (30 mg in 15 mL; 100 µL), the mixture
was vigorously stirred at room temperature for ca. 1 min.
After standing at room temperature for 15 min, the reaction
mixture was analyzed by chiral HPLC. Chiral HPLC
[column, DEVELOSIL ODS-HG-5 (Nomura Chemical Co.,
Ltd., Japan); 4.6 mm φ × 250 mm; eluent, 50 mM NaH2-
PO4 + H3PO4 (pH ) 3.5)/CH3CN/i-PrOH ) 80/15/5; flow
rate, 1.0 mL/min; column temperature, 40 °C; detection, 254
nm]; the retention times of 1-[(R)-1-ethyl-4-methylhexahy-
dro-1,4-diazepin-6-yl]-3-(2,3,4,6-tetra-O-acetyl-â-D-glucopy-
ranosyl)thiourea (31) and 1-[(S)-1-ethyl-4-methylhexahydro-
1,4-diazepin-6-yl]-3-(2,3,4,6-tetra-O-acetyl-â-D-glucopyrano-
syl)thiourea (32) were 11.5 and 12.5 min, respectively.
(b) A solution of 16 (33.5 g, 0.12 mol) in a mixture of
EtOH (300 mL) and H2O (30 mL) was hydrogenated over
10% Pd-C (3.35 g) at room temperature until TLC indicated
almost no starting material remained. The catalyst was
filtered off, and the filtrate was concentrated to give 18.0 g
(quantitative yield, >99% ee) of 1 as a pale brown oil. The
resulting 1 was identified with the sample obtained above,
>99.5% ee) of 28 as a white powder: mp 223-228 °C.
1
[R]27 ) -8.1° (c ) 2.12, H2O). H NMR (DMSO-d6) δ
D
1.13 (t, 3H, J ) 7.5 Hz, CH2Me), 2.42 (s, 3H, C6H4Me),
2.46 (s, 3H, Me), 2.6-3.25 (m, 6H), 3.93 (m, 1H), 7.44 (d,
2H, J ) 8.5 Hz, arom H), 7.85 (d, 2H, J ) 7.5 Hz, arom
H), 9.16 (br, 2H); MS m/z 286 (MH+); IR 2982, 2775, 2718,
1331, 1153 cm-1. Anal. Calcd for C13H23N3O2S‚2HCl: C,
43.57: H, 7.03: N, 11.73; S, 8.95; Cl, 19.79. Found: C,
43.45; H, 7.10; N, 11.67; S, 8.74; Cl, 19.57. Chiral HPLC
[column, SUMICHIRAL OA-4900; 4.6 mm φ × (250 mm
× 2); eluent, hexane/THF/MeOH/CF3CO2H ) 50/45/5/0.5;
flow rate, 1.0 mL/min; column temperature, room temper-
ature; detection, 235 nm]; the retention times of 28 and its
enantiomer were 41.2 and 48.3 min, respectively.
(R)-1-Ethyl-4-methyl-6-(p-toluenesulfonyl)aminohexa-
hydro-1,4-diazepine (29). Glyoxal solution (40% aqueous,
105.4 g, 0.73 mol) and BH3‚Et3N complex (257.1 g, 2.2 mol)
was added successively dropwise to a suspension of 28 (200
g, 0.56 mol) in MeOH (2000 mL) at room temperature. The
mixture was stirred at the same temperature for 16 h. HCl
solution (6 N aqueous, 559 mL) was added at <5 °C, and
the mixture was heated to reflux for 2 h and cooled to room
temperature. After evaporation of MeOH, the resulting
aqueous solution was washed with AcOEt, basified with
NaHCO3(s), and extracted with AcOEt. The extract was then
concentrated to dryness to give 173 g (quantitative yield) of
29 as an oil, which was used in the next step without further
1
on the basis of H NMR comparison.
(R)-5-Bromo-N-(1-ethyl-4-methylhexahydro-1,4-diaz-
epin-6-yl)-2-methoxy-6-methylaminopyridine-3-carboxa-
mide Difumarate (AS-8112). Ethyl chloroformate (46.9 g,
0.43 mol) and a solution of 1 (65.0 g, 0.41 mol) in AcOEt
(130 mL) were successively added dropwise to a mixture of
5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid7
(102.5 g, 0.39 mol), Et3N (43.7 g, 0.43 mol), and AcOEt
(975 mL) at kept ca. 3 °C. The mixture was stirred at the
same temperature for 0.5 h. The insoluble materials were
filtered off, and the filtrate was washed with H2O and dried
over anhydrous MgSO4. The solvent was evaporated to give
160 g of (R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1,4-
diazepin-6-yl)-2-methoxy-6-methylaminopyridine-3-carboxa-
mide as a solid, which was converted into the difumarate in
34
•
Vol. 6, No. 1, 2002 / Organic Process Research & Development

the usual manner [fumaric acid (95 g)/EtOH (800 mL)] to
CONH); MS m/z 401 (MH+); IR 3360, 1666, 1601, 1512,
1275 cm-1. Anal. Calcd for C16H26BrN5O2‚2C4H4O4: C,
45.58: H, 5.42: N, 11.07; Br, 12.63. Found: C, 45.78; H,
5.43; N, 11.11; Br, 12.62.
afford 192.0 g (77%) of AS-8112: mp 149-151 °C. [R]27
D
1
) -4.4° (c ) 2.13, MeOH). H NMR (DMSO-d6) δ 1.05
(t, 3H, J ) 7 Hz, CH2Me), 2.48 (s, 3H, Me), 2.52 (m, 1H),
2.58-3.07 (m, 10H), 2.93 (d, 3H, J ) 5 Hz), 3.99 (s, 3H),
4.18 (m, 1H), 6.59 (s, 4H, fumaric acid), 6.99 (d, 1H, J ) 5
Hz, NHMe), 8.10 (s, 1H, Py-4), 8.37 (d, 1H, J ) 8.5 Hz,
Received for review August 20, 2001.
OP010068E
Vol. 6, No. 1, 2002 / Organic Process Research & Development
•
35