Integration of solventless reaction in a multi-step process: Application to an efficient synthesis of PA-824

Article abstract of DOI:10.1002/adsc.200700119

In order to improve redundant synthetic processes, the integration of a solventless reaction has proved to be useful for gaining high reaction mass efficiency (RME) as well as reducing the amount of solvents. This concept was applied to synthesis of PA-82

Full text of DOI:10.1002/adsc.200700119

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DOI: 10.1002/adsc.200700119
Integration of Solventless Reaction in a Multi-Step Process:
Application to an Efficient Synthesis of PA-824
Akihiro Orita,a Kai Miwa,a Genta Uehara,a and Junzo Oteraa,*
a
Department of Applied Chemistry, Okayama University of Science, Ridai-cho, Okayama 700-0005, Japan
Fax : (+81)-86-256-4292; e-mail: otera@high.ous.ac.jp
Received: March 2, 2007; Published online: September 6, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: In order to improve redundant synthetic mary hydroxy group under solventless conditions
processes, the integration of a solventless reaction was also feasible. As a consequence, the overall yield
has proved to be useful for gaining high reaction of the target compound was nearly tripled, and thus
mass efficiency (RME) as well as reducing the the RME values were increased more than 2.5 times
amount of solvents. This concept was applied to syn- while the amount of necessary solvents was de-
thesis of PA-824, a potential antituberculosis drug. creased to less than 1/3.
Thus, the solventless ring-opening reaction of glycid-
yl silyl ether with dinitroimidazole was connected to
succeeding solution reactions. The ring-opening of Keywords: atom economy; cesium; glycidyl ethers;
glycidol followed by selective silylation of the pri- imidazoles; one-pot reaction; solventless reaction
Introduction
in multistep processes have been undertaken because
an apparatus to connect the mechanochemical reac-
The improvement of redundant processes for synthe- tions to the next solution reaction is not readily avail-
sizing pharmaceuticals and fine chemicals is a chal- able. However, we disclosed that mechanical forces
lenge for chemists in terms of atom economy[1] or pro- are not always required for solventless reactions to
cess efficiency.[2] For example, the E-factors of phar- occur. Simply standing a solid film obtained by evapo-
maceutical production processes are claimed to be ration of the reactant solution drives the reaction
more than 103 times larger than those of the most effi- faster rather than continuing the reaction in solu-
cient oil-refining processes.[2] Integration of multistep tion.[5] Consequently, we have been intrigued by the
synthetic processes into one-pot provides one of the integration of a solventless reaction which requires no
effective solutions to this problem. Actually, we had mechanical forces and a normal solution reaction in
previously exemplified that the execution of sequen- one-pot.
tial reactions in one-pot occasionally gave rise not
PA-824 (1) is the target of choice in this study since
only to the simplification of manipulations but also to it has been receiving intensive attention as a potential
an increase in the overall yield.[3] To realize such an antituberculosis drug. The effectiveness of this com-
integration, the conditions for the respective reactions pound was revealed in 1997[6] and phase I clinical
should be compatible, and, in particular, the common trials are now underway by the Global Alliance for
solvents need to be shared through a sequence of the TB Drug Development.[7] Scheme 1 depicts the syn-
reactions. It may happen, however, that the best sol- thetic route for 1 originally put forth by the Patho-
vent system for one reaction is not always the best for Genesis group (PG process).[6a] The initial step is the
the others. The present study stemmed from an idea ring-opening of glycidyl TBSether 3a by 2,4-dinitro-
that the use of a solventless reaction would allow an imidazole (2), and the resulting TBSalcohol 4a is
unrestricted choice of the best solvent in the reaction converted to the corresponding THP ether 5. Desily-
that follows.
lation of this compound with TBAF spontaneously in-
The solventless reactions that have made remark- duces cyclization to give 6a, deprotection of which
able advances recently[4] are usually performed by provides 7. The final step is benzylation of this alco-
grinding reactants with a pestle in a mortar and, ac- hol to arrive at 1 in 17% overall yield. In this paper,
cordingly, few attempts to incorporate such reactions we report that the incorporation of a solventless reac-
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Table 1. Ring-opening reaction of glycidyl silyl ethers by di-
nitroimidazoles.[a]
[a]
TBS=t-BuMe2Si; TIPS=i-Pr3Si.
PG process.
[b]
THPRoute
With these results in hand, we connected the above-
established solventless reaction to the downstream re-
actions. First, the PG process was modified by use of
3b in a stepwise manner (THP/SW) (Scheme 2). In
addition to the initial solventless step i, the succeed-
ing steps were improved. The yield of the tetrahydro-
pyranylation was increased from 79% to 87% in tolu-
ene, which avoided the use of hazardous CH2Cl2. The
desilylation followed by cyclization (81% yield) step
Scheme 1. PG process. DHP=dihydropyran; PPTS=pyridi-
nium p-toluenesulfonate; TBAF=Bu4NF; r.t.=room tem-
perature; c.c.=column chromatography; recryst.=recrystal-
lization.
tion gives rise to dramatic improvements in terms of was also superior to that in the PG process (73%
synthetic and process chemistries.
yield). Dehydropyranylation was simplified by use of
12 N HCl to give a higher yield (91%) compared to
the original method (79%). As a result, the overall
yield of 7 was increased to 55% from the 24% yield
in the PG process. Then the process was integrated
Results
We ascribed the low overall yield in the PG process (THP/IP-1). The ring-opening and tetrahydropyrany-
primarily to the inefficiency of the initial ring-opening lation reactions (steps i and iia) were run consecutive-
reaction: only a 53% yield of 4a based on 2 was ob- ly without isolation of 4b. To a flask containing the
tained even by use of 1.5 equivs. of 3a in EtOH at pasty crude product of 4b resulting from the solvent-
708C. We thus invoked the solventless protocol. A less ring-opening reaction were added toluene, dihy-
mixture of 2 and 3a (1.5 equivs.) was stirred at 708C dropyran (DHP) and pyridinium p-toluenesulfonate
by a magnetic bar in a flask. Note that no mechanical (PPTS) in this order. Toluene had proved to be the
forces were necessary for effective mixing to yield a best solvent for this reaction in separate trials. After
non-viscous paste, allowing us to execute the ordinary 24 h, the desired THP ether 8a was obtained in 79%
manipulations that are employed in organic synthesis. yield based on 2. Then, this compound was converted
The yield of 4a was found to be higher than that of to 7 without isolation of 6a by a one-pot two-step op-
the reaction in EtOH (Table 1). More remarkably, the eration. After completion of desilylation concomitant
amount of 3a could be reduced to 1.2 equivs. The use with spontaneous cyclization in THF (step iiia),
of the corresponding TIPSether 3b provided some- MeOH and one drop of 12 N HCl were added to the
what higher yields of the TIPSderivative 4b in com- reaction mixture to detach the THP group (step iva)
parison with 3a, hence, prompting us to use this ether to furnish 7 in 69% yield based on 8a. Preliminarily,
in place of 3a in this study.
MeOH had been found to be the best solvent for the
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Scheme 2. THP route initiated by solventless reaction (for abbreviations, see Scheme 1).
deprotection reaction, yet the reaction proceeded (DMAP) in step iib’ could be adjusted on the assump-
smoothly even in the presence of THF. It should be tion that the yield of the step i was the same as that
mentioned, however, that although 7 obtained directly in CIN/SW. Next, the following two steps were inte-
from 6a could be purified simply by reprecipitation grated. To a THF solution of crude 6b resulting from
(THP/SW), the crude product obtained by the two- desilylation of 8b followed by spontaneous cyclization
step procedure required column chromatography (step iiib) were in situ added MeOH and TiCATHRE(UGN O-i-Pr)4
before recrystallization. The evaluation of the new (step ivb’). The deprotective transesterification of 6b
protocol in comparison with the PG process was furnished 7 in 86% yield based on 8b. The reaction
made at this stage because the remaining benzylation took place smoothly even in the presence of THF as
step is common for both processes. The overall yield well as the adjusted amount of TiACTHER(UNG O-i-Pr)4 based on
of 7 through the four steps in both THP/SW and the estimated yield of 6b, yet the preliminary column
THP/IP-1 was 55%, showing the advantage of the chromatography prior to reprecipitation was necessa-
new protocols over the PG process which provides 7 ry to obtain pure 7. The overall yield of 7 based on 2
only in 24% overall yield (Scheme 1). Alternatively, was 68%. Integration of step i and the succeeding
the solventless ring-opening reaction could be con- two reactions (steps iib’ and iiib’ where the amounts
nected to the succeeding two steps in one pot as well of reagents were adjusted as above) was also feasible
to directly arrive at 6a, deprotection of which furnish- (CIN/IP-2). Although 6b thus obtained was contami-
ed 7 in 46% overall yield (THP/IP-2).
nated by a small amount of inseparable impurities
even after column chromatography, deprotection of
this product furnished pure 7 in 60% overall yield.
Apparently, the cinnamate routes also afforded much
higher yields than the original process.
Cinnamate Route
The use of cinnamyl ester in place of the THP ether
as a protecting group gave rise to higher overall
yields (Scheme 3). The stepwise cinnamate protocol Glycidol Route
afforded a 66% overall yield of 7 (CIN/SW). Notably,
in contrast to the desilylation of THP derivative 8a The use of the parent glycidol in place of the glycidyl
that required 3.0 equivs. of TBAF, 8b was converted silyl ethers was achieved (Scheme 4). The ring-open-
to 6b with only 1.1 equivs. of TBAF. In CIN/IP-1, the ing of glycidol by 2 was carried out by catalysis with
solventless reaction (step i) and cinnamyl ester forma- CsF under solventless conditions. Thus, a mixture of
tion with dicyclohexylcarbodiimide (DCC) (step iib’) 2, glycidol (1.3 equivs.) and CsF (0.1 equiv.) was
in toluene were smoothly integrated to give 8b in stirred at room temperature for 18 h. To this mixture
79% yield based on 2. Note that the amounts of cin- was added DMF, TIPSCl (2.5 equivs.), imidazole
namic acid, DCC, and N,N-dimethylaminopyridine (3.0 equivs.), and DMAP (0.3 equivs.). The solution
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Scheme 3. Cinnamate route initiated by solventless reaction (for abbreviations, see Scheme 1).
Scheme 4. Glycidol route initiated by solventless reaction (for abbreviations, see Scheme 1).
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was heated at 608C for 1 h to furnish 4b in 82% yield (2)]. HPLC analysis of this compound showed the en-
based on 2. The selective silylation of the primary hy- antiomer excess to be >99%.
droxy group of intermediate 9 was realized, and the
integration of steps v and vi is crucial because 9 is dif-
ficult to isolate due to its high solubility in water. Discussion
Note that a significant drop of the yield of 4b (15–
20%) was observed when the ring-opening reaction The advantage of incorporation of the solventless re-
was carried out in DMF or CH3CN solution, indica- action is two-fold. First, the yield of the ring-opening
tive of the advantage of the solventless reaction. reaction is increased. Second, the best solvent can be
Then, 4b thus obtained was transformed to 7 accord- chosen at will for the next reactions in a one-pot
ing to the same procedure as CIN/SW to give a 64% manner. A one-pot reaction in solution was not feasi-
overall yield. Next, by integration of the last two ble with the ring-opening reaction of glycidyl ethers.
steps as in CIN/IP-1, the same overall yield was at- The reaction was best carried out in EtOH, but this
tained (GL/IP-1). Finally, three steps from 4b to 7 solvent was not employable for the next protection
were integrated (GL/IP-2). Notably, the two-compo- steps. The integration of steps i and iia or iib afforded
nent solvent system for desilylation (step iiib’) and 8a or 8b in slightly higher or nearly equal yield as 8a
even the three-component solvent system for depro- in THP/IP-1 or 8b CIN/IP-1 as compared with that in
tection of the THP group (step ivb’) worked smoothly THP/SW (74%=85%”87%) or CIN/SW (78%=
although the overall yield was slightly lowered. Final- 85%”92%). Apparently, these results arose from the
ly, 7 obtained according to the above three route was choice of the best solvent in the second step. By con-
converted to 1 by the PG method in 70% yield.
trast, further incorporation of step iiia in THP/IP-2
resulted in a decrease of the yield of 6a (51%) from
that in THP/SW (60%=85%”87%”81%) due to
the employment of the mixed solvent system which
may not be optimal for the reaction.[8] As described
Enantiomer Excess
Our protocols have the chiral origin in enantiopure above, the ring-opening of glycidol followed by selec-
(R)-glycidol or its silyl ethers which are prepared tive silylation could take place in solution, but the
from (R)-1-choloropropane-2,3-diol of >99% ee. yield was lower than that by the solventless protocol.
Thus, it is of great importance to ascertain that no
No significant difference in the overall yields was
racemization occurred during manipulations in the observed between the stepwise and integrated pro-
above protocols. This was done by measuring the en- cesses of the three routes. This is ascribed to the
antiomer excesses of 7 and 1. Although we could not counterbalance between the two conflicting factors in-
obtain good resolutions in chiral HPLC of 7 itself, a duced by integration of multi-step processes. The re-
distinct separation of peaks was attained with its ace- duced material loss resulting from avoidance of the
tate 10 [Eq. (1)], which confirmed >99% ee for all isolation and purification of the intermediates serves
to advantage while subjection of the intermediates
contaminated by impurities and by-products to the
next reaction works unfavorably. Moreover, the steps
iva and ivb’ in THP/IP-1 and CIN/IP-1 or GL/IP-1, re-
spectively, were carried out in THF/MeOH. It is op-
erationally convenient that the THF employed in the
former step need not be removed, yet the co-exis-
tence of this solvent might have induced a reduction
of the yields in the second reactions to some extent.
compounds produced in this study. The enantiomer This is reflected in the necessity of the column chro-
excess of 1 also could be determined to be >99%. It matography prior to reprecipitation for purification of
is worthy of note that the CsF-catalyzed ring-opening 7. The similar situation might be true for the steps
of glycidol proved to induce no racemization. The iiia, iiib’, and ivb’ in THP/IP-2, CIN/IP-2, and GL/IP-
product diol could be isolated as its diacetate 11 [Eq. 2, respectively.
The evaluation of the new protocols initiated by
the solventless reactions with reference to the PG
process from the viewpoint of process chemistry is
summarized in Table 2, in which a comparison is
made based on the overall procedure leading to 1.
Simple reaction mass efficiency (RME)[9] excluding
reaction and postreaction solvents was determined as
a ratio of the mass of product vs. the mass of total
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Table 2. Comparison between PG and new processes.
work-up is necessary for three intermediates, 4b, 8a
or 8b, and 6a or 6b, together with reprecipitation for
7. On the other hand, the integrated protocols, THP/
IP-1 and CIN/IP-1, require column chromatography
twice and reprecipitation once. Note that preliminary
column chromatography prior to reprecipitation is
necessary for purification of crude 7 obtained by the
consecutive two-step procedure. Nevertheless, skip-
ping column chromatography for 4b and 6a or 6b in
these integrated protocols helps diminish the amount
of solvents to a great extent. More favorably, the pro-
tocols, THP/IP-2 and CIN/IP-2, are free from the
column chromatographic purification of 7 because the
crude product can be purified solely by reprecipita-
tion, leading to the least consumption of solvents. In
the glycidol protocols, 4b should be isolated even in
the integrated processes, thus consuming larger
amounts of solvents. As a whole, the integrated cinna-
[a]
TBS=t-BuMe2Si; TIPS=i-Pr3Si.
[b]
PG process.[a] Based on the 70% yield of conversion mate routes gave rise to a great improvement from a
from 7 to 1.
viewpoint of process chemistry: CIN/IP-1 is the best
in terms of RME while CIN/IP-2 in terms of the sol-
vent consumption.
[b]
[c]
RME=1 produced (kg)/total amount of chemicals em-
ployed (kg).
The amount of solvents used in reactions and postreac-
tions to produce 1 kg of 1; estimated to be accurate
within 15%. The amount of solvents used for reactions
only are given in parentheses.
Conclusions
In summary, incorporation of a solventless reaction in
chemicals used. These data are based on flask-scale integrated processes has proved to be very useful for
experiments and the conditions given here are far designing efficient multistep processes. In particular,
from the optimum in terms of process chemistry.[10] the flexibility to choose a solvent in the reaction to
Nevertheless, the essential advantage of the new pro- follow is of great help for integration of the steps. It
tocols over the PG process is apparent even at this should be pointed out that the most energy intensive
preliminary stage. The use of the solventless reaction steps in chemical industry are those for separation
gave rise to higher RME values than the PG process. and purification of intermediates.[11] The integration
This is mainly attributable to the increase of yield in serves well for saving energy as well as raw materials.
the initial solventless ring-opening although the in- The validity of this concept has been exemplified by
crease of yields in the respective downstream steps new efficient protocols for synthesizing PA-824.
also contributes to some extent as is apparent from
the comparison between the stepwise processes and
the PG process. The RME values of the glycidol pro-
tocols are not so high as expected from the relatively
Experimental Section
high overall yields. This is mainly attributable to em-
ployment of excess amounts of TIPSCl and imidazole
in step vi. Nevertheless, the absence of a demand for
the separate synthesis of glycidyl silyl ethers is highly
advantageous from an economical point of view.
General Remarks
All reactions were carried out under an atmosphere of
argon with freshly distilled solvents, unless otherwise noted.
There are no significant differences in the RME Tetrahydrofuran (THF) was distilled from sodium/benzo-
phenone. Other solvents such as toluene and DMF were dis-
tilled from CaH2. Silica gel (Daiso gel IR-60) was used for
column chromatography. NMR spectra were recorded at
258C on JEOL Lambda 300 and JEOL Lambda 500 instru-
ments and calibrated with tetramethylsilane (TMS) as an in-
ternal reference. Optical purity was determined by HPLC
with a CHIRALCEL OD-H column. Elemental analyses
were performed by the Perkin–Elmer PE 2400. (R)-Glycidol
(99.3% ee) was supplied by Daiso Co. Glycidyl silyl ethers
3a[12] and 3b[13] were prepared according to the reported pro-
values between the integrated processes and stepwise
processes, a quite natural outcome because the basi-
cally same routes are involved in both cases. Thus, the
amounts of solvents used for the reactions also do not
significantly differ as given in parentheses of the last
column in Table 2. On the other hand, big differences
emerge if the postreaction solvents employed for
work-up, column chromatography and reprecipitation
are taken into account. In the stepwise protocols,
column chromatographic purification after usual cedure.[13]
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The organic layer was washed with NaCl solution (10 mL)
and dried over MgSO4. After evaporation, the residue was
subjected to column chromatography on silica gel (10:90
EtOAc/hexane) to furnish 8a; yield: 747 mg (79% based on
2). RME for 8a: 0.506; required solvents for production of
1 kg of 8a: 6780 L.
Product 7: To a THF solution (5 mL) of 8a (473 mg,
1.0 mmol) was added slowly a THF solution of TBAF
(1.0M, 3.0 mL, 3.0 mmol) at 08C. After the solution had
been stirred for 1 h at room temperature, MeOH (30 mL)
was added. Then, one drop of 12N HCl was added at 08C,
and the solution was stirred for 1 h at room temperature.
The residue obtained by evaporation of the reaction mixture
was subjected to column chromatography on silica gel
(10:90 EtOAc/MeOH). Further purification of the product
thus obtained by reprecipitation from MeOH (3 mL) fur-
nished pure 7; yield: 128 mg (69% based on 8a; >99% ee
as diacetate based on HPLC). RME for 7: 0.102; required
solvents for production of 1 kg of 7: 31634 L.
THP/SW
Product 4b: A powdery mixture of 2 (316mg, 2.0mmol) and
3b (553mg, 2.4mmol) was heated at 708C for 16h with stir-
ring by a magnetic bar in a flask. The pasty product was sub-
jected to column chromatography on silica gel (10–30:90–10
EtOAc/hexane) to furnish 4b; yield: 660mg (85%); mp 64–
658C; [a]19: +29.5 (c 1.00, THF); H NMR (DMSO-d6): d=
1
0.97–1.22 D(m, 3H), 1.11 (d, J=5.6 Hz, 18H), 3.64 (dd, J=
10.2, 7.2 Hz, 1H), 3.83 (dd, J=10.2, 4.7 Hz, 1H), 4.01–4.03
(m, 1H), 4.40 (dd, J=13.5, 9.2 Hz, 1H), 4.86 (dd, J=13.5,
3.2 Hz, 1H), 5.39 (d, J=5.5 Hz, 1H), 8.73 (s, 1H); 13C NMR
(DMSO-d6): d=11.3, 17.6, 54.0, 65.5, 68.9, 127.1, 141.8; anal.
calcd. for C15H28N4O6Si: C 46.37, H 7.26, N 14.42; found: C
46.32, H 7.48, N 14.27. RME for 4b: 0.762; required solvents
for production of 1 kg of 4b: 4530 L.
Product 8a: To a toluene solution (10 mL) of 4b (777 mg,
2.0 mmol) were added DHP (0.547 mL, 6.0 mmol) and
PPTS(100 mg, 0.4 mmol). The mixture was stirred for 24 h
at room temperature. The reaction mixture was combined
with saturated aqueous NaHCO3 (10 mL) and extracted
with EtOAc (10 mL”3). The organic layer was washed with
NaCl solution (10 mL) and dried over MgSO4. After evapo-
ration, the residue was subjected to column chromatography
on silica gel (10:90 EtOAc/hexane) to furnish 8a; yield:
822 mg (87% as an inseparable 1:1 mixture of atropisom-
ers): 1H NMR (DMSO-d6): d=1.09–1.27 (m, 21H), 1.30–
1.84 (m, 6H), 3.18–4.66 (m, 7H), 4.79 4.96 (dd, J=13.8,
3.4 Hz, 1H), 8.69 (s, 0.5H), 8.81 (s, 0.5H); 13C NMR
(DMSO-d6): d=11.2 11.3, 17.6 17.7, 19.1 19.8, 24.6 24.8, 30.1
30.3, 51.6 51.9, 61.9 62.8, 63.3 64.0, 74.1 76.3, 97.9 99.3, 126.9
127.2, 128.3, 141.7 141.8. RME for 8a: 0.593; required sol-
vents for production of 1 kg of 8a: 4953 L.
Product 6a: To a THF solution (5 mL) of 8a (473 mg,
1.0 mmol) was added slowly a THF solution of TBAF
(1.0M, 3.0 mL, 3.0 mmol) at 08C. After the solution had
been stirred for 1 h at room temperature, saturated aqueous
NaHCO3 (10 mL) was added. The organic layer was evapo-
rated and the residue was extracted with CHCl3 (10 mL”3).
The CHCl3 solution was washed with water (10 mL) and
brine (10 mL). The residue obtained by drying (MgSO4) fol-
lowed by evaporation was subjected to column chromatog-
raphy on silica gel (5:95 MeOH/EtOAc) to furnish 6a;
yield: 218 mg (81%). RME for 6a: 0.174; required solvents
for production of 1 kg of 6a: 23208 L.
THP/IP-2
Product 6a: A toluene solution of 8a obtained as above was
combined with THF (10 mL). To this solution was added a
THF solution of TBAF (1.0M, 6.0 mL, 6.0 mmol) at 08C,
and the solution was stirred at room temperature for 1 h. Sa-
turated aqueous NaHCO3 (10 mL) was added. The organic
layer was evaporated and the residue was extracted with
CHCl3 (10 mL”3). The CHCl3 solution was washed with
water (10 mL) and brine (10 mL). The residue obtained by
drying (MgSO4) followed by evaporation was subjected to
column chromatography on silica gel (5:95 MeOH/EtOAc)
to furnish 6a; yield: 275 mg (51% based on 2). RME for 6a:
0.090; required solvents for production of 1 kg of 6a:
18482 L.
Product 7: An MeOH solution (6.0 mL) of 6a (54 mg,
0.2 mmol) and one drop of 12 N HCl was stirred at room
temperature for 2 h. The residue obtained by evaporation
was recrystallized from MeOH (2 mL) to furnish 7; yield:
34 mg (91%; >99% ee as diacetate based on HPLC). RME
for 7: 0.625; required solvents for production of 1 kg of 7:
237 L.
CIN/SW
Product 7: A MeOH solution (6.0 mL) of 6a (54 mg,
0.2 mmol) and one drop of 12N HCl was stirred at room
temperature for 2 h. The residue obtained by evaporation
was recrystallized from MeOH (2 mL) to furnish 7; yield:
34 mg (91%;>99% ee as diacetate based on HPLC). RME
for 7: 0.625; required solvents for production of 1 kg of 7:
237 L.
Product 8b: To a toluene solution of 4b (777 mg, 2.0 mmol)
were added cinnamic acid (356 mg, 2.4 mmol) and DMAP
(49 mg, 0.4 mmol) at room temperature. Then, a pyridine so-
lution of DCC (1.2M, 1.68 mL, 2.0 mmol) was added drop-
wise at 08C, and the solution was stirred at room tempera-
ture for 2 h. Saturated aqueous NaHCO3 was added and the
mixture was extracted with EtOAc (10 mL”3). The organic
layer was washed with brine (10 mL) and dried (MgSO4).
The residue obtained by evaporation was subjected to
column chromatography on silica gel (30:70 CH2Cl2/hexane)
to furnish 8b; yield: 954 mg (92%): [a]2D4: À86.7 (c 1.00
THP/IP-1
Product 8a: A powdery mixture of 2 (316 mg, 2.0 mmol)
and 3b (553 mg, 2.4 mmol) was heated at 708C for 16 h with
stirring by a magnetic bar in a flask. To the resulting pasty
product 4b were added toluene (10 mL), DHP (0.547 mL,
6.0 mmol), and PPTS(100 mg, 0.4 mmol) at room tempera-
ture. The mixture was stirred for 24 h at this temperature.
The reaction mixture was combined with saturated aqueous
NaHCO3 (10 mL) and extracted with EtOAc (10 mL”3).
1
THF); H NMR (DMSO-d6): d=0.99–1.13 (m, 3H), 1.04 (d,
J=5.2 Hz, 18H), 3.99 (d, J=4.6 Hz, 2H), 4.77 (dd, J=14.3,
8.9 Hz, 1H), 4.96 (dd, J=14.3, 3.1 Hz, 1H), 5.41 (m, 1H),
6.50 (d, J=16.2 Hz, 1H), 7.45 (m, 3H), 7.60–7.66 (m, 3H),
8.83 (s, 1H); 13C NMR (DMSO-d6): d=11.3, 17.7, 51.1, 62.5,
71.9, 117.0, 127.0, 128.3, 129.0, 130.8, 133.7, 141.7, 142.1,
145.4, 165.3; anal. calcd. for C24H34N4O7Si: C 55.58, H 6.61,
2142
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Integration of Solventless Reaction in a Multi-Step Process
FULL PAPERS
N 10.80; found: C 55.64, H 6.35, N 10.50. RME for 8b:
0.598; required solvents for production of 1 kg of 8b:
3214 L.
and the solution was stirred at room temperature for 1 h.
Aqueous work-up as described in protocol 3 followed by
column chromatography on silica gel (30:70 to 20:80
EtOAc/hexane) furnished 6b; yield: 467 mg (74% based on
2 with a trace amount of impurities). RME for 6b: 0.224; re-
quired solvents for production of 1 kg of 6b: 8728 L.
Product 7: An MeOH solution (40 mL) of 6b as obtained
above (supposed to be a pure compound, 315 mg, 1.0 mmol)
and TiACHTREU(NG O-i-Pr)4 (2.84 mg, 0.01 mmol) was heated under
reflux for 12 h. The reaction mixture was filtered through a
thin pad of silica gel/MeOH (100 mL) to remove precipi-
tates derived from TiACHTRE(UNG O-i-Pr)4 and the filtrate was evaporat-
ed. After CHCl3 (30 mL) had been added to the residue, 7
was obtained as a CHCl3-insoluble powder by filtration and
drying under vacuum; yield: 150 mg (81%; >99% ee as di-
acetate based on HPLC). RME for 7: 0.472; required sol-
vents for production of 1 kg of 7: 1134 L.
Product 6b: To a THF solution (5 mL) of 8b (519 mg,
1.0 mmol) was slowly added a THF solution of TBAF
(1.0M, 1.1 mL, 1.1 mmol) at 08C, and the solution was
stirred at room temperataure for 1 h. Aqueous work-up as
described in protocol 4 followed by column chromatography
on silica gel (20:80 EtOAc/hexane) furnished 6b; yield:
287 mg (91%): m.p. 228–2308C; [a]2D4: À115.7 (c 1.00 THF);
1H NMR (DMSO-d6): d=4.30 (d, J=13.8 Hz, 1H), 4.43 (dd,
J=13.8, 3.4 Hz, 1H), 4.64 (m, 2H), 5.54 (s, 1H), 6.69 (d, J=
15.9 Hz, 1H), 7.40 (m, 3H), 7.66–7.74 (m, 3H), 8.08 (s, 1H);
13C NMR (DMSO-d6): d=46.8, 62.7, 68.3, 117.2, 118.1,
128.6, 128.9, 130.8, 133.8, 142.1, 146.0, 146.8, 165.4; anal.
calcd. for C15H13N3O5: C 57.14, H 4.16, N 13.33; found: C
57.04, H 3.96, N 13.34. RME for 6b: 0.357; required solvents
for production of 1 kg of 6b: 17629 L.
Product 7: An MeOH solution (40 mL) of 6b (315 mg,
1.0 mmol) and TiACHTREUNG(O-i-Pr)4 (2.84 mg, 0.01 mmol) was heated
GL/SW
under reflux for 12 h. The reaction mixture was filtered
through a thin pad of silica gel/MeOH (100 mL) to remove
precipitates derived from TiACHTRE(UNG O-i-Pr)4 and the filtrate was
evaporated. After CHCl3 (30 mL) had been added to the
residue, 7 was obtained as CHCl3-insoluble powder by filtra-
tion and drying under vacuum; yield: 172 mg (93%; >99%
ee as diacetate based on HPLC). RME for 7: 0.541; required
solvents for production of 1 kg of 7: 988 L.
Product 4b: A flask containing CsF (76 mg, 0.5 mmol) was
heated with a flame under vacuum. After cooling the flask,
2 (790 mg, 5.0 mmol) and glycidol (0.431 mL, 6.5 mmol)
were charged and stirred by a magnetic bar at room temper-
ature. After 18 h, DMF (5 mL) was added to dissolve the re-
action mixture. The solution was combined with a DMF so-
lution (15 mL) of imidazole (1.021 g, 15.0 mmol) and
DMAP (183 mg, 1.5 mmol) and stirred for 30 min at room
temperature. Then, TIPSCl (2.65 mL, 12.5 mmol) was added
at 08C and the solution was heated at 608C for 1 h. Then,
the reaction mixture was combined with saturated NaHCO3
(10 mL) and filtered through a celite pad. The filtrate was
extracted with EtOAc (15 mL”3). The organic layer was
washed with water (10 mL) and brine (10 mL), dried
(MgSO4), and evaporated. The residue was subjected to
column chromatography on silica gel (10:90–30:70 EtOAc/
hexane) to afford 4b; yield: 1.592 g (82%). RME for 4b:
0.322; required solvents for production of 1 kg of 4b:
6382 L.
CIN/IP-1
Product 8b: To the pasty product 4b obtained as above were
added toluene (8 mL), cinnamic acid (302 mg, 2.04 mmol)
and DMAP (42 mg, 0.34 mmol) at room temperature. Then,
a pyridine solution of DCC (1.2M, 1.43 mL, 1.7 mmol) was
added dropwise at 08C, and the solution was stirred at room
temperature for 2 h. Saturated aqueous NaHCO3 was added
and the mixture was extracted with EtOAc (10 mL”3). The
organic layer was washed with brine (10 mL) and dried
(MgSO4). The residue obtained by evaporation was subject-
ed to column chromatography on silica gel (10:90–20:80
EtOAc/hexane) to furnish 8b; yield: 819 mg (79% based on
2). RME for 8b: 0.524; required solvents for production of
1 kg of 8b: 6172 L.
The following procedure is the same as CIN/SW.
GL/IP-1
Conversion of 8b to 7 without isolation of 6b was performed
in the same manner as CIN/IP-1.
Product 7: To a THF solution (5.0 mL) of 8b (519 mg,
1.0 mmol) was slowly added a THF solution of TBAF
(1.0M, 1.1 mL, 1.1 mmol) at 08C. The solution was stirred at
room temperature for 1 h and combined with MeOH
GL/IP-2
(40 mL). Then, TiCAHTRE(UNG O-i-Pr)4 (2.64 mg, 0.0093 mmol) was
Product 7: To a toluene solution (10 mL) of 4b (777 mg,
2.0 mmol), cinnamic acid (356 mg, 2.4 mmol), and DMAP
(49 mg, 0.4 mmol) was slowly added a pyridine solution of
DCC (1.2M, 1.68 mL, 2.0 mmol) at 08C. The solution was
stirred at room temperature for 2 h and combined with THF
(8.0 mL). To this solution was added a THF solution of
TBAF (1.0M, 2.0 mL, 2.0 mmol) at 08C and the solution
was stirred at room temperature for 1 h. Then, MeOH
added, and the reaction mixture was heated under reflux for
19 h. After evaporation, the residue was subjected to
column chromatography on silica gel (10:90 MeOH/
EtOAc). Further purification of the product thus obtained
by reprecipitation form MeOH (3 mL) furnished 7; yield:
159 mg (86% based on 8b; >99% ee as diacetate based on
HPLC). RME for 7: 0.196; required solvents for production
of 1 kg of 7: 31706 L.
(80 mL) and TiCAHTRE(UNG O-i-Pr)4 (5.3 mg, 0.019 mmol) were added.
The reaction mixture was heated under reflux for 19 h and
evaporated. The residue was subjected to column chroma-
tography on silica gel (gradient EtOAc/MeOH). The prod-
uct thus obtained was further purified by reprecipitation
from MeOH to give 7; yield: 267 mg (72%; >99% ee as
CIN/IP-2
Product 6b: A toluene solution of 8b obtained as above was
combined with THF (10 mL) at r.t. Then, a THF solution of
TBAF (1.0M, 2.0 mL, 2.0 mmol) was slowly added at 08C,
Adv. Synth. Catal. 2007, 349, 2136 – 2144
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asc.wiley-vch.de
2143

Akihiro Orita et al.
FULL PAPERS
acetate based on HPLC). RME for 7: 0.126; required sol-
vents for production of 1 kg of 4b: 22889 L.
silica gel (50:50 EtOAc/hexane) to furnish 11; yield: 1.23 g
(78%); >99% ee based on HPLC; 1H NMR (500 MHz,
DMSO-d6): d=1.95 (s, 3H), 2.05 (s, 3H), 4.21 (dd, J=12.2,
4.9 Hz, 1H), 4.34 (dd, J=12.2, 3.8 Hz, 1H), 4.75 (dd, J=
14.4, 8.3 Hz, 1H), 4.83 (dd, J=14.4, 3.8 Hz, 1H), 5.39–5.44
(m, 1H), 8.80 (s, 1H); 13C NMR (125 MHz, DMSO-d6): d=
20.4, 20.5, 50.6, 62.2, 68.9, 126.9, 141.7, 142.2, 169.7, 170.1;
Anal. Calcd for C10H12N4O8: C, 37.98; H 3.82; N, 17.72.
Found: C, 37.97; H, 3.68; N, 17.95.
Conversion of 7 to 1
To DMF solution (5 mL) of 7 (185 mg, 1.0 mmol) and 4-
CF3C6H4CH2Br (0.19 mL, 1.2 mmol) was added NaH
(24 mg, 1 mmol) at À508C. The mixture was stirred for 1 h
at this temperature and 12 h at room temperature. The reac-
tion mixture was combined with saturated aqueous
NaHCO3 (10 mL) and extracted with CH2Cl2 (10 mL”3).
The organic layer was washed with water (10 mL) and brine
(10 mL). After drying (MgSO4) and evaporation, the residue
was subjected to column choromatography on silica gel
(EtOAc). The product thus obtained was recrystallized from
hot methanol (3 mL) to give 1; yield: 251 mg (70%); mp
149–1508C; [a]2D5: À44.7 (c 1.00 MeOH); >99% ee based on
References
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1
HPLC; H NMR (DMSO-d6): d=4.30 (m, 3H), 4.53 (d, J=
12.2 Hz, 1H), 4.74 (m, 3H), 7.41 (d, J=7.95 Hz, 2H), 7.50
(d, J=7.60 Hz, 2H), 8.10 (s, 1H); 13C NMR (DMSO-d6): d=
46.7, 66.6, 67.8, 68.7, 118.0, 120.9, 129.4, 137.3, 142.1, 147.1,
147.7; anal. calcd. for C14H12N3O5F3: C 46.81, H 3.37, N
11.70; found: C 46.58, H 3.34, N 11.67. RME for 1: 0.485;
required solvents for production of 1 kg of 1: 8210 L.
Determination of Enantiomeric Excess for 10
To a pyridine solution (5 mL) of 7 (92.6 mg, 0.5 mmol) was
added Ac2O (0.14 mL, 1.5 mmol) and DMAP (6.1 mg,
0.05 mmol) at room temperature. After the solution had
been stirred for 14 h at room temperature, saturated aque-
ous NaHCO3 (10 mL) was added. The aqueous layer was ex-
tracted with AcOEt (10 mL”3). The AcOEt solution was
washed with water (10 mL) and brine (10 mL). The residue
obtained by drying (MgSO4) followed by evaporation was
subjected to column chromatography on silica gel (70:30
EtOAc/hexane) to furnish 10; yield: 106 mg (93%): >99%
ee based on HPLC; 1H NMR (500 MHz, DMSO-d6): d=
2.04 (s, 3H), 4.21 (dt, J=14.0, 2.3 Hz, 1H), 4.37 (dd, J=
14.0, 3.7 Hz, 1H), 4.52 (dt, J=12.3, 2.3 Hz, 1H), 4.59 (dd,
J=12.3, 1.3 Hz, 1H), 5.39 (m, 1H), 8.06 (s, 1H); 13C NMR
(125 MHz, DMSO-d6): d=20.7, 46.7, 62.3, 68.2, 117.9, 142.1,
146.7, 169.6; anal. calcd. for C8H9N3O5: C 42.30, H 3.99, N
18.50; found: C 42.47, H 4.01, N 18.30.
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Determination of Enantiomeric Excess for 11
Compound 9 prepared by the procedure GL/SW, pyridine
(10 mL) and Ac2O (1.42 mL, 15 mmol) were added. After
the solution had been stirred for 12 h at room temperature,
saturated aqueous NaHCO3 (25 mL) was added. The aque-
ous layer was extracted with AcOEt (30 mL”3). The
AcOEt solution was washed with water (50 mL) and brine
(50 mL). The residue obtained by drying (MgSO4) followed
by evaporation was subjected to column chromatography on
[10] See Supporting Information for calculations of RME
and the amount of solvents.
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2144
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Adv. Synth. Catal. 2007, 349, 2136 – 2144