A scaleable synthesis of dutasteride: A selective 5α-reductase inhibitor

Article abstract of DOI:10.1021/op700068g

An improved and scaleable process for Dutasteride (1), a synthetic 4-azasteroid derivative essentially used for the treatment of prostate diseases, is described

Full text of DOI:10.1021/op700068g

Organic Process Research & Development 2007, 11, 842–845
A Scaleable Synthesis of Dutasteride: A Selective 5r-Reductase Inhibitor†
‡
,§
Komati Satyanarayana, Katkam Srinivas, Vurimidi Himabindu, and Ghanta Mahesh Reddy*
Department of Research and DeVelopment, Dr. Reddy’s Laboratories Ltd., Integrated Product DeVelopment, Unit-III, Plot No.
16, S.V. Co-Op. Industrial Estate, Bollaram, Jinnaram, Medak Dist-502 325, A.P, India, and Institute of Science and
Technology, Center for EnVironmental Science, J. N. T. UniVersity, Kukatpally, Hyderabad-500 072, A.P, India
1
Abstract:
8, which was converted to the corresponding acid halide and
reacted with 2,5-bis(trifluoromethyl) aniline (9) to give Dutas-
teride 1 in an overall yield of 5.13%.
An improved and scaleable process for Dutasteride (1), a synthetic
4-azasteroid derivative essentially used for the treatment of
This process suffers from several disadvantages such as (a)
the large number of stages; (b) carryover impurities from
compounds 5, 6, and 7 leading to several byproducts in
subsequent stages; (c) difficulty in controlling the impurities in
the active pharmaceutical ingredient (API) obtained from this
process; and (d) low overall yield (5.13%). These factors made
the process less viable for commercial production. Other
prostate diseases, is described.
Introduction
Dutasteride (1) is a selective inhibitor of the type 1 and type
1
2
isoforms of steroid 5R-reductase (5 AR), an intracellular
enzyme that converts testosterone to 5R-dihydrotestosterone
1c,4b,c
reported synthetic procedures have similar drawbacks.
(DHT). Dutasteride (1) is currently available in the market as
Herein we report an economic, efficient, and impurities-free
synthesis of Dutasteride that meets regulatory quality require-
2
a drug for benign prostatic hyperplasia under the brand name
of AVODART and is used for the treatment of prostate diseases
such as prostate cancer, acne, male pattern baldness, hirsutism,
5
ments with an overall yield of around 40%, involving a new
one-pot procedure for the condensation of 10 and 11 by
Ullmann–Goldberg-type condensation. Our process involved a
shorter synthetic sequence, starting from 3-oxo-4-aza-5R-
androstane-17ꢀ-carboxylic acid (5).
3
and prostate gland enlargement. The first reported synthetic
4a
method for this molecule involves a seven-step synthetic
sequence (Scheme 1). Oxidation of 3-oxo-4-androstene-17ꢀ-
carboxylic acid (2) and subsequent treatment with aqueous
sodium permanganate and sodium periodate at reflux in tert-
butanol yielded the 5-oxo-a-nor-3,5-secoandrostan-3-oic acid
derivative 3. Reaction of 3 with ammonia in refluxing ethylene
glycol yielded 4-aza-androst-5-en-3-one 4, which was subjected
to hydrogenation at 60–70 °C under 40–60 psi pressure in the
presence of platinum oxide catalyst to furnish 4-aza-5R-
androstan-3-one 5. Esterification of 5 with methanol and
sulphuric acid and subsequent dehydrogenation of the resultant
compound 6 using 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ)
and bis(trimethylsilyl) trifluoroacetamide (BSTFA) afforded
steroidal ester 7. Hydrolysis of 7 with caustic lye in water and
methanol mixture yielded dehydrocarboxylic acid intermediate
Results and Discussion
In our efforts to develop a robust and scaleable route for
Dutasteride 1, we have chosen 3-oxo-4-aza-5R-androstane-17ꢀ-
carboxylic acid (5), a commercially available compound, as
6
starting material. Thus oxidation of compound 5 with DDQ,
BSTFA, and triflic acid in toluene followed by a usual workup
and recrystallisation from dichloromethane and methanol di-
rectly afforded compound 8 with 99.5 % purity and 85% yield
(Scheme 2). Dehydrocarboxylic acid derivative 8 was treated
with thionyl chloride in the presence of a catalytic amount of
pyridine and further reacted with ammonia to give compound
1
0 as a crystalline solid powder with 90–92% yield with 99.5%
†
Dr. Reddy’s communication no. IPDO-IPM-00053.
To whom correspondence should be addressed. E-mail: reddyghanta@
purity (vide HPLC). Condensation of 10 with 2-iodo-1,4-
bis(trifluoromethyl) benzene 11 in the presence of potassium
carbonate/sodium carbonate/sodium methoxide/sodium hydroxide/
potassium hydroxide as a base, in dimethyl formamide/toluene/
*
7
yahoo.com.
‡
J. N. T. University.
Present address: Department of Research and Development, Inogent
§
Laboratories Private Limited (a GVK BIO company), 28A, IDA, Nacharam,
Hyderabad-500 076, India.
(
1) (a) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; Jobson, R. B.;
(
(
(
5) Reddy, M. S. N.; Srinivasulu, G.; Srinivas, K.; Satyanarayana, K.;
Mayur, D. K. U.S. Patent 2005/0059692A1, 2005.
Primika, R. L.; Berman, C.; Brooks, J. R. J. Med. Chem. 1984, 27,
1
690–1701. (b) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.;
6) Bhattacharya, A.; DiMichele, L. M.; Dolling, Ulf.-H.; Douglas, A. W.;
Grabowski, J. J. E. J. Am. Chem. Soc. 1988, 110, 3318–3319.
7) Synthesis of 2-Iodo-1,4-bis(trifluoromethyl) Benzene (11). Diazoti-
zation of 1,4-bis(trifluoromethyl) aniline in the presence of sodium
nitrite, hydrochloric acid, and water as medium generates diazonium
ions, which will react with potassium iodide at 5–10 °C to obtain
intermediate 11.
Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.;
Brooks, J. R.; Berman, C. J. Med. Chem. 1986, 29, 2298–2315. (c)
Rasmusson, G. H.; Reynolds, G. F. U.S. Patent 4,760,071, 1988.
2) Gormley, G. J.; Stoner, E.; Bruskewitz, R. C.; Imperato-McGinley,
J.; Walsh, P. C.; McConnell, J. D.; Andriole, G. L.; Geller, J.; Bracken,
B. R.; Tenover, J. S. N. Engl. J. Med. 1992, 327, 1185–1191.
3) Imperato-McGinley, J.; Peterson, R. E.; Gautier, T.; Sturla, E. N. Engl.
J. Med. 1979, 300, 1233–1237.
(
(
(
4) (a) Batchelor, K. W.; Frye, S. V.; Dorsey, Jr., G. F.; Mook, Jr., R. A.
U.S. Patent 5,565,467, 1996. (b) Rasmusson, G. H.; Johnston, D. B. R.;
Arth, G. E. U.S. Patent 4,377,584, 1983. (c) Cainelli, G.; Martelli,
G.; Panunzio, M.; Spunta, G.; Nannini, G.; di Salle, E. U.S. Patent
Tetrakis(trifluoromethyl)biphenyls: Sidney, D. R.; Markarian, M.;
4
,732,897, 1988.
Schwarz, M. J. Am. Chem. Soc. 1953, 75, 4967–4969.
8
42
•
Vol. 11, No. 5, 2007 / Organic Process Research & Development
10.1021/op700068g CCC: $37.00  2007 American Chemical Society
Published on Web 08/18/2007

Scheme 1. Reported synthetic scheme of Dutasteridea
a
Reagents and conditions: (a) aq NaMnO
4
, NaIO
4
, tert-butanol, 75 °C, 30–45 min; (b) dry ethylene glycol, NH
3
,180 °C, 1 h; (c) CH
3 2 2
CO H, PtO , 60–70 °C, 6 h
under H
2
/50 psi; (d) MeOH, H SO ; (e) DDQ, BSTFA in dioxane, 10–12 h; (f) caustic lye, MeOH, H
2
4
2
O; (g) SOCl2, toluene/CH
2
2
Cl /THF, 9, 70 °C.
Scheme 2. Synthetic scheme of Dutasteridea
a
2 3 2 3
Reagents and conditions: (a) DDQ, BSTFA, triflic acid, toluene,10–12 h, 85%; (b) SOCl , pyridine, toluene, NH , 90–92%; (c) Cu powder, K CO , o-xylene,
1
40–150 °C, 50–52 h, 52.61%.
dimethyl acetamide/dimethyl sulfoxide/dimethyl imidazole as
solvent medium, at high temperatures were unsuccessful. When
fully characterized.17 Overoxidation18 of 5 led to an impurity
12, and impurity 13 was formed from traces of 5 in the
amidation reaction of corresponding dehydroderivative 8. Traces
of the 5ꢀ-isomer of 5 present in 5 leads to the formation of the
8–16
the reaction was conducted
using copper powder and
potassium carbonate without using any solvent (neat reaction),
the reaction proceeded but formation of impurities was very
high. However, when the reaction was conducted by using
copper powder and potassium carbonate in o-xylene solvent
medium at a temperature of 140–150 °C, 1 was obtained in
19,20
corresponding 5ꢀ-isomer
of Dutasteride, 14 (Scheme 3). A
robust purification method was developed to control all of these
impurities in 1, so that they were at less than 0.01% levels in
the pharma (vide HPLC), thus fulfilling all regulatory specifica-
tions. The overall yield and purity of the Dutasteride obtained
from this process at scale-up level are summarized in Table 1.
63% crude yield. Recrystallisation from acetonitrile and hy-
drochloric acid and a second recrystallization from a tetrahy-
drofuran/water mixture resulted in substantial purification of
1. Further purification of 1 by dissolving in methanol followed
Conclusion
We have provided an industrially viable manufacturing
process for Dutasteride, which is substantially free from
impurities and meets the regulatory requirements.
by carbon treatment, filtration, and dilution of the filtrate with
water, furnished Dutasteride 1 having >99.8% purity. Com-
pounds 12, 13, and 14 were observed as impurities in Dutas-
teride 1 synthesized by our process. They were isolated and
Experimental Section
(
(
8) Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174–2185.
9) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359–1370.
A Waters model alliance 2695 separation module equipped
with a Waters 2996 photo diode array UV detector was used
in recording HPLC. Mass spectra were obtained using a
Shimadzu QP-8000R mass spectrometer with an electron energy
(
(
(
10) Lindley, J. Tetrahedron 1984, 40, 1433–1456.
11) Fanta, P. E. Synthesis 1974, 1, 9–21.
12) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl.
1
13
set to 1.5 kV. H NMR and C NMR were recorded in CDCl
3
1
990, 29, 977–991.
13) Kiyomori, A.; Marcoux, J. F.; Buchawald, S. L. Tetrahedron Lett.
999, 40, 2657–2660.
14) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
(
(
(
(
1
(17) Satyanarayana, K.; Srinivas, K.; Himabindu, V.; Reddy, G. M.
DiePharmazie 2007. Accepted for publication.
1
24, 7421–28.
(18) Williams, J. M.; Marchesini, G.; Robert, A. R.; Dolling, U.-H.;
Grabowski, J. J. E. J. Org. Chem. 1995, 60, 5337–5340.
15) Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.; Sakamoto, S. J. Med.
Chem. 1996, 39 (20), 3971–3979.
(19) Young, M.-H.; Kyung, L.-I. K.; Gha, S. P.; Hyun, P. C.; Lee, J.-C.;
Chang, Y.-K. US pat. No. 2006/0019979A1, 2006.
16) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong,
P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600–7601.
(20) Solomons, W. E.; Doorenbos, N. J. J. Pharma. Sci. 1974, 63, 19–23.
Vol. 11, No. 5, 2007 / Organic Process Research & Development
•
843

Scheme 3. Synthetic scheme of Dutasteride impurities
Table 1. Impurities in Dutasteride (1) by HPLC
no.
purity
desmethyl (12)
dihydro impurity (13)
ꢀ-isomer (14)
overall yield (%)
01
02
03
99.89
99.91
99.93
0.01
ND
ND
NDa
ND
ND
ND
0.01
0.01
40.3
40.8
40.0
a
ND ) not detected.
6
and DMSO-d , using 200 and 50 MHz, respectively, on a
filtered and washed with methanol (100 mL) and dried at 60–70
Varian Gemini 200 MHz FT NMR spectrometer; the chemical
shifts are reported in δ ppm relative to TMS.
°C under reduced pressure to give the title compound. Yield
+
85 g (85.5%); mp 295–297 °C; M/S m/z 318 M + H; purity
1
3-Oxo-4-aza-5r-androst-1-ene-17-ꢀ-carboxylic Acid (8).
by HPLC 99.5%; H NMR (CDCl
3
) δ 6.79 (d, J ) 10.0 Hz,
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (85.3
g, 0.375 mol) in dry toluene (1500.0 mL) was heated to
azeotropic reflux for 2 h. The reaction mixture was cooled to
1H), 5.82 (d, J ) 10.0 Hz, 1 H), 5.7 (s, 1H), 3.35 (t, 1H), 1.63
(m, 2H), 1.08 (m, 2H), 1.50 (m, 1H), 1.75 (m, 2H), 2.13 (m,
2H), 1.26 (m, 1H), 1.40 (m, 2H), 1.90 (m, 2 H), 2.37 (t, 1H),
13
25–35 °C, and 3-oxo-4-aza-5R-androstane-17ꢀ-carboxylic acid
0.80 (s, 3H), 0.99 (s, 3H), 7.51 (s, br, 1H); C NMR (DMSO-
) δ 11.9, 13.4, 21.1, 21.1, 23.6, 24.1, 25.7, 29.3, 35.3, 37.8,
39.3, 44.8, 47.5, 55.7, 58.3, 123.0, 150.7, 166.7, 171.3. Anal.
Calcd for C19 : C 71.89, H 8.57, N 4.41, O 15.12. Found:
(100 g, 0.313 mol), bis(trimethylsilyl) trifluoroacetamide (322.2
d
6
g, 1.25 mol) and triflic acid (1.6 mL, 0.018 mol) were added.
The reaction mixture was heated to 105–108 °C for 10–12 h
under nitrogen atmosphere. After the reaction mixture was
cooled to 50–60 °C, water (250 mL) was added, and the
obtained solid was filtered. The wet material was then taken
into water (100 mL), heated to 50–60 °C, and stirred for 30
min. The obtained solid was filtered under reduced pressure.
The same process was repeated, and the filtered solid was
washed with water (100 mL). The wet solid was added to
acetone (500 mL), which was then heated to reflux temperature
for 20–30 min. The resulting reaction mixture was cooled to
H27NO
3
C 71.92, H 8.53, N 4.46, O 15.16. DSC: 315.09 and 336.7 °C.
3-Oxo-4-aza-5r-androst-1-ene-17-ꢀ-carboxamide (10). A
solution of 3-oxo-4-aza-5R-androst-1-ene-17ꢀ-carboxylic acid
(50.0 g, 0.157 mol) and toluene (750 mL) was heated at
azeotropic reflux condition for 30–60 min. The resulting solution
was cooled to 25 to 35 °C under nitrogen atmosphere. Pyridine
(6.3 mL, 0.077 mol) was added to the cooled solution, which
was then stirred for about 15 min. Then, thionyl chloride (14.0
mL, 0.188 mol) was added slowly for over a period of 20 min.
The resulting reaction mixture was maintained at 25–35 °C for
2–3 h, and then ammonia gas was passed through the reaction
mixture till the reaction was completed (8–10 h). After the
completion, the reaction mixture was filtered and washed with
toluene (100 mL). The resulting solid was dried for 1–2 h. The
resultant solid was slurried in water (500 mL), and
the solid was filtered and washed with water (50.0 mL) to get
the reaction mass pH up to 6.5–7.5. The obtained solid was
dried at 70–75 °C to yield 50.0 g, which was dissolved in a
mixture of methylene chloride and methanol (8:2, 2250 mL)
2
5–35 °C and maintained for 30–45 min. The obtained solid
was filtered under reduced pressure and washed with acetone
50.0 mL). The filtered wet compound was added into a mixture
of methylene chloride and methanol (600 mL), in the ratio of
:2, which was stirred at 25–35 °C for 20–30 min. Then 80%
(
8
of the solvent was distilled off under reduced pressure. After
the reaction mass cooled to 25–35 °C, methanol (300 mL) was
added. The solvent around 100 mL was again distilled off under
reduced pressure. The reaction mixture was cooled to 25–35
°C and maintained for about 30 min. The obtained solid was
8
44
•
Vol. 11, No. 5, 2007 / Organic Process Research & Development

and stirred for 30 min at 25–35 °C. Insoluble material was
removed by filtration, and the organic solution was washed with
h. The reaction mixture was cooled to 25–35 °C, maintained
for 3–4 h at the same temperature, and filtered, and the solid
was washed with o-xylene (12.5 mL) and dried for 2 h under
reduced pressure. The dried solid was added to ethyl acetate
(750 mL), which was then heated to reflux for 30 min. The
refluxed acetate solution was filtered to remove insoluble
impurities with the help of an additional 500 mL of ethyl
acetate. The filtrate was washed with aqueous ammonium
2
% aqueous sodium hydroxide solution (3 × 63.0 mL). The
solvent was distilled off about 70–80% at below 50 °C under
reduced pressure. Methanol (150.0 mL) was added to the
reaction mass, and about 50–60% of the solvent was distilled
off under reduced pressure. After the reaction mass was stirred
for 10–20 min at 25–35 °C, the obtained solid was filtered,
washed with methanol (100.0 mL), and dried at 60–70 °C. Yield
4
chloride solution (5.0 g of NH Cl dissolved in 100 mL of water)
+
1
4
(
1
(
5.0 g (90.28%), mp 298–302; M/S m/z 317 M + H; H NMR
CDCl ) δ 6.79 (d, J ) 10.0 Hz, 1H), 5.82 (d, J ) 10.0 Hz,
H), 5.7 (s, 1H), 3.35 (t, 1H), 1.63 (m, 2H), 1.08 (m, 2H), 1.50
m, 2H), 1.75 (m, 2H) 2.13 (m, 2H),1.26 (m, 1H), 1.40 (m,
H), 1.90 (m, 2H), 2.37 (t, 1H), 0.80 (s, 3H), 0.99 (s, 3H), 7.51
at 60–65 °C, followed by water (2 × 125 mL) at 50–60 °C.
The solvent was distilled off 70–75% under reduced pressure,
and the remaining solution was cooled to 25–35 °C. The
separated solid was filtered, washed with ethyl acetate (25 mL),
and dried at 65–70 °C under reduced pressure. The obtained
solid was added to a mixture of acetonitrile and hydrochloric
acid (95.0 mL acetonitrile/5.0 mL of HCl), heated to 55–60
3
2
13
(
2
1
s, 1H); C NMR (DMSO-d
6
) δ 11.9, 13.4, 21.1, 21.1, 23.6,
4.1, 25.7, 29.3, 35.3, 37.8, 39.3, 44.8, 47.5, 55.7, 58.3,123.0,
50.7, 166.7, 171.3. Anal. Calcd for C19 : C 72.12, H
.92, N 8.85, O 10.11. Found: C 72.22, H 8.90, N 8.89, O 10.14.
DSC: 362.71 °C.
°C, cooled to 5–10 °C, filtered, and washed with same mixture
28 2 2
H N O
(10.0 mL). The obtained solid was taken into a 1:1 mixture of
8
tetrahydrofuran and water (375 mL), which was then heated to
reflux for dissolution. After refluxing for 15 min, the hot solution
was filtered. The filtrate was cooled to 25–35 °C and maintained
for 2 h. The precipitated solid was filtered, washed with a (1:
2-Iodo-1,4-bis(trifluoromethyl)benzene (11). A mixture of
water (250 mL) and hydrochloric acid (2385 mL, 26.2 mol)
was taken into a round bottom flask and cooled to 0–5 °C. 2,5-
Bis(trifluoromethyl) aniline (250 g, 1.09 mol) was added at 0–5
1) mixture of tetrahydrofuran and water (25 mL), and dissolved
in methanol (175 mL), followed by carbon treatment (1.2 g).
The filtrates were added to water (438 mL) at 25–35 °C for
°C, and the resulting solution was stirred for 10 min. A solution
of sodium nitrite (94.1 g, 1.36 mol) in water (415 mL) was
added slowly to the reaction mass over a period of 30 min at
the same temperature. The reaction mixture was stirred for 10
min, followed by addition of a solution of potassium iodide
20–30 min. Further, the reaction mass was maintained at the
same temperature for 30–60 min, filtered, and washed with
water (50.0 mL). The product was dried at 80–90 °C. Yield
2
2.0 g (52.61%); purity 99.89%; mp 254–258 °C; Cu-content
(
225 g, 1.36 mol) in water (585 mL), for 30 min. After the
resulting reaction mixture was heated to 60–70 °C for about
–4 h, it was cooled to 25–35 °C and extracted with methylene
+
not detected, heavy metals <10 ppm; MS m/z 529 M + H;
1
H NMR, (CDCl
0.0 Hz, 1 H), 5.70 (s, br, 1H), 3.35 (t, 1H), 1.63 (m, 2H), 1.08
m, 2H), 1.50 (m, 1H), 1.75 (m, 2H), 2.13 (m, 2H), 1.26 (m,
H), 2.29 (m, 2H), 2.37 (t, 1H), 0.80 (s, 3H), 0.99 (t, 3H), 7.51
3
) δ 6.79 (d, J ) 10.0 Hz, 1H), 5.82 (d, J )
3
1
(
1
chloride (2 × 250 mL). The combined organic layer was
washed with 5% sodium thiosulfite solution (2 × 250 mL).
Finally, the organic layer was washed with water (2 × 250 mL),
and the separated organic layer was distilled off under reduced
pressure to give the title compound. Yield 352.61 g (95%);
(
8
s, 1H), 8.77 (s, 1H), 7.73 (d, J ) 8.4 Hz, 1H), 7.45 (d, J )
.4Hz, 1H); C NMR (DMSO-d ) δ 11.9, 13.4, 21.1 23.6 24.1,
6
13
+
25.7, 29.3, 35.3, 37.8, 39.3, 44.8, 47.5, 55.7, 58.3, 59.5,
120.3,121.7, 123.0, 126.7, 126.7, 136.3, 150.7, 166.7, 171.3.
purity by HPLC 98.5%; bp 89–92 °C; MS m/z 341 M + H;
1
H NMR (CDCl
.45 (d, J ) 8.4 Hz, 1H); C NMR (DMSO-d
24.4, 124.8, 126.7, 135.0.
7ꢀ-N-[2,5-Bis(trifluoromethyl)phenyl]carbamoyl-4-aza-
r-androst-1-ene-3-one (Dutasteride). A mixture of potassium
3
) δ 8.77 (s, 1H), 7.73 (d, J ) 8.4 Hz, 1H),
Anal. Calcd for C27
2
2
H
30
F
6
N
2
O
2
: C 61.36, H 5.72, N 5.30, O
7.62. Found: C 61.35, H 5.68, N 5.27, O 27.60. DSC:
50.36 °C.
13
7
1
6
) δ 120.3, 121.7,
1
5
Acknowledgment
carbonate (11 g, 0.079 mol) and xylene (125 mL) was heated
to azeotropic reflux temperature for 2 h to remove water
azeotropically. The xylene mixture was cooled to about 30–40
We thank the management of Dr. Reddy’s Laboratories Ltd.
for supporting this work. Co-operation from the project col-
leagues is highly appreciated.
°C, and 3-oxo-4-aza-5R-androst-1-ene-17ꢀ-carboxamide (25 g,
0
.079 mol), copper powder (15.1 g, 0.237 mol), and 2-iodo-
Received for review March 23, 2007.
OP700068G
1,4-bis(trifluoromethyl) benzene (81 g, 0.238 mol) were added.
Then, the resulting mixture was heated to 140–150 °C for 50–52
Vol. 11, No. 5, 2007 / Organic Process Research & Development
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