Note: Descriptions are shown in the official language in which they were submitted.
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
TITLE OF THE INVENTION
OXIDATION PROCESS USING TEMPO
BACKGROUND OF THE INVENTION _
Oxidation is one of the most fundamental transformations
in organic synthesis and there are numerous methods reported in the
literature. (Hudlicky, M. "Oxidations In Organic Chemistry", ACS
Monograph No. 186 American Chemical Society Washington D.C.
(1990).) However, relatively few methods exist for the oxidation of
primary alcohols to the corresponding carboxylic acids. The most
commonly used ones are Cr03/H2SO4 (Bowden; Heilbron; Jones; Weedon
J. Chem. Soc., 1946, 39; Bowers; H.; Jones; L. J. Chem. Soc., 1953, 2548;
Millar, J. G.; Oehlschlager, A. C.; Wong, J. W. J. Org. Chem. 1983, 48,
4404.), RuCl3/H5I06 (Carlsen, P. H. J.; Katsuki, T.; Martin V. S.;
Sharpless, K. B. J. Org. Chem. 1981, 46, 3936.) and TEMPO/NaClO
(Nooy, A. E. J. de; Besemer, A. C.; Bekkum, H. v. Synthesis, 1996, 1153.;
Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52,
2559.; Miyazawa, T.; Endo, T.; Shiihashi, S.; Okawara, M. J. Org.
Chem. 1985, 50, 1332). A two-step process involving Swern oxidation
(Mancuso, A. J.; Huang, S-L., Swern, D. J. Org. Chem. 1978, 43, 2480.;
Mancuso, A. J.; Brownfan, D. S.; Swern, D. J. Org. Chem. 1979, 44,
4148.; Ireland, R.; Norbeck, D. J. Org. Chem. 1985, 50, 2198.) followed by
oxidation of the resulting aldehyde with NaC102 (Lindgren, B. O.;
Nilsson, T. Acta~ Chem. Scand. 1973, 27, 888.; Dalcanale, .E.; Montanari,
F. J. Org. Chem. 1986, 51, 567) is another option. All of these procedures
have some limitations and disadvantages and new methods for the
oxidation of primary alcohols to the carboxylic acids are still desired.
(Schroder, M.; Griffith, W. P. J. Chem. Soc. Chem. Comm. 1979, 58.;
and Paquette, L. A.; Dressel, J.; Pansegrau, P. D. Tetrahedron Lett. .
1987; 28, 4965. )
The present invention relates to an oxidation using sodium
chlorite in the presence of a catalytic amount of TEMPO and sodium
hypochlorite which converts a primary alcohol to a carboxylic acid. This
oxidation method avoids the disposal issues associated with running a
Jones oxidation (Cr03/HZS04) reaction, as well as reducing the
CA 02327890 2000-10-06
WO 99/52849 PCTNS99/07466
2
epimerization of any a-chiral centers and is a one step procedure. For
substrates prone to chlorination with the TEMPO-NaClO protocol, the
present invention reduces this problem.
SUMMARY OF THE INVENTION
The present invention discloses a process for preparing a
compound of Formula I:
R'-C02H
wherein:
R1 is:
a) H,
b) C 1-Cg alkyl,
c) C2-Cg alkynyl,
d) Cg-C7 cycloalkyl,
e) aryl,
f) heteroaryl, or
g) heterocyclyl;
C1-Cg alkoxy, C1-Cg alkyl, C2-Cg alkynyl, or C3-Cg cycloalkyl, are
unsubstituted or substituted with one, two or three
substituents selected from the group consisting of OH,
C02R4, Br, Cl, F, I, CF3, C1-Cg alkoxy, Cg-Cg cycloalkyl,
aryl, heteroaryl, heterocyclyl, and CO(CH2)nCH3,
aryl is defined as phenyl or naphthyl , which is unsubstituted or
substituted with one, two or three substituents selected from
the group consisting of OH, C02R4, Br, Cl, F, I, CF3, C1-Cg
alkoxy, C1-Cg alkyl, C2-Cg alkynyl, or Cg-Cg cycloalkyl,
CO(CH2)nCH3, or when aryl is substituted on adjacent
carbons they can form a 5- or 6-membered fused ring
having one, two or three heteroatoms selected from O, N,
and S, this ring is unsubstituted or substituted on carbon or
nitrogen with one, two or three substituents selected from
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
3
the group consisting of OH, C02R4, Br, Cl, F, I, CFg, C1-Cg
alkoxy, C1-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-Cg
cycloalkyl, and CO(CH2)nCH3;
heteroaryl is defined as a 5- or 6-membered aromatic ring
containing 1, 2 or 3 heteroatoms selected from O, N and S ,
which is unsubstituted or substituted with one, two or three
substituents selected from the group consisting of OH,
C02R4, Br, Cl, F, I, CFg, C1-Cg alkoxy, C1-Cg alkyl, C2-Cg
alkynyl, Cg-Cg cycloalkyl, CO(CH2)nCHg, and additionally
the 5- or 6-membered aromatic ring can be benzofused and
unsubstituted or substituted with one, two or three
substituents as described above;
heterocyclyl is defined as a 5- or 6-membered, non-aromatic ring
containing 1, 2 or 3 heteroatoms selected from O, N and S ,
which may contain one or two double bonds and which is
unsubstituted or substituted with one, two or three
substituents selected from the group consisting of OH,
C02R4, Br, Cl, F, I, CFg, C1-Cg alkoxy, C1-Cg alkyl, C2-Cg
alkynyl, or Cg-Cg cycloalkyl, CO(CH2)nCH3, and
additionally the 5- or 6-membered ring can be benzofused
and unsubstituted or substituted with one, two or three
substituents as described above;
n is: 0 to 5;
t is: 0, 1 or 2;
R4 is: H, or C1-Cg alkyl; or
comprising the following steps:
1) adding to a compound of Formula II in a solvent,
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
4
R~-CH20H
I I
a solution of phosphate buffer to maintain a pH of about 4.0 _
to about 8.0;
2) maintaining the phosphate-buffered biphasic mixture of the
compound of Formula II at about 0°C to about 50°C;
3) adding a catalytic amount of TEMPO to the mixture; and
4) charging the TEMPO/phosphate-buffered biphasic mixture
with a solution of sodium chlorite and a catalytic amount of
sodium hypochlorite to oxidize to the compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses a process for preparing a
compound of Formula I:
R1-C02H
wherein:
R1 is:
a) H,
b) C1-Cg alkyl,
c) C2-Cg alkynyl,
d) Cg-C7 cycloalkyl,
e) aryl,
f) heteroaryl, or
g) heterocyclyl;
C1-Cg alkoxy, C1-Cg alkyl, C2-Cg alkynyl, or Cg-Cg cycloalkyl, are
unsubstituted or substituted with one, two or three
substituents selected from the group consisting of: OH,
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
C02R4, Br, Cl, F, I, CF3, C1-Cg alkoxy, C3-Cg cycloalkyl,
aryl, heteroaryl, heterocyclyl, and CO(CH2)nCH3,
aryl is defined as phenyl or naphthyl , which is unsubstituted or -
substituted with one, two or three substituents selected from
5 the group consisting of OH, C02R4, Br, Cl, F, I, CF3, C1-Cg
alkoxy, C1-Cg alkyl, C2-Cg alkynyl, or C3-Cg cycloalkyl,
CO(CH2)nCH3, or when aryl is substituted on adjacent
carbons they can form a 5- or 6-membered fused ring
having one, two or three heteroatoms selected from O, N,
and S, this ring is unsubstituted or substituted on carbon or
nitrogen with one, two or three substituents selected from
the group consisting of OH, C02R4, Br, Cl, F, I, CF3, C1-Cg
alkoxy, C1-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-Cg
cycloalkyl, and CO(CH2)nCH3;
heteroaryl is defined as a 5- or 6-membered aromatic ring
containing 1, 2 or 3 heteroatoms selected from O, N and S ,
which is unsubstituted or substituted with one, two or three
substituents selected from the group consisting o~ OH,
C02R4, Br, Cl, F, I, CF3, C1-Cg alkoxy, C1-Cg alkyl, C2-Cg
alkynyl, C3-Cg cycloalkyl, CO(CH2)nCH3, and additionally
the 5- or 6-membered aromatic ring can be benzofused and
unsubstituted or substituted with one, two or three
substituents as described above;
heterocyclyl is defined as a 5- or 6-membered, non-aromatic ring
containing 1, 2 or 3 heteroatoms selected from O, N and S ,
which may contain one or two double bonds and which is
unsubstituted or substituted with one, two or three
substituents selected from the group consisting of OH,
C02R4, Br, Cl, F, I, CF3, C1-Cg alkoxy, C1-Cg alkyl, C2-Cg
alkynyl, Cg-Cg cycloalkyl, CO(CH2)nCH3, and additionally
the 5- or 6-membered ring can be benzofused and
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
6
unsubstituted or substituted with one, two or three
substituents as described above;
n is: 0 to 5; -
t is: 0, 1 or 2;
R,4 is: H, or C1-Cg alkyl; or
comprising the following steps:
1) adding to a compound of Formula II in a solvent,
R'-CH20H
I I
a solution of phosphate buffer to maintain a pH of about 4.0
to about $.0;
2) maintaining the phosphate-buffered biphasic mixture of the
compound of Formula II at about 0°C to about 50°C;
3) adding a catalytic amount of TEMPO to the mixture; and
4) charging the TEMPO/phosphate-buffered biphasic mixture
with a solution of sodium chlorite and a catalytic amount of
sodium hypochlorite to oxidize to the compound of Formula I.
The process as recited above, wherein the solvent is selected
from the group consisting of: acetonitrile, tetrahydrofuran, acetone,
tertiary C4-Ce alcohol, diethyl ether, DME (dimethyl ether), diglyme,
triglyme, MTBE (methyl t-butyl ether), toluene, benzene, hexane,
pentane, dioxane, dichloromethane, chloroform, carbon tetrachloride,
or a mixture of said solvents.
The process as recited above, wherein the phosphate buffer
comprises an aqueous mixture of NaOH, KOH, NaH2P04, KH2P04,
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
7
Na2HP04, and K2HP04, sufficient to maintain a pH of about 4.0 to about
8.0, and preferably a pH of about 6.5 to about 7Ø
The process as recited above, wherein TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy, free radical) is used in about 1.0 to about -
10.0 mole percent, preferably about 5.0 to about 7.0 mole percent.
The process as recited above, wherein sodium chlorite is
used in about 1.0 to about 3.0 equivalents, and preferably about 2.0
equivalents relative to the compound of Formula II.
The process as recited above, wherein sodium hypochlorite
is used in about 1.0 to about 7.0 mole percent, preferably about 2.0 to
about 5.0 mole percent.
The process as recited above, wherein the reaction
temperature is about 0°C to about 50°C, and preferably about
35°C to
about 40°C.
The process as recited above, wherein the reaction time is
up to about 24 hours, and preferably between about 2 and about 4 hours.
It is further understood that the substituents recited above
would include the definitions recited below.
The alkyl substituents recited above denote straight and
branched chain hydrocarbons of the length specified such as methyl,
ethyl, isopropyl, isobutyl, tert-butyl, neopentyl, isopentyl, etc.
Cycloalkyl denotes rings composed of 3 to 8 methylene
groups, each of which may be substituted or unsubstituted with other
hydrocarbon substituents, and include for example cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
The alkoxy substituent represents an alkyl group as
described above attached through an oxygen bridge.
The aryl substituent represents phenyl and 1-naphthyl or 2-
naphthyl, including aryls substituted with a 5- or 6-membered fused
ring, such as an unsubstituted and substituted methylenedioxy,
oxazolyl, imidazolyl, or thiazolyl ring.
The heteroaryl substituent represents a carbazolyl, furanyl,
thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazalyl,
pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl.
CA 02327890 2000-10-06
WO 99/52849 PCTNS99/07466
8
The heterocyclyl substituent represents, oxazolidinyl,
thiazolidinyl, thiazolidinyl, oxadiazolyl, or thiadiazolyl.
Each of the above substituents (alkyl, alkynyl, alkoxy,
cycloalkyl, aryl, heteroaryl, and heterocyclyl) can be either -
unsubstituted or substituted as defined within the description.
Recently, in an attempt to oxidize primary alcohols, such as lm:
O--1
O
C02H OH
Bu
OMe
1m
to the corresponding carboxylic acid, we found that RuCl3/H5I06 protocol
offered low yield of the desired products. ee Carlsen, P. H. et al. J. Org.
Chem. 1981, 46, 3936. It was probably due to the destruction of electron
rich aromatic ring. TEMPO catalyzed oxidation with bleach also gave
low yield due to significant chlorination of the aromatic rings. See A. E.
J. de Nooy, et al. Synthesis, 1996, 1153.; P. L. Anelli, et al. S. J. Org.
Chem. 1987,
52, 2559. and T. Miyazawa, et al. J. Org. Chem. 1985, 50, 1332. The synthesis
of ~m is decribed in Merck Case No. 20127PV, entitled "Oxidation
Process Using TEMPO" which is being filed simultaneously with this
application.
In order to eliminate the chlorination problem, a few other
oxidants (H202, AcO2H, t-Bu02H etc.) were examined, but no satisfactory
results was obtained. Finally, when sodium chlorite (NaC102) was used
as the oxidant, the product were obtained in 70-90% yield. The reaction
appeared to be very slow ( 1-2%/hour) but generally went to completion
overnight (~20 hours). More careful monitoring of the reaction indicated
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
9
that it was self accelerating process e.g. the conversion was less than
5% after one hour but reached ~90% in only 6 hours. Apparently, some
more active species was generated as the reaction progress. Sodium
hypochlorite (NaClO, bleach) was believed to be the most likely -
candidate. Indeed, when lOmol% of bleach was added to the reaction
mixture, the reaction was accelerate dramatically. It reached >50%
conversion in one hour and finished in approximately three hours.
SCHEME 1
R~~OH
Formula II
TEMPO,
NaCl02,
NaClO
R ~ CO2H
Formula I
The reaction was then optimized regard to further reduce
the chlorination and enhance the safety for scale up. The reaction was
faster at lower pH, but it was accompanied by increased chlorination. It
was slower at lower temperature as expected, but surprisingly, the
chlorination level appeared to be slightly elevated. Increasing the
amount of TEMPO and bleach increased the reaction rate, but the
TEMPO/NaClO ratio should be >2 to reduce the chances of chlorination.
The bleach was added slowly and simultaneously with NaC102 to the
batch at 35 °C to prevent build up of the oxidant and the risk of a run
away reaction. It should be noted that mixing of bleach and NaC102
prior to the addition is not advised since some toxic and potentially
explosive chlorine dioxide (C102) may be generated.
Next, a number of primary aicohols were oxidized to the
carboxylic acids and the results are summarized in Table 1. In general,
the reaction were very smooth and the yield were excellent (85-100%).
CA 02327890 2000-10-06
WO 99/52849 PCTNS99/0'1466
Chiral alcohols lg, 1j, and 1k were oxidized to the corresponding
carboxylic acid without any racemization of the labile chiral centers.
Mostly notably, for substrates prone to chlorination (1c-lh),
our new procedure gave much better yields. The most dramatic
5 demonstration of the superiority of our new procedure was revealed in
entry 5. When 1e was treated with NaClO and catalytic TEMPO, the
desired product was obtained in less than 5% yield. One of the major
side product was isolated and identified to be the chlorinated compound 4,
CI
~C02H
OMe
10 based on NMR studies. On the other hand, our TEMPO/NaC102 protocol
offered essentially quantitative yield of 2e.
CA 02327890 2000-10-06
WO 99/52849 PCT/US99l07466
Table 1: TEMPO Catalyzed Oxidation of Primary Alcohols to Carboxylic
Acids
Substrate Product Yield Yield
(NaCIO ) (NaCIO)
Ph~OH ph.C02H 98% -
1a 2a
Ph~OH pn~C02H 100% -
1b 2b
OH I \ CO H 99% 65%
2
/ OMe / OMe
1c 2c
OH l w C02H 100% 86%
Me0 ~ Me0 2d
1d
OH I \ CO H 96% <5%
2
/ /
OMe 1 a OMe 2e
Br Br 96% 80%
C02H
\ OOH I \
/ /
OMe 1 f OMe 2f
CA 02327890 2000-10-06
WO 99/52$49 PCT/US99/07466
12
Table 1: (Cont.) TEMPO Catalyzed Oxidation of Primary Alcohols to
Carboxylic Acids
Substrate Product Yield Yield
(NaCI02) (NaCIO)
Br Br 92% 6U%
OH I ~ C02H
OMe 1 g OMe 2g
OH Ph = C02H 90% 20%
Ph - 2h
1h
95%
Ph' v OH Ph CO H 2i
1i 2
HO O H02C O 95%
1' N N
Ph~"'~ Ph""'
O O
1 j 2j
Ph~OH Ph~C02H 85%
NHCBZ NHCBZ
1k 2k
OH I ~ C02H 100% -
02N / , 02N /
ii 21
In conclusion, an efficient and environmentally benign
procedure for the oxidation of primary alcohols to the carboxylic acids
has been developed. In this procedure, NaClOz is used as the
stoichiometric oxidant in the presence of catalytic amount of TEMPO
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
13
and bleach (NaClO). Most primary alcohols were oxidized in essentially
quantitative yield. Compared with TEMPO/NaClO/CH2C12 protocol, the
amount of chlorination of electron rich aromatic rings in the substrates
were dramatically reduced and the yield and purity of the products -
improved. Additionally, no chlorinated solvent is used.
The instant invention can be understood further by the
following examples, which do not constitute a limitation of the invention.
General
All substrates and reagents were obtained
commercially, except 1g (See Examples 2-5 decribing the preparation of
this primary alcohol) and used without purification. 'H and 13C NMR
spectra were recorded at 250 and 62.5 MHz respectively. The products
were identified by comparing their NMR spectra with those of
commercial materials except for 2g and 2j. The yields were determined
by reverse phase HPLC with Zorbax SB-Phenyl or YMC ODS-AM
columns and MeCN/0.1% H3P04 as the mobile phase.
EXAMPLE 1
Oxidation of Primary Alcohol-TEMPO Oxidation
NaCl02
R' OH TEMPO R1C02H
Formula II NaClO Formula I
A mixture of the primary alcohol 1 (40 mmol) in
MeCN (200 mL) and sodium phosphate buffer (0.67 M, pH= 6.7 ) was
heated to 35 °C. TEMPO (436 mg, 2.8 mmol) was added then a solution of
sodium chlorite (9.14 g 80%, 80.0 mmol in 40 mL water) and a solution of
dilute bleach ( 1.06 mL 5.25% bleach diluted into 20 mL, 2.Omo1%) were
added simultaneously in 2 hours.*
*Do not mix the sodium chlorite solution and bleach prior to
the addition since the mixture appears to be unstable. The
addition should be carried out as follows: approximately
20% of the sodium chlorite solution is added followed by 20%
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
14
of the dilute bleach. Then the rest of the NaC102 solution
and dilute bleach are added simultaneously in 2 hours. The
reaction is slightly exothermic.
The mixture was stirred at 35 °C until the reaction is -
complete (<2A% SM, 2-4 h) then cooled to rt. Water (300 mL) was added
and the pH was adjusted to 8.0 with 2.0 N NaOH (~48 mL). The reaction
was quenched by pouring into cold (0 °C) Na2S03 solution (12.2 g in 200
mL water) maintained < 20 °C. The pH of the aqueous layer should be
8.5-9.0 After stirring for 0.5 hour at rt, MTBE (200 mL) was added with
stirring. The organic layer was separated discarded. More MTBE (300
mL) was added and aqueous layer was acidified with 2.0 N HCl 0100
mL) with stirring to pH = 3-4. The organic layer was washed with water
(2 x 100 mL), brine (150 mL) to give a solution of the crude carboxylic acid
2 in 90-95% yield.
EXAMPLE 2
Preparation of 2-bromo-5-methoxybenzyl alcohol
Br Br
C02H
~OH
(/ ~/
OMe OMe
Sodium borohydride (8.6 g) is slurried in THF (150mL
KF=150 ~,g/mL) in a round bottom flask equipped with a thermocouple,
an addition funnel, a nitrogen inlet a mechanical stirrer and a cooling
bath. 2-Bromo-5-methoxybenzoic acid (50 g) is dissolved in THF (100mL
KF= 150 ~,g/mL) is added to the sodium borohydride slurry over 45 min
while maintaining the temperature at 20-25°C. The reaction must be
controlled with intermittent cooling and by careful monitoring of the
addition rate. The mixture is aged for 30 min at 20-25°C. Boron
trifluoride etherate (36.9 g) is added over a period of 30 min at 30-
35°C.
The addition of boron trifluoride etherate produces a delayed
exotherm and should be added slowly in order to control the reaction
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
temperature. The resulting white slurry is aged for 1 h at 30-35°C and
then sampled for HPLC assay. A peak at RT = 8.7 min is an impurity
related to the starting material. The acid is at RT = 9.lmin.
The reaction mixture is cooled to 15°C and carefully -
5 quenched into a cold ( 10 °C) saturated ammonium chloride solution (
150
mL) while maintaining the temperature < 25°C.
Ethyl acetate (500 mL) is added and the layers are
separated. The organic layer is washed with water (100 mL) and then
transfered to a 1L round bottom flask equipped for distillation. The
10 solution was concentrated and charged with fresh ethyl acetate. This is
repeated until a solution with a volume of 200 mL has KF<200
p.g/mL.The solvent is then switched to DMF to give the final volume of
200 mL with a KF<200 ~g/mL.
15 EXAMPLE 3
Preparation of 2-bromo-5-methoxybenzyl chloride
Br Br
~OH I ~ ~CI
OMe OMe
The DMF solution of the benzyl alcohol (91.3 g in 400mL
KF=300 ~,g/mL) is charged to a 2 L flask equipped with a mechanical
stirrer, thermocouple, NZ inlet, and cooling bath. The solution is cooled
to 0-5°C and the addition funnel is charged with thionyl chloride (55.0
g).
The thionyl chloride is added over a period of 45 min while maintaining
the temperture 5-10°C. The mixture is aged for 1 h at 5°C and
assayed by
HPLC.
The addition funnel is charged with water (400 mL) which
is added dropwise to the reaction mixture over a period of 30 min. while
maintaining the temperture < 15°C. The temperature is controlled by
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
16
cooling and monitoring the rate of addition. The initial addition of water
is highly exothermic. Using large excess of thionyl chloride results in a
more exothermic quench. If the quench temperture is not controlled,
hydrolysis of the benzyl chloride back to the alcohol may result. _
The resulting thick white slurry is aged for 1 h at 0-5°C.
The benzyl chloride is isolated by filtration. The cake is washed with
(1:1) DMF:H20 (100mL) and then water (200 mL). The solid is dried in
vacuo to give 93 g of the benzyl chloride( 94% yield, 96 A%).
HPLC assay: Column: Waters Symmetry C8, 4.6 x 250mm; UV
Detection: 220 nm; Column Temp: 25 °C; Flow rate: 1 mL / min.;
Eluent:
CH3CN:H20:0.1% H3P04 (70:30); RT (benzyl alcohol) = 3.9 min; RT
(benzyl chloride) = 7.3 min.; and RT (DMF) = 2.6 min.
EXAMPLE 4
Preparation of the Acetonide of N-propanoyl (1R,2S)-cis-aminoindanol
O
H2N.. ~N.
Ho,,,. ~ o,,,. ~ \
i i
A 5 L 3-neck round bottom flask equipped with a
mechanical stirrer, N2 inlet, thermocouple probe, heating mantle, and
addition funnel is charged with (1R,2S)-cis-aminoindanol (100 g),
tetrahydrofuran { 1.2 L, KF 120 ~.g/mL), and triethylamine (96 mL, KF
500 ~g/mL). The resulting slurry is heated under a N2 atmosphere to 40-
45°C giving a yellow solution. Propionyl chloride (59 mL) is charged to
an
addition funnel and added to the solution while maintaining the
temperature at 45-50°C.
The temperature is controlled by rate of propionyl chloride
addition and a cooling bath. HPLC assay shows >99% amide formed.
Methanesulfonic acid (3 mL) is added to the reaction slurry. 2-
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
17
Methoxypropene ( 140 mL) is charged to an addition funnel and added
over 30 minutes at a temperature of 50°C.
The addition of 2-methoxypropene is mildly exothermic. The
temperature is maintained by the rate of addition and a heating -
mantle. The reaction remains a slurry but does become less thick.
The reaction slurry is aged for 1-2 hours at 50°C. HPLC
assay at this point shows <0.5A% of the amide remaining. The amide is
not removed in the isolation so it is important to push the reaction to
completion. The reaction slurry is cooled to 0-5°C and quenched by
addition of 5% aqueous sodium carbonate solution (1 L) and heptane (1
L). The layers are stirred and separated and the organic is washed with
water (300 mL).
HPLC assay at this point shows the acetonide in >98A% and
>90% yield. The acetonide/THF/heptane solution is filtered into a 2 L
round bottom flask and the solution is distilled to a final volume of
700mL. Heptane (1L) is added and the solution is distilled to a final
volume of 700mL. The distillation is done under partial vacuum at
-50°C. NMR assay at this point shows < 2 mol% THF. The solution is
allowed to cool and is seeded with acetonide at 35-40°C. The thick
slurry
is aged for 1 hour at ambient temperature then cooled to 0-5°C and aged
for 1 hour. The slurry is filtered and the cake is washed with cold
heptane (200 mL) and air dried to yield acetonide as a crystalline white
solid (141.1 g, 85% yield, 99.6 A%).
EXAMPLE 5
Alkylation of the Acetonide with 2-bromo-5-methoxybenzyl chloride.
Br
O ~ CI
Br
OH
OMe
I
i LiHMDS, THF, -10°C OMe
2) HCI
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
18
A THF solution (2L, KF< 200 ~,g/mL) of the acetonide (252
g) and the benzyl chloride (255 g) is cooled to -10°C. Lithium
bis(trimethylsilyl)amide (1.45 L) is added dropwise over 5 h at 0-2°C.
The
mixture is then aged for 1.5 h and assayed by HPLC.
The reaction is quenched by adding aqueous saturated
ammonium chloride solution ( 1 L). The initial addition of the
ammonium chloride should be slow in order to control the foaming. The
rate can be increased when the foaming subsides.
The quenched reaction is then transfered into a mixture of
aqueous ammonium chloride (1.5 L), water (0.5 L), and ethyl acetate (3
L). The mixture is then agitated for 15 min and the layers are separated.
The organic layer is washed with water (1 L) and brine (0.5 L). The ethyl
acetate solution is concentrated to a low volume and solvent switched to
1,4-dioxane. The dioxane solution is adjusted to a final volume of 1.$ L.
The dioxane solution of the coupled product is charged to a
12 L round bottom flask and 6 M HCl ( 1.5 L) is charged. The mixture is
heated to reflux and monitored by HPLC.
The mixture is cooled to 20°C and MTBE (3 L) is added. The
mixture is agitated for 15 min and the layers are separated. The organic
layer is washed with water (1 L). The MTBE solution of the crude acid is
extracted with 0.6 M sodium hydroxide (2 L). The aqueous solution of the
sodium salt of the acid is combined with MTBE (2.5 L) and cooled to
10°C.
The two phase mixture is acidified with 5.4 M sulfuric acid
(250 mL), agitated for 15 min, settled and the layers separated. The
MTBE solution of the acid is washed with water (0.5 L). The MTBE
solution of the acid is dried by distilation and then solvent switched to
THF. The final volume of the THF is 2 L with a KF < 250 ~.g/mL.
HPLC assav: column: Waters Symmetry; Eluent: acetontrile: water:
phosphoric acid (70:30:0.1); Flow rate: 1 mlJmin.; RT (acetonide)= 4.5
min.; RT (benzyl chloride) = 7.5 min.; RT (coupled product) = 11.5 min.;
RT (aminondanol) = 1.7 min.; RT (hydroxyamide) = 1.7 min.; and RT
(acid) = 4.5 min.
CA 02327890 2000-10-06
WO 99/SZ849 PCTNS99/07466
19
EXAMPLE 6
Preparation of 3-(2-bromo-5-methoxyphenyl)-2-methylpropanol
Br O Br
\ ~ ~OH NaBH4/BF3{Et20) I \ OH
/ THF / '
OMe OMe
Sodium borohydride (33 g) is slurried in THF (0.5 L KF=200
~.g/mL) in a round bottom flask. The THF solution (2 L) of the acid is
added to the sodium borohydride slurry over 1 h while maintaining the
temperature at 20-25°C.
The reaction is controlled with a cooling bath and by
carefully monitoring the addition rate. A nitrogen sweep and proper
venting of the hydrogen is also important.
The mixture is aged for 30 min at 20-25 °C. Boron trifluoride
etherate (152 g) is added over 1 h at 30-35 °C. The addition produces a
delayed exotherm and should be carefully monitored in order to control
the reaction temperature. The resulting milky white slurry is aged for 1
h at 30 °C and sampled for HPLC assay.
The reaction mixture is cooled to 15 °C and carefully
quenched in a cold (10°C) ammonium chloride solution (1.5 L) while
maintaing the temperature at 25 °C. The rate of hydrogen evolution is
controlled by the rate of the addition of the mixture into the ammonium
chloride. The quenched mixture is distilled in vaccuo to remove the
THF. The aqueous layer is extracted with MTBE ( 1.5 L) and the organic
layer is dried by flushing with additional MTBE. The MTBE solution is
then solvent switched to hexanes and adjusted to a volume of 350 mL and
seeded. The slurry is aged far 2 h at 20 °C and then cooled to 0-5
°C aged
for 1 h and filtered. The cake is washed with cold hexanes (200 mL). The
solid is dried under a nitrogen sweep. The isolated solid (164 g) is >
99A% by HPLC and > 99%ee.
CA 02327890 2000-10-06
WO 99/52849 PCT/US99/07466
HPLC: Column: Waters Symmetry C8; Solvent: acetonitrile:water:
phosphoric acid (50:50:0.1); Flow rate: 1mL /min.; Detection: 220 nm; RT
(acid) = 10.2 min.; RT (alcohol) = 10.7min.
Chiral HPLC: Column: Chiracel OD-H; Hexane:2-propanol (97:3); Flow -
5 rate: 1 mL/ min.; Detection: 220 nm; RT minor isomer = 21 min.; and RT
major isomer = 23 min.
EXAMPLE 7
Preparation of 3-(2-bromo-5-methoxyphenyl)-2-methylpropanoic acid
Br Br O
\ ~ ~OH TEMPO, NaCl02, I \ OH
NaClO
10 OMe OMe
The acid was prepared following the general procedure
recited in Example 1.
2g:1H NMR (CDCh) 8: 7.44 (d, J=8.7 Hz, 1H), 6.78 (d, J=3.1 Hz,
15 1H), 6.66 (dd, J=8.7, 3.1 Hz, 1H), 3.75 (s, 3H), 3.13 (dd, J=13.1, 6.8
Hz, 1H), 2.98-2.84 (m, 1H), 2.77 (dd, J=13.1, 7.4 Hz, 1H), 1.23 (d,
J=6.9 Hz, 3H).
2j:1H N'~LIR (CDCh) 8: 9.0-8.0 (broad, 1 H), 7.47-?.30 (m, 5H), 5.71
(d, J = 7.7 Hz, 1H), 4.43 (d, J = 7.7 Hz, 1H), 2.70-2.40 (m, 2H), 2.33-
20 2.27 (m, 1H), 2.17-1.80 (m, 3H), 1.58 (s, 3H).
~C NMR (CDCI?,$: 172.04,169.48,137.52, 128.73, 126.16, 94.66,
77.05, 64.34, 34.52, 29.91, 23.45, 17.28.
Anal. Calcd for Cy H~~( : C, 65.44; H, 6.22; N, 5.09. Found C, 65.31; H,
6.15; N, 4.98.
