PROCESS FOR PREPARATION OF SUBSTITUTED AMINO ALCOHOLS
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of substituted
aminoalcohols which are useful in the preparation of tubulin inhibitors which are
useful in the treatment of cancer.
BACKGROUND OF THE INVENTION
There is still a need in the art for cytotoxic agents for use in cancer therapy.
In particular, there is a need for cytotoxic agents which inhibit or treat the growth of
tumors which have an effect similar to paclitaxel and interfere with the process of
microtubule formation. Additionally, there is a need in the art for agents which
accelerate tubulin polymerization and stabilize the assembled microtubules.
Described in copending case Docket No. AM 101270, application number
60/505,544, filed September 24, 2003 is a series of 6-[(substituted)phenyl]-
triazolopyrimidine compounds having the structural formula
which are microtubule inhibitors and useful in the treatment of cancer.
Useful in the preparation of the above described 6-[(substituted)phenyl]-
triazolopyrimidine compounds are a series of substituted amino alcohols of the
formula HO-(CHz)n-NR1R2.
Described by Kabalka, George W.; Li, Nan-Sheng; and Pace, R. David,
Synthetic Communications (1995), 25(14), 2135-43 is the preparation of amino
alcohols by the N-t-butoxycarbonyl protection of primary and secondary amines via a
hydroboration-oxidn reaction sequence.
Disclosed by Artyushin, O. I.; Petrovskii, P. V.; Mastryukova, T. A.; Kabachnik, M.
I. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1991), (9), 2154-7 is
the simple synthesis of 3-(alkylamino)-1-propanols by condensing for example
NH2(CH2)30H with CIC02Me in CH2CI2 containing Na2C03 which gave
MeNH(CH2)3OH in 37% yield.
A. Parkkinen et al, Journal of Physical Organic Chemistry, (1991), 4(1), 53-7
describes the hydrolytic decomposition of methyltetrahydrooxazines to afford for
example MeNH(CH2)3OH .
Described by Powell, John; James, Nadine;'Smith, Stuart J., Synthesis (1986),
(4), 338-40 is the preparation of MeNH(CH2)3OH by the lithium aluminum hydride
reduction of formamide HC(0)NH(CH2)3OH in the presence of triethanolamine.
Kashima, Choji; Harada, Kazuo; Omote, Yoshimori, Canadian Journal of
Chemistry (1985), 63(2), 288-90 describe the synthetic procedures where in the
presence of NaH, the methylation of H2NCH2CH2OH by Me2S04 in THF gave mainly
H2NCH2CH2OMe, MeNHCH2CH2OMe, and Me2NCH2CH2OMe, whereas with LiH or
CaH2 the products were MeNHCH2CH2OH and Me2NCH2CH2OH. Similar results
were obtained with H2N(CH2)3OH to give MeHN(CH2)3OH.
Described by Felfoldi, K.; Laszlavik, M.; Bartok, M.; Karpati, E. Acta Physica et
Chemica (1980), 26(3-4), 163-9 is the preparation of numerous compounds which
include for example MeHN(CH2)3OH by reaction of CI(CH2)3OH with methylamine in
ethanol in an autoclave in 55% yield. However, the preparation method produces a
flammable solvent and so is not sufficient to prepare the substituted amino alcohols
and in particular, 3-methylamino-propan-1-ol.
Katritzky, Alan R.; Baker, Victor J.; Brito-Palma, Fernando M. S. Journal of the
Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999)
(1980), (11), 1739-45 describe the preparation for example of MeHN(CH2)3OH by
reduction of C2H5OC(0)(CH2)2NHMe with lithium aluminum hydride in 56% yield.
Described by Jourdain, F.; Pommelet, J. C; Tetrahedron Lett.; 35; 10; 1994;
1545-1548, is the preparation of amino alcohols in which the chloroalcohols are
reacted with an excess of amine in the presence of ethanol or aniline in toluene.
S. D. Goldberg; and W. F. Whitmore; J.Amer.Chem.Soc; 59; 1937; 2280-
2282 describe the preparation of monoalkylaminopropanols wherein the
aminopropanol is reacted with trimethylene oxide made from trimethylene
bromohydrin and 50% sodium hydroxide. However, the reaction was effected by the
action of trimethyleneoxide and trimethylene bromohydrin on the aminopropanol.
Described by S. Searles and V. P. Gregory; J.Amer.Chem.Soc.; 76; 1954;
2789-2790 is the preparation, for example, wherein 3-methylamino-1-propanol is
formed by reaction of a 25% aqueous solution of methylamine and trimethylene oxide
in an autoclave at 150°C for 12 hours and then collecting the product by distillation.
Kurihara et al.; YKKZAJ; Yakugaku Zasshi; 74; 1954; 763; Chem.Abstr.;
1955; 11646 describe the preparation of alkylaminopropanols wherein a mixture of
sodium, ammonium acetate, allyl alcohol and alkylamine are reacted in an autoclave
at 130-150°C for 7 hours. Prepared using the described conditions is for example
3-methylamino-1 -propanol.
Described by Cherbuliez.E. et al.; HCACAV; Helv.Chim.Acta; FR; 50; 1967;
331-346 is the alkylation for example of amino-3-propanol-1 with methyl iodide and
the product 3-methylamino-propan-1-ol is purified by chromatography.
While the above described processes may be used to prepare substituted
amino alcohols there is a need for a simpler process which can be used for larger
scale preparations.
SUMMARY OF THE INVENTION
The present invention provides a process for producing a series of substituted
amino alcohols of the formula HO-(CH2)n-NR1R2 wherein R1 and R2 are each
independently H or CrC3 alkyl; or
R1 and R2 when optionally taken together with the nitrogen atom to which each is
attached form a 4 to 6 membered saturated heterocyclic ring having 1-2 nitrogen
atoms and 0-1 oxygen atoms or 0-1 sulfur atoms, and optionally substituted with R3;
R3 is C1-C3 alkyl; which comprises reacting a haloalcohol of the formula X-(CH2)n-OH
wherein X is bromo, chloro or iodo and n is an integer of 2 to 7 with an amine
HNR1R2 in an aqueous solution.
The described process may optionally contain an iodine source catalyst.
DEFINITIONS
The term base means an alkali metal hydroxide, alkali metal carbonate or
alkali metal bicarbonate.
The term alkali metal hydroxide means lithium, potassium or sodium hydroxide.
The term alkali metal carbonate means lithium, potassium or sodium carbonate.
The term alkali metal bicarbonate means lithium, potassium or sodium bicarbonate.
The term alkali metal iodide means lithium, potassium or sodium iodide.
The term alkali metal hydride means lithium, potassium or sodium hydride.
The term iodide source catalyst means alkali metal iodides or tetraalkylammonium
iodides.
The term heterocyclic ring as used herein means a saturated heterocyclic ring
having 4 to 6 members having 1-2 nitrogen atoms, 0-1 oxygen atoms or 0-1 sulfur
atoms optionally substituted with d-C3 alkyl. Non-limiting representative examples
include: morpholine, piperidine, pyrrolidine, piperazine, azetidine and N-methyl-
piperazine.
The term alkyl means a straight or branched alkyl moiety of 1 to 3 carbon
atoms.
The term organic solvent means a solvent selected from the group methanol,
ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, diethylether, 1,4-
dioxane, toluene and dichloromethane.
Dicarboxylic acid salts include the succinate or f umarate salt.
DETAILED DESCRIPTION OF THE INVENTION
A process for the preparation of a substituted amino alcohol of the formula
HO-(CH2)n-NR1R2 wherein R1 and R2 are each independently H or CrC3 alkyl; or
R1 and R2when optionally taken together with the nitrogen atom to which each is
attached form a 4 to 6 membered saturated heterocyclic ring having 1-2 nitrogen
atoms and 0-1 oxygen atoms or 0-1 sulfur atoms, and optionally substituted with R3;
n is an integer of 2 to 7; R3 is C|-C3 alkyl; comprising the reaction of a haloalcohol of
the formula HO-(CH2)n-X, where X is CI, Br or I, with an amine HNR1R2, in water as
solvent at a temperature range of about 20°C to about 90CC.
Optionally the preparation of substituted amino alcohols of the formula
HO-(CH2)n-NR1Rz is in the presence of a catalytic amount of an iodide source
catalyst which includes alkali metal iodides or tetraalkylammonium iodides.
The preferred iodide source catalysts are alkali metal iodides and the most
preferred is sodium and potassium iodide.
An embodiment of this process is wherein the optional amount of an iodide
source catalyst used is the catalytic amount in the range of about 1 mole % to about
100 mole %. A preferred range is about 2 mole % to about 10 mole %. The most
preferred catalytic amount is about 5 mole %.
Another embodiment of this process is wherein the mole ratio of haloalcohol
to amine is in the range of about 1:1 to about 1:15. A preferred mole ratio of
haloalcohol to amine is in the range of about 1:2 to about 1:8. The most preferred
mole ratio of haloalcohol to amine is about 1:4.
The process may be carried out at a temperature range of about 15°C to
about 90°C. A preferred temperature range is about 20°C to about 50 °C. The most
preferred temperature is about 25°C.
The process may be carried out in the range of about 8 h to about 72 h. A
preferred time range is about 10 h to about 24 h. The most preferred time for the
process to be carried out is about 15 h.
A preferred embodiment is where n is 2 to 4.
A particularly preferred embodiment is where n is 3.
An embodiment of this process is where R1 and R2 are each independently H
or CVC3 alkyl.
An embodiment of this process is where R1 is H and R2 is methyl.
An embodiment of this process is where X is CI.
A process for the preparation of the aminoalcohol of the formula:
HO-(CH2)n-NR1R2
wherein: •
R1 and R2 are each independently H or CrC3 alkyl; or
R1 and R2when optionally taken together with the nitrogen atom to which each is
attached form a 4 to 6 membered saturated heterocyclic ring having 1-2 nitrogen
atoms and 0-1 oxygen atoms or 0-1 sulfur atoms, and optionally substituted with R3;
n is an integer of 2 to 7; R3 is C^Ca alkyl;
comprising the steps of:
a. reacting a haloalcohol of the formula HO-(CH2)n-X, where X is CI, Br or I, with
an amine HNR1R2, in water to form an aminoalcohol of the formula
HO-(CH2)n-NR1R2;
b. concentrating;
c. adding a base;
d. concentrating;
e. extracting with organic solvent;
f. filtering;
g. concentrating to a residue and collecting the product.
Optionally the residue collected may be collected and purified by distillation.
The process may optionally include an iodide source catalyst.
Additionally, provided is a process for the preparation of a 6-
[(substituted)phenyl]-triazolopyrimidine of the formula
wherein:
R1 and R2 are each independently H or CrC3 alkyl; or
R1 and R2when optionally taken together with the nitrogen atom to which each is
attached form a 4 to 6 membered saturated heterocyclic ring having 1 -2 nitrogen
atoms and 0-1 oxygen atoms or 0-1 sulfur atoms, and optionally substituted with R3;
R5 is CF3 or C2FS;
R4isHorCi-C3alkyl;
R3 is C1-C3 alkyl;
n is an integer of 2 to 4;
X is CI or Br;
or a pharmaceutical^ acceptable dicarboxylic acid salt or hydrate thereof
which comprises:
a. reacting a haloalcohol of the formula HO-(CH2)n-X, where X is CI, Br or I,
with an amine HNR1R2, in water to form an aminoalcohol of the formula
HO-(CH2)n-NR1R2;
b. concentrating;
c. adding a base;
d. concentrating;
e. extracting with organic solvent;
f. filtering;
g. concentrating to a residue and collecting the aminoalcohol of the formula
HO-(CH2)n-NR1R2;
h. reacting the aminoalcohol HO-(CH2)n-NR1R2 with an alkali metal hydride
for about 30 minutes in tetrahydrofuran at about 10 to 40°C, adding the amine
product
and heating to about 60° C for about 12 to 20 h to obtain the 6-
[(substituted)phenyl]-triazolopyrimidine product

i. reacting the 6-[(substituted)phenyl]-triazolopyrimidine product with a
dicarboxylic acid of the formula

wherein the dashed line is an optional bond, in t-butylmethyl ether to obtain the 6-
[(substituted)phenyl]- triazolopyrimidine product dicarboxylic acid salt

j. optionally treating the 6-[(substituted)phenyl]- triazolopyrimidine product
dicarboxylic acid salt with water to obtain the 6-
[(substituted)phenyl]-triazoIopyrimidine as the hydrated salt.
The described process may optionally include an iodide source catalyst.
Preferably the dicarboxylic acid salt of the 6-[(substituted)phenyl]-triazolopyrimidine is
the succinic acid salt and more preferably as the anhydrous salt is treated with a
saturated atmosphere of (80-100%) relative humidity of water to form the hydrated
salt and in particular the dihydrated salt.
Preferred bases include alkali metal hydroxide, alkali metal carbonate or alkali metal
bicarbonate.
More preferred bases are alkali metal carbonates.
A particularly preferred base is potassium carbonate.
Preferred organic solvents include methyl alcohol, isopropyl alcohol or ethyl acetate.
The following examples are presented to illustrate certain embodiments of the
present invention, but should not be construed as limiting the scope of this invention.
Example 1
In a 3L flask, 3-chloro-1-propanol (50.0 g, 0.53 mol, 98%, Aldrich C4.640-3) is
dissolved in methylamine solution (1L, 40 wt.% in water, Aldrich 42,646-6) and
heated to reflux for 3 days. The reaction is cooled to room temperature and the
solvent is reduced in vacuo to -150 mL To the reaction mixture, potassium
carbonate (50 g) is added and the remainder of solvent is removed. The residue is
suspended in methanol (200 mL) and filtered through a plug of silica gel (200 g).
The plug is washed with methanol (2 x 100 mL), the organic layers are combined,
and the solvents are removed to give an orange oil. The oil is distilled at -1-2 mm
Hg from room temperature to 60°C with an oil bath and a distillation trap. The
distillation afforded 3-methylamino-propan-1-ol as a clear, colorless liquid (22.0 g),
BP 165-167°C (760 torr), C4HnNO, MW 89.14
Example 2
A mixture of 30 g of sodium iodide, 500 g of 3-chloro-1 -propanol and 4000 mL
of methylamine solution (40 wt.% in water, Aldrich 42,646-6) is stirred at room
temperature for about 17 h. The solvent is reduced in vacuo to -700-800 mL. To the
reaction mixture, potassium carbohate (500 g) is added and the remainder of water is
removed to a residue which is distilled with toluene to afford a residue. The residue
is suspended in methanol (2000 mL), filtered and the cake washed with methanol (2
x 1000 mL). The methanol layers are combined, and the solvents are removed to
give an oil. The oil is distilled to afford 3-methylamino-propan-1-ol as a clear,
colorless liquid (352.0 g), BP 90-95°C (8 mm), C^NO, MW 89.14
WHATjS CLA1ME&4ST-
1. A process for the preparation of a substituted amino alcohol of the formula
HO-(CH2)n-NR1R2 wherein R1 and R2 are each independently H or CrC3 alkyl; or
R1 and R2 when optionally taken together with the nitrogen atom to which each is
attached form a 4 to 6 membered saturated heterocyclic ring having 1-2 nitrogen
atoms and 0-1 oxygen atoms or 0-1 sulfur atoms, and optionally substituted with R3;
n is an integer of 2 to 7; R3 is C1-C3 alkyl; comprising the reaction of a haloalcohol of
the formula HO-(CH2)n-X, where X is CI, Br or I, with an amine HNR1R2, in water as
solvent at a temperature range of ^boup20°C tq^bouy90°C. u >/"
2. A process ^ccojrjlinjjjB) claim 1 further comprising an iodide source catalyst.
3. A process according to claim 2 wherein the iodide source catalyst is present
in a catalytic amount.
4. A process according to claim 2 or claim 3 wherein the iodide source catalyst
is an alkali metal iodide or a tetraalkylammonium iodide.
5. A process according to claim 4 wherein the alkali metal iodide is sodium or
potassium iodide.
6. A process according to any one of claims 3 to 5 wherein the catalytic
amount of iodide source catalyst is present in ^bouf 1 mole % to^boupl 00
mole %.
7. A process according to claim 6 wherein the catalytic amount of iodide
source catalyst is present in (&out 5 mole % to 10 mole %.
8. A process acc^rdingjp claim 7 wherein the iodide source catalyst is present
iry^bout^mole %.
9. A process according to any one of claims 1 to 8 wherein the temperature
range isffi)5ut;20 to^boS)50 °C.
10. A process according to claim 9 wherein the temperature is^GoulT250C.
11. A process according to any one of claims 1 to 10 wherein X is CI.
12. A process according to any one of claims 1 to 11 wherein n is 2 to 4.
13. A process according to claim 12 wherein n is 3.
14. A process according to any one of claims 1 to 13 wherein the mole ratio of
haloalcohol to amine is in the range of(£bou£)l:1 to^Blqyp1:15.
15. A process according to claim 14 wherein the mole ratio of haloalcohol to
amine is in the range of(€bout)1.2 tc{about)l .8.
16. A process according to claim 14 wherein the mole ratio of haloalcohol to
amine is^about) 1:4.
17. A process according to any one of claims 1 to 16 wherein Ft1 and R2 are
each independently H or C1-C3 alkyl.
18. A process according to claim 17 wherein R1 is H and R2 is methyl.
19. A process according to any one of claims 1 to 18 in which the
aminoalcohol reaction product is subjected to steps comprising:
a. concentrating;
b. adding a base;
c. concentrating;
d. extracting with organic solvent;
e. filtering;
f. concentrating to a residue and collecting the product.
20. A process according to claim 19 wherein the base is an alkali metal
hydroxide, alkali metal carbonate or alkali metal bicarbonate.
21. A process according to claim 20 wherein the base is an alkali metal
carbonate.
22. A process according to claim 21 wherein the alkali metal carbonate is
potassium carbonate.
23. The process according to claim 19 wherein the organic solvent is
selected from the group methanol, ethanol, isopropanol, ethyl acetate,
acetonitrile, tetrahydrofuran, diethylether, 1,4-dioxane, toluene and dichloromethane.
24. A process according to any one of claims 19 to 23 wherein the organic
solvent is methyl alcohol, isopropyl alcohol and ethyl acetate.
25. A process for the preparation of a 6-[(substituted)phenyl]-triazolopyrimidine of
the formula
wherein:
R1 and R2 are each independently H or C^-Ca alkyl; or
R1 and R2when optionally taken together with the nitrogen atom to which each is
attached form a 4 to 6 membered saturated heterocyclic ring having 1 -2 nitrogen
atoms and 0-1 oxygen atoms or 0-1 sulfur atoms, and optionally substituted with R3;
R5 is CF3 or C2FS;
R4isHorC,-C3alkyl;
R3 is C,-C3 alkyl;
n is an integer of 2, 3, or 4;
X is CI or Br;
or a pharmaceutical acceptable dicarboxylic acid salt or hydrate thereof
which comprises:
a. reacting an aminoalcohol HO-(CH2)n-NR1R2 prepared by a process according
to any one of claims 1 to 25 with an alkali metal hydride for^ibojyt&O minutes
in tetrahydrofuran at(£boyl)lO to 40°C, adding the amine product
and heating tc^abouJ^O0 C Jo(aboyp12 to 20 hours to obtain the 6-
[(substituted)phenyl]-triazolopyrimidine product

b. reacting the 6-[(substituted)phenyl]-triazolopyrimidine product with a
dicarboxylic acid of the formula

wherein the dashed line is an optional bond, in t-butylmethyl ether to obtain the 6-
[(substituted)phenyl]- triazolopyrimidine product dicarboxylic acid salt

c. optionally treating the 6-[(substituted)phenyl]- triazolopyrimidine product
dicarboxylic acid salt with water to obtain the 6-
[(substituted)phenyl]-triazo!opyrimidine as the hydrated salt.
26. The process according to claim 25 wherein the dihydrated salt is obtained.

There is provided a process for the preparation of substituted amino alcohols HO-(CH2)n-NR1R2 from haloalcohols
HO-(CH2)n-X, where X is C1, Br or I, bz reaction with an amine HNR1R2, in water as solvent at a temperature range of about 20°C
to about 90°C optionally in the presence of a catalytic amount of an iodide source3 metal iodides. The haloalcohols are useful in the
preparation of 6-[(substituted)phenyl]-triazolopyrimidine compounds which are useful in the treatment of cancer.