U.S. patent application number 11/201878 was filed with the patent office on 2006-02-16 for process for preparing tamsulosin.
This patent application is currently assigned to SCINOPHARM TAIWAN LTD.. Invention is credited to Meihua Xie.
Application Number | 20060036113 11/201878 |
Document ID | / |
Family ID | 35800874 |
Filed Date | 2006-02-16 |
United States Patent
Application |
20060036113 |
Kind Code |
A1 |
Xie; Meihua |
February 16, 2006 |
Process for preparing tamsulosin
Abstract
The present invention relates to a process for preparing
Tamsulosin, an anti-benign prostatic hyperplasia drug, which
comprises converting o-ethoxyphenoxyethanol to a corresponding
sulfonate, and reacting the sulfonate with
(R)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide by
condensation to produce Tamsulosin.
Inventors: |
Xie; Meihua; (JiangSu,
CN) |
Correspondence
Address: |
LADAS & PARRY
26 WEST 61ST STREET
NEW YORK
NY
10023
US
|
Assignee: |
SCINOPHARM TAIWAN LTD.
|
Family ID: |
35800874 |
Appl. No.: |
11/201878 |
Filed: |
August 11, 2005 |
Current U.S.
Class: |
564/80 |
Current CPC
Class: |
C07C 303/40 20130101;
C07C 303/28 20130101; C07C 309/66 20130101; C07C 311/37 20130101;
C07C 303/28 20130101; C07C 303/40 20130101 |
Class at
Publication: |
564/080 |
International
Class: |
C07C 307/10 20060101
C07C307/10 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 16, 2004 |
CN |
200410058397.6 |
Claims
1. A process for preparing Tamsulosin, which comprises the
following step: reacting o-ethoxyphenoxyethanol sulfonate of
Formula (3) with
R-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide of Formula (4)
at a temperature of about 40 to 100.degree. C. by condensation to
produce Tamsulosin: ##STR10## wherein R is (C.sub.1-C.sub.6)alkyl
or phenyl substituted by halogen, nitro and/or
(C.sub.1-C.sub.6)alkyl.
2. The process according to claim 1, wherein said reaction is
conducted at a temperature of about 50 to 80.degree. C.
3. The process according to claim 2, wherein said reaction is
conducted at a temperature of about 55 to 65.degree. C.
4. The process according to claim 1, wherein said reaction is
conducted in the presence of a solvent.
5. The process according to claim 4, wherein said solvent is an
aprotic organic solvent.
6. The process according to claim 4, wherein said solvent is
selected from the group consisting of N,N-dimethylformamide (DMF),
dimethyl sulphoxide (DMSO), N,N-dimethylacetamide (DMAC) and
mixtures thereof.
7. The process according to claim 1, wherein an acid scavenger is
used in the reaction.
8. The process according to claim 7, wherein said acid scavenger is
an organic amine, an inorganic base or combinations thereof.
9. The process according to claim 8, wherein said organic amine is
selected from the group consisting of an organic tertiary amine,
pyridine and mixtures thereof.
10. The process according to claim 9, wherein said organic amine is
selected from the group consisting of triethylamine, pyridine and
mixtures thereof.
11. The process according to claim 8, wherein said inorganic base
is selected from the group consisting of KOH, NaOH,
K.sub.2CO.sub.3, NaHCO.sub.3 and mixtures thereof.
12. The process according to claim 1, wherein said reaction is
conducted in the presence of a catalyst.
13. The process according to claim 12, wherein said catalyst is a
monovalent inorganic iodide.
14. The process according to claim 12, wherein said catalyst is
selected from the group consisting of potassium iodide (KI), sodium
iodide (NaI), copper iodide (CuI) and mixtures thereof.
15. A process for preparing o-ethoxyphenoxyethanol sulfonate, which
comprises the following step: reacting o-ethoxyphenoxyethanol of
Formula (2) with sulfonyl chloride of Formula RSO.sub.2Cl at a
temperature of about -10 to 10.degree. C., to produce
o-ethoxyphenoxyethanol sulfonate of Formula (3), ##STR11## wherein
R is (C.sub.1-C.sub.6)alkyl or phenyl substituted by halogen, nitro
and/or (C.sub.1-C.sub.6)alkyl.
16. The process according to claim 15, wherein said reaction is
conducted at a temperature of about -5 to 5.degree. C.
17. The process according to claim 16, wherein said reaction is
conducted at a temperature of about 0 to 5.degree. C.
18. The process according to claim 15, wherein said reaction is
conducted in the presence of a solvent.
19. The process according to claim 18, wherein said solvent is
selected from the group consisting of chloromethane, chloroethane,
benzene, substituted benzene, pyridine and mixtures thereof.
20. The process according to claim 19, wherein said solvent is
selected from the group consisting of dichloromethane,
trichloromethane, dichloroethane, benzene, toluene and mixtures
thereof.
21. A process for preparing Tamsulosin, which sequentially
comprises the following steps: (i) reacting o-ethoxyphenoxyethanol
of Formula (2) with sulfonyl chloride of Formula RSO.sub.2Cl at a
temperature of about -10 to 10.degree. C., to form
o-ethoxyphenoxyethanol sulfonate of Formula (3); ##STR12## and (ii)
reacting o-ethoxyphenoxyethanol sulfonate of Formula (3) with
R-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide of Formula (4)
at a temperature of about 40 to 100.degree. C. by condensation to
produce Tamsulosin; ##STR13## wherein R is (C.sub.1-C.sub.6)alkyl
or phenyl substituted by halogen, nitro and/or
(C.sub.1-C.sub.6)alkyl.
22. The process according to claim 21, wherein said step (i) is
conducted at a temperature of about -5 to 5.degree. C.
23. The process according to claim 22, wherein said step (i) is
conducted at a temperature of about 0 to 5.degree. C.
24. The process according to claim 21, wherein the step (i) is
conducted in the presence of a solvent.
25. The process according to claim 24, wherein said solvent is
selected from the group consisting of chloromethane, chloroethane,
benzene, substituted benzene, pyridine and mixtures thereof.
26. The process according to claim 25, wherein said solvent is
selected from the group consisting of dichloromethane,
trichloromethane, dichloroethane, benzene, toluene and mixtures
thereof.
27. The process according to claim 21, wherein said step (ii) is
conducted at a temperature of about 50 to 80.degree. C.
28. The process according to claim 27, wherein said step (ii) is
conducted at a temperature of about 55 to 65.degree. C.
29. The process according to claim 21, wherein said step (ii) is
conducted in the presence of a solvent.
30. The process according to claim 29, wherein said solvent is an
aprotic organic solvent.
31. The process according to claim 29, wherein said solvent is
selected from the group consisting of N,N-dimethylformamide (DMF),
dimethyl sulphoxide (DMSO), N,N-dimethylacetamide (DMAC) and
mixtures thereof.
32. The process according to claim 21, wherein an acid scavenger is
used in step (ii).
33. The process according to claim 32, wherein said acid scavenger
is an organic amine, an inorganic base or combinations thereof.
34. The process according to claim 33, wherein said organic amine
is selected from the group consisting of an organic tertiary amine,
pyridine and mixtures thereof.
35. The process according to claim 34, wherein said organic amine
is selected from the group consisting of triethylamine, pyridine
and mixtures thereof.
36. The process according to claim 33, wherein said inorganic base
is selected from the group consisting of KOH, NaOH,
K.sub.2CO.sub.3, NaHCO.sub.3 and mixtures thereof.
37. The process according to claim 21, wherein said step (ii) is
conducted in the presence of a catalyst.
38. The process according to claim 37, wherein said catalyst is a
monovalent inorganic iodide.
39. The process according to claim 37, wherein said catalyst is
selected from the group consisting of: potassium iodide (KI),
sodium iodide (NaI), copper iodide (CuI) and mixtures thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for preparing
Tamsulosin, an anti-benign prostatic hyperplasia drug.
DESCRIPTION OF THE PRIOR ART
[0002] The chemical name of Tamsulosin is
(R)-(-)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesul-
fonamide hydrochloride, with the following structural formula (1):
##STR1##
[0003] Tamsulosin is a selective antagonist of
.alpha..sub.1c-receptor, which was clinically used for treating
hypertension initially, and now is mainly used for treating benign
prostatic hyperplasia. Tamsulosin was developed by Yamanouchi
Pharmaceutical Co., Ltd. of Japan and firstly commercialized in
Japan in 1996. Yamanouchi Pharmaceutical Co. Ltd. owns a patent, EP
0 034 432 (published on Aug. 26, 1981), for Tamsulosin.
[0004] EP 0 034 432 to Imai et al. discloses a synthetic route of
Tamsulosin as follows: ##STR2##
[0005] EP 0 257 787 to Okada et al. (published on Mar. 2, 1988) and
U.S. Pat. No. 4,731,478 to Niigata et al. (published on Mar. 15,
1988) disclose that Tamsulosin is prepared, with a yield of
approximately 40%, by condensation of
R-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide with
1-bromo-2(o-ethoxyphenoxy)ethane. The synthetic route is as
follows: ##STR3##
[0006] J of Labeled Compounds and Radiopharmaceuticals(I), 171
(1988) by William J. Wheler discloses that Tamsulosin is prepared
by condensation of 2-(2-ethoxyphenoxy)-acetaldehyde with
R-(-)-5(2-aminopropyl)-2-methoxybenzenesulfonamide and followed by
reduction. In the reaction, the use of 5% Pd/C can obtain a
reduction yield of 32.8%, and the use of NaBH.sub.3CN can obtain a
reduction yield of 57.2%. The synthetic route is as follows:
##STR4##
[0007] WO 03/037850 A1 to Hoorn et al. (published on May 8, 2003)
discloses that Tamsulosin is prepared by condensation of
2-methoxy-5-(2-oxopropyl)-5 benzenesulfonamide with
2-(2-ethoxyphenoxy)-1-ethanamine and followed by reduction to
afford DL-Tamsulosin, which is then salified with
(+)camphor-10-sulphonic acid, resolved into individual optical
isomers, and then recrystallized four times to produce Tamsulosin,
with a yield of 8.9%. The synthetic route is as follows:
##STR5##
SUMMARY OF THE INVENTION
[0008] The present invention relates to a novel process for
preparing Tamsulosin, which includes reacting
o-ethoxyphenoxyethanol with sulfonyl chloride to produce a
sulfonate, and then condensating the resulted sulfonate with an
optically active amine,
(R)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide to produce
Tamsulosin. The synthetic route is as follows: ##STR6##
DETAILED DESCRIPTION OF THE INVENTION
[0009] The present invention relates to a novel process for
preparing Tamsulosin, which includes reacting
o-ethoxyphenoxyethanol with sulfonyl chloride to produce a
sulfonate, and then condensating the resulted sulfonate with an
optically active amine,
(R)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide to produce
Tamsulosin. The synthetic route is as follows: ##STR7##
[0010] Specifically, the process of the present invention includes
the following two steps: (i) reacting o-ethoxyphenoxyethanol
(compound (2)) with sulfonyl chloride of Formula RSO.sub.2Cl to
produce o-ethoxyphenoxyethanol sulfonate (compound (3)), wherein R
is (C.sub.1-C.sub.6)alkyl, such as methyl and ethyl, or phenyl
substituted by halogen, nitro and/or (C.sub.1-C.sub.6)alkyl (such
as methyl), preferably substituted at the ortho, para, or meta
position; and (ii) reacting the compound (3) with
(R)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide (compound
(4)) with a suitable organic amine and/or inorganic base as an acid
scavenger at a temperature of about 40 to 100.degree. C., in the
presence of a catalyst and a suitable solvent, to prepare
Tamsulosin.
[0011] The detailed reaction steps and conditions are described as
follows:
[0012] Step (i): ##STR8##
[0013] The compound (2) is dissolved into an organic solvent (the
suitable solvent is selected from the group consisting of
chloromethane (preferably dichloromethane and/or trichloromethane),
chloroethane (preferably dichloroethane), benzene, substituted
benzene (preferably toluene), pyridine, other similar organic
solvents and mixtures thereof, stirred until they are fully
dissolved, and cooled to about -10 to 10.degree. C., preferably
about -5 to 5.degree. C., more preferably about -5 to 0.degree. C.
Then, sulfonyl chloride of Formula RSO.sub.2Cl (wherein R is
(C.sub.1-C.sub.6)alkyl, such as methyl and ethyl, or phenyl
substituted by halogen, nitro and/or (C.sub.1-C.sub.6)alkyl (such
as methyl), preferably substituted at the ortho, para, and meta
position) is added dropwise into the mixture. After addition, the
reaction is carried out at a temperature of about 0 to 10.degree.
C., preferably about 0 to 5.degree. C., until the compound (2)
disappears. The reacting solution is gradually added into ice water
to isolate white solids, which are then filtered, washed and dried
to obtain the corresponding sulfonate (compound (3)), with a yield
of 65-90%. Step (ii) ##STR9##
[0014] The compound (3), an organic amine and/or inorganic base as
an acid scavenger, a catalyst and a suitable solvent are added into
a reaction flask and heated to about 40-50.degree. C., and then the
compound (4) is added in portions; wherein the organic amine as an
acid scavenger is selected from the group consisting of an organic
tertiary amine, pyridine and mixtures thereof, preferably the group
consisting of triethylamine, pyridine and mixtures thereof; and the
inorganic base as an acid scavenger is selected from the group
consisting of KOH, NaOH, K.sub.2CO.sub.3, NaHCO.sub.3, the like and
mixtures thereof; the catalyst is selected from the group
consisting of monovalent inorganic iodides, preferably the group
consisting of potassium iodide (KI), sodium iodide (NaI), copper
iodide (CuI) and mixtures thereof; the proper solvent is an aprotic
organic solvent, preferably selected from the group consisting of
N,N-dimethylformamide (DMF), dimethyl sulphoxide (DMSO),
N,N-dimethylacetamide (DMAC), the like and mixtures thereof. After
the addition of the compound (4), the reaction mixture is heated at
a temperature of about 50-100.degree. C., preferably about
50-80.degree. C., more preferably about 55-65.degree. C., until the
compound (3) disappears. Then, the mixture is cooled to room
temperature, added with water, extracted with ethyl acetate or the
like, distilled off the solvent under reduced pressure, and added
with an organic solvent containing HCl (preferably selected from
the group consisting of ethyl acetate-HCl, CH.sub.3OH--HCl,
EtOH--HCl, (CH.sub.3).sub.2CHOH--HCl and mixtures thereof) to
isolate white solids, which are then recrystallized with an aqueous
methanol, various aqueous, alcohols, acetone, or dissolvants of
above in mixure with ethyl acetate, methyl tert-butyl ether,
benzene and/or toluene to produce Tamsulosin, with a yield of
55-70%.
EXAMPLES
Example 1
o-ethoxyphenoxyethanol-methylsulfonate
[0015] 50.0 g (0.28 mol) o-ethoxyphenoxyethanol and 197 g pyridine
are added into a reaction flask, stirred until they are fully
dissolved, and then cooled to -5 to 0.degree. C. During stirring,
53.1 g (0.46 mol) methyl sulfonyl chloride is added gradually into
the flask at a temperature controlled at -5 to 0.degree. C. After
addition, the reaction lasts for 3 to 4 hours at a temperature of 0
to 5.degree. C. After the reaction is complete, the reacting
solution is added gradually into 350 ml ice water under stirring at
a temperature controlled at 0 to 5.degree. C. to isolate gradually
white solids, which are then filtered, and the filter cake is
rinsed three times with 150 ml water until there is no smell of
pyridine, and then dried to obtain 61.9 g title compound. Yield:
85.0%; purity: 99.83% (HPLC).
Example 2
(R)-(-)-5-[2-[(2-ethoxyphenoxy)ethyl]amino]-propyl-2-methoxybenzenesulfona-
mide hydrochloride (Tamsulosin)
[0016] 27.7 g (0.11 mol) o-ethoxyphenoxyethanol-methylsulfonate,
20.0 g (0.082 mol)
R-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, 7.5 g (0.09
mol) NaHCO.sub.3, 1.36 g potassium iodide (KI) and 80 ml
dimethylformamide (DMF) are placed into a reaction flask, which is
supplied with N.sub.2, heated to 55 to 65.degree. C. and reacted
for 11 hours. After the reaction is complete, the reacting solution
is cooled to room temperature, added with 600 ml water, and
extracted three times with 500 ml ethyl acetate. Then, the ethyl
acetate extract solutions are combined, rinsed twice with 100 ml
water, dried with anhydrous magnesium sulfate, and distilled off
ethyl acetate under reduced pressure. After that, the residue is
dissolved in ethanol and filtered while it is still warm. The
filtrate is cooled to room temperature, and EtOH--HCl is added
gradually until the filtrate has a pH of 2. White solids are
isolated. Thereafter, the solids are recrystallized with aqueous
ethanol to isolate white crystals, which are then filtered, washed
with ethanol, and dried to obtain 20.4 g title compound. Yield:
56.9%.
* * * * *