U.S. patent application number 12/702471 was filed with the patent office on 2010-06-03 for process for oseltamivir phosphate.
This patent application is currently assigned to HETRO DRUGS LIMITED. Invention is credited to Dasari Muralidhara Reddy, Bandi Parthasaradhi Reddy, Rapolu Raji Reddy, Kura Rathnakar Reddy, Kesireddy Subash Chander Reddy.
Application Number | 20100137632 12/702471 |
Document ID | / |
Family ID | 38066948 |
Filed Date | 2010-06-03 |
United States Patent
Application |
20100137632 |
Kind Code |
A1 |
Parthasaradhi Reddy; Bandi ;
et al. |
June 3, 2010 |
PROCESS FOR OSELTAMIVIR PHOSPHATE
Abstract
The present invention provides an improved and commercially
viable process for the preparation of oseltamivir phosphate. Thus,
for example, ethyl
(3R,4R,5S)-4-amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carbo-
xylate is acetylated with acetic anhydride in methylene chloride in
the presence of triethyl amine in the absence of water to give
ethyl
(3R,4R,5S)-4-(acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-car-
boxylate.
Inventors: |
Parthasaradhi Reddy; Bandi;
(Hyderabad, IN) ; Rathnakar Reddy; Kura;
(Hyderabad, IN) ; Raji Reddy; Rapolu; (Hyderabad,
IN) ; Muralidhara Reddy; Dasari; (Hyderabad, IN)
; Subash Chander Reddy; Kesireddy; (Hyderabad,
IN) |
Correspondence
Address: |
CAESAR, RIVISE, BERNSTEIN,;COHEN & POKOTILOW, LTD.
11TH FLOOR, SEVEN PENN CENTER, 1635 MARKET STREET
PHILADELPHIA
PA
19103-2212
US
|
Assignee: |
HETRO DRUGS LIMITED
Hyderabad
IN
|
Family ID: |
38066948 |
Appl. No.: |
12/702471 |
Filed: |
February 9, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11718359 |
May 1, 2007 |
7687658 |
|
|
PCT/IN2005/000381 |
Nov 25, 2005 |
|
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|
12702471 |
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Current U.S.
Class: |
560/125 |
Current CPC
Class: |
C07C 231/12 20130101;
C07C 247/14 20130101; C07C 231/12 20130101; C07C 233/52 20130101;
C07C 2601/16 20170501 |
Class at
Publication: |
560/125 |
International
Class: |
C07C 229/48 20060101
C07C229/48 |
Claims
1. A process for preparation of the acetyl compound of formula Ill:
##STR00012## which comprises acetylating the amino compound of
formula II: ##STR00013## with acetic anhydride in an organic
solvent in the presence of an organic or inorganic base in the
absence of water to give the acetyl compound of formula Ill.
2. The process as claimed in claim 1, wherein the organic base used
is an organic amine base such as triethyl amine, trimethyl amine,
tributyl amine and n-butyl amine; and inorganic base is selected
from the group consisting of sodium bicarbonate and potassium
bicarbonate.
3. The process as claimed in claim 2, wherein the organic amine
base is triethyl amine.
4. The process as claimed in claim 2, wherein the inorganic base is
sodium bicarbonate.
5. The process as claimed in claim 1, wherein the acetylation
reaction is carried out at about 0-35.degree. C.
6. The process as claimed in claim 5, wherein the reaction is
carried out at about 10-30.degree. C.
7. The process as claimed in claim 6, wherein the reaction is
carried out at about 15-25.degree. C.
8. The process as claimed in claim 1, wherein the organic solvent
is selected from chlorinated hydrocarbon solvents such as methylene
chloride, ethylene dichloride and chloroform; hydrocarbon solvents
such as n-hexane; and a mixture thereof.
9. The process as claimed in claim 8, wherein the organic solvent
is methylene chloride.
Description
FILELD OF THE INVENTION
[0001] The present invention provides an improved and commercially
viable process for the preparation of oseltamivir phosphate.
BACKGROUND OF THE INVENTION
[0002] U.S. Pat. No. 5,763,483, which is herein incorporated by
reference, disclosed carbocyclic compounds and pharmaceutically
acceptable salts thereof. Among them Oseltamivir, chemically Ethyl
(3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-car-
boxylate is a orally active inhibitor of influenza virus
neuraminidase. Oseltamivir is represented by the following
structure:
##STR00001##
[0003] Various processes for preparation of oseltamivir were
disclosed, for example, in U.S. Pat. No. 5,763,483, J. Org. Chem.,
Vol. 63, No. 13, 1998 (page: 4545-4550), J. Amer. Chem. Soc., Vol.
115, No. 4, 1997 (Page: 681-690), U.S. Pat. No. 5,952,375 and PCT
Publication No. WO 99/44185.
[0004] In the preparation of oseltamivir, the compound of formula
B:
##STR00002##
is a key intermediate. According to the prior art processes, the
intermediate of the formula B was prepared by acetylation of the
compound of formula A:
##STR00003##
with acetic anhydride in hexanes or methylene chloride in the
presence of aqueous sodium bicarbonate; or with acetyl chloride and
pyridine. The base such as sodium bicarbonate is normally used to
convert the acetic acid formed as by-product into a water soluble
salt such as sodium acetate and the salt formed is extracted into
water present so as to move the equilibrium towards the formation
of acetylated product of the formula B.
[0005] We have surprisingly found, in contrary to the prior art
process and process normally followed, that acetylation reaction of
compound of formula A proceeds with acetic anhydride in an organic
solvent in the presence of an organic or inorganic base in the
absence of water, cleanly to obtain acetyl derivative of the
formula B in better purity and in better yield.
[0006] In the preparation of oseltamivir, the azide intermediate of
formula B is reduced to the corresponding amine, (oseltamivir) of
the formula C:
##STR00004##
[0007] According to the prior art process, the reduction was
carried out with hydrogen gas and a catalyst such as platinum on
carbon or Lindlar's catalyst or reducing reagent such as trialkyl
or triaryl phosphine.
[0008] We have found that the reduction of the compound of formula
B to obtain the compound of formula C may be carried out using
hydrogen sulfide or Na.sub.2S under suitable conditions in an
advantageous manner.
DETAILED DESCRIPTION OF THE INVENTION
[0009] According to one aspect of the present invention, there is
provided a process for preparing the acetyl compound of formula
III:
##STR00005##
which comprises acetylating the amino compound of formula II:
##STR00006##
with acetic anhydride in an organic solvent in the presence of an
organic or inorganic base in the absence of water to give the
acetyl compound of formula III. `The absence of water` refers to
the content of water in the reaction mass is less than 1.0%,
preferably less than 0.5% and more preferably less than 0.2% of the
reaction mass by volume.
[0010] Preferable organic base used in the reaction is an organic
amine base such as triethyl amine, trimethyl amine, tributyl amine
and n-butyl amine; and preferable inorganic base is selected from
the group consisting of sodium bicarbonate and potassium
bicarbonate. More preferable organic amine base is triethyl amine
and more preferable inorganic base is sodium bicarbonate.
[0011] The reaction is preferably carried out at about 0-35.degree.
C., more preferably at about 10-30.degree. C. and still more
preferably at about 15-25.degree. C.
[0012] Preferable organic solvent used in reaction is selected from
chlorinated hydrocarbon solvents such as methylene chloride,
ethylene dichloride and chloroform; hydrocarbon solvents such as
n-hexane; and a mixture thereof. More preferable organic solvent is
selected from methylene chloride, n-hexane and a mixture thereof.
Most preferable organic solvent is methylene chloride.
[0013] After the reaction is completed, the reaction mass may then
be subjected to usual work up such as washings, extractions
etc.
[0014] According to another aspect of the present invention, there
is provided a process for preparing the oseltamivir of formula
I:
##STR00007##
or a pharmaceutically acceptable salt thereof; which comprises
reducing the compound of formula III:
##STR00008##
with hydrogen sulfide in presence of pyridine or ethanol or water
or a mixture thereof; or with Na.sub.2S in presence of an organic
amine base in an alcoholic solvent to give oseltamivir of formula I
and optionally converting oseltamivir formed into a
pharmaceutically acceptable acid addition salts of oseltamivir.
[0015] The reduction reaction is preferably carried out with
hydrogen sulfide in presence of pyridine.
[0016] Preferable organic amine base used in the reduction reaction
with Na.sub.2S is triethyl amine or trimethyl amine and more
preferable organic amine base being triethyl amine. Preferable
alcoholic solvent is methanol, ethanol or isopropyl alcohol and
more preferable alcoholic solvent being methanol.
[0017] The reduction reaction is preferably carried out at about
0-45.degree. C., more preferably at about 10-35.degree. C. and
still more preferably at about 20-35.degree. C.
[0018] According to another aspect of the present invention, there
is provided an improved process for preparing the oseltamivir of
formula I:
##STR00009##
or a pharmaceutically acceptable salt thereof; which comprises: a)
acetylating the amino compound of formula II:
##STR00010##
with acetic anhydride in an organic solvent in the presence of an
organic or inorganic base in the absence of water to give the
acetyl compound of formula III:
##STR00011##
b) reducing the compound of formula III with hydrogen sulfide in
presence of pyridine or ethanol or water or a mixture thereof; or
with Na.sub.2S in presence of an organic amine base in an alcoholic
solvent to give oseltamivir of formula I and optionally converting
oseltamivir formed into a pharmaceutically acceptable acid addition
salts of oseltamivir.
[0019] Preferable organic base used in step-(a) is an organic amine
base such as triethyl amine, trimethyl amine, tributyl amine and
n-butyl amine; and preferable inorganic base is selected from the
group consisting of sodium bicarbonate and potassium bicarbonate.
More preferable organic amine base is triethyl amine and more
preferable inorganic base is sodium bicarbonate.
[0020] The reaction in step-(a) is preferably carried out at about
0-35.degree. C., more preferably at about 10-30.degree. C. and
still more preferably at about 15-25.degree. C.
[0021] Preferable organic solvent used in step-(a) is selected from
chlorinated hydrocarbon solvents such as methylene chloride,
ethylene dichloride and chloroform; hydrocarbon solvents such as
n-hexane; and a mixture thereof. More preferable organic solvent is
selected from methylene chloride, n-hexane and a mixture thereof.
Most preferable organic solvent is methylene chloride.
[0022] The reaction in step-(b) is preferably carried out with
hydrogen sulfide in presence of pyridine.
[0023] Preferable organic amine base used in the reaction with
Na.sub.2S in step-(b) is triethyl amine or trimethyl amine and more
preferable organic amine base being triethyl amine. Preferable
alcoholic solvent used in the reaction in step-(b) is methanol,
ethanol or isopropyl alcohol and more preferable alcoholic solvent
being methanol.
[0024] The reaction in step-(b) is preferably carried out at about
0-45.degree. C., more preferably at about 10-35.degree. C. and
still more preferably at about 20-35.degree. C.
[0025] The invention will now be further described by the following
non-limiting examples.
Example 1
Step-I:
[0026] Ethyl
(3R,4R,5S)-4-Amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate
(14 gm) was added to triethyl amine (10 gm) and methylene chloride
(110 ml) and then the contents were cooled to 20.degree. C. To the
contents added acetic anhydride (5.6 gm) at 20-25.degree. C. for 1
hour and then stirred for 3 hours at 20-25.degree. C. The reaction
mass was quenched into water (140 ml) and then separated the
layers. The organic layer was washed with 8% sodium bicarbonate
solution (140 ml) and then washed with 30% sodium chloride solution
(140 ml). The organic layer was distilled and recrystallized from
n-hexane (70 ml) to give 8.5 gm of Ethyl
(3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethyl
propoxy)-1-cyclohexene-1-carboxylate.
[0027] Step-II:
Ethyl
(3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-
-1-carboxylate (8.5 gm) was dissolved in tetrahydrofuran (130 ml)
and then triphenyl phosphine (10.5 gm) and water (50 ml) are added.
The contents were heated to reflux, refluxed for 5 hours and then
distilled off the solvent under vacuum. To the reaction mass added
ethyl acetate (80 ml), washed with 30% sodium chloride solution (50
ml) and distilled off the solvent completely under vacuum. Acetone
(130 ml) was added to the residue, heated to reflux, under reflux
the mixture of H.sub.3PO.sub.4 (3 gm) and ethyl acetate (50 ml) was
slowly added during 1 hour and then refluxed for 1 hour. The
reaction mass was cooled to 25.degree. C. and stirred for 2 hours
at 20-25.degree. C. Filtered the solid, washed with acetone (10 ml)
and dried at 60-65.degree. C. for 4 hours to yield 6.5 gm of
oseltamivir phosphate (HPLC Purity: 99.6%).
Example 2
[0028] Ethyl (3 R,4R,5S)-4-(Acetylam
ino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (8.5
gm) was added to pyridine (200 ml) and then bubbled
[0029] H.sub.2S gas for 3 hours at 25-35.degree. C. Stopped the
bubbling of H.sub.2S gas and then the reaction mixture was stirred
for 5 hours at 25-35.degree. C. The reaction mass was flushed with
N.sub.2 gas for 20-30 minutes and distilled off the solvent
completely under reduced pressure keeping the bath temperature
below 50.degree. C. To the residue added ethyl acetate (100 ml) and
washed with 30% sodium chloride solution (50 ml). Distilled off the
ethyl acetate completely under reduced pressure. Acetone (100 ml)
was added to the residue, heated to reflux, under reflux the
mixture of H.sub.3PO.sub.4 (3.2 gm) and ethanol (25 ml) was slowly
added during 1 hour 30 minutes and then refluxed for 2 hours. The
reaction mass was cooled to 25.degree. C. and then stirred for 2
hours at 20-25.degree. C. Filtered the solid, washed with acetone
(10 ml) and dried at 60-65.degree. C. for 4 hours to give 6.9 gm of
oseltamivir phosphate (HPLC purity: 99.8%).
* * * * *