PURIFICATION OF TEGASEROD MALEATE
RELATED APPLICATIONS
The present application claims the benefit of United States Provisional Patent
Application No. 60/620,732 filed on October 19, 2004, which is incorporated herein
by reference.
FIELD OF THE INVENTION
The present invention relates to a process for the purification of tegaserod
maleate.
BACKGROUND OF THE INVENTION
Tegaserod maleate is an aminoguanidine indole 5HT4 agonist for the
treatment of irritable bowel syndrome (DBS), and is marketed as Zelnorm®.
The chemical name for Tegaserod maleate is: l-(5-Methoxy-lH~indol-3-
ylmethyleneamino)-3-pentylguanidinemonomaleate.
The chemical structure of Tegaserod maleate is:
Tegaserod maleate is disclosed in the US patent No. 5,510,353 and in its EP
equivalent 505322 Bl (example 13 in both of them). The patent also describes the
preparation of tegaserod base by reacting indole-3-carbaldehyde and aminoguanidine
in a protic solvent in the presence of inorganic or organic acid (example 2a describes
the reaction in methanol and hydrochloric acid). Although the melting point for
tegaserod maleate is given (190°C in Table 1, example 13), no information about its
preparation and purification is provided.
The process described in US '353 provides tegaserod free base containing an
impurity of Tegaserod (TGS-dimer) at RRT 1.06, having the molecular weight of
g/mol. In table 1 (below) the analysis of the tegaserod base so obtained is described.
A process for preparing tegaserod maleate is described in co-pending US
application serial number 11/115,871 filed on April 26, 2005, which comprises
reacting N-amino-N'-pentylguanidme hydroiodide (AGP-HI) with 5-Methoxy-lHindole-
3-carbaldehyde (5-MICHO) in water or an organic solvent in the presence of
maleic acid to precipitate tegaserod maleate, with the proviso that another acid is not
used.
SUMMARY OF THE INVENTION
In one embodiment, the present invention relates to a method of purifying
Tegaserod maleate comprising: combining tegaserod maleate and a mixture of a first
organic solvent; adding an inorganic base; maintaining the reaction mixture at a
temperature of from about room temperature to about the boiling temperature of the
mixture, for a sufficient time to obtain a precipitate; combining the precipitate with a
second organic solvent and a maleic acid with or without water at a temperature of
from about room temperature to about the boiling temperature of the mixture for a
sufficient time to obtain a precipitate; and recovering the Tegaserod maleate.
In another embodiment, the present invention relates to a method of purifying
Tegaserod maleate comprising: combining tegaserod maleate, and a mixture of a first
organic solvent; adding an inorganic base and an organic carboxylic acid; maintaining
the mixture at a temperature of from about room temperature to about the boiling
temperature of the mixture, for a sufficient time to obtain a precipitate; combining the
precipitate with a second organic solvent and a maleic acid with or without water;
maintaining the mixture at a temperature of from about room temperature to about the
boiling temperature of the mixture for a sufficient time to obtain a precipitate; and
recovering the tegaserod maleate. The tegaserod maleate produced by the process of
the present invention contains less than about 0.02% area by HPLC of the dimmer
impurity and of the impurities at RRT 2.01 and RRT 0.89.
In another embodiment, the present invention provides an isolated compound,
wherein R is selected from the group consisting of; saturated and unsaturated,
branched and linear Ci-C4 alkanes, Ci-C4 ethers, Ci-C3 alcohols, Cg-Cio aromatic
hydrocarbons and amides. Preferably, R is selected from the group consisting of:
CH2OCH3, CH2CH=C(CH3)2, CO-N(CH3)2, CH3, C2H5, C3H7, benzoyloxy, CO-tert-
C4H9, CO-N(C2H5)2, CH2-CO-N(CH3)2, CH2-CH2-N(CH3)2, (CH2)2-O-CH3, (CH2)2-
OH, isobutoxy, 2, 3-di(OH)-propoxy and acetoxy. More preferably, R is methyl.
When R is a methyl group, the chemical name of this compound is: Bis-((5-
Methoxyindol-3-yl)methylene) Carbonimidic dihydrazide Hydrochloride, and this
compound is a tegaserod dimer (TGS-dimer).
TGS-dimer is characterized by !H NMR (500 MHz, DMSO d6) §(ppm): 1 1 .73
(s, 2H), 8.53 (s, 2H), 7.89 (s, 4H), 7.75 (s, 2H), 7.37 (d, J=S.7 Hz, 2H), 6.87 (d, J-7,9
Hz, 2H), 3.87 (s, 6H); by 13C{!H}NMR analysis (125 MHz) d (ppm): 154.83, 152.03,
146.32, 132.18, 124.76, 112.73, 112.65, 110.48, 104.41, 55.56; by FAB mass
spectrometry analysis showing the following data: m/z=404.1 ([M-H]+, 100%) and by
IR(KBr) v cm'1: 3385 (N-H), 2944 (C-H), 1641, 1637, 1613 (ON), 1528, 1485 (C^
Car). The derivative may be used as an HPLC marker or as an indicator for purity in a
process.
In yet another embodiment, the present invention provides a method for
c) adding a mineral acid until a reaction mixture having a pH of about 2 to about 3 is
obtained;
d) maintaining the reaction mixture at a temperature from about room temperature to
about boiling temperature of the reaction mixture to obtain a precipitate; and
e) recovering a tegaserod derivative
wherein R is selected from the group consisting of; saturated and unsaturated,
branched and linear Ci-C4 alkalies, Q-C4 ethers, Ci-C3 alcohols, Ce-Cio aromatic
hydrocarbons and amides. Preferably, R is selected from the group consisting of:
CH2OCH3, CH2CH=C(CH3)2, CO-N(CH3)2, CH3, C2H5, C3H7, benzoyloxy, CO-tert-
C4H9, CO-N(C2H5)2, CH2-CO-N(CH3)2, CH2-CH2-N(CH3)2, (CH2)2-O-CH3, (CH2)2-
OH, isobutoxy, 2, 3-di(OH)-propoxy and acetoxy.
More preferably, R is methyl.
When R is a methyl group the chemical name of the compound in step b) is 5-
methoxy-1 H-indole-3-carbaldehyde (MICHO).
hi yet another embodiment, the present invention provides a method for
preparing crystalline forms of tegaserod maleate having an amount of the impurity
TGS-dimer of less than about 0.02% by area percent HPLC comprising;
a) obtaining one or more samples of one or more tegaserod maleate batches;
b) measuring the level of tegaserod dimer in each of the samples of (a);
c) selecting the tegaserod maleate batch that comprises a level of the
tegaserod dimer of less than about 0.02% by area percent HPLC based on
the measurement or measurements conducted in (b); and
d) using the batch selected in (c) to prepare said tegaserod maleate.
Preferably, the tegaserod maleate is in a crystalline form.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term "MICHO" refers to 5-Methoxy-lH-indole-3-
carbaldehyde
As used herein the term "TGS" refers to Tegaserod.
As used herein the term TGS-diiner refers to Bis-((5-Methoxyindol-3-
yl)methylene) Carbonimidic dihydrazide.
The present invention relates to a method of purifying tegaserod maleate
Comprising: combining tegaserod maleate and a mixture of a first organic solvent;
adding an inorganic base; maintaining the reaction mixture at at a temperature of from
about room temperature to about the boiling temperature of the mixture, for a
sufficient time to obtain a precipitate; combining the precipitate with a second organic
solvent and a maleic acid with or without water at at a temperature of from about
room temperature to about the boiling temperature of the mixture for a sufficient time
to obtain a precipitate and recovering the Tegaserod maleate.
Preferably, the first organic solvent is a Cj, to Cy ester. More preferably, the
first organic solvent is isobutyl acetate or ethyl acetate.
Preferably, the mixture of the first organic solvent and water is 1:1 volumes.
Preferably, the mixture is maintained at room temperature, i.e., from a
temperature of about 15°C to a temperature of about 25°C.
Preferably, the inorganic base is an alkaline metal hydroxide or an alkaline
earth metal hydroxide. More preferably, the inorganic base is selected from a group
consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium
hydroxide and calcium hydroxide. Most preferably, the inorganic base is sodium
hydroxide.
Preferably, the inorganic base is added as an aqueous solution. Alternatively, it
can be added as a solid, and than water is also added.
Preferably, the amount of inorganic base added is 10 mol equivalents.
Preferably the reaction mixture is maintained at said temperature for more
than about 2 hours. More preferably, for about 24 hours.
Preferably, the second organic solvent is selected from the group consisting of:
a Cr Cg alcohol, C\- €4 ketones, d- Cv ethers, €3- C? esters, acetonitrile and
dioxane. More preferably, the second organic solvent is selected from the group
comprising: methanol, ethanol, isopropanol, acetonitrile, butanol, acetone, dioxane,
methyl ethyl ketone, tetrahydrofuran, ethyl lactate and ethyl acetate. Most preferably,
the second organic solvent is ethyl acetate.
Preferably, combining the precipitate with a second organic solvent and a
maleic acid is performed in the presence of water.
Preferably, the TGS maleate that is obtained by this method contains an
amount of less than about 0.02% area by HPLC of the dimer impurity and of the
impurities at RE.T 2.01 and KRT 0.89.
One preferred process according to the present invention is depicted in the
following scheme:
In another embodiment, the present invention relates to a method of purifying
Tegaserod maleate comprising: combining tegaserod maleate, and a mixture of a first
organic solvent; adding an inorganic base and an organic carboxylic acid; maintaining
the mixture at a temperature of from about room temperature to about the boiling
temperature of the mixture, for a sufficient time to obtain a precipitate; combining the
precipitate with a second organic solvent and a maleic acid with or without water, at a
temperature of from about room temperature to about the boiling temperature of the
mixture for a sufficient time to obtain a precipitate and recovering the tegaserod
maleate.
Preferably, the acid has pKa higher than about 2. More preferably the acid is
€2 to C-6 organic carboxylic acid. Most preferably, the acid is acetic acid.
Preferably, the first organic solvent is Ca to Cj ester, a Ci to Cg alcohol, a C(, to
da aromatic hydrocarbon solvent, a Ci to C? alkane or a C2 to Cs ether. More
preferably, the first organic solvent is ethanol.
The inorganic base is preferably as described above-
Preferably, the mixture of the first organic solvent and water is 1:1 volumes.
Preferably, after adding the acid, the reaction mixture is maintained at said
temperature for more than about 5 hours. More preferably, for about 24 hours.
Preferably, after adding the acid, the mixture is maintained at about room
temperature
Preferably, combining the precipitate with a second organic solvent and a
maleic acid is performed in the presence of water.
Preferably, the precipitate is combined with the second organic solvent at a
temperature of from about room temperature to about 85°C, preferably at about 70°C.
The recovering of the TGS maleate can be performed by any means known in
the art, such as filtration.
The product obtained may be dried under suitable conditions. The product is
preferably dried by heating at a temperature of about 30°C to about 60°C, more
preferably about 45°C. The drying is preferably carried under reduced pressure, more
preferably a vacuum having a pressure of less than about lOOmmHg.
One preferred process according to the present invention is depicted in the
In particular, the method of the present invention is particularly suitable for
reducing the TGS dimer impurity, and is also suitable for reducing the impurities
having RRTs of 0.89 and 2.01. These impurities tend to discolour the final product
The TGS maleate that is obtained by the present invention contains an amount
of less than about 0.02% area by HPLC of the dimmer impurity and of the impurities
atRRT2.01 and RRT 0.89.
Table 2 (below) presents two examples in which the color in the starting
material disappeared at the end of the process, and the level of TGS-dimer was
reduced to less than 0.02% area by HPLC.
Table 2: Purification results of the TGS maleate
The purified tegaserod maleate prepared according to the process described
above, may be used for the preparation of tegaserod maleate crystalline forms.
The present invention provides an isolated compound having the formula I;
NH HO,
wherein R is selected from the group consisting of: saturated and unsaturated,
branched and linear Q-C4 alkanes, Q-C4 ethers, Ci-C3 alcohols, Cg-Qo aromatic
hydrocarbons and amides. Preferably, R is selected from the group consisting of:
CH2OCH3, CH2CH=C(CH3)2, CO-N(CH3)2, CH3, C2H5; C3H7, benzoyloxy, CO-tert-
C4H9, CO-N(C2H5)2, CH2-CO-N(CH3)2, CH2-CH2-N(CH3)2, (CH2)2-O-CH3, (CH2)2-
OH, isobutoxy, 2, 3-di(OH)-propoxy and acetoxy. More preferably, R is methyl.
When R is a methyl group, the chemical name of thr compound is: Bis-((5-
Methoxyindol-3-yl)methylene) Carbommidic dihydrazide iydrochloride, and this
compound is a tegaserod dimer (TGS-dimer).
TGS-dimer is characterized by !H NMR (500 MHz, DMSO d6) 8(ppm): 11.73
(s, 2H), 8.53 (s, 2H), 7.89 (s, 4H), 7.75 (s, 2H), 7.37 (d, .7=8.7 Hz, 2H), 6.87 (d, J=1.9
Hz, 2H), 3.87 (s, 6H); by 13C{'H}NMR analysis (125 MHz) d (ppm): 154.83, 152.03,
146.32, 132.18, 124.76, 112.73, 112.65, 110.48, 104.41, 55.56; by FAB mass
spectrometry analysis showing the following data: m/z=404.1 ([M-H]T, 100%) and by
IR(KBr) v cm'1: 3385 (N-H), 2944 (C-H), 1641, 1637, 1613 (C=N), 1528, 1485 (Car-
c) adding a mineral acid until a reaction mixture having a pH of about 2 to about 3 is
obtained;
d) maintaining the reaction mixture at a temperature from about room temperature to
about boiling temperature of reaction mixture to obtain a precipitate; and
e) recovering a tegaserod derivative,
wherein R is selected from the group consisting of: saturated and misaturated,
branched and linear CpC4 alkanes, Q-C.4 ethers, Ci-C3 alcohols, Ce-Cio aromatic
hydrocarbons and amides. Preferably, R is selected from the group consisting of:
CH2OCH3, CH2CH=C(CH3)2, CO-N(CH3)2, CH3, C2H5, C3H7, benzoyloxy, CO-tert-
C4H9, CO-N(C2H5)2, CH2-CO-N(CH3)2, CH2-CH2-N(CH3)2, (CH2)2-O-CH3, (CH2)2-
OH, isobutoxy, 2, 3-di(OH)-propoxy and acetoxy.
More preferably, R is methyl.
When R is a methyl group the chemical name of the compound in step b) is 5-
methoxy-lH-indole-3-carbaldehyde [MICHO].
Preferably, the acid is selected form the group consisting of inorganic acids
such as: HC1, HBr, HsPC^ and H2SO4 or an organic acid such as any carboxylic acid.
Most preferably, the acid is HC1. Preferably, the reaction mixture is maintained at
70°C for about 20 minutes to about 1 hour, more preferably for 30 minutes, and
subsequently at about room temperature for about 10 hours to about 14 hours, more
preferably overnight, while stirring.
The compound of formula II used in the above process is commercially
The isolated TGS-dimer of the invention can be used as a reference marker
(purity marker) for TGS maleate. hi the context of the present invention, a reference
marker (purity marker) is a compound that is an impurity in a principal compound
such as an active pharmaceutical ingredient (API). Detection or quantification of a
reference marker by a suitable analytical technique establishes and defines the purity
of, for example, the API; either in bulk, for example as obtained from synthesis, or as
isolated from a pharmaceutical dosage form that includes the API. Manufacturing lot
release criteria can be established with reference to a particular amount or
concentration of a reference marker in the bulk product. Detection and quantification
of the reference marker in the API of a pharmaceutical dosage form can serve as a
measure of the shelf-life of the pharmaceutical dosage form.
Those skilled in the art of drug manufacturing research ~nd development
understand that a compound in a relatively pure state can be aioo used as a "reference
standard." A reference standard is similar to a reference marker, which is used for
qualitative analysis only, but is used to quantify the amount of the compound of the
reference standard in an unknown mixture, as well. A reference standard is an
"external standard," when a solution of a known concentration of the reference
standard and an unknown mixture are analyzed using the same technique. (Strobel p.
924, Snyder p. 549, Snyder, L.R.; Kirkland, J.J. Introduction to Modem Liquid
Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the
compound in the mixture can be determined by comparing the magnitude of the
detector response. See also U.S. Patent No. 6,333,198, incorporated herein by
reference.
The present invention provides a method for preparing crystalline forms of
tegaserod maleate having an amount of the TGS-dimer of less than about 0.02% by
area percent HPLC. This method includes starting with a tegaserod maleate sample
comprising a sufficiently low level of TGS-dimer. Preferably, the amount of TGSdinier
in the tegaserod maleate sample is about 0.02% or more by area percent HPLC.
Preferably, the tegaserod maleate is in crystalline forms.
The crystalline forms prepared according to the method provided herein may
be the crystalline forms described in co-pending US 2005/0165085A1 published on
July 28, 2005, i.e., crystalline forms A, B, Bl, B2, B3, C, D, E, F, H and J .
The method provided in the present invention comprises;
a) obtaining one or more samples of one or more TGS maleate batches;
b) measuring the level of TGS-dimer in each of the samples of (a);
c) selecting the TGS maleate batch that comprises a level of the tegaserod
dimer of less than about 0.02% by area percent HPLC based on the
measurement or measurements conducted in (b); and
d) using the batch selected in (c) to prepare said crystalline forms of TGS
maleate.
This invention also provides a method of preparing a composition comprising
crystalline form of TGS maleate, having TGS-dimer in an amount of less than about
0.02% by area percent HPLC, which method comprises;
a) purifying a composition comprising TGS maleate and TGS-dimer until a
composition comprising less than about 0.02% TGS dimer by area percent
HPLC is obtained; and
b) using the composition resulting from (a) to prepare a composition comprising
a crystalline form of TGS maleate.
Methods of purification of the composition of TGS maleate and TGS-dimer
that can be used in this invention include the method described above.
The present invention further provides a method of preparing a composition
comprising a crystalline form of TGS maleate, that comprises TGS-dimer in an
amount of less than about 0.02% by area percent HPLC. This method comprises;
a) obtaining one or more samples of one or more TGS maleate batches;
b) measuring the level of TGS-dimer in each of the samples of (a);
c) if the quantity of the TGS-dimer measured in b) is about 0.02% area by
HPLC or more, purifying the sample until the quantity of the TGS-dimer is less than
about 0.02% by weight, and synthesizing a crystalline form of TGS maleate from the
sample so purified; or
d) if the quantity of TGS-dimer measured in b) is less than about 0.02%
by weight, synthesizing a crystalline form of TGS maleate from the TGS maleate of
step b).
The purifying in step c) may be performed according to the purification
processes of TGS maleate described above.
Having described the invention with reference to certain preferred
embodiments, other embodiments will become apparent to one skilled in the art from
consideration of the specification. The invention is further defined by reference to the
following examples describing in detail the preparation of the composition and
methods of use of the invention. It will be apparent to those skilled in the art that
many modifications., both to materials and methods, may be practiced without
departing from the scope of the invention.
mg/mL. The Standard solutions have to be prepared and injected immediately.
Preparation of Sample Solution
Preparing a solution of TGS maleate having a final concentration of about
0.4mg/mL in a diluent. The standard solutions have to be prepared and injected
immediately.
Procedure for detecting the impurities
Inject standard and sample solutions into the chromatograph and continue the
chromatogram up to 63 min. The areas of the impurities peaks in each solution is
determined using a suitable integrator. Peaks which appear in a diluent place and peak
with RUT 1.06, if detected, must be disregarded (it is identified as TGS1 tautomer).
In the above calculation imp i identifies an impurity measured/detected.
Example 2 - Purification of Tegaserod maleate in ethyl acetate/water (70 °C)
To a mixture of 10 g TGS-maleate in 280 mL ethyl acetate/water (1:1) was
added 25.6 g of NaOH (47%) and stirred at room temperature for 24 hours. The
resulting precipitate was filtrated and washed with 210 mL water (3 x 70 mL).
To a mixture of the resulting solid in 60 mL EtOAc at 70 °C, was added a solution of
3.33 g maleic acid in 30 mL ethyl acetate/water (95:5) during 1/2 hour, stirred at the
same temperature for an additional 2 hrs, and at room temperature for overnight. The
solid was filtered off and washed with ethyl acetate / water 95:5 (31.5 mL in three
portions). After drying on vacuum oven at 45°C for 15hrs, 9.18g of TGS maleate
were obtained as an off white powder (chemical yield: 93.36%, purity: 99.96%).
Example 3 - Purification of TeRaserod maleate in ethyl acetate/water (room
temperature)
To a mixture of 4 g TGS-maleate in 112 mL ethyl acetate/water (1:1) was
added 10.3 g of NaOH (47%) and stirred at room temperature for 24 hours. The
resulting precipitate was filtrated and washed with 84 mL water (3 x 28 mL).
To a mixture of the resulting solid in 24 mL ethyl acetate was added a solution of 1.33
g maleic acid in 13 mL ethyl acetate/water (95:5) during 1/2 hour, and stirred
overnight. The solid was filtered off and washed with ethyl acetate/water 95:5 (30
mL in three portions). After drying on vacuum oven at 45 °C for 15 hrs, 3.33 g of
TGS maleate were obtained as an off white powder (chemical yield: 83.25%, purity:
99.97%).
Example 4 - Purification of Tegaserod maleate in isobutyl acetate/water (70 °C)
To a mixture of 4 g TGS-maleate in 112 mL isobutyl acetate/water (1:1) was
added 10.3 g of NaOH (47%) and stirred at room temperature for 24 hours. The
resulting precipitate was filtrated and washed with 84 mL water (3 x 28 mL).
To a mixture of the resulting solid in 60 mL ethyl acetate at 70 °C, was added a
solution of 1.33 g maleic acid in 13 mL ethyl acetate/water (95:5) during 1/2 hour,
stirred at the same temperature for an additional 2 hrs, and overnight at room
temperature. The solid was filtered off and washed with ethyl acetate / water 95:5
(31.5 mL in three portions). After drying on vacuum oven at 45 °C for 15 hs, 2.58 g
of TGS maleate were obtained as an off white powder (chemical yield: 64.50 %,
purity: 99.98 %).
Example 5 - Purification of Tegaserod maleate with acetic acid
To a mixture of 1 g TGS maleate in 40 mL ethanol/water (3:1) was added 2.6
g of NaOH (47%) followed by 3.45 mL acetic acid and stirred at room temperature
for 24 hours. The resulting precipitate was filtrated and washed with 30 mL water.
To a mixture of the resulting solid in 8 mL ethyl acetate was added a solution of 0.33
g maleic acid in 3 mL ethyl acetate/water (95:5) during 20 minutes, and stirred
overnight. The solid was filtered off and washed with ethyl acetate / water 95:5 (30
mL in three portions). After drying on vacuum oven at 45 °C for 15 hs, 0.73 g of TGS
maleate were obtained as an off white powder (chemical yield: 73.00%, purity:
99.95%).
SYNTHETIC PROCESSES
Example 6 - Preparation of TGS-dimer
A three neck flask equipped with mechanical stirrer and thermometer, was charged
with a mixture of 10 g of diaminoguanidine-HCl in 250 mL of water, 30.70 g of
MICHO followed by HC1 (37%) until pH 2-3. The mixture was stirred at 70 °C for
half hour and at room temperature for overnight. The resulting solid was filtrated and
washed with 140 mL water (2 x 70 mL) and triturated in 250 mL ethyl acetate for 2
hours. After filtration and washing with ethyl acetate (2 x 125 mL) the wet material
was dried on vacuum oven (45 °C, overnight) giving TGS-dirner (32 g, 91% yield,
98% purity by HPLC).

Claims
1. A method of purifying Tegaserod maleate comprising;
a) combining tegaserod maleate, a first organic solvent and an inorganic base
to obtain a reaction mixture;
b) maintaining the reaction mixture at a temperature of from about room
temperature to about the boiling temperature of the reaction mixture to
obtain a precipitate;
c) combining the precipitate with a second organic solvent and a maleic acid
with or without water at a temperature of from about room temperature to
about the boiling temperature of the mixture; and
d) recovering the purified Tegaserod maleate.
2. A method of purifying Tegaserod maleate comprising;
a) combining tegaserod maleate and a first organic solvent to obtain a reaction
mixture;
b) combining the reaction mixture with an inorganic base and an organic
carboxylic acid;
c) maintaining the reaction mixture obtained in step b) at a temperature of from
about room temperature to about the boiling temperature of the reaction
mixture to obtain a precipitate;
d) combining the precipitate with a second organic solvent and a solution of
maleic acid, the second organic solvent, and water at a temperature of from
about room temperature to about the boiling temperature of the mixture; and
e) recovering the purified Tegaserod maleate.
3. The method of any one of claims 1 and 2, wherein the reaction mixture is
maintained at about room temperature.
4. The method of claim 1, wherein the first organic solvent is a C^-Cj ester.
5. The method of claim 4, wherein the first organic solvent is selected from the
group consisting of isobutyl acetate and ethyl acetate.
6. The method of any one of claims 1 and 2, wherein the inorganic base is in an
*
aqueous solution.
7. The method of claim 2, wherein the first organic solvent is selected from the
group consisting of a d-C4 alcohol, a Ce-C^ aromatic solvent, a CpC? alkane
or a C2-C$ ether.
8. The method of claim 7, wherein the first organic solvent is ethanol.
9. The method of any one of claims 1 and 2, wherein the mixture of the first
organic solvent and water is 1:1 volumes.
10. The method of any one of claims 1 and 2, wherein the amount of inorganic base
added is 10 mol equivalents
11. The method of any one of claims 1 and 2, wherein the second organic solvent is
selected from the group consisting of: a C\- Cs alcohol, d- C4 ketones, C\- Cj
ethers, Ca- C? esters, acetonitrile, dioxane and tetrahydrofuran.
12. The method according to claim 11, wherein the second organic solvent is
selected from the group consisting of methanol, ethanol, isopropanol,
acetonitrile, butanol, acetone, dioxane, methylethyl ketone, tetrahydrofurane,
ethyl lactate, and ethyl acetate.
13. The method according to claim 11, wherein the second organic solvent is ethyl
acetate.
14. The method of claim 1, wherein the reaction mixture is maintained in step b) for
a period of more than about 2 hours.
15. The method of claim 2, wherein the reaction mixture is maintained in step c) for
a period of more than about 5 hours.
16. The method of claim 2, wherein the organic carboxy1 ;c acid of step b) has a pKa
higher than about 2.
17. The method of claim 16, wherein said organic carboxylic acid is acetic acid.
18. The method of any one of claims 1 and 2, wherein the precipitate is comb; 3d
with the second organic solvent at a temperature of about room temperature to
about 70°C.
19. The method of any one of claims 1 and 2, wherein combining the precipitate
with a second organic solvent and a maleic acid is performed in the presence of
water.
20. The method of any one of claims 1 and 2, wherein recovering of the purified
tegaserod maleate comprises filtration.
21. The method of any one of claims 1 and 2, further comprising drying the purified
tegaserod maleate.
22. The method of any one of claims 1 and 2, wherein the purified tegaserod
maleate contains an amount of less than about 0.02% area by HPLC of the dimer
impurity and of the impurities at RRT 2.01 and RRT 0,89.
23. An isolated compound of the formula I;
wherein R is selected from the group consisting of: saturated and unsaturated
branched and linear C\-C^ alkanes, Ci-C4 ethers, Ci-C3 alcohols, Ce-Cio
aromatic hydrocarbons and amides.
24. The isolated compound of claim 23, wherein R is selected from the group
consisting of: CH2OCH3, CH2CH=C(CH3)2, CO-N(CH3)2, CH3> C2H5, C3H7,
benzoyloxy, CO-tert-C4H9, CO-N(C2H5)2, CH2-CO-N(CH3)2, CH2-CH2-
N(CH3)2> (CH2)2-O-CH3, (CH2)2-OH, isobutoxy, 2, 3-di(OH)-propoxy and
acetoxy.
25. The isolated compound of claim 24, wherein R is methyl.
26. The isolated compound of claim 25, characterized by data selected from: JH
NMR (500 MHz, DMSO d6) 8(ppm): 11.73 (s, 2H), 8.53 (s, 2H), 7.89 (s, 4H),
7.75 (s, 2H), 7.37 (d, .7=8.7 Hz, 2H), 6.87 (d, J=7.9 Hz, 2H), 3.87 (s, 6H); by
"C^HJNMR analysis (125 MHz) d (ppm): 154.83, 152.03, 146.32, 132.18,
124.76, 112.73, 112.65, 110.48, 104.41, 55.56; by FAB mass spectrometry
analysis showing the following data: m/z=404.1 ([M-H]+, 100%) and by
IR(KBr) v cm'1: 3385 (N-H), 2944 (C-H), 1641, 1637, 1613 (ON), 1528, 1485
(Car-Car).
27. A method of using the isolated compound of claim 25 as a reference marker.
28. The method of claim 27, wherein the reference marker is an HPLC marker or an
indicator for purity in a process.
29. A method of using the isolated compound of claim 25 as a reference standard.
30. A method for preparing the isolated compound of claim 23, comprising the steps
a) mixing diaminoguanidine-HCl with water;
b) adding a compound of formula II;
and an acid until a reaction mixture having a pH of about 2 to about 3 is
obtained, wherein R is saturated and unsaturated, branched and linear Q-C4
alkanes, Ci-C4 ethers, Q-C3 alcohols, Cg-Cio ai'omatic hydrocarbons and
amides;
c) maintaining the reaction mixture at a temperature from about room
temperature to about boiling temperature of reaction mixture to obtain a
precipitate; and
d) recovering a tegaserod derivative.
31. The method of claim 30, wherein R is selected from the group consisting of:
CH2OCH3, CH2CH=C(CH3)2, CO-N(CH3)2, CH3, C2H5, C3H7, benzoyloxy,
CO-tert-C4H9, CO-N(C2H5)2, CH2-CO-N(CH3)2, CH2-CH2-N(CH3)2, (CH2)2-OCH3,
(CH2)2-OH, isobutoxy, 2, 3-di(OH)-propoxy and acetoxy.
32. The method of claim 30, wherein R is methyl.
33. The method of to claim 30, wherein the acid is an inorganic acid selected from
the group consisting of HC1, HBr, H2SO4, and H3PO4, or a carboxylic acid
34. The method of to claim 33, wherein the acid is HC1.
35. The method of claim 30, wherein the rear n mixture i - maintained at about
70°C.
36. A method for preparing crystalline forms tegaserod maleate having an amount
of the impurity tegaserod dimer (TGS-dimer) of less than about 0.02% by area
percent HPLC comprising;
a) obtaining one or more samples of one or more tegaserod maleate batches;
b) measuring the level of tegaserod dimer in each of the samples of (a);
c) selecting the tegaserod maleate batch that comprises a level of the tegaserod
dimer of less than about 0.02% by area percent HPLC based on the
measurement or measurements conducted in (b); and
d) using the batch selected in (c) to prepare said tegaserod maleate in
crystalline form.
37. A method of preparing a composition comprising crystalline form of TGS
maleate, having TGS-dimer in an amount of less than about 0.02% by area
percent HPLC, which method comprises;
a) purifying a composition comprising TGS maleate and TGS-dimer until a
composition comprising less than about 0.02% TGS dimer by area percent
HPLC is obtained; and
b) using the composition resulting from (a) to prepare a composition
comprising a crystalline form of TGS maleate.
38. The method according to claim 37, wherein the purifying a composition
comprising tegaserod maleate and a tegaserod dimer is performed according to
claims 1 or 2.
39. A method of preparing a composition comprising crystalline form of TGS
maleate, having TGS-dimer in an amount of less than about 0.02% by area
percent HPLC, which method comprises;
a) obtaining one or more samples of one or more TGS maleate batches;
b) measuring the level of TGS-dimer in each of the samples of (a);
c) if the quantity of the TGS-dimer measured in b) is about 0.02% area by
HPLC or more, purifying the sample until the quantity of the TGS-dimer is
less than about 0.02% by weight, and synthesizing a crystalline form of TGS
maleate from the sample so purified; or
d) if the quantity of TGS-dimer measured inb) is less than about 0.02% by
weight, synthesizing a crystalline form of TGS maleate from the TGS
40. The method according to claim 39, wherein the purifying a composition
comprising tegaserod maleate and a tegaseroc: dimer is performed according to claim 1 or 2.