FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(See Section 10; Rule 13)
10
Title: “A single step process for the preparation of
15 omadacycline tosylate of formula (X)”
20
Applicants: SUMAR BIOTECH LLP
25
Address: Plot No.: 112, 113, 114, G.I.D.C. Estate, Tal:
Gozaria, Dist: Mehsana-382825, Gujarat, India.
30
35
Nationality: An Indian Company
40
45
The following specification describes the nature of the invention
and the manner in which it is to be performed:
Page 2 of 17
5 FIELD OF THE INVENTION
The present invention relates to a process for the preparation of
Omadacycline tosylate of formula (X). More particularly, the present
invention relates to a single step process for the preparation of
omadacycline tosylate of formula (X) in which the single step process
10 starts with using minocycline hydrochloride of formula (1) as starting
material and give final omadacycline tosylate of formula (X) without
isolating any intermediate of the process.

N N H H OH
NH2
OH O OH O O
OH
.HCl
S
O
O OH
H
N
O
OH OH O OHOH O
NH2
N N
Formula (1) Formula (X)
15
BACKGROUND OF THE INVENTION
Omadacycline tosylate of formula (X) is a compound selected from
group of 9-aminomethyl substituted minocycline compounds, a class
of tetracycline antibiotic compounds. Omadacycline tosylate of
20 formula (X) is used for the treatment of community acquired bacterial
pneumonia infections and acute bacterial skin infections caused by
susceptible microorganisms.
S
O
O OH
H
N
O
OH OH O OHOH O
NH2
N N
Formula (X)
25 It is also known by its IUPAC name (4S,4aS,5aR,12aR)-4,7-
bis(dimethylamino)-9-[(2,2-dimethylpropyl amino)methyl]-1,10,11,12atetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-
carboxamide;4-methylbenzene sulfonic acid.
Omadacycline tosylate may be represented with the chemical formula
30 (X).
The current synthesis of omadacycline, depicted in Scheme-1, has
been used for multi-kilogram preparations and is described in US
9434680 B2.
Minocycline has several reactive functional groups and the C2 primary
35 amide is more reactive towards electrophiles than C9 or the C10. Due
to this fact, the first step of Scheme-1 requires nearly three equivalents
of the N’-(hydroxymethyl)-phthalimide in triflic acid yielding a bissubstituted aminomethyl phtalimide tetracycline compound. In the
second step of Scheme-1, the phthalimides are de-protected with a
Page 3 of 17
5 large excess of methylamine in alcoholic solution to afford a bissubstituted aminomethyl tetracycline intermediate.
Scheme-1: Synthesis of omadacycline using minocycline as
substrate and N’-(hydroxymethyl) phtalimide as reagent:
10
In the third step of Scheme-1, the resulting intermediate is reacted
with hydrogen under hydrogenation conditions to form a C9-
15 substituted aminomethyl tetracycline intermediate. In the fourth step
of Scheme-1, the formed compound is reacted with pivaldehyde under
hydrogenation conditions to afford omadacycline. After reverse-phase
chromatographic purification, pH adjustment and precipitation the
desired product is afforded as an amorphous, unstable solid. For a
20 long-term manufacturing route, the challenges of the instability of the
aminomethyl intermediate and chromatographic column purification
step must be overcome.
WO2022248865A1 has disclosed a process for the preparation of 9-
25 aminomethyl tetracycline compounds including omadacycline and its
salt wherein semicontinuous and continuous flow processes have
been disclosed.
In a continuous flow process as disclosed in the said patent, the whole
synthetic sequence of the method of the present invention may be
30 carried out from the minocycline reacted in step a) to the 9-
aminomethyl tetracycline compound formed in step d) without the use
of batch reactors, without the need to isolate the 9-aminomethyl
tetracycline intermediate formed in step b) and in the absence of a
hydrogenation reaction prior to step c) or d). Alternatively, in a semi
35 continuous flow process, two of steps a), b) and c) or d) may be carried
without the use of batch reactors, without the need to isolate
Page 4 of 17
5 intermediate products between the reaction steps. The steps a) and b)
of the method of the present invention may operate in a continuous
manner, steps b) and c) of the method of the present invention may
operate in a continuous manner, or steps b) and d) of the method of
the present invention may operate in a continuous manner. Where
10 steps b) and c) or steps b) and d) operate in a continuous manner, the
9-aminomethyl tetracycline intermediate formed in step b) may be
used directly in step c) or d).
According to the said patent, continuous flow technologies use process
intensification (e.g. high temperatures and pressure) and improved
15 mass and heat transfer to increase selectivity and overcome the
challenges of purification, low yields and the isolation of an unstable
intermediate. It has been found that it is possible to synthesize a 9-
aminomethyl tetracycline intermediate directly from 2,9-(methylamidesubstituted) minocycline compound by using higher temperatures that
20 are only feasible by using flow chemistry technologies at low residence
time.
In the above patent, the process of all steps including step a to d, is
carried out at a higher temperature up to 3000C and a pressure up to
500 psi, the higher temperature and higher pressure may cause major
25 industrial accidents and damages to human beings, properties and
hence is not a commercially viable process.
Scheme-2: Impurities formed in the first step (Reaction between
Minocycline HCl and N-hydroxymethyl phthalimide):
30
As shown in scheme-2 and as disclosed in the prior art methods, in
the reaction between minocycline Hcl and N-hydroxymethyl
phthalimide, 2-substituted, 9-substituted, and tri-substituted
Page 5 of 17
5 compounds are also formed as impurities along with bis-substituted
compound of formula (3) and the proportion of those
compounds/impurities are not small. Among above all, only bissubstituted compound of formula (3) is useful in preparation of
omadacyline tosylate.
10 The 2-position substitution impurity cannot be changed into a next
product through a subsequent process, but becomes a starting
material and cannot be recycled, so that the raw material is wasted,
and the 9-position substitution and the tri-position substitution can
be converted into a product in the next process, but the reaction time
15 is prolonged, and the production cost is also increased.
Hence, there is a demand of providing a simple, easy to operate,
industry & economically viable and environment friendly, single step
process for the preparation of omadacycline tosylate of formula (X)
20 from minocycline hydrochloride of formula (1). Applicant has found
that the proposed processes for the preparation of omadacycline
tosylate of formula (X) provide increased yield of omadacycline tosylate
of formula (X) with improved quality having lesser amounts of
impurities in the final product.
25
OBJECTS OF THE INVENTION
Accordingly, the main object of the present invention is to overcome
the problems faced by the prior art processes in the preparation of
omadacycline tosylate of formula (X).
30
There is an object of the present invention to provide a simple,
environment friendly, robust, easy to operate, industry & economically
viable and single step environment friendly process for the preparation
of omadacycline tosylate of formula (X) from minocycline
35 hydrochloride of formula (1).
It is also an object to provide a process for the preparation of
omadacycline tosylate of formula (X) from minocycline hydrochloride
of formula (1) that provides increased yield of omadacycline tosylate of
40 formula (X) with improved quality having lesser amounts of impurities
in the final product.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a single step process for the
45 preparation of omadacycline tosylate of formula (X) in which the single
step process starts with using minocycline hydrochloride of formula
(1) as starting material and give final omadacycline tosylate of formula
Page 6 of 17
5 (X) without isolating the intermediate in any of the steps of the
process.

N N H H OH
NH2
OH O OH O O
OH
.HCl
S
O
O OH
H
N
O
OH OH O OHOH O
NH2
N N
Formula (1) Formula (X)
10 Proposed Route of synthesis along with the brief process for the
preparation of omadacycline tosylate of formula (X) is shown as
follows:
Scheme-3: Route of Synthesis for Preparation of omadacycline
tosylate of formula (X):
N N H H OH
NH2
OH O OH O O OH
N
O
O
OH
N N
H H
O O OH O OH
N
O
O
OH
HN
O
O O
N N
H H
OH O OH O OH
H2N
OH
NH2
. O HCl
N O O
1
minocycline
hydrochloride
3
H
N
O
OH OH O OH
OH O
NH2
N N
6
omadacycline
free base
S
O
O OH
H
N
O
OH OH O
OH
OH O
NH2
N N
X
omadacycline
tosylate
O
5
2
4
PTSA
EthyleneDiamine
Ethylenediamine
PtO2
PTSA
15
The present invention provides a simple, environment friendly, robust,
easy to operate, industry & economically viable and single step
process for the preparation of omadacycline tosylate of formula (X)
20 from minocycline hydrochloride of formula (1).
The present innovators have comprehensively and successfully
investigated the possibility of developing a single step process for the
preparation of omadacycline tosylate of formula (X).
Page 7 of 17
5 The major differences between the Route of synthesis and process of
the present invention as per the scheme-3 and in the prior art
methods are as follows:
(i) In the present invention, the whole process is carried out as a
single step process and no intermediates of any step is isolated and
10 carried forward directly for the next step until the final omadacycline
tosylate of formula (X) is obtained.
(ii) p-toluene sulphonic acid (PTSA) is used in the present invention
in place of methane sulphonic acid, triflic acid or sulfuric acid in the
first step, p-toluene sulphonic acid is not reported in any of the prior
15 art processes.
(iii) Ethylenediamine is used in place of methyl amine in the second
step, ethylenediamine is not reported in any of the prior art
processes.
(iv) ethylenediamine is used in place of triethyl amine in the third
20 step, Ethylenediamine is not reported in any of the prior art
processes.
(v) platinum oxide (PtO2) is used as hydrogenating agent, platinum
oxide is not reported in any of the prior art processes.
25 Methyl amine which is reported in the prior art processes, is included
in List 1 precursor due to its use in methamphetamine narcotic drug
hence the use of methylamine should be done under strict
observation. Methyl amine is gaseous in nature and is available in
gaseous form or as % molar solution in methanol, ethanol, water or
30 Tetrahydrofuran. Use of molar solution of methyl amine in the
reaction may increase the complexity due to its solution in any of the
above listed solvents which actually, may not a part of the reaction
and additional activity like distillation, filtration, washing etc. is
required to be carried out after completion of the reaction that makes
35 the process lengthy and tedious. Further, due to its gaseous nature,
methylamine may escape from the reaction easily hence either more
quantity of methyl amine is required or reaction has to carried out at a
temperature near to 00C to maintain the pH of the reaction mass to
complete the reaction. Also, due to escape of methyl amine from the
40 reaction, pH of reaction mass differs which lead to incomplete reaction
or it may lead to impurities as described above.
Also, methyl amine in the reaction is not recyclable and for every
reaction process, fresh methyl amine has to be used which may create
environmental issues.
45 While ethylenediamine used in the present invention, is a liquid in
nature having boiling point of 1160C that makes easy to maintain pH
of the reaction mass throughout the reaction even at a temperature
Page 8 of 17
5 between 200C to 800C and thus ethylenediamine plays an important
role in completion of the reaction. It is also possible that ethylene
diamine can be recovered and may be used in the reaction again.
Thus, recycling of ethylenediamine may reduce the environmental
issues.
10
Methane sulphonic acid, triflic acid and sulfuric acid are strong acids
have been used in the prior art processes, all are liquid in nature
hence utmost care has to be taken while using either of two in the
reaction process or handling it or storing it as chemical. While p15 toluene sulphonic acid (PTSA) used in the present invention is also a
strong acid but solid in nature hence the weighing it for reaction
purpose or storing it as chemical is much easier than methane
sulphonic acid, triflic acid or sulfuric acid.
20 According to the present invention, a single step process for the
preparation of omadacycline tosylate of formula (X) is provided, the
said process comprises:
i. Reacting minocycline hydrochloride of formula (1) with Nhydroxymethyl phthalimide of formula (2) in presence of p25 toluene sulphonic acid in alcoholic solvent at a temperature
between 250C to 800C to give tris protected minocycline of
formula (3) in alcoholic solvent;
ii. Adding ethylene diamine at a temperature between 00C to 100C
to get pH between 8.5 to 9.5 followed by removal of solid mass
30 through filtration and distilling alcoholic solvent to get oily mass
of compound of formula (4);
iii. Adding ethyl acetate, pilvadehyde of formula (5), and 5%
platinum oxide (PtO2) into oily mass of compound of formula (4)
and stirring the reaction mass at a temperature between 200C to
35 400C under continuous passing of hydrogen gas at a pressure
between 0.5 to 0.8 psi for 5 to 7 hours followed by removal of
Platinum oxide (PtO2) from the reaction mass and adjusting pH
between 8-9 using ehthylenediamine to give omadacycline free
base of formula (6) in ethyl acetate solvent;
40 iv. Adding p-toluene sulphonic acid to adjust pH between 3.5 to 4.5
and stirring it at a temperature between 00C to 100C followed by
filtration to give Omadacycline tosylate of formula (X).
Now, each step of a single step is explained as follows:
Step-i:
45 The role of temperature, addition of p-toluene sulphonic acid, Nhydorxymethyl phthalimide is important to increase the percentage
Page 9 of 17
5 (%) formation of tris protected minocycline of formula (3) and to
eliminate or to reduce the percentage (%) formation of mono and bis
protected minocycline hence the reaction is carried out at a
temperature between 250C to 800C.
Minocycline HCl of formula (1): N-hydroxymethyl phthalimide (2): p10 toluene sulphonic acid is taken in a mole ratio between 1:2-4:0.03-
0.1.
Alcoholic solvent is added in a volume between 5 to 20 volumes for
proper mixing of the reaction mass. Alcoholic solvent is selected from
but not limited to methyl alcohol (MeOH), ethyl alchol (EtOH) or
15 isopropyl alchohol (IPA).
During the reaction of step-i, online HPLC analysis is carried out, it
confirms that in step-i, tris protected minocycline of formula (3) is
obtained as a major product while mono and bis protected
minocycline is obtained in about 2-5% after completion of the
20 reaction.
After completion of the reaction of step-i, tris protected minocycline of
formula (3) which is in the alcoholic solvent is further taken for step-ii.
It is to be noted here that the tris protected minocycline of formula (3)
25 may be taken for step-ii with or without isolation of it. More
preferably, tris protected minocycline of formula (3) may be taken for
step-ii without isolation as it will save time, men power and resources.
While conducting step-ii, there is no need to transfer the reaction
30 mass and the same vessel or apparatus may be used for carrying out
step-ii.
Step-ii:
In the reaction, ethylene diamine is added in excess volume to the
alcoholic reaction mass containing tris protected minocycline of
35 formula (3).
The volume of ethylene diamine is kept between 10 to 15 volumes by
adjusting pH between 8.5 to 9.5. The selection of ethylene diamine
replaces methyl amine use in the reaction. The whole reaction is
carried out at a temperature between 00C to 100C.
40 Use of ethylene diamine, volume of ethylene diamine, pH and
temperature play an important role in step-ii. If volume of ethylene
diamine or temperature range or pH range is higher or lower than the
decided range, it will give undesired products or impurities that will
ultimately decrease the quality and quantity of the obtained
45 compound of formula (4).
Page 10 of 17
5 After completion of the reaction of step-ii, solid mass is removed
through filtration and filtrate containing alcoholic solvent is removed
using vacuum distillation at a temperature between 30-450C. During
vacuum distillation, excess of ethylene diamine is also removed along
with alcohol.
10
After distilling out alcoholic solvent completely from step-ii, oily mass
containing compound of formula (4) is further taken for hydrogenation
reaction i.e. step-iii.
Step-iii:
15 Step-iii is carried out in the pressure reaction vessel. The reaction
vessel is degassed by passing nitrogen gas and ensures the absence of
oxygen gas in the reaction vessel. The oily mass containing compound
of formula (4) is transferred to the pressure reaction vessel. Ethyl
acetate, pilvadehyde of formula (5), and 5% platinum oxide (PtO2) is
20 added into oily mass of compound of formula (4) and stirred the
reaction mass at a temperature between 200C to 400C under
continuous passing of hydrogen gas at a pressure between 0.5 to 0.8
psi for 5 to 7 hours.
After completion of the reaction, Platinum oxide (PtO2) is removed from
25 the reaction mass through filtration. Ethylene diamine is added to the
filtrate to adjust pH between 8 to 9 which will give omadacycline free
base of formula (6) in ethyl acetate solvent.
In the above step-iii, ethyl acetate is used in a volume between 5 to 15
30 volumes and pivaldehyde of formula (5) is added in 0.5 to 1 volume.
The said ethyl acetate filtrate containing omadacycline free base of
formula (6) is washed with water several times. Charcoal treatment at
a temperature between 40 to 500C is given to the ethyl acetate filtrate
35 to remove undesired impurities, unreacted pivaldehyde and ethylene
diamine from ethyl acetate filtrate. The treated ethyl acetate filtrate
containing omadacycline free base of formula (6) is taken for next
step-iv.
40 Step-iv:
The reaction is carried out in same solvent and tosylate salt of
omadacycline is prepared using p-toluene sulphonic acid (p-TSA) at a
pH between 3.5 to 4.5.
The addition of p-toluene sulphonic acid (p-TSA) is crucial and it
45 should be added in a quantity to adjust the pH of the reaction mass
between 3.5 to 4.5. pH and temperature play an important role in
Page 11 of 17
5 formation and isolation of the final Omadacycline tosylate of formula
(X).
After addition of 0.5 to 1 mole ratio of p-toluene sulphonic acid (pTSA), the reaction mass is stirred at a temperature between 00C to
100C and filtered it to give Omadacycline tosylate of formula (X).
10
After completion of the reaction, the reaction mass is filtered and
washed with solvent selected from water, methanol, ethanol or methyl
t-butyl ether (MTBE) to give pure omadacycline tosylate of formula (X).
Optionally, the reaction mass may also be taken further for
15 purification as per the prior art processes to obtain pure omadacycline
tosylate of formula (X).
The Omadacycline tosylate of formula (X) obtained with the said
process is having HPLC purity between 98% to 99.8% including
20 tautomer of it.
EXAMPLES:
A single step process for the preparation of Omadacycline
tosylate of formula (X) as per Scheme-3:
25 Minocycline hydrochloride of formula (1) is added to the alcoholic
solvent followed by addition of p-toluene sulphonic acid (PTSA) and Nhydroxymethyl phthalimide of formula (2) at a temperature between
25-30°C, heated to 60-80°C and stirred for 10 to 12 hrs at the same
temperature to get mixture of mono, bis and tris protected minocycline
30 of formula (3). The said mixture is cooled to 0-5°C and adjusted pH
between 8.5 to 9.5 with the addition of ethylenediamine. The reaction
mass is stirred at 0-100C for half an hour and filtered to remove the
solid mass for the reaction mass. Reaction mass then taken for
distillation to remove alcoholic solvent to get compound of formula (4)
35 as an oily mass. Ethyl acetate is added in the said oily mass, and dried
it over drying agent to remove moisture from the reaction mass.
Transfer the reaction mixture to the pressure vessel and remove the
oxygen completely from the pressure vessel by purging nitrogen gas
into the vessel. Pivaldehyde of formula (5) is added in the said mass
40 followed by addition of hydrogenation catalyst 5% PtO2, the said mass
is then carried forward for hydrogenation through passing of hydrogen
gas at a pressure between 0.5 to 0.8 psi at a temperature between 20
to 30°C and stirred the mass for 5 to 7 hours along with continuous
passing of hydrogen gas at the same temperature. After completion of
45 the reaction, filtered the reaction mass to get clear reaction mass
followed by adjusting pH of the mass between 8 to 9 using
ethylenediamine to give omadacycline free base of formula (6) in ethyl
Page 12 of 17
5 acetate solvent. Water wash is given to the said mass followed by giving
the charcoal treatment to the said mass at a temperature between
400C to 500C to remove the impurities, unreacted pivaldehyde and/or
ethylenediamine. Omadacycline free base of formula (6) remained in
ethyl acetate is further reacted with p-toluene sulphonic acid at a pH
10 between 3.5 to 4.5 and at a temperature between 0-100C followed by
filtration and washing it with solvent to give omadacycline tosylate of
formula (X).
Following are the examples provided with comparative examples as
15 per the prior art processes for each step.
Step-i: Preparation of compound of formula (3):
Examples with different parameters are provided as follows:
Sr.
No.
Minocycline
Hcl (1)
(mole ratio)
Solvent
and its
volume
Nhydorxymeth
yl pthalimide
(2) (mole
ratio) AND
reaction
time
Acid
catalyst
mole
Ratio
Tempe
-rature
(oC)
HPLC
result
As per the process of the present invention
01 1 Methanol
(10v)
2
(8 to 10 hrs)
p-TSA
(0.1)
40-60 Complies
02 1 Methanol
(10v)
2
(8 to 10 hrs)
p-TSA
(0.1)
40-60 Complies
03 1 Ethanol
(15v)
2.5
(8 to 10 hrs)
p-TSA
(0.1)
40-60 Complies
04 1 Ethanol
(15v)
4
(8 to 10 hrs)
p-TSA
(0.04)
40-60 Complies
05 1 IPA
(16)
4.75
(10 to 12 hrs)
p-TSA
0.05
60-80 Complies
06 1 IPA
(18)
4.75
(10 to 12 hrs)
p-TSA
0.05
60-80 Complies
As per Prior art Processes:
07 1 Toluene
(15)
4
(10-15 hrs)
H2SO4
(0.1)
50-70 Complies
08 1 Toluene
(15)
4
(10-15 hrs)
Me-SO3H
(0.1)
50-70 Complies
09 1 Toluene
(15)
4
(10-15 hrs)
Triflic acid
(0.1)
50-70 Complies
Page 13 of 17
5 Step-ii: Preparation of compound of formula (4):
Examples with different parameters are provided as follows:
Sr.
No.
solvent Base
(mole
ratio)
pH Time Temperature (oC)
HPLC result
As per the process of the present invention
01 ---- Ehtylene
diamine
(10)
6.5–7.8 15-20
minutes
10-20 Complies (90%)
02 ---- Ehtylene
diamine
(10)
6.5–7.1 15-20
minutes
10-20 Complies (90%)
03 ---- Ehtylene
diamine
(12)
8.5-9.5 30
minutes
0-10 Complies (92%)
04 ---- Ehtylene
diamine
(14)
8.5-9.5 30
minutes
0-10 Complies (92%)
05 ---- Ehtylene
diamine
(14)
8.5-9.5 30
minutes
0-10 Complies (92%)
As per Prior art Processes:
06 methanol Methyl
diamine
(10)
5.5-6.5 30
minutes
20-30 Not complies
07 water Methyl
diamine
(10)
5.5-6.5 30
minutes
20-30 Not complies
08 --- Methyl
diamine
(12)
5.5-6.5 15-20
minutes
20-30 Not complies
09 --- Methyl
amine
(14v)
6.5-7.7 15-20
minutes
10-20 Not complies
10
Page 14 of 17
5 Step-iii: Preparation of omadacycline free base (6):
Examples with different parameters are provided as follows:
Sr.
No.
Solvent
(Volume)
Pivaldehyde
(volume)
Catalyst
(%)
Temp
erature
(oC)
Base &
pH
HPLC result
01 Ethyl
acetate
(5)
0.5 PtO2
(5%)
20-30 Ethylene
diamine
(8-9)
Complies (95%)
02 Ethyl
acetate
(10)
1 PtO2
(5%)
20-30 Ethylene
diamine
(8-9)
Complies (95%)
03 Ethyl
acetate
(15)
0.5 PtO2
(5%)
20-30 Ethylene
diamine
(8-9)
Complies (95%)
04 Ethyl
acetate
(5)
1 PtO2
(5%)
20-30 Ethylene
diamine
(8-9)
Complies (95%)
05 Ethyl
acetate
(5)
0.8 PtO2
(5%)
20-30 Ethylene
diamine
(8-9)
Complies (95%)
As per Prior art Processes:
06 Ethanol
(8)
1 Pd/C 0-10 Methylene
diamine
(5-6)
Complies (48%)
07 Ethanol
(10)
1 PtO2 20-30 Methylene
diamine
(7-8)
Complies (50%)
08 Methanol
(7)
1 PtO2 0-10 Methylene
diamine
(7-8)
NA
09 Methanol
(5)
1.5 PtO2 20-30 Methylene
diamine
(8-9)
Complies (50%)
10 Toluene
(4)
1.5 Pd/C 20-30 Methylene
diamine
(8-9)
Complies (55%)
11 Toluene
(8)
1.25 PtO2 10-20 Ammonia
(7-8)
Complies (56%)
Page 15 of 17
12 THF
(5.5)
05 PtO2 0-10 TEA
(8-9)
NA
5
Step-iv: Preparation of omadacycline tosylate (X):
Examples with different parameters are provided as follows:
(As per present invention):
Sr.
No.
p-TSA
(mole ratio)
pH Temperature
(oC)
HPLC result
(% purity)
Yield
of (X)
(w/w)
01 0.6 1-2 20-30 Not complies ----
02 0.8 2-3 0-10 90 0.4
03 0.8 2-3 0-10 95 0.4
04 0.8 3.5-4.5 0-10 97 0.5
05 0.75 3.5-4.5 0-10 98 0.6
10 ADVANTAGES OF THE PRESENT INVENTION
1. The process for the preparation of omadacycline tosylate of formula
(X) is a single step process.
2. The process of the present invention is a simple, environment
friendly, robust, easy to operate, industry & economically viable
15 process.
3. The said process provides increased yield of omadacycline tosylate
of formula (X) with improved quality having lesser amounts of
impurities in the final product.
20
Page 16 of 17
5 We claim:
1. A single step process for the preparation of omadacycline
tosylate of formula (X) comprises the steps:
i. Reacting minocycline hydrochloride of formula (1) with Nhydroxymethyl phthalimide of formula (2) in presence of p10 toluene sulphonic acid in 5-20 volumes of alcoholic solvent
at a temperature between 250C to 800C to give tris
protected minocycline of formula (3) in alcoholic solvent;
ii. Adding 10 to 15 volumes of ethylene diamine at a
temperature between 00C to 100C to get pH between 8.5 to
15 9.5 followed by removal of solid mass through filtration and
distilling alcoholic solvent to get oily mass of compound of
formula (4);
iii. Adding 5 to 15 volumes of ethyl acetate, 0.5 to 1 volume of
pilvadehyde of formula (5), and 5% platinum oxide (PtO2)
20 into oily mass of compound of formula (4) and stirring the
reaction mass at a temperature between 200C to 400C
under continuous passing of hydrogen gas at a pressure
between 0.5 to 0.8 psi for 5 to 7 hours followed by removal
of Platinum oxide (PtO2) from the reaction mass and
25 adjusting pH between 8-9 using ehthylenediamine to give
omadacycline free base of formula (6) in ethyl acetate
solvent;
iv. Adding 0.5 to 1 mole ratio of p-toluene sulphonic acid
(pTSA) to adjust pH between 3.5 to 4.5 and stirring it at a
30 temperature between 00C to 100C followed by filtration to
give Omadacycline tosylate of formula (X).
2. The process for the preparation of omadacycline tosylate of
formula (X) as claimed in claim-1 wherein in step-i, alcoholic
solvent is selected from methanol, ethanol or Isopropyl alcohol
35 (IPA).
3. The process for the preparation of omadacycline tosylate of
formula (X) as claimed in claim-1 wherein in step-i, minocycline
Page 17 of 17
5 HCl of formula (1): N-hydroxymethyl phthalimide (2): p-toluene
sulphonic acid (pTSA) is taken in a mole ratio between 1:2-
4:0.03-0.1.
4. The process for the preparation of omadacycline tosylate of
formula (X) as claimed in claim-1 wherein after completion of
10 step-iii, water wash and charcoal treatment is given to the ethyl
acetate filtrate.