Description:Field of the Invention
The present invention relates to an improved process for the preparation of minoxidil or
minoxidil sulfate. The present invention further relates to a process for making 2,4-diamino-6-
chloropyrimidine 3-oxide, a key intermediate in the preparation of minoxidil or minoxidil
5 sulfate, which is cost effective and economically significant.
Background of the Invention
Minoxidil, approved by FDA as a hypertensive agent, which effectively stimulates the hair
growth in externally used dilute solutions in both male and female including androgenic
alopecia and it’s widely used in therapeutic cosmetics. Minoxidil is chemically known as 2,4-
10 diamino-6-piperidinylpyrimidine-3-oxide having the molecular formula C9H15N5O and
chemical structure of minoxidil is as below:
Minoxidil
N
+
N
O
–
H2N NH2
N
Minoxidil sulfate is an active form converted from minoxidil by sulfotransferase enzymes in
the outer root sheath of hair. Minoxidil sulfate is the active form required for both the promotion
15 of hair regrowth and the vasodilatory effects of minoxidil. Minoxidil sulfate is chemically
known as 2,6-diamino-4-piperidin-1-ylpyrimidin-1-ium-1-yl) sulfate having the molecular
formula C9H15N5O4S and chemical structure of minoxidil sulfate is as below:
Minoxidil Sulfate
N+
N
O
H N 2 NH2
N
S
O O
O–
The US patent No. 4287338 (Assigned to UpJohn Company) disclosed the minoxidil sulfate
20 preparation process in example 1 in three methods (Method A, Method B and Method C).
Method A involves reaction of minoxidil with pyridine-sulfur trioxide in the presence of DMF.
3
Followed by crystallization with DMF and water. Method B involves reaction of minoxidil
with trimethylamine-sulfur trioxide complex in the presence of DMF. Followed by
crystallization with DMF and water. Method C involves recrystallization of minoxidil sulfate
with DMF and ethyl acetate, further crystallized from acetonitrile.
5 The Indian Patent Application No. 02130CHE2014 disclosed the industrially improved process
for the preparation of minoxidil intermediate 2,4-diamino-6-chloropyrimidine-3-oxide process
from 2,4-diamino-6-chloro pyrimidine with the use of phthalic anhydride and urea hydrogen
peroxide adduct in methanol, yields 72%.
The Indian Patent Application No. 2005KOL00103 disclosed the preparation of 2,4-diamino-
10 6-chloropyrimidine-3-oxide from 2,4-diamino-6-chloropyrimidine with the use of phthalic
anhydride and urea hydrogen peroxide adduct in methanol, yields 72%.
The Indian Patent Application No. 202221004404 (Assigned to Intas Pharma), disclosed the
preparation of minoxidil sulfate by reacting minoxidil and chlorosulfonic acid in methylene
chloride provides crude minoxidil sulfate. Also disclosed the process for purification by mixing
15 crude minoxidil sulfate in acetone and followed by filtration. The pure minoxidil sulfate was
isolated by adding water to the filtrate.
The Chinese Patent No. CN113979952 disclosed the preparation of minoxidil, as shown in
scheme-1. First step involves reaction of 2,4-diamino-6-chloropyrimidine with mchloroperbenzoicacid
in ethanol to obtain 2,4-diamino-6-chloropyrimidine-3-N-oxide. Second
20 step involves reaction of 2,4-diamino-6-chloropyrimidine-3-N-oxide with piperidine to obtain
crude minoxidil. Further, the purification of crude minoxidil with the use of IPA and water to
obtain pure minoxidil have the yield of 85%.
N
H2N N NH2
Cl
O
OH
O
Cl
NH
CH3CH2OH
N
N
+
H2N NH2
Cl
O
–
N
N
+
H2N NH2
N
O
–
Scheme-1
25 The Chinese Patent No. CN107235919 disclosed the preparation of minoxidil by reacting 2,4-
diamino-6-chloropyrimidine with m-chloroperbenzoicacid in chloroform to obtain 2,4-
diamino-6-chloropyrimidine-3-N-oxide, which further reacting with piperidine and potash
4
solids in acetone to obtain crude minoxidil. Purification process involves by mixing crude
minoxidil in IPA, followed by petroleum ethers to obtain pure minoxidil having the yield of
75%.
The Chinese Patent No. CN115572265 disclosed the minoxidil preparation method, as shown
5 in scheme-2, with the yields of 82.7%.
N
H2N N NH2
Cl
O
OH
O
NH
N
N
+
H2N NH2
Cl
O
–
N
N
+
H2N NH2
N
O
–
H
2
O, TEA
H
2
O, K
2
CO
3
EtOH, H
2
O
Scheme-2
Besides the availability of different processes for the preparation of minoxidil or minoxidil
sulfate (including purification) in state of the art, there is a need for an alternative, cost effective
10 and economically significant process which improves the yields of minoxidil or minoxidil
sulfate and of intermediates thereof.
The prior art process for the preparation of minoxidil or minoxidil sulfate by employing urea
hydrogen peroxide adduct and phthalic anhydride results lesser yield. And making such urea
hydrogen peroxide adduct is highly hazardous, which contains more ionic contents, and this
15 may cause to explosive while making the adduct. Further, Inventors of the present invention
provides an improved process for the preparation of minoxidil or minoxidil sulfate by making
an intermediate monoperoxyphthalic acid. Also, Inventors of the present invention surprisingly
found that employing monoperoxyphthalic acid (prepared by given process) in the process of
making 2,4-diamino-6-chloropyrimidine 3-oxide, a key intermediate for the preparation of
20 minoxidil or minoxidil sulfate, provides improved yield quantity of minoxidil or minoxidil
sulfate. Also helps to reduce the impurity formation, ultimately improving the quality of
minoxidil or minoxidil sulfate.
Objective of the Invention
The main objective of the present invention is to provide an improved process for the
25 preparation of minoxidil or minoxidil sulfate.
5
In yet another objective of the present invention is to provide a process for making 2,4-diamino-
6-chloropyrimidine 3-oxide, a key intermediate in the preparation of minoxidil or minoxidil
sulfate.
Summary of the Invention
5 One aspect of the present invention is to provide an improved process for the preparation of
minoxidil of formula IA,
Formula IA
N
+
N
O
–
H2N NH2
N
comprising the steps of:
(a) providing a mixture of phthalic anhydride, sodium bicarbonate and hydrogen peroxide
10 in a suitable solvent;
(b) stirring the mixture obtained in step (a) at 0°C to 15°C for a suitable time period to
provide monoperoxyphthalic acid of formula V;
O
O
OH
OH
O
Formula V
(c) reacting 2,4-diamino-6-chloropyrimidine of formula IV
N
N
H2N NH2
Cl
15 Formula IV
with monoperoxyphthalic acid of formula V obtained in step (b) and sodium
bicarbonate in a suitable solvent at 30°C to 40°C to provide 2,4-diamino-6-
chloropyrimidine 3-oxide of formula III;
6
N
+
N
O
–
H2N NH2
Cl
Formula III
(d) optionally purifying the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III
resulted in step (c);
(e) reacting the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III obtained from step
5 (c) or step (d) with piperidine and a phase transfer catalyst in water to obtain minoxidil
of formula IA; and
(f) optionally purifying the minoxidil of formula IA.
Another aspect of the present invention is to provide a process for the preparation of minoxidil
sulfate of formula I,
Formula I
N+
N
O
H N 2 NH2
N
S
O O
O–
10
(i) providing a mixture of minoxidil of formula IA in a solvent under stirring;
(ii) adding sulfuric acid to the mixture of step (i) at the temperature below 35°C;
(iii) allowing the mixture obtained in step (ii) to reflux;
(iv) cooling the resultant of step (iii) to obtain a solid; and
15 (v) isolating the minoxidil sulfate of formula I.
Yet another aspect of the present invention is to provide a process for making 2,4-diamino-6-
chloropyrimidine 3-oxide of formula III, a key intermediate in the preparation of minoxidil or
minoxidil sulfate, comprising the steps of:
(a) providing a mixture of sodium bicarbonate in a suitable solvent and hydrogen
20 peroxide;
(b) cooling the reaction mixture obtained in step (a) to 0°C to 15°C;
(c) adding phthalic anhydride to the cooled mixture obtained in step (b);
7
(d) stirring the mixture obtained in step (c) at 0°C to 15°C for a suitable time period to
obtain monoperoxyphthalic acid of formula V;
O
O
OH
OH
O
Formula V
(e) reacting 2,4-diamino-6-chloropyrimidine of formula IV
N
N
H2N NH2
Cl
5 Formula IV
with monoperoxyphthalic acid of formula V obtained in step (d) and sodium
bicarbonate in a suitable solvent at 30°C to 40°C to obtain 2,4-diamino-6-
chloropyrimidine 3-oxide of formula III; and
N
+
N
O
–
H2N NH2
Cl
Formula III
10 (f) optionally purifying the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III.
Detailed description of the Invention
In an embodiment the present invention provides an improved process for the preparation of
minoxidil of formula IA,
Formula IA
N
+
N
O
–
H2N NH2
N
15 comprising the steps of:
(a) providing a mixture of phthalic anhydride, sodium bicarbonate and hydrogen peroxide
in a suitable solvent;
8
(b) stirring the mixture obtained in step (a) at 0°C to 15°C for a suitable time period to
provide monoperoxyphthalic acid of formula V;
O
O
OH
OH
O
Formula V
(c) reacting 2,4-diamino-6-chloropyrimidine of formula IV
N
N
H2N NH2
Cl
5 Formula IV
with monoperoxyphthalic acid of formula V obtained in step (b) and sodium
bicarbonate in a suitable solvent at 30°C to 40°C to provide 2,4-diamino-6-
chloropyrimidine 3-oxide of formula III;
N
+
N
O
–
H2N NH2
Cl
Formula III
10 (d) optionally purifying the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III
resulted in step (c);
(e) reacting the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III obtained from
step (c) or step (d) with piperidine and a phase transfer catalyst in water to obtain
minoxidil of formula IA; and
15 (f) optionally purifying the minoxidil of formula IA.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the
mixture of phthalic anhydride, sodium bicarbonate and hydrogen peroxide in a suitable solvent
in step (a) is a suspension.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the
20 step (a) providing a mixture of phthalic anhydride, sodium bicarbonate and hydrogen peroxide
in a suitable solvent, further comprising the steps of:
9
(i)
cooling the mixture of sodium bicarbonate in a suitable solvent and hydrogen peroxide; and
(ii)
adding phthalic anhydride into the contents of step (i) to obtain the said mixture.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein cooling the mixture of sodium bicarbonate in a suitable solvent and hydrogen peroxide in step 5 (i) is between 0°C to 15°C, preferably 2°C to 15°C.
In one embodiment of process for the preparation of minoxidil of formula IA, wherein the step (b), stirring the mixture at 0°C to 15°C for a suitable time is 1 to 5 hrs, preferably 2 to 4 hrs.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the suitable solvent is selected from methanol, ethanol, isopropanol, acetone, ethyl acetate and 10 dichloromethane, preferably selected from methanol, ethanol, and isopropanol, more preferably methanol.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the suitable solvent is methanol.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the 15 hydrogen peroxide is selected between 10% to 80% of aqueous hydrogen peroxide, preferably 30% to 60% of aqueous hydrogen peroxide, more preferably 45% to 55% of aqueous hydrogen peroxide.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the step (d) purifying the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III, comprising the 20 steps of:
(i)
providing a mixture of 2,4-diamino-6-chloropyrimidine 3-oxide of formula III in water under stirring;
(ii)
maintaining the temperature of the mixture obtained in step (i) at 75°C to 85°C for a period of 40 to 60 minutes; 25
(iii)
cooling the resulted reaction mixture of step (ii) to 25°C to 35°C;
(iv)
adjusting pH of the reaction mixture obtained from step (iii) not less than 9.0; and
(v)
isolating the pure 2,4-diamino-6-chloropyrimidine 3-oxide of formula III.
10
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein providing a mixture of 2,4-diamino-6-chloropyrimidine 3-oxide of formula III in water under stirring in step (i) is a suspension.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein cooling the reaction mixture of step (iii) is preferably to 27°C to 32°C. 5
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein adjusting pH of reaction mixture not less than 9.0 in step (iv) by use of aqueous NaOH or aqueous KOH, preferably aqueous NaOH.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein isolating the pure 2,4-diamino-6-chloropyrimidine 3-oxide of formula III in step (v) is by 10 filtering and washing with water.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the phase transfer catalyst in step (e), is selected from tetrabutylammonium bromide, tetrabutylammonium iodide and tetrabutylammonium chloride, preferably tetrabutylammonium bromide; and the amount of phase transfer catalyst is selected between 15 0.5% to 3% w/w, preferably 1% to 2.5%, more preferably 2%.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the phase transfer catalyst step (e), is tetrabutylammonium bromide.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the step (e) reacting the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III with piperidine 20 and/or phase transfer catalyst in water to obtain minoxidil, further comprising the steps of:
(i)
heating the mixture of 2,4-diamino-6-chloropyrimidine 3-oxide of formula III in water, phase transfer catalyst and piperidine at temperature between 70°C to 100°C;
(ii)
adding an aqueous base solution of NaOH, KOH, Na2CO3, NaHCO3 or its mixtures thereof, into the reaction mixture obtained in step (i); 25
(iii)
maintaining the temperature of the reaction mixture obtained in step (ii) under stirring for a period between 2 to 15 hrs;
(iv)
cooling the contents obtained in step (iii); and
(v)
isolating minoxidil of formula IA.
11
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein
heating the mixture of the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III in water,
phase transfer catalyst and piperidine in step (i) is preferably at the temperature between 90°C
to 95°C.
5 In one embodiment of the process for the preparation of minoxidil of formula IA, wherein
isolating minoxidil of formula IA in step (v) comprising, filtering and washing with water.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the
step (f) purifying the minoxidil of formula IA, further comprising the steps of:
(i) providing a solution of crude minoxidil in methanol and water;
10 (ii) adding a catalytic amount of EDTA to the solution obtained in step (i);
(iii) heating the reaction mixture to 65°C to 70°C;
(iv) filtering the contents obtained from step (iii);
(v) distilling the resulted filtrate from step (iv); and
(vi) isolating pure minoxidil of formula IA.
15 In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the
catalytic amount of EDTA in step (ii) is selected between 0.1% to 1%, preferably 0.1 to 0.2 %.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein
before the filtering in step (iv), stirring the reaction mixture for a period of 30 to 180 minutes.
In one embodiment of the process for the preparation of minoxidil of formula IA, wherein the
20 isolating pure minoxidil of formula IA in step (vi) comprising, cooling the resultant of step (v)
to 0°C to 5°C; stirring the contents at the same temperature for an hour; filtering; and washing
with water.
In another embodiment the present invention provides a process for the preparation of
minoxidil sulfate of formula I,
Formula I
N+
N
O
H N 2 NH2
N
S
O O
O–
25
12
(i)
providing a mixture of minoxidil of formula IA in a solvent under stirring;
(ii)
adding sulfuric acid to the mixture of step (i) at the temperature below 35° C;
(iii)
allowing the mixture obtained in step (ii) to reflux;
(iv)
cooling the resultant of step (iii) to obtain a solid; and
(v)
isolating the minoxidil sulfate of formula I. 5
In one embodiment of the process for the preparation of minoxidil sulfate of formula I, wherein the mixture of minoxidil in step (i) is a solution.
In one embodiment of the process for the preparation of minoxidil sulfate of formula I, wherein the suitable solvent is selected from methanol, ethanol, isopropanol, acetone, ethyl acetate and dichloromethane, preferably selected from methanol, ethanol, and isopropanol, more 10 preferably methanol.
In one embodiment of the process for the preparation of minoxidil sulfate of formula I, wherein the suitable solvent is methanol.
In one embodiment of the process for the preparation of minoxidil sulfate of formula I, wherein the sulfuric acid in step (ii), is preferably 0.2 to 0.25 equivalent. 15
In one embodiment of the process for the preparation of minoxidil sulfate of formula I, wherein the step (iii) allowing the mixture to reflux is for a period of 2 to 3 hrs, preferably 2 hrs.
In one embodiment of the process for the preparation of minoxidil sulfate of formula I, wherein the step (iv), cooling the resultants is preferably between 0°C to 10°C, more preferably 0°C to 5°C. 20
In one embodiment of the process for the preparation of minoxidil sulfate of formula I, wherein the step (v) further comprising, filtering and washing with suitable solvent.
In one embodiment of the process for the preparation of minoxidil sulfate of formula I, wherein the step (v) further comprising, filtering and washing with methanol.
In yet another embodiment the present invention provides a process for making 2,4-diamino-25 6-chloropyrimidine 3-oxide of formula III, a key intermediate in the preparation of minoxidil or minoxidil sulfate, comprising the steps of:
(a)
providing a mixture of sodium bicarbonate in a suitable solvent and hydrogen peroxide;
(b)
cooling the reaction mixture obtained in step (a) to 0°C to 15°C;
(c)
adding phthalic anhydride to the cooled mixture obtained in step (b); 30
13
(d) stirring the mixture obtained in step (c) at 0°C to 15°C for a suitable time period to
obtain monoperoxyphthalic acid of formula V;
O
O
OH
OH
O
Formula V
(e) reacting 2,4-diamino-6-chloropyrimidine of formula IV
N
N
H2N NH2
Cl
5 Formula IV
with monoperoxyphthalic acid of formula V obtained in step (d) and sodium
bicarbonate in a suitable solvent at 30°C to 40°C to obtain 2,4-diamino-6-
chloropyrimidine 3-oxide of formula III; and
N
+
N
O
–
H2N NH2
Cl
Formula III
10 (f) optionally purifying the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III.
In one embodiment of the process for making 2,4-diamino-6-chloropyrimidine 3-oxide of
formula III, wherein the step (a), providing a mixture of sodium bicarbonate in a suitable
solvent and hydrogen peroxide is a suspension.
In one embodiment of the process for making 2,4-diamino-6-chloropyrimidine 3-oxide of
15 formula III, wherein the suitable solvent is selected from methanol, ethanol, isopropanol,
acetone, ethyl acetate and dichloromethane, preferably selected from methanol, ethanol, and
isopropanol, more preferably methanol.
In one embodiment of the process for making 2,4-diamino-6-chloropyrimidine 3-oxide of
formula III, wherein the suitable solvent is methanol.
20 In one embodiment of the process for making 2,4-diamino-6-chloropyrimidine 3-oxide of
formula III, wherein the step (d), stirring the reaction mixture is preferably a period between 1
to 3 hrs, more preferably 2 hrs.
14
In one embodiment of the process for making 2,4-diamino-6-chloropyrimidine 3-oxide of formula III, wherein the step (f), further comprising the steps of:
(i)
providing a suspension of 2,4-diamino-6-chloropyrimidine 3-oxide of formula III in water under stirring;
(ii)
maintaining the temperature of the suspension obtained in step (i) at 75°C to 85°C for 5 a period of 40 to 60 minutes;
(iii)
cooling the resultant obtained in step (ii) to 25°C to 32°C;
(iv)
adjusting pH of cooled mixture obtained in step (iii) not less than 9.0 by using aqueous NaOH or aqueous KOH; and
(v)
isolating the pure 2,4-diamino-6-chloropyrimidine 3-oxide of formula III. 10
In one embodiment of the process for making 2,4-diamino-6-chloropyrimidine 3-oxide of formula III, wherein the step (v) further comprising, filtering and washing with water.
Definitions:
As used herein the present invention, the term "suitable solvent" refers to the solvent selected from methanol, ethanol, isopropanol, acetone, ethyl acetate and dichloromethane, 15 preferably selected from methanol, ethanol, and isopropanol, more preferably methanol.
As used herein the present invention, the term "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.
As used herein the present invention, the term "RT" or “room temperature’ is refers the temperature between 25°C to 35°C. 20
Abbreviations:
FDA – Food and Drug Administration; DMF – dimethyl formamide; MPA – monoperoxyphthalic acid; IPA – isopropyl alcohol or isopropanol; MDC – methylene dichloride; TBAB – Tetrabutylammonium bromide; NaOH – sodium hydroxide; KOH – potassium hydroxide; Na2CO3 – sodium carbonate; NaHCO3 – sodium bicarbonate; EDTA – 25 Ethylenediaminetetraacetic acid; hrs – hours; mins – minutes; % – percentage; w/w – weight by weight; °C – degree Celsius; HPLC – High-performance liquid chromatography; eq – equivalent; g – gram(s); mL – milli litter; RT – room temperature; aq – aqueous.
15
The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.
EXAMPLES
Example-1: Preparation of monoperoxyphthalic acid 5
To a stirred suspension of sodium bicarbonate (23 g) in methanol (500 mL) and 50% aq. hydrogen peroxide (143 g) was added under cooling. Followed by phthalic anhydride was added to the reaction mixture and stirred for 4 hrs at 0 to 15°C. The reaction mass was tested for monoperoxyphthalic acid (MPA) content by HPLC. The reaction mass was taken as such for the next step. 10
Example-2: Preparation of monoperoxyphthalic acid
To a stirred suspension of phthalic anhydride (20.5g) in acetonitrile (30ml), aqueous ammonia (0.5ml), and 50% aq. hydrogen peroxide (14.10g) were added under at 40°C and stirred for 2 hrs. The reaction mixture was cooled to room temperature to obtain monoperoxyphthalic acid.
Example-3: Preparation of monoperoxyphthalic acid 15
To a stirred suspension of phthalic anhydride (20.5g) in IPA (30mL), aqueous ammonia (0.5ml), and 50% hydrogen peroxide (14.10g) were added at 40°C and stirred for 2hrs. The reaction mixture was cooled to room temperature to obtain monoperoxyphthalic acid.
Example-4: Preparation of monoperoxyphthalic acid
To a stirred suspension of phthalic anhydride (20.5g) in ethyl acetate (30mL), aqueous 20 ammonia (0.5ml), and 50% hydrogen peroxide (14.10g) was added at 45-50°C and stirred for 1-2hrs. The reaction mixture was cooled to room temperature to obtain monoperoxyphthalic acid.
Example-5: Preparation of monoperoxyphthalic acid
To a stirred suspension of phthalic anhydride (20.5g) in MDC (30mL), aqueous ammonia 25 (0.5ml), and 50% hydrogen peroxide (14.10g) were added at 30-35°C and stirred for 1-2hrs. The mixture was cooled room temperature to obtain monoperoxyphthalic acid.
Example-6: Preparation of 2,4-diamino-6-chloropyrimidine-3-oxide
16
To a stirred suspension of 2,4-diamino-6-chloropyrimidine (10g) in acetonitrile (60 mL), and monoperoxyphthalic acid (prepared from Example-2) was added at 40-45°C. The reaction mixture was stirred for 2 – 3 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0 to 10°C and filtered to obtain 2,4-diamino-6-chloropyrimidine-3-oxide (12g). 5
Example-7: Preparation of 2,4-diamino-6-chloropyrimidine-3-oxide
To a stirred suspension of 2,4-diamino-6-chloropyrimidine (10g) in IPA (60 mL), and monoperoxyphthalic acid (prepared from Example-3) was added at 40-45°C. The reaction mixture was stirred for 2 – 3 hrs at the same temperature. After completion of the reaction, reaction mixture was cooled to 0 to 10°C and filtered to obtain 2,4-diamino-6-10 chloropyrimidine-3-oxide (7g).
Example-8: Preparation of 2,4-diamino-6-chloropyrimidine-3-oxide
To a stirred suspension of 2,4-diamino-6-chloropyrimidine (10g) in ethyl acetate (60 mL), and monoperoxyphthalic acid (prepared from Example-4) was added at 40-45°C. The reaction mixture was stirred for 2 – 3 hrs at the same temperature. After completion of the reaction, the 15 reaction mixture was cooled to 0 to 10°C and filtered to obtain 2,4-diamino-6-chloropyrimidine-3-oxide (4g).
Example-9: Preparation of 2,4-diamino-6-chloropyrimidine-3-oxide
To a stirred suspension of 2,4-diamino-6-chloropyrimidine (10g) in MDC (60 mL), and monoperoxyphthalic acid (prepared from Example-5 was added at 40-45°C. The reaction 20 mixture was stirred for 2 – 3 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0 to 10°C, filtered to obtain 2,4-diamino-6-chloropyrimidine-3-oxide (3g).
Example-10: Preparation of 2,4-diamino-6-chloropyrimidine-3-oxide
To a stirred suspension of 2,4-diamino-6-chloropyrimidine (100 g), sodium bicarbonate (35 g) 25 in methanol (400 mL) was added monoperoxyphthalic acid solution at 30°C to 45°C. The reaction conversion was tested by HPLC. Once the reaction was completed, the reaction mixture was cooled and filtered to obtain crude wet cake of the title compound.
The crude wet cake obtained above was mixed with water (300 mL) and heated to 80±5°C. Then the reaction mixture was cooled to RT, adjusted pH of the reaction mass alkaline using 30
17
aq. NaOH solution. The solid obtained was filtered, washed with water, and dried to obtain pure 2,4-diamino-6-chloropyrimidine-3-oxide. Yield 95% and HPLC purity > 98.64%.
Example-11: Preparation of minoxidil crude
To a stirred suspension of 2,4-diamino-6-chloropyrimidine-3-oxide (170 g) in water (300 mL) was added catalytic quantity of TBAB. Then the reaction mixture was heated to 55°C to 80°C. 5 Piperidine (89 g) was added to the reaction mixture at the same temperature followed by the temperature was raised to 90°C to 95°C. Then the aq. NaOH solution (21 g) was added to the reaction mixture and then stirring was continued for another 10 hrs at same temperature. The reaction conversion was tested by HPLC. Once the reaction was completed, the reaction mixture was cooled, filtered and washed with water to obtain crude minoxidil. Yield 97% and 10 HPLC purity 99.40%.
Example-12: Purification of minoxidil pure
Minoxidil crude (94 g) was dissolved in methanol (752 mL) and water (164.5 g) by heating at 60°C to 65°C. Catalytic quantity of EDTA (0.188 g) was added to the reaction mixture under stirring. The resulted clear solution was concentrated obtain solid mass. The obtained solid 15 mass was cooled. Then the solid obtained was filtered, washed with water, and dried to obtain pure minoxidil. Yield 97-98% and Purity 99.95%.
Example-13: Preparation of minoxidil sulfate
To a stirred solution of minoxidil crude (100 g) in methanol (300 mL) and con sulphuric acid (11.24 g) was added at below 35°C. Then the reaction mixture was refluxed for 2 hrs and cooled 20 to obtain solid. The obtained solid was filtered, washed with methanol, and dried under vacuum to obtain minoxidil sulphate. Yield 98-99% and HPLC purity 99.93%.
Different embodiments of the invention are possible to achieve the best method of performance and to obtain the product as stated above to meet the object of the invention. It will be understood that skilled persons, with many modifications, variations, and adaptations, may 25 carry out the invention into practice without departing from its spirit or exceeding the scope of claims in describing the invention for the purpose of illustration.
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Advantages of the present invention:
1.
The monoperoxyphthalic acid used to make 2,4-diamino-6-chloropyrimidine 3-oxide as key intermediate for preparing minoxidil or minoxidil sulfate provides improved yield quantity of minoxidil or minoxidil sulfate.
2.
The yield obtained by the process of the present invention is 98-99% (minoxidil is 97-5 98% and minoxidil sulfate is 98-99%)
3.
Impurity formation is controlled by the claimed process, ultimately improves the quality.
4.
The purity obtained by present invention is more than 99.9%. (minoxidil is 99.95% and minoxidil sulfate is 99.93%). 10
5.
The process involved in the present invention for the preparation of minoxidil or minoxidil sulfate is easily scalable, operational friendly and robust, does not involve usage of any hazardous reagents and commercially viable. , Claims:1. An improved process for the preparation of minoxidil of formula IA,
Formula IA
N
+
N
O
–
H2N NH2
N
comprising the steps of:
(a) providing a mixture of phthalic anhydride, sodium bicarbonate and hydrogen peroxide
in a suitable solvent;
(b) stirring the mixture obtained in step (a) at 0°C to 15°C for a suitable time period to
provide monoperoxyphthalic acid of formula V;
O
O
OH
OH
O
Formula V
(c) reacting 2,4-diamino-6-chloropyrimidine of formula IV
N
N
H2N NH2
Cl
Formula IV
with monoperoxyphthalic acid of formula V obtained in step (b) and sodium
bicarbonate in a suitable solvent at 30°C to 40°C to provide 2,4-diamino-6-
chloropyrimidine 3-oxide of formula III;
N
+
N
O
–
H2N NH2
Cl
Formula III
(d) optionally purifying the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III
resulted in step (c);
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(e) reacting the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III obtained from step
(c) or step (d) with piperidine and a phase transfer catalyst in water to obtain minoxidil
of formula IA; and
(f) optionally purifying the minoxidil of formula IA.
2. A process for the preparation of minoxidil sulfate of formula I,
Formula I
N+
N
O
H N 2 NH2
N
S
O O
O–
(i) providing a mixture of minoxidil of formula IA in a solvent under stirring;
(ii) adding sulfuric acid to the mixture of step (i) at the temperature below 35°C;
(iii) allowing the mixture obtained in step (ii) to reflux;
(iv) cooling the resultant of step (iii) to obtain a solid; and
(v) isolating the minoxidil sulfate of formula I.
3. A process for making 2,4-diamino-6-chloropyrimidine 3-oxide of formula III,
N
+
N
O
–
H2N NH2
Cl
Formula III
a key intermediate in the preparation of minoxidil or minoxidil sulfate, comprising the steps
of:
(a) providing a mixture of sodium bicarbonate in a suitable solvent and hydrogen peroxide;
(b) cooling the reaction mixture obtained in step (a) to 0°C to 15°C;
(c) adding phthalic anhydride to the cooled mixture obtained in step (b);
(d) stirring the mixture obtained in step (c) at 0°C to 15°C for a suitable time period to
obtain monoperoxyphthalic acid of formula V;
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O
O
OH
OH
O
Formula V
(e) reacting 2,4-diamino-6-chloropyrimidine of formula IV
N
N
H2N NH2
Cl
Formula IV
with monoperoxyphthalic acid of formula V obtained in step (d) and sodium
bicarbonate in a suitable solvent at 30°C to 40°C to obtain 2,4-diamino-6-
chloropyrimidine 3-oxide of formula III; and
N
+
N
O
–
H2N NH2
Cl
Formula III
(f) optionally purifying the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III.
4. The process according to claim 1, wherein the step (a) providing a mixture of phthalic
anhydride, sodium bicarbonate and hydrogen peroxide in a suitable solvent, further comprising
the steps of:
(i) cooling the mixture of sodium bicarbonate in a suitable solvent and hydrogen peroxide;
and
(ii) adding phthalic anhydride into the contents of step (i) to obtain the said mixture.
5. The process according to anyone of the claims 1 to 4, wherein the suitable solvent is
selected from methanol, ethanol, isopropanol, ethyl acetate and dichloromethane, preferably
selected from methanol, ethanol, and isopropanol, more preferably methanol.
6. The process according to claim 1, wherein the hydrogen peroxide is selected from 10%
to 80% of aqueous hydrogen peroxide, preferably 30% to 60% of aqueous hydrogen peroxide,
more preferably 45% to 55% of aqueous hydrogen peroxide.
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7. The process according to claim 1, wherein the step (d) purifying the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III, comprising the steps of:
(i)
providing a mixture of 2,4-diamino-6-chloropyrimidine 3-oxide of formula III in water under stirring;
(ii)
maintaining the temperature of the mixture obtained in step (i) at 75°C to 85°C for a period of 40 to 60 minutes;
(iii)
cooling the resulted reaction mixture of step (ii) to 25°to 35°C;
(iv)
adjusting pH of the reaction mixture obtained from step (iii) not less than 9.0; and
(v)
isolating the pure 2,4-diamino-6-chloropyrimidine 3-oxide of formula III.
8. The process according to claim 1, wherein the step (e) reacting the 2,4-diamino-6-chloropyrimidine 3-oxide of formula III with piperidine and/or phase transfer catalyst in water to obtain minoxidil, further comprising the steps of:
(i)
heating the mixture of 2,4-diamino-6-chloropyrimidine 3-oxide of formula III in water, phase transfer catalyst and piperidine at temperature between 70°C to 100°C;
(ii)
adding an aqueous base solution of NaOH, KOH, Na2CO3, NaHCO3 or its mixtures thereof, into the reaction mixture obtained in step (i);
(iii)
maintaining the temperature of the reaction mixture obtained in step (ii) under stirring for a period between 2 to 15 hrs;
(iv)
cooling the contents obtained in step (iii); and
(v)
isolating minoxidil of formula IA.
9. The process according to claim 1, wherein step (e), the phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium iodide and tetrabutylammonium chloride, preferably tetrabutylammonium bromide; and the amount of phase transfer catalyst is selected between 0.5% to 3% w/w, preferably 1% to 2.5%, more preferably 2%.
10. The process according to claim 1, wherein the step (f) purifying the minoxidil of formula IA, further comprising the steps of:
(i)
providing the solution of crude minoxidil in methanol and water;
(ii)
adding a catalytic amount of EDTA to the solution obtained in step (i);
(iii)
heating the reaction mixture to 65°C to 70°C;
(iv)
filtering the contents obtained from step (iii);
(v)
distilling the resulted filtrate from step (iv); and
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(vi)
isolating pure minoxidil of formula IA.