Indian Patents. 224735:NEW PROCESS FOR THE MANUFACTURE OF 6-CHLORO-2,4-DIAMINOPYIMIDINE-3-OXIDE.

Title of Invention	NEW PROCESS FOR THE MANUFACTURE OF 6-CHLORO-2,4-DIAMINOPYIMIDINE-3-OXIDE.
Abstract	A new process for the preparation of the key intermediate 6-Chloro-2,4- diaminopyrimidine-3-oxide from 6-Chloro-2, 4-diaminopyrimidine using urea-hydrogen peroxide complex and phthalic anhydride in a suitable organic solvent, in a definite molar ratio, at a predetermined temperature, for a certain duration of time.

Full Text	FIELD OF INVENTION The invention relates to a new process for the preparation of 6-Chloro-2,4- diaminopyrimidine-3-oxide, a versatile intermediate for the production of many cosmetic ingredients. This involves the N-oxidation of 6-Chloro-2,4-diaminopyrimidine using urea-hydrogen peroxide as an oxygen source and phthalic anhydride as a carrier. BACKGROUND OF INVENTION Process for the preparation of 6-Chloro-2,4-diaminopyrimidine-3-oxide from 6- Chloro-2,4-diaminopyrimidine using different oxidizing agents, is disclosed in different literatures. US patent 3,644,364 claims the use of several perbenzoic acids as the oxygen source with the preferred solvent alcohol, at 0 to 10 °C, but the reported yield of the final product is around 44%. Journal of Hetrocyclic Chemistry, 73 (1972) reports the same N-oxidation using 90% Hydrogen peroxide in Trifluroacetic acid. After keeping for several days, the reaction was worked up to obtain the product in yields of 65%. US patent 5,126,456 claims a process for the preparation of 6-Piperidino-2,4- diaminopyrimidine 3-oxide, commonly known as Minoxidil, in which at least one of the two amino groups of the compound is protected by an isocyanate having formula R-N=C=O where 'R' represents an alkyl group. The resulting Urea derivative is then oxidized to produce the corresponding N-oxide, which is then reacted with Piperidine. The protective group(s) is / are then eliminated by reaction with an organic / or inorganic base. US patent 3,382,247 describes a process which consists in the reaction of a phenolate an 6-Chloro-2,4-diaminopyrimidine to produce the 6-Phenoxy compound. This is oxidized to the corresponding 3-oxide by meta chloro perbenzoic acid (MCPA). The above patent teaches us the process for the synthesis of N-oxide using a protective - oxidation - deprotection sequence. The treatment of 6-Chloro-2,4-diamino pyrimidine with different isocyanates yielded Urea derivatives predominantly at the 4- amino site. This indicated the 4-amino group to be more reactive (presumably more basic) than the 2-amino group. FR 2,632,954 discloses the use of Hydrogen peroxide and Phthalic anhydride in ethanol for Pyrimidine N-oxide preparation. However all the above process have several drawbacks - 1. Oxygen sources used, like MCPA are expensive contrasted with present invention. 2. Require complicated procedures for intermediates before proceeding to next step as opposed to simpler procedures disclosed in present invention. 3. Much longer reaction time is required because the number of steps are more than this invention. 4. Reactions are carried out at a higher temperature than this invention. 5. Conventional reagents used are potentially more hazardous being explosive in nature where as this invention discloses use of reagents which are non- explosive in nature. 6. Because of the number of reaction steps and purification required in all the steps, overall yields are much lower (as aforesaid) than in this new invention where only 2 steps are involved (eg. for Minoxidil) and no purification of the intermediate is required which are non-obvious inventive steps constituting this invention. In view of the above, it is the subject of the present invention to provide a novel process for the preparation of this key intermediate, which no longer suffers from above drawbacks and is simple to carry to industrial scale. It is a further object to obtain the end products in substantially better yield and to a high degree of purity free from all the impurities that are possible when we go for protection and deprotection reactions eg. preparation of phenolate and its removal after the reaction. OBJECT OF INVENTION It is an object of this invention to provide a new process for the preparation of the key intermediate 6-Chloro-2,4-diaminopyrimidine-3 -oxide having formula (I), Another object of this invention is to provide a new process for the preparing 6- Chloro-2,4-diaminopyrimidine-3-oxide from the above intermediate using urea hydrogen peroxide complex in combination phthalic anhydride as an oxygen carrier. Still another object of this invention is to provide a new process, which yields around 72% final product, 6-Chloro-2, 4-diaminopyrimidine-3-oxide. The other objects and features of the present invention will become apparent from the following description. STATEMENT OF THE INVENTION A new process for the preparation of 6-Chloro-2, 4-diaminopyrimidine-3- oxide from 6-Chloro-2,4-diaminopyrimidine using urea-hydrogen peroxide complex and phthalic anhydride in a suitable organic solvent, in a definite molar ratio, at a predetermined temperature for a certain duration of time. DESCRIPTION OF THE INVENTION According to the invention, it is found that preparation of 6-Chloro-2,4- diaminopyrimidine-3-oxide having formula (I), (I) from 6-Chloro-2,4-diaminopyrimidine having formula (II), can be carried out by using urea-hydrogen peroxide adduct having formula (III) as an oxidizing agent, which has been successfully replacing the potentially explosive hydrogen peroxide in several reactions. CO(NH2)2.H2O2 (III) It is observed that the greater reactivity of the 4-amino group in the above compound could be explained if an oxidizing agent could carry anchoring group such as COOH or SO3H, which could form hydrogen bonding with the 4-amino group and hold the oxidizing group (peracid) close to the 3-position. This anchimeric assistance would not only increase the selectivity at 3-position but also increase the rate of oxidation. Accordingly, a suitable oxidizing agent e.g. monoperacid of a dicarboxylic acid like monoperphthalic has been selected for the preparation of 3-oxide derivative. The above mentioned oxidation process is investigated using urea-hydrogen peroxide as an oxygen source, various dicarboxylic acid anhydrides as oxygen carriers in various alcoholic solvents, chlorinated solvents, esters and ethers. The molar ratios of the oxygen donor and oxygen carrier to the target amine were varied from 1:1:1 to 10:10:1 for optimization. A representative process for preparation of 6-Chloro-2,4- diaminopyrimidine-3 -oxide is explained below: Dissolve 4.44 Kg. (3 moles) of phthalic anhydride in 6 liter of methanol. To the well-stirred solution, 3.22 Kg. (3.4 moles) of urea-hydrogen peroxide complex is added and stirred at 20.30°C temperature for 3 hours (reagent A). To a well stirred solution of 1.44 Kg. (1 mole) of 2,4-diamino-6-chloropyrimidine in 7.5 liter of methanol, Reagent A is slowly added at 20-30°C temperature and the reaction mixture is stirred at 20-30°C temperature for another 3 hours. The progress of the reaction is monitored by thin layer chromatography (TLC). Upon completion of the reaction, the mixture is cooled and maintained at 0 to 10°C for 1 hour to complete precipitation. The solid obtained is filtered, washed with small quantities of chilled methanol and dried (yield 72%). 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 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. WE CLAIM: 1. A new process for the preparation of 6-Chloro-2, 4-diaminopyrimidine-3-oxide having formula (I), from the key intermediate 6-Chloro-2, 4-diaminopyrimidine, having formula (II), can be carried out by using oxidizing agent urea-hydrogen peroxide, having formula (III), CO(NH2)2.H2O2 (III) and phthalic anhydride in a suitable organic solvent at a definite molar ratio in a predetermined temperature for a certain duration of time. 2. Process as claimed in claim 1, wherein the molar ratio of phthalic anhydride, urea-hydrogen peroxide complex and 6-Chloro-2,4-diaminopyrimidineis 3.0:3.4:1. 3. Process as claimed in claim 1, wherein the organic solvent is alcohol, chlorinated solvents, esters and ethers. 4. Process as claimed in claim 1, wherein the organic solvent is alcohol. 5. Process as claimed in claim 1, wherein the reaction temperature is 20 to 30°C. 6. Process as claimed in claim 1, wherein the desired product is obtained by filtration after cooling the reaction mixture at 0 to 10 °C for 1 hour. 7. Process as claimed in claim 1, wherein the duration of time of reaction is 2 to 5 hours. 8. Process as claimed in preceding claims substantially as herein described. A new process for the preparation of the key intermediate 6-Chloro-2,4- diaminopyrimidine-3-oxide from 6-Chloro-2, 4-diaminopyrimidine using urea-hydrogen peroxide complex and phthalic anhydride in a suitable organic solvent, in a definite molar ratio, at a predetermined temperature, for a certain duration of time.

Full Text

FIELD OF INVENTION
The invention relates to a new process for the preparation of 6-Chloro-2,4-
diaminopyrimidine-3-oxide, a versatile intermediate for the production of many cosmetic
ingredients. This involves the N-oxidation of 6-Chloro-2,4-diaminopyrimidine using
urea-hydrogen peroxide as an oxygen source and phthalic anhydride as a carrier.
BACKGROUND OF INVENTION
Process for the preparation of 6-Chloro-2,4-diaminopyrimidine-3-oxide from 6-
Chloro-2,4-diaminopyrimidine using different oxidizing agents, is disclosed in different
literatures.
US patent 3,644,364 claims the use of several perbenzoic acids as the oxygen
source with the preferred solvent alcohol, at 0 to 10 °C, but the reported yield of the final
product is around 44%.
Journal of Hetrocyclic Chemistry, 73 (1972) reports the same N-oxidation using
90% Hydrogen peroxide in Trifluroacetic acid. After keeping for several days, the
reaction was worked up to obtain the product in yields of 65%.
US patent 5,126,456 claims a process for the preparation of 6-Piperidino-2,4-
diaminopyrimidine 3-oxide, commonly known as Minoxidil, in which at least one of the
two amino groups of the compound is protected by an isocyanate having formula
R-N=C=O where 'R' represents an alkyl group. The resulting Urea derivative is then
oxidized to produce the corresponding N-oxide, which is then reacted with Piperidine.
The protective group(s) is / are then eliminated by reaction with an organic / or inorganic
base.
US patent 3,382,247 describes a process which consists in the reaction of a
phenolate an 6-Chloro-2,4-diaminopyrimidine to produce the 6-Phenoxy compound. This
is oxidized to the corresponding 3-oxide by meta chloro perbenzoic acid (MCPA).
The above patent teaches us the process for the synthesis of N-oxide using a
protective - oxidation - deprotection sequence. The treatment of 6-Chloro-2,4-diamino
pyrimidine with different isocyanates yielded Urea derivatives predominantly at the 4-
amino site. This indicated the 4-amino group to be more reactive (presumably more
basic) than the 2-amino group.
FR 2,632,954 discloses the use of Hydrogen peroxide and Phthalic anhydride in
ethanol for Pyrimidine N-oxide preparation.
However all the above process have several drawbacks -
1. Oxygen sources used, like MCPA are expensive contrasted with present
invention.
2. Require complicated procedures for intermediates before proceeding to next
step as opposed to simpler procedures disclosed in present invention.
3. Much longer reaction time is required because the number of steps are more
than this invention.
4. Reactions are carried out at a higher temperature than this invention.
5. Conventional reagents used are potentially more hazardous being explosive in
nature where as this invention discloses use of reagents which are non-
explosive in nature.
6. Because of the number of reaction steps and purification required in all the
steps, overall yields are much lower (as aforesaid) than in this new invention
where only 2 steps are involved (eg. for Minoxidil) and no purification of the
intermediate is required which are non-obvious inventive steps constituting
this invention.
In view of the above, it is the subject of the present invention to provide a novel
process for the preparation of this key intermediate, which no longer suffers from above
drawbacks and is simple to carry to industrial scale. It is a further object to obtain the end
products in substantially better yield and to a high degree of purity free from all the
impurities that are possible when we go for protection and deprotection reactions eg.
preparation of phenolate and its removal after the reaction.
OBJECT OF INVENTION
It is an object of this invention to provide a new process for the preparation of the
key intermediate 6-Chloro-2,4-diaminopyrimidine-3 -oxide having formula (I),
Another object of this invention is to provide a new process for the preparing 6-
Chloro-2,4-diaminopyrimidine-3-oxide from the above intermediate using urea hydrogen
peroxide complex in combination phthalic anhydride as an oxygen carrier.
Still another object of this invention is to provide a new process, which yields
around 72% final product, 6-Chloro-2, 4-diaminopyrimidine-3-oxide.
The other objects and features of the present invention will become apparent from
the following description.
STATEMENT OF THE INVENTION
A new process for the preparation of 6-Chloro-2, 4-diaminopyrimidine-3-
oxide from 6-Chloro-2,4-diaminopyrimidine using urea-hydrogen peroxide complex and
phthalic anhydride in a suitable organic solvent, in a definite molar ratio, at a
predetermined temperature for a certain duration of time.
DESCRIPTION OF THE INVENTION
According to the invention, it is found that preparation of 6-Chloro-2,4-
diaminopyrimidine-3-oxide having formula (I),

(I)
from 6-Chloro-2,4-diaminopyrimidine having formula (II),

can be carried out by using urea-hydrogen peroxide adduct having formula (III) as an
oxidizing agent, which has been successfully replacing the potentially explosive
hydrogen peroxide in several reactions.
CO(NH2)2.H2O2
(III)
It is observed that the greater reactivity of the 4-amino group in the above
compound could be explained if an oxidizing agent could carry anchoring group such as
COOH or SO3H, which could form hydrogen bonding with the 4-amino group and hold
the oxidizing group (peracid) close to the 3-position. This anchimeric assistance would
not only increase the selectivity at 3-position but also increase the rate of oxidation.
Accordingly, a suitable oxidizing agent e.g. monoperacid of a dicarboxylic acid like
monoperphthalic has been selected for the preparation of 3-oxide derivative.
The above mentioned oxidation process is investigated using urea-hydrogen
peroxide as an oxygen source, various dicarboxylic acid anhydrides as oxygen carriers in
various alcoholic solvents, chlorinated solvents, esters and ethers. The molar ratios of the
oxygen donor and oxygen carrier to the target amine were varied from 1:1:1 to 10:10:1
for optimization. A representative process for preparation of 6-Chloro-2,4-
diaminopyrimidine-3 -oxide is explained below:
Dissolve 4.44 Kg. (3 moles) of phthalic anhydride in 6 liter of methanol. To the
well-stirred solution, 3.22 Kg. (3.4 moles) of urea-hydrogen peroxide complex is added
and stirred at 20.30°C temperature for 3 hours (reagent A). To a well stirred solution of
1.44 Kg. (1 mole) of 2,4-diamino-6-chloropyrimidine in 7.5 liter of methanol, Reagent A
is slowly added at 20-30°C temperature and the reaction mixture is stirred at 20-30°C
temperature for another 3 hours. The progress of the reaction is monitored by thin layer
chromatography (TLC). Upon completion of the reaction, the mixture is cooled and
maintained at 0 to 10°C for 1 hour to complete precipitation. The solid obtained is
filtered, washed with small quantities of chilled methanol and dried (yield 72%).
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 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.
WE CLAIM:
1. A new process for the preparation of 6-Chloro-2, 4-diaminopyrimidine-3-oxide
having formula (I),
from the key intermediate 6-Chloro-2, 4-diaminopyrimidine, having formula (II),

can be carried out by using oxidizing agent urea-hydrogen peroxide, having
formula (III),
CO(NH2)2.H2O2
(III)
and phthalic anhydride in a suitable organic solvent at a definite molar ratio in a
predetermined temperature for a certain duration of time.
2. Process as claimed in claim 1, wherein the molar ratio of phthalic anhydride,
urea-hydrogen peroxide complex and 6-Chloro-2,4-diaminopyrimidineis
3.0:3.4:1.
3. Process as claimed in claim 1, wherein the organic solvent is alcohol, chlorinated
solvents, esters and ethers.
4. Process as claimed in claim 1, wherein the organic solvent is alcohol.
5. Process as claimed in claim 1, wherein the reaction temperature is 20 to 30°C.
6. Process as claimed in claim 1, wherein the desired product is obtained by
filtration after cooling the reaction mixture at 0 to 10 °C for 1 hour.
7. Process as claimed in claim 1, wherein the duration of time of reaction is 2 to 5
hours.
8. Process as claimed in preceding claims substantially as herein described.
A new process for the preparation of the key intermediate 6-Chloro-2,4-
diaminopyrimidine-3-oxide from 6-Chloro-2, 4-diaminopyrimidine using urea-hydrogen
peroxide complex and phthalic anhydride in a suitable organic solvent, in a definite molar
ratio, at a predetermined temperature, for a certain duration of time.

Documents:

00103-kol-2005-abstract.pdf

00103-kol-2005-claims-1.1.pdf

00103-kol-2005-claims.pdf

00103-kol-2005-correspondene-1.1.pdf

00103-kol-2005-correspondene-1.2.pdf

00103-kol-2005-correspondene-1.3.pdf

00103-kol-2005-correspondene-1.4.pdf

00103-kol-2005-correspondene-1.5.pdf

00103-kol-2005-correspondene.pdf

00103-kol-2005-description(complete).pdf

00103-kol-2005-description(provisional).pdf

00103-kol-2005-form-1.pdf

00103-kol-2005-form-18-1.1.pdf

00103-kol-2005-form-18.pdf

00103-kol-2005-form-2-1.1.pdf

00103-kol-2005-form-2.pdf

00103-kol-2005-form-9.pdf

00103-kol-2005-p.a.pdf

103-kol-2005-granted-abstract.pdf

103-kol-2005-granted-claims.pdf

103-kol-2005-granted-correspondence.pdf

103-kol-2005-granted-description (complete).pdf

103-kol-2005-granted-examination report.pdf

103-kol-2005-granted-form 1.pdf

103-kol-2005-granted-form 18.pdf

103-kol-2005-granted-form 2.pdf

103-kol-2005-granted-pa.pdf

103-kol-2005-granted-reply to examination report.pdf

103-kol-2005-granted-specification.pdf

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Patent Number

224735

Indian Patent Application Number

103/KOL/2005

PG Journal Number

43/2008

Publication Date

24-Oct-2008

Grant Date

22-Oct-2008

Date of Filing

07-Feb-2005

Name of Patentee

KOP RESEARCH CENTRE PVT. LTD.

Applicant Address

PLOT NO 36 B, JIGANI INDUSTRIAL AREA, ROAD NO 3 & 5 ANEKAL TALUK, BANGALORE, KARNATAKA-562,106 , INDIA. AND PAWAN KUMAR MAHESHWARI C/O M/S. SINGHANIA & CO. #E-1, FIRST FLOOR, 75-C, PARK STREET, KOLKATA-700 016, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. RANGANATHAN K.R.	PLOT NO 36 B, JIGANI INDUSTRIAL AREA, ROAD NO 3 & 5 ANEKAL TALUK, BANGALORE, KARNATAKA-562106, INDIA

PCT International Classification Number

C07D 239/28

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA